A 29-year-old white man with no chronic medical problems presents to the emergency department with shortness of breath, left-sided pleuritic chest pain, cough, and hemoptysis. These symptoms began abruptly 1 day ago and have persisted. He also has mild pain and swelling in both calves. He denies having any fever, night sweats, or chills. On further questioning, he reports having taken a long, nonstop driving trip that lasted 8 hours 1 week ago.

His medical history is negative, and he specifically reports no history of deep venous thrombosis or pulmonary embolism. He underwent appendectomy 10 years ago but has had no other operations. He does not take any medications. His family history is noncontributory and is negative for venous thromboembolism. He smokes and uses alcohol occasionally but not illicit drugs.

Examination. He appears to be in considerable distress because of his chest pain. His temperature is 100.4°F (38.0°C), blood pressure 125/70 mm Hg, heart rate 125 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation 92% on room air, and body mass index 19 kg/m².

Chest examination reveals diminished vesicular breathing in the left base, which is normal to percussion without added sounds. Both calves are swollen and tender to palpation without skin discoloration. The rest of his examination is normal.

Laboratory values:

• White blood cell count 9.3 × 10⁹/L (reference range 4.5–11.0)
• Hemoglobin 15.9 g/dL (14.0–17.5)
• Platelets 205 × 10⁹/L (150–350)
• Sodium 140 mEq/L (136–142)
• Potassium 3.9 mEq/L (3.5–5.0)
• Chloride 108 mEq/L (96–106)
• Bicarbonate 23 mEq/L (21–28)
• Blood urea nitrogen 14 mg/dL (8–23)
• Creatinine 0.9 mg/dL (0.6–1.2)
• Glucose 95 mg/dL (70–110)
• International normalized ratio (INR) 0.90 (0.00–1.2)
• Partial thromboplastin time 27.5 seconds (24.6–31.8)
• Creatine phosphokinase 205 U/L (39–308)
• Troponin T < 0.015 ng/mL (0.01–0.045).

Pulmonary embolism is diagnosed

Factor V Leiden is diagnosed, and the patient recovers with treatment

Anticoagulation is started in the emergency department.

Given this patient’s young age and clot burden, a hypercoagulable state is suspected. Thrombophilia screening is performed, with tests for the factor V Leiden mutation, the prothrombin G20210A mutation, and antiphospholipid and lupus anticoagulant antibodies. The rest of the thrombophilia panel, including antithrombin III, factor VIII, protein C, and protein S, is deferred because the levels of these substances would be expected to change during the acute thrombosis.

The direct test for factor V Leiden mutation is positive for the heterozygous type. The test for the prothrombin G20210A mutation is negative, and his antiphospholipid antibody levels, including the lupus anticoagulant titer, are within normal limits.

The patient is kept on a standard regimen of unfractionated heparin, overlapped with warfarin (Coumadin) until his INR is 2.0 to 3.0 on 2 consecutive days. His hospital course is uneventful and his condition gradually improves.

He is discharged home to continue on oral anticoagulation for 6 months with a target INR of 2.0 to 3.0. Two weeks after completing his anticoagulation therapy, his levels of antithrombin III, factor VIII, protein C, and protein S are all within normal limits.

FACTOR V LEIDEN IS COMMON

Factor V Leiden is the most common inherited thrombophilia, with a prevalence of 3% to 7% in the general US population,¹ approximately 5% in whites, 2.2% in Hispanics, and 1.2% in blacks.² Its prevalence in patients with venous thromboembolism, however, is 50%.^1,3 The annual incidence of venous thromboembolism in patients with factor V Leiden is 0.5%.^4,5

MORE COAGULATION, LESS ANTICOAGULATION

Factor V has a critical position in both the coagulant and anticoagulant pathways. Factor V Leiden results in a hypercoagulable state by both increasing coagulation and decreasing anticoagulation.

This mutation causes factor V to be resistant to being cleaved and inactivated by activated protein C, a condition known as APC resistance. As a result, more factor Va is available within the prothrombinase complex, increasing coagulation by increased generation of thrombin.^6–8

Furthermore, a cofactor formed by cleavage of factor V at position 506 is thought to support activated protein C in degrading factor VIIIa (in the tenase complex), along with protein S. People with factor V Leiden lack this cleavage product and thus have less anticoagulant activity from activated protein C. The increased coagulation and decreased anticoagulation appear to contribute equally to the hypercoagulable state in factor V Leiden-associated APC resistance.^9–11

Heterozygosity for the factor V Leiden mutation accounts for 90% to 95% of cases of APC resistance. A much smaller number of people are homozygous for it.¹

People who are homozygous for factor V Leiden are at higher risk of venous thromboembolism than those who are heterozygous for it, since the latter group’s blood contains both factor V Leiden and normal factor V. The normal factor V allows anticoagulation via the second pathway of inactivation of factor VIIIa by activated protein C, giving some protection against thrombosis. In people who are homozygous for factor V Leiden, the lack of normal factor V acting as an anticoagulant protein results in a higher thrombotic risk.^9–11

Other factor V mutations may also cause APC resistance

Although factor V Leiden is the only genetic defect for which a causal relationship with APC resistance has been clearly determined, other, rarer hereditary factor V mutations or polymorphisms have been described, such as factor V Cambridge (Arg306Thr)¹² and factor V Hong Kong (Arg306Gly).¹³ These mutations may result in APC resistance, but their clinical association with thrombosis is less clear.¹⁴ Factor V Liverpool (Ile359Thr) is associated with a higher risk of thrombosis, apparently because of reduced APC-mediated inactivation of factor Va and because it is a poor cofactor with activated protein C for the inactivation of factor VIIIa.¹⁵

An R2 haplotype has also been described in association with APC resistance.^16,17 The phenomenon may be due to a reduction in activated protein C cofactor activity.⁹ However, not all studies have been convincing regarding the role of this haplotype in clinical disease.¹⁸ Coinheritance of this haplotype with factor V Leiden may increase the risk of venous thromboembolism above that associated with factor V Leiden alone.¹⁹

Although factor V Leiden is the most common cause of inherited APC resistance, other changes in hemostasis cause acquired APC resistance and may contribute to the thrombotic tendency in these patients.^20–22 The most common causes of acquired APC resistance include elevated factor VIII levels,^23–25 pregnancy,^26–28 use of oral contraceptives,^29,30 and antiphospholipid antibodies.³¹

USUALLY MANIFESTS AS DEEP VEIN THROMBOSIS

Factor V Leiden usually manifests as deep vein thrombosis with or without pulmonary embolism, but thrombosis in unusual locations also occurs.³²

The risk of a first episode of venous thromboembolism is two to five times higher with heterozygous factor V Leiden. However, even though the relative risk is high, the absolute risk is low. Furthermore, despite the higher risk of venous thrombosis, there is no evidence that heterozygosity for factor V Leiden increases the overall mortality rate.^4,33–36

In people with homozygous factor V Leiden or with combined inherited thrombophilias, the risk of venous thromboembolism is increased to a greater degree: it is 20 to 50 times higher.^7,8,37–39 However, whether the risk of death is higher is not clear.

VENOUS THROMBOEMBOLISM IS MULTIFACTORIAL

The pathogenesis of venous thromboembolism is multifactorial and involves an interaction between inherited and acquired factors. Very often, people with factor V Leiden have additional risk factors that contribute to the development of venous clots, and it is very unusual for them to have thrombosis in the absence of these additional factors.

These factors include older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy. They increase the risk of venous thrombosis in normal individuals as well, but more so in people with factor V Leiden.^40–43

Testing for other known causes of thrombophilia may also be pursued. These include elevated homocysteine levels, the factor II (prothrombin) G20210A mutation, anticardiolipin antibody, lupus anticoagulant, and deficiencies of antithrombin III, protein C, and protein S.

Factor V Leiden by itself does not appear to increase the risk of arterial thrombosis, ie, heart attack and stroke.^{33,38,44–46}

Family history: A risk indicator for venous thrombosis

Family history is an important indicator of risk for a first venous thromboembolic event, regardless of other risk factors identified. The risk of a first event is two to three times higher in people with a family history of thrombosis in a first-degree relative. The risk is four times higher when multiple family members are affected, at least one of them before age 50.⁴⁷

In people with genetic thrombophilia, the risk of thrombosis (especially unprovoked thrombosis at a young age) is also higher in those with a strong family history than in those without a family history. In those with factor V Leiden, the risk of venous thromboembolism is three to four times higher if there is a positive family history. The risk is five times higher in carriers of factor V Leiden with a family history of venous thromboembolism before age 50, and 13 times higher in those with more than one affected family member.⁴⁷

Possible shared environmental factors or coinheritance of other unidentified genetic factors may also contribute to the higher susceptibility in thrombosis-prone families.

TESTING FOR APC RESISTANCE AND FACTOR V LEIDEN

The factor V Leiden mutation can be detected directly by genetic testing of peripheral blood mononuclear cells. This method is relatively time-consuming and expensive, however.

At present, the most cost-effective approach is to test first for APC resistance using a second-generation coagulation assay—the modified APC sensitivity test. In this clot-based method, the patient’s sample is prediluted with factor V-deficient plasma to eliminate the effect of lupus anticoagulants and factor deficiencies that could prolong the baseline clotting time, and heparin is inactivated by polybrene. Then either an augmented partial-thromboplastin-time-based assay or a tissue-factor-dependent factor V assay is performed.

This test is nearly 100% sensitive and specific for factor V Leiden, in contrast to the first-generation, or classic, APC sensitivity test, which lacked specificity and sensitivity for it.^{9–11,48–60} This modification also permits testing of patients receiving anticoagulants or who have abnormal augmented partial thromboplastin times due to coagulation factor deficiencies.

A positive result on the modified APC sensitivity test should be confirmed by a direct genetic test for the factor V Leiden mutation. An APC resistance assay is unnecessary if a direct genetic test is used initially.

HOW LONG TO GIVE ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM?

Patients who have had an episode of venous thromboembolism have to be treated with anticoagulants.

In general, the initial management of venous thromboembolism in patients with heritable thrombophilias is no different from that in any other patient with a clot. Anticoagulants such as warfarin are given at a target INR of 2.5 (range 2.0–3.0).³² The duration of treatment is based on the risk factors that resulted in the thrombotic event.

After a first event, some authorities recommend anticoagulant therapy for 6 months.³² A shorter period (3 months) is recommended if there is a transient risk factor (eg, surgery, oral contraceptive use, travel, pregnancy, the puerperium) and the thrombosis is confined to distal veins (eg, the calf veins).³²

Factor V Leiden does not necessarily increase the risk of recurrent events in patients who have a transient risk factor. Therefore, people who are heterozygous for this mutation do not usually need to be treated lifelong with anticoagulants if they have had only one episode of deep vein thrombosis or pulmonary embolism, given the risk of bleeding associated with anticoagulation, unless they have additional risk factors.

Conditions in which indefinite anticoagulation may be required after careful consideration of the risks and benefits are:

• Life-threatening events such as near-fatal pulmonary embolism
• Cerebral or visceral vein thrombosis
• Recurrent thrombotic events
• Additional persistent risk factors (eg, active malignant neoplasm, extremity paresis, and antiphospholipid antibodies)
• Combined thrombophilias (eg, combined heterozygosity for factor V Leiden and the prothrombin G20210A mutation)
• Homozygosity for factor V Leiden.^32,46,48

Factor V Leiden by itself or combined with other thrombophilic abnormalities is not associated with a higher risk of recurrent venous thromboembolism during warfarin therapy (a possible exception is the combination of factor V Leiden plus antiphospholipid antibodies).^32,34 Furthermore, current evidence suggests that no thrombophilic defect is a clinically important risk factor for recurrent venous thromboembolism after anticoagulant therapy is stopped. All these facts indicate that clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.^{32,35,36,61–63}

PRIMARY PROPHYLAXIS IN PATIENTS WITH FACTOR V LEIDEN

Factor V Leiden is only one of many risk factors for deep vein thrombosis or pulmonary embolism. If carriers of factor V Leiden have never had a blood clot, then they are not routinely treated with an anticoagulant. Rather, they should be counseled about reducing or eliminating other factors that may add to their risk of developing a clot in the future.

Usually, the effect of risk factors is additive: the more risk factors present, the higher the risk.^46,50 Sometimes, however, the effect of multiple risk factors is more than additive.

Some risk factors, such as genetics or age, are not alterable, but many can be controlled by medications or lifestyle modifications. Therefore, general measures and precautions are recommended to minimize the risk of thrombosis. For example:

Losing weight (if the patient is overweight) is an important intervention for risk reduction, since obesity is probably the most common modifiable risk factor for developing blood clots.

Avoiding long periods of immobility is recommended. For example, if the patient is taking a long car ride (more than 2 hours), then stopping every few hours and walking around for a few minutes is a good way to keep the blood circulating. If the patient has a desk job, getting up and walking around the office periodically is advised. On long airplane trips, a walk in the aisle every so often and preventing dehydration by drinking plenty of fluids and avoiding alcohol are recommended.

Wearing elastic stockings with a graduated elastic pressure may prevent deep venous thrombosis from developing on long flights.^63–65

Staying active and getting regular exercise through such activities as walking, bicycling, or swimming are helpful.

Avoiding smoking is critical.^50,63

Thromboprophylaxis is recommended for most acutely ill hospitalized patients, especially those confined to bed with additional risk factors. Guidelines for prophylaxis are based on an individualized risk assessment and not on thrombophilia status. Prophylactic anticoagulation is routinely recommended for patients undergoing major high-risk surgery, such as an orthopedic, urologic, gynecologic, or bariatric procedure. Any excess thrombotic risk conferred by thrombophilia is likely small compared with the risk of surgery, and recommendations on the duration and intensity of thromboprophylaxis are not based on thrombophilic status.^46,48

Education. Pain, swelling, redness of a limb, unexplained shortness of breath, and chest pain are the most common symptoms of deep vein thrombosis and pulmonary embolism.^46,50 It is crucial to teach patients with factor V Leiden to recognize these symptoms and to seek early medical attention in case they experience any of them.

SCREENING FAMILY MEMBERS FOR THE FACTOR V LEIDEN MUTATION

Factor V Leiden by itself is a relatively mild thrombophilic defect that does not cause thrombosis in all carriers, and there is no evidence that early diagnosis reduces rates of morbidity or mortality. Therefore, routine screening of all asymptomatic relatives of affected patients with venous thrombosis is not recommended. Rather, the decision to screen should be made on an individual basis.^50,66

Screening may be beneficial in selected cases, especially when patients have a strong family history of recurrent venous thrombosis at a young age (younger than 50 years) and the family member has additional risk factors for venous thromboembolism such as oral contraception or is planning for pregnancy.^32,48,49,66

A 29-year-old white man with no chronic medical problems presents to the emergency department with shortness of breath, left-sided pleuritic chest pain, cough, and hemoptysis. These symptoms began abruptly 1 day ago and have persisted. He also has mild pain and swelling in both calves. He denies having any fever, night sweats, or chills. On further questioning, he reports having taken a long, nonstop driving trip that lasted 8 hours 1 week ago.

His medical history is negative, and he specifically reports no history of deep venous thrombosis or pulmonary embolism. He underwent appendectomy 10 years ago but has had no other operations. He does not take any medications. His family history is noncontributory and is negative for venous thromboembolism. He smokes and uses alcohol occasionally but not illicit drugs.

Examination. He appears to be in considerable distress because of his chest pain. His temperature is 100.4°F (38.0°C), blood pressure 125/70 mm Hg, heart rate 125 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation 92% on room air, and body mass index 19 kg/m².

Chest examination reveals diminished vesicular breathing in the left base, which is normal to percussion without added sounds. Both calves are swollen and tender to palpation without skin discoloration. The rest of his examination is normal.

Laboratory values:

• White blood cell count 9.3 × 10⁹/L (reference range 4.5–11.0)
• Hemoglobin 15.9 g/dL (14.0–17.5)
• Platelets 205 × 10⁹/L (150–350)
• Sodium 140 mEq/L (136–142)
• Potassium 3.9 mEq/L (3.5–5.0)
• Chloride 108 mEq/L (96–106)
• Bicarbonate 23 mEq/L (21–28)
• Blood urea nitrogen 14 mg/dL (8–23)
• Creatinine 0.9 mg/dL (0.6–1.2)
• Glucose 95 mg/dL (70–110)
• International normalized ratio (INR) 0.90 (0.00–1.2)
• Partial thromboplastin time 27.5 seconds (24.6–31.8)
• Creatine phosphokinase 205 U/L (39–308)
• Troponin T < 0.015 ng/mL (0.01–0.045).

Pulmonary embolism is diagnosed

Factor V Leiden is diagnosed, and the patient recovers with treatment

Anticoagulation is started in the emergency department.

Given this patient’s young age and clot burden, a hypercoagulable state is suspected. Thrombophilia screening is performed, with tests for the factor V Leiden mutation, the prothrombin G20210A mutation, and antiphospholipid and lupus anticoagulant antibodies. The rest of the thrombophilia panel, including antithrombin III, factor VIII, protein C, and protein S, is deferred because the levels of these substances would be expected to change during the acute thrombosis.

The direct test for factor V Leiden mutation is positive for the heterozygous type. The test for the prothrombin G20210A mutation is negative, and his antiphospholipid antibody levels, including the lupus anticoagulant titer, are within normal limits.

The patient is kept on a standard regimen of unfractionated heparin, overlapped with warfarin (Coumadin) until his INR is 2.0 to 3.0 on 2 consecutive days. His hospital course is uneventful and his condition gradually improves.

He is discharged home to continue on oral anticoagulation for 6 months with a target INR of 2.0 to 3.0. Two weeks after completing his anticoagulation therapy, his levels of antithrombin III, factor VIII, protein C, and protein S are all within normal limits.

FACTOR V LEIDEN IS COMMON

Factor V Leiden is the most common inherited thrombophilia, with a prevalence of 3% to 7% in the general US population,¹ approximately 5% in whites, 2.2% in Hispanics, and 1.2% in blacks.² Its prevalence in patients with venous thromboembolism, however, is 50%.^1,3 The annual incidence of venous thromboembolism in patients with factor V Leiden is 0.5%.^4,5

MORE COAGULATION, LESS ANTICOAGULATION

Factor V has a critical position in both the coagulant and anticoagulant pathways. Factor V Leiden results in a hypercoagulable state by both increasing coagulation and decreasing anticoagulation.

This mutation causes factor V to be resistant to being cleaved and inactivated by activated protein C, a condition known as APC resistance. As a result, more factor Va is available within the prothrombinase complex, increasing coagulation by increased generation of thrombin.^6–8

Furthermore, a cofactor formed by cleavage of factor V at position 506 is thought to support activated protein C in degrading factor VIIIa (in the tenase complex), along with protein S. People with factor V Leiden lack this cleavage product and thus have less anticoagulant activity from activated protein C. The increased coagulation and decreased anticoagulation appear to contribute equally to the hypercoagulable state in factor V Leiden-associated APC resistance.^9–11

Heterozygosity for the factor V Leiden mutation accounts for 90% to 95% of cases of APC resistance. A much smaller number of people are homozygous for it.¹

People who are homozygous for factor V Leiden are at higher risk of venous thromboembolism than those who are heterozygous for it, since the latter group’s blood contains both factor V Leiden and normal factor V. The normal factor V allows anticoagulation via the second pathway of inactivation of factor VIIIa by activated protein C, giving some protection against thrombosis. In people who are homozygous for factor V Leiden, the lack of normal factor V acting as an anticoagulant protein results in a higher thrombotic risk.^9–11

Other factor V mutations may also cause APC resistance

Although factor V Leiden is the only genetic defect for which a causal relationship with APC resistance has been clearly determined, other, rarer hereditary factor V mutations or polymorphisms have been described, such as factor V Cambridge (Arg306Thr)¹² and factor V Hong Kong (Arg306Gly).¹³ These mutations may result in APC resistance, but their clinical association with thrombosis is less clear.¹⁴ Factor V Liverpool (Ile359Thr) is associated with a higher risk of thrombosis, apparently because of reduced APC-mediated inactivation of factor Va and because it is a poor cofactor with activated protein C for the inactivation of factor VIIIa.¹⁵

An R2 haplotype has also been described in association with APC resistance.^16,17 The phenomenon may be due to a reduction in activated protein C cofactor activity.⁹ However, not all studies have been convincing regarding the role of this haplotype in clinical disease.¹⁸ Coinheritance of this haplotype with factor V Leiden may increase the risk of venous thromboembolism above that associated with factor V Leiden alone.¹⁹

Although factor V Leiden is the most common cause of inherited APC resistance, other changes in hemostasis cause acquired APC resistance and may contribute to the thrombotic tendency in these patients.^20–22 The most common causes of acquired APC resistance include elevated factor VIII levels,^23–25 pregnancy,^26–28 use of oral contraceptives,^29,30 and antiphospholipid antibodies.³¹

USUALLY MANIFESTS AS DEEP VEIN THROMBOSIS

Factor V Leiden usually manifests as deep vein thrombosis with or without pulmonary embolism, but thrombosis in unusual locations also occurs.³²

The risk of a first episode of venous thromboembolism is two to five times higher with heterozygous factor V Leiden. However, even though the relative risk is high, the absolute risk is low. Furthermore, despite the higher risk of venous thrombosis, there is no evidence that heterozygosity for factor V Leiden increases the overall mortality rate.^4,33–36

In people with homozygous factor V Leiden or with combined inherited thrombophilias, the risk of venous thromboembolism is increased to a greater degree: it is 20 to 50 times higher.^7,8,37–39 However, whether the risk of death is higher is not clear.

VENOUS THROMBOEMBOLISM IS MULTIFACTORIAL

The pathogenesis of venous thromboembolism is multifactorial and involves an interaction between inherited and acquired factors. Very often, people with factor V Leiden have additional risk factors that contribute to the development of venous clots, and it is very unusual for them to have thrombosis in the absence of these additional factors.

These factors include older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy. They increase the risk of venous thrombosis in normal individuals as well, but more so in people with factor V Leiden.^40–43

Testing for other known causes of thrombophilia may also be pursued. These include elevated homocysteine levels, the factor II (prothrombin) G20210A mutation, anticardiolipin antibody, lupus anticoagulant, and deficiencies of antithrombin III, protein C, and protein S.

Factor V Leiden by itself does not appear to increase the risk of arterial thrombosis, ie, heart attack and stroke.^{33,38,44–46}

Family history: A risk indicator for venous thrombosis

Family history is an important indicator of risk for a first venous thromboembolic event, regardless of other risk factors identified. The risk of a first event is two to three times higher in people with a family history of thrombosis in a first-degree relative. The risk is four times higher when multiple family members are affected, at least one of them before age 50.⁴⁷

In people with genetic thrombophilia, the risk of thrombosis (especially unprovoked thrombosis at a young age) is also higher in those with a strong family history than in those without a family history. In those with factor V Leiden, the risk of venous thromboembolism is three to four times higher if there is a positive family history. The risk is five times higher in carriers of factor V Leiden with a family history of venous thromboembolism before age 50, and 13 times higher in those with more than one affected family member.⁴⁷

Possible shared environmental factors or coinheritance of other unidentified genetic factors may also contribute to the higher susceptibility in thrombosis-prone families.

TESTING FOR APC RESISTANCE AND FACTOR V LEIDEN

The factor V Leiden mutation can be detected directly by genetic testing of peripheral blood mononuclear cells. This method is relatively time-consuming and expensive, however.

At present, the most cost-effective approach is to test first for APC resistance using a second-generation coagulation assay—the modified APC sensitivity test. In this clot-based method, the patient’s sample is prediluted with factor V-deficient plasma to eliminate the effect of lupus anticoagulants and factor deficiencies that could prolong the baseline clotting time, and heparin is inactivated by polybrene. Then either an augmented partial-thromboplastin-time-based assay or a tissue-factor-dependent factor V assay is performed.

This test is nearly 100% sensitive and specific for factor V Leiden, in contrast to the first-generation, or classic, APC sensitivity test, which lacked specificity and sensitivity for it.^{9–11,48–60} This modification also permits testing of patients receiving anticoagulants or who have abnormal augmented partial thromboplastin times due to coagulation factor deficiencies.

A positive result on the modified APC sensitivity test should be confirmed by a direct genetic test for the factor V Leiden mutation. An APC resistance assay is unnecessary if a direct genetic test is used initially.

HOW LONG TO GIVE ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM?

Patients who have had an episode of venous thromboembolism have to be treated with anticoagulants.

In general, the initial management of venous thromboembolism in patients with heritable thrombophilias is no different from that in any other patient with a clot. Anticoagulants such as warfarin are given at a target INR of 2.5 (range 2.0–3.0).³² The duration of treatment is based on the risk factors that resulted in the thrombotic event.

After a first event, some authorities recommend anticoagulant therapy for 6 months.³² A shorter period (3 months) is recommended if there is a transient risk factor (eg, surgery, oral contraceptive use, travel, pregnancy, the puerperium) and the thrombosis is confined to distal veins (eg, the calf veins).³²

Factor V Leiden does not necessarily increase the risk of recurrent events in patients who have a transient risk factor. Therefore, people who are heterozygous for this mutation do not usually need to be treated lifelong with anticoagulants if they have had only one episode of deep vein thrombosis or pulmonary embolism, given the risk of bleeding associated with anticoagulation, unless they have additional risk factors.

Conditions in which indefinite anticoagulation may be required after careful consideration of the risks and benefits are:

• Life-threatening events such as near-fatal pulmonary embolism
• Cerebral or visceral vein thrombosis
• Recurrent thrombotic events
• Additional persistent risk factors (eg, active malignant neoplasm, extremity paresis, and antiphospholipid antibodies)
• Combined thrombophilias (eg, combined heterozygosity for factor V Leiden and the prothrombin G20210A mutation)
• Homozygosity for factor V Leiden.^32,46,48

Factor V Leiden by itself or combined with other thrombophilic abnormalities is not associated with a higher risk of recurrent venous thromboembolism during warfarin therapy (a possible exception is the combination of factor V Leiden plus antiphospholipid antibodies).^32,34 Furthermore, current evidence suggests that no thrombophilic defect is a clinically important risk factor for recurrent venous thromboembolism after anticoagulant therapy is stopped. All these facts indicate that clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.^{32,35,36,61–63}

PRIMARY PROPHYLAXIS IN PATIENTS WITH FACTOR V LEIDEN

Factor V Leiden is only one of many risk factors for deep vein thrombosis or pulmonary embolism. If carriers of factor V Leiden have never had a blood clot, then they are not routinely treated with an anticoagulant. Rather, they should be counseled about reducing or eliminating other factors that may add to their risk of developing a clot in the future.

Usually, the effect of risk factors is additive: the more risk factors present, the higher the risk.^46,50 Sometimes, however, the effect of multiple risk factors is more than additive.

Some risk factors, such as genetics or age, are not alterable, but many can be controlled by medications or lifestyle modifications. Therefore, general measures and precautions are recommended to minimize the risk of thrombosis. For example:

Losing weight (if the patient is overweight) is an important intervention for risk reduction, since obesity is probably the most common modifiable risk factor for developing blood clots.

Avoiding long periods of immobility is recommended. For example, if the patient is taking a long car ride (more than 2 hours), then stopping every few hours and walking around for a few minutes is a good way to keep the blood circulating. If the patient has a desk job, getting up and walking around the office periodically is advised. On long airplane trips, a walk in the aisle every so often and preventing dehydration by drinking plenty of fluids and avoiding alcohol are recommended.

Wearing elastic stockings with a graduated elastic pressure may prevent deep venous thrombosis from developing on long flights.^63–65

Staying active and getting regular exercise through such activities as walking, bicycling, or swimming are helpful.

Avoiding smoking is critical.^50,63

Thromboprophylaxis is recommended for most acutely ill hospitalized patients, especially those confined to bed with additional risk factors. Guidelines for prophylaxis are based on an individualized risk assessment and not on thrombophilia status. Prophylactic anticoagulation is routinely recommended for patients undergoing major high-risk surgery, such as an orthopedic, urologic, gynecologic, or bariatric procedure. Any excess thrombotic risk conferred by thrombophilia is likely small compared with the risk of surgery, and recommendations on the duration and intensity of thromboprophylaxis are not based on thrombophilic status.^46,48

Education. Pain, swelling, redness of a limb, unexplained shortness of breath, and chest pain are the most common symptoms of deep vein thrombosis and pulmonary embolism.^46,50 It is crucial to teach patients with factor V Leiden to recognize these symptoms and to seek early medical attention in case they experience any of them.

SCREENING FAMILY MEMBERS FOR THE FACTOR V LEIDEN MUTATION

Factor V Leiden by itself is a relatively mild thrombophilic defect that does not cause thrombosis in all carriers, and there is no evidence that early diagnosis reduces rates of morbidity or mortality. Therefore, routine screening of all asymptomatic relatives of affected patients with venous thrombosis is not recommended. Rather, the decision to screen should be made on an individual basis.^50,66

Screening may be beneficial in selected cases, especially when patients have a strong family history of recurrent venous thrombosis at a young age (younger than 50 years) and the family member has additional risk factors for venous thromboembolism such as oral contraception or is planning for pregnancy.^32,48,49,66

A 29-year-old white man with no chronic medical problems presents to the emergency department with shortness of breath, left-sided pleuritic chest pain, cough, and hemoptysis. These symptoms began abruptly 1 day ago and have persisted. He also has mild pain and swelling in both calves. He denies having any fever, night sweats, or chills. On further questioning, he reports having taken a long, nonstop driving trip that lasted 8 hours 1 week ago.

His medical history is negative, and he specifically reports no history of deep venous thrombosis or pulmonary embolism. He underwent appendectomy 10 years ago but has had no other operations. He does not take any medications. His family history is noncontributory and is negative for venous thromboembolism. He smokes and uses alcohol occasionally but not illicit drugs.

Examination. He appears to be in considerable distress because of his chest pain. His temperature is 100.4°F (38.0°C), blood pressure 125/70 mm Hg, heart rate 125 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation 92% on room air, and body mass index 19 kg/m².

Chest examination reveals diminished vesicular breathing in the left base, which is normal to percussion without added sounds. Both calves are swollen and tender to palpation without skin discoloration. The rest of his examination is normal.

Laboratory values:

• White blood cell count 9.3 × 10⁹/L (reference range 4.5–11.0)
• Hemoglobin 15.9 g/dL (14.0–17.5)
• Platelets 205 × 10⁹/L (150–350)
• Sodium 140 mEq/L (136–142)
• Potassium 3.9 mEq/L (3.5–5.0)
• Chloride 108 mEq/L (96–106)
• Bicarbonate 23 mEq/L (21–28)
• Blood urea nitrogen 14 mg/dL (8–23)
• Creatinine 0.9 mg/dL (0.6–1.2)
• Glucose 95 mg/dL (70–110)
• International normalized ratio (INR) 0.90 (0.00–1.2)
• Partial thromboplastin time 27.5 seconds (24.6–31.8)
• Creatine phosphokinase 205 U/L (39–308)
• Troponin T < 0.015 ng/mL (0.01–0.045).

Pulmonary embolism is diagnosed

Factor V Leiden is diagnosed, and the patient recovers with treatment

Anticoagulation is started in the emergency department.

Given this patient’s young age and clot burden, a hypercoagulable state is suspected. Thrombophilia screening is performed, with tests for the factor V Leiden mutation, the prothrombin G20210A mutation, and antiphospholipid and lupus anticoagulant antibodies. The rest of the thrombophilia panel, including antithrombin III, factor VIII, protein C, and protein S, is deferred because the levels of these substances would be expected to change during the acute thrombosis.

The direct test for factor V Leiden mutation is positive for the heterozygous type. The test for the prothrombin G20210A mutation is negative, and his antiphospholipid antibody levels, including the lupus anticoagulant titer, are within normal limits.

The patient is kept on a standard regimen of unfractionated heparin, overlapped with warfarin (Coumadin) until his INR is 2.0 to 3.0 on 2 consecutive days. His hospital course is uneventful and his condition gradually improves.

He is discharged home to continue on oral anticoagulation for 6 months with a target INR of 2.0 to 3.0. Two weeks after completing his anticoagulation therapy, his levels of antithrombin III, factor VIII, protein C, and protein S are all within normal limits.

FACTOR V LEIDEN IS COMMON

Factor V Leiden is the most common inherited thrombophilia, with a prevalence of 3% to 7% in the general US population,¹ approximately 5% in whites, 2.2% in Hispanics, and 1.2% in blacks.² Its prevalence in patients with venous thromboembolism, however, is 50%.^1,3 The annual incidence of venous thromboembolism in patients with factor V Leiden is 0.5%.^4,5

MORE COAGULATION, LESS ANTICOAGULATION

Factor V has a critical position in both the coagulant and anticoagulant pathways. Factor V Leiden results in a hypercoagulable state by both increasing coagulation and decreasing anticoagulation.

This mutation causes factor V to be resistant to being cleaved and inactivated by activated protein C, a condition known as APC resistance. As a result, more factor Va is available within the prothrombinase complex, increasing coagulation by increased generation of thrombin.^6–8

Furthermore, a cofactor formed by cleavage of factor V at position 506 is thought to support activated protein C in degrading factor VIIIa (in the tenase complex), along with protein S. People with factor V Leiden lack this cleavage product and thus have less anticoagulant activity from activated protein C. The increased coagulation and decreased anticoagulation appear to contribute equally to the hypercoagulable state in factor V Leiden-associated APC resistance.^9–11

Heterozygosity for the factor V Leiden mutation accounts for 90% to 95% of cases of APC resistance. A much smaller number of people are homozygous for it.¹

People who are homozygous for factor V Leiden are at higher risk of venous thromboembolism than those who are heterozygous for it, since the latter group’s blood contains both factor V Leiden and normal factor V. The normal factor V allows anticoagulation via the second pathway of inactivation of factor VIIIa by activated protein C, giving some protection against thrombosis. In people who are homozygous for factor V Leiden, the lack of normal factor V acting as an anticoagulant protein results in a higher thrombotic risk.^9–11

Other factor V mutations may also cause APC resistance

Although factor V Leiden is the only genetic defect for which a causal relationship with APC resistance has been clearly determined, other, rarer hereditary factor V mutations or polymorphisms have been described, such as factor V Cambridge (Arg306Thr)¹² and factor V Hong Kong (Arg306Gly).¹³ These mutations may result in APC resistance, but their clinical association with thrombosis is less clear.¹⁴ Factor V Liverpool (Ile359Thr) is associated with a higher risk of thrombosis, apparently because of reduced APC-mediated inactivation of factor Va and because it is a poor cofactor with activated protein C for the inactivation of factor VIIIa.¹⁵

An R2 haplotype has also been described in association with APC resistance.^16,17 The phenomenon may be due to a reduction in activated protein C cofactor activity.⁹ However, not all studies have been convincing regarding the role of this haplotype in clinical disease.¹⁸ Coinheritance of this haplotype with factor V Leiden may increase the risk of venous thromboembolism above that associated with factor V Leiden alone.¹⁹

Although factor V Leiden is the most common cause of inherited APC resistance, other changes in hemostasis cause acquired APC resistance and may contribute to the thrombotic tendency in these patients.^20–22 The most common causes of acquired APC resistance include elevated factor VIII levels,^23–25 pregnancy,^26–28 use of oral contraceptives,^29,30 and antiphospholipid antibodies.³¹

USUALLY MANIFESTS AS DEEP VEIN THROMBOSIS

Factor V Leiden usually manifests as deep vein thrombosis with or without pulmonary embolism, but thrombosis in unusual locations also occurs.³²

The risk of a first episode of venous thromboembolism is two to five times higher with heterozygous factor V Leiden. However, even though the relative risk is high, the absolute risk is low. Furthermore, despite the higher risk of venous thrombosis, there is no evidence that heterozygosity for factor V Leiden increases the overall mortality rate.^4,33–36

In people with homozygous factor V Leiden or with combined inherited thrombophilias, the risk of venous thromboembolism is increased to a greater degree: it is 20 to 50 times higher.^7,8,37–39 However, whether the risk of death is higher is not clear.

VENOUS THROMBOEMBOLISM IS MULTIFACTORIAL

The pathogenesis of venous thromboembolism is multifactorial and involves an interaction between inherited and acquired factors. Very often, people with factor V Leiden have additional risk factors that contribute to the development of venous clots, and it is very unusual for them to have thrombosis in the absence of these additional factors.

These factors include older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy. They increase the risk of venous thrombosis in normal individuals as well, but more so in people with factor V Leiden.^40–43

Testing for other known causes of thrombophilia may also be pursued. These include elevated homocysteine levels, the factor II (prothrombin) G20210A mutation, anticardiolipin antibody, lupus anticoagulant, and deficiencies of antithrombin III, protein C, and protein S.

Factor V Leiden by itself does not appear to increase the risk of arterial thrombosis, ie, heart attack and stroke.^{33,38,44–46}

Family history: A risk indicator for venous thrombosis

Family history is an important indicator of risk for a first venous thromboembolic event, regardless of other risk factors identified. The risk of a first event is two to three times higher in people with a family history of thrombosis in a first-degree relative. The risk is four times higher when multiple family members are affected, at least one of them before age 50.⁴⁷

In people with genetic thrombophilia, the risk of thrombosis (especially unprovoked thrombosis at a young age) is also higher in those with a strong family history than in those without a family history. In those with factor V Leiden, the risk of venous thromboembolism is three to four times higher if there is a positive family history. The risk is five times higher in carriers of factor V Leiden with a family history of venous thromboembolism before age 50, and 13 times higher in those with more than one affected family member.⁴⁷

Possible shared environmental factors or coinheritance of other unidentified genetic factors may also contribute to the higher susceptibility in thrombosis-prone families.

TESTING FOR APC RESISTANCE AND FACTOR V LEIDEN

The factor V Leiden mutation can be detected directly by genetic testing of peripheral blood mononuclear cells. This method is relatively time-consuming and expensive, however.

At present, the most cost-effective approach is to test first for APC resistance using a second-generation coagulation assay—the modified APC sensitivity test. In this clot-based method, the patient’s sample is prediluted with factor V-deficient plasma to eliminate the effect of lupus anticoagulants and factor deficiencies that could prolong the baseline clotting time, and heparin is inactivated by polybrene. Then either an augmented partial-thromboplastin-time-based assay or a tissue-factor-dependent factor V assay is performed.

This test is nearly 100% sensitive and specific for factor V Leiden, in contrast to the first-generation, or classic, APC sensitivity test, which lacked specificity and sensitivity for it.^{9–11,48–60} This modification also permits testing of patients receiving anticoagulants or who have abnormal augmented partial thromboplastin times due to coagulation factor deficiencies.

A positive result on the modified APC sensitivity test should be confirmed by a direct genetic test for the factor V Leiden mutation. An APC resistance assay is unnecessary if a direct genetic test is used initially.

HOW LONG TO GIVE ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM?

Patients who have had an episode of venous thromboembolism have to be treated with anticoagulants.

In general, the initial management of venous thromboembolism in patients with heritable thrombophilias is no different from that in any other patient with a clot. Anticoagulants such as warfarin are given at a target INR of 2.5 (range 2.0–3.0).³² The duration of treatment is based on the risk factors that resulted in the thrombotic event.

After a first event, some authorities recommend anticoagulant therapy for 6 months.³² A shorter period (3 months) is recommended if there is a transient risk factor (eg, surgery, oral contraceptive use, travel, pregnancy, the puerperium) and the thrombosis is confined to distal veins (eg, the calf veins).³²

Factor V Leiden does not necessarily increase the risk of recurrent events in patients who have a transient risk factor. Therefore, people who are heterozygous for this mutation do not usually need to be treated lifelong with anticoagulants if they have had only one episode of deep vein thrombosis or pulmonary embolism, given the risk of bleeding associated with anticoagulation, unless they have additional risk factors.

Conditions in which indefinite anticoagulation may be required after careful consideration of the risks and benefits are:

• Life-threatening events such as near-fatal pulmonary embolism
• Cerebral or visceral vein thrombosis
• Recurrent thrombotic events
• Additional persistent risk factors (eg, active malignant neoplasm, extremity paresis, and antiphospholipid antibodies)
• Combined thrombophilias (eg, combined heterozygosity for factor V Leiden and the prothrombin G20210A mutation)
• Homozygosity for factor V Leiden.^32,46,48

Factor V Leiden by itself or combined with other thrombophilic abnormalities is not associated with a higher risk of recurrent venous thromboembolism during warfarin therapy (a possible exception is the combination of factor V Leiden plus antiphospholipid antibodies).^32,34 Furthermore, current evidence suggests that no thrombophilic defect is a clinically important risk factor for recurrent venous thromboembolism after anticoagulant therapy is stopped. All these facts indicate that clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.^{32,35,36,61–63}

PRIMARY PROPHYLAXIS IN PATIENTS WITH FACTOR V LEIDEN

Factor V Leiden is only one of many risk factors for deep vein thrombosis or pulmonary embolism. If carriers of factor V Leiden have never had a blood clot, then they are not routinely treated with an anticoagulant. Rather, they should be counseled about reducing or eliminating other factors that may add to their risk of developing a clot in the future.

Usually, the effect of risk factors is additive: the more risk factors present, the higher the risk.^46,50 Sometimes, however, the effect of multiple risk factors is more than additive.

Some risk factors, such as genetics or age, are not alterable, but many can be controlled by medications or lifestyle modifications. Therefore, general measures and precautions are recommended to minimize the risk of thrombosis. For example:

Losing weight (if the patient is overweight) is an important intervention for risk reduction, since obesity is probably the most common modifiable risk factor for developing blood clots.

Avoiding long periods of immobility is recommended. For example, if the patient is taking a long car ride (more than 2 hours), then stopping every few hours and walking around for a few minutes is a good way to keep the blood circulating. If the patient has a desk job, getting up and walking around the office periodically is advised. On long airplane trips, a walk in the aisle every so often and preventing dehydration by drinking plenty of fluids and avoiding alcohol are recommended.

Wearing elastic stockings with a graduated elastic pressure may prevent deep venous thrombosis from developing on long flights.^63–65

Staying active and getting regular exercise through such activities as walking, bicycling, or swimming are helpful.

Avoiding smoking is critical.^50,63

Thromboprophylaxis is recommended for most acutely ill hospitalized patients, especially those confined to bed with additional risk factors. Guidelines for prophylaxis are based on an individualized risk assessment and not on thrombophilia status. Prophylactic anticoagulation is routinely recommended for patients undergoing major high-risk surgery, such as an orthopedic, urologic, gynecologic, or bariatric procedure. Any excess thrombotic risk conferred by thrombophilia is likely small compared with the risk of surgery, and recommendations on the duration and intensity of thromboprophylaxis are not based on thrombophilic status.^46,48

Education. Pain, swelling, redness of a limb, unexplained shortness of breath, and chest pain are the most common symptoms of deep vein thrombosis and pulmonary embolism.^46,50 It is crucial to teach patients with factor V Leiden to recognize these symptoms and to seek early medical attention in case they experience any of them.

SCREENING FAMILY MEMBERS FOR THE FACTOR V LEIDEN MUTATION

Factor V Leiden by itself is a relatively mild thrombophilic defect that does not cause thrombosis in all carriers, and there is no evidence that early diagnosis reduces rates of morbidity or mortality. Therefore, routine screening of all asymptomatic relatives of affected patients with venous thrombosis is not recommended. Rather, the decision to screen should be made on an individual basis.^50,66

Screening may be beneficial in selected cases, especially when patients have a strong family history of recurrent venous thrombosis at a young age (younger than 50 years) and the family member has additional risk factors for venous thromboembolism such as oral contraception or is planning for pregnancy.^32,48,49,66

On examination, her blood pressure is 138/70 mm Hg, respiratory rate 18 breaths/minute, and heart rate 80 beats/minute. Her abdomen is soft. She has never undergone abdominal surgery. She is not taking any medications that may have caused urine discoloration.

Plain radiography of the abdomen reveals no abnormal gas. Laboratory test results are as follows:

• White blood cell count 15.1 × 10⁹/L (reference range 4–11), with 85% neutrophils (reference range 39.5%–74%)
• C-reactive protein 6.27 mg/dL (reference range 0.0–1.0)
• Blood urea nitrogen 54 mg/dL (reference range 8–25)
• Serum creatinine 2.5 mg/dL (0.70–1.40)
• Estimated glomerular filtration rate 20 mL/min/1.73 m² (< 60 is sufficient for the diagnosis of chronic kidney disease)
• Liver function tests are normal
• Urine pH 8.0 (4.80–7.80); urine is positive for nitrates and for marked pyuria and bacteriuria.

Urine culture yields more than 100,000 colony-forming units of Pseudomonas aeruginosa, Morganella morganii, and Proteus vulgaris. These results and the patient’s presentation point to a diagnosis of purple urine bag syndrome. After placement of a new urinary catheter and 7 days of intravenous ciprofloxacin (Cipro) 250 mg every 12 hours, the color of her urine returns to normal.

PURPLE URINE BAG SYNDROME

Purple urine bag syndrome is rare, and catheter-associated urinary tract infection is the main cause.¹ However, it has also been associated with intestinal intussusception.² In our patient, the examination and radiography ruled out intussusception.

Factors reported to be involved in the development of this syndrome include older age, female sex, chronic constipation, chronic urinary catheterization, alkaline (common) or acidic (uncommon) urine, and a higher bacterial load in the urine.^3,4

The pathogenesis of purple-colored urine^4,5 is thought to start with the metabolism of dietary tryptophan by intestinal bacteria to indole. Indole is then absorbed into the portal circulation and is converted to indoxyl sulfate, which is excreted into the urine. In vitro experiments^4,5 have shown that certain bacteria in the urine produce indoxyl sulfatase and indoxyl phosphatase, which break down indoxyl sulfate to indoxyl. Indoxyl can then be converted to indigo or indirubin in alkaline⁵ or acidic⁴ urine. When blue indigo and red indirubin mix together, the result is purple.^4,5

Bacteria that possess indoxyl sulfatase or indoxyl phosphatase include P aeruginosa, M morganii, P vulgaris, Escherichia coli, and Providencia species.^5,6 However, not all bacteria of the same species produce the enzymes required for the formation of purple urine.⁵ This may explain the rarity of this syndrome despite the common occurrence of urinary tract infection in patients with risk factors for purple urine bag syndrome.

CHRONIC KIDNEY DISEASE: A POTENTIAL RISK FACTOR

Chronic kidney disease was shown to be a risk factor for purple urine bag syndrome in a small cohort study of Taiwanese patients.⁷ The serum and urine levels of indoxyl sulfate increased markedly in patients who had chronic kidney disease or who were undergoing dialysis because of impaired renal clearance.⁶ Furthermore, indoxyl sulfate, which plays an important role in this syndrome, is also cytotoxic and may increase the rate of renal failure in uremic rats.⁴

Although purple urine itself is usually considered benign,³ it should prompt an evaluation for urinary tract infection, especially in patients with kidney disease. Failure to treat the underlying infection can lead to septicemia or Fourier gangrene.^1,3

On examination, her blood pressure is 138/70 mm Hg, respiratory rate 18 breaths/minute, and heart rate 80 beats/minute. Her abdomen is soft. She has never undergone abdominal surgery. She is not taking any medications that may have caused urine discoloration.

Plain radiography of the abdomen reveals no abnormal gas. Laboratory test results are as follows:

• White blood cell count 15.1 × 10⁹/L (reference range 4–11), with 85% neutrophils (reference range 39.5%–74%)
• C-reactive protein 6.27 mg/dL (reference range 0.0–1.0)
• Blood urea nitrogen 54 mg/dL (reference range 8–25)
• Serum creatinine 2.5 mg/dL (0.70–1.40)
• Estimated glomerular filtration rate 20 mL/min/1.73 m² (< 60 is sufficient for the diagnosis of chronic kidney disease)
• Liver function tests are normal
• Urine pH 8.0 (4.80–7.80); urine is positive for nitrates and for marked pyuria and bacteriuria.

Urine culture yields more than 100,000 colony-forming units of Pseudomonas aeruginosa, Morganella morganii, and Proteus vulgaris. These results and the patient’s presentation point to a diagnosis of purple urine bag syndrome. After placement of a new urinary catheter and 7 days of intravenous ciprofloxacin (Cipro) 250 mg every 12 hours, the color of her urine returns to normal.

PURPLE URINE BAG SYNDROME

Purple urine bag syndrome is rare, and catheter-associated urinary tract infection is the main cause.¹ However, it has also been associated with intestinal intussusception.² In our patient, the examination and radiography ruled out intussusception.

Factors reported to be involved in the development of this syndrome include older age, female sex, chronic constipation, chronic urinary catheterization, alkaline (common) or acidic (uncommon) urine, and a higher bacterial load in the urine.^3,4

The pathogenesis of purple-colored urine^4,5 is thought to start with the metabolism of dietary tryptophan by intestinal bacteria to indole. Indole is then absorbed into the portal circulation and is converted to indoxyl sulfate, which is excreted into the urine. In vitro experiments^4,5 have shown that certain bacteria in the urine produce indoxyl sulfatase and indoxyl phosphatase, which break down indoxyl sulfate to indoxyl. Indoxyl can then be converted to indigo or indirubin in alkaline⁵ or acidic⁴ urine. When blue indigo and red indirubin mix together, the result is purple.^4,5

Bacteria that possess indoxyl sulfatase or indoxyl phosphatase include P aeruginosa, M morganii, P vulgaris, Escherichia coli, and Providencia species.^5,6 However, not all bacteria of the same species produce the enzymes required for the formation of purple urine.⁵ This may explain the rarity of this syndrome despite the common occurrence of urinary tract infection in patients with risk factors for purple urine bag syndrome.

CHRONIC KIDNEY DISEASE: A POTENTIAL RISK FACTOR

Chronic kidney disease was shown to be a risk factor for purple urine bag syndrome in a small cohort study of Taiwanese patients.⁷ The serum and urine levels of indoxyl sulfate increased markedly in patients who had chronic kidney disease or who were undergoing dialysis because of impaired renal clearance.⁶ Furthermore, indoxyl sulfate, which plays an important role in this syndrome, is also cytotoxic and may increase the rate of renal failure in uremic rats.⁴

Although purple urine itself is usually considered benign,³ it should prompt an evaluation for urinary tract infection, especially in patients with kidney disease. Failure to treat the underlying infection can lead to septicemia or Fourier gangrene.^1,3

On examination, her blood pressure is 138/70 mm Hg, respiratory rate 18 breaths/minute, and heart rate 80 beats/minute. Her abdomen is soft. She has never undergone abdominal surgery. She is not taking any medications that may have caused urine discoloration.

Plain radiography of the abdomen reveals no abnormal gas. Laboratory test results are as follows:

• White blood cell count 15.1 × 10⁹/L (reference range 4–11), with 85% neutrophils (reference range 39.5%–74%)
• C-reactive protein 6.27 mg/dL (reference range 0.0–1.0)
• Blood urea nitrogen 54 mg/dL (reference range 8–25)
• Serum creatinine 2.5 mg/dL (0.70–1.40)
• Estimated glomerular filtration rate 20 mL/min/1.73 m² (< 60 is sufficient for the diagnosis of chronic kidney disease)
• Liver function tests are normal
• Urine pH 8.0 (4.80–7.80); urine is positive for nitrates and for marked pyuria and bacteriuria.

Urine culture yields more than 100,000 colony-forming units of Pseudomonas aeruginosa, Morganella morganii, and Proteus vulgaris. These results and the patient’s presentation point to a diagnosis of purple urine bag syndrome. After placement of a new urinary catheter and 7 days of intravenous ciprofloxacin (Cipro) 250 mg every 12 hours, the color of her urine returns to normal.

PURPLE URINE BAG SYNDROME

Purple urine bag syndrome is rare, and catheter-associated urinary tract infection is the main cause.¹ However, it has also been associated with intestinal intussusception.² In our patient, the examination and radiography ruled out intussusception.

Factors reported to be involved in the development of this syndrome include older age, female sex, chronic constipation, chronic urinary catheterization, alkaline (common) or acidic (uncommon) urine, and a higher bacterial load in the urine.^3,4

The pathogenesis of purple-colored urine^4,5 is thought to start with the metabolism of dietary tryptophan by intestinal bacteria to indole. Indole is then absorbed into the portal circulation and is converted to indoxyl sulfate, which is excreted into the urine. In vitro experiments^4,5 have shown that certain bacteria in the urine produce indoxyl sulfatase and indoxyl phosphatase, which break down indoxyl sulfate to indoxyl. Indoxyl can then be converted to indigo or indirubin in alkaline⁵ or acidic⁴ urine. When blue indigo and red indirubin mix together, the result is purple.^4,5

Bacteria that possess indoxyl sulfatase or indoxyl phosphatase include P aeruginosa, M morganii, P vulgaris, Escherichia coli, and Providencia species.^5,6 However, not all bacteria of the same species produce the enzymes required for the formation of purple urine.⁵ This may explain the rarity of this syndrome despite the common occurrence of urinary tract infection in patients with risk factors for purple urine bag syndrome.

CHRONIC KIDNEY DISEASE: A POTENTIAL RISK FACTOR

Chronic kidney disease was shown to be a risk factor for purple urine bag syndrome in a small cohort study of Taiwanese patients.⁷ The serum and urine levels of indoxyl sulfate increased markedly in patients who had chronic kidney disease or who were undergoing dialysis because of impaired renal clearance.⁶ Furthermore, indoxyl sulfate, which plays an important role in this syndrome, is also cytotoxic and may increase the rate of renal failure in uremic rats.⁴

Although purple urine itself is usually considered benign,³ it should prompt an evaluation for urinary tract infection, especially in patients with kidney disease. Failure to treat the underlying infection can lead to septicemia or Fourier gangrene.^1,3

A 75-year-old man was admitted to the hospital with new-onset atrial fibrillation. He underwent rate control, and a heparin infusion was started. Warfarin (Coumadin) 10 mg was added on the second hospital day. Two days later, the heparin infusion was discontinued when the international normalized ratio (INR) was in the therapeutic range.

Q: Which is the most likely diagnosis?

• Pyoderma gangrenosum
• Cutaneous vasculitis
• Warfarin-induced skin necrosis
• Ecthyma gangrenosum
• Dermatitis herpetiformis

A: The most likely diagnosis is warfarin-induced skin necrosis, a rare paradoxical complication that occurs in 0.01% to 0.1% of patients receiving this drug.¹ Microthrombosis leads to necrosis of the skin and subcutaneous tissues, arising within 2 to 10 days after the start of anticoagulation therapy, although in rare cases it can occur months to years later.^2,3

The most common risk factors include the unopposed use of warfarin (ie, unopposed by heparin at the start of therapy), using higher doses of warfarin during the initiation of anticoagulation, and inadequate overlap with an effective parenteral anticoagulant. Patients with protein C or S deficiency, heparin-induced thrombocytopenia,⁴ resistance to activated protein C, antithrombin deficiency, and lupus anticoagulant have also been reported to be at risk.

The most common sites affected are areas with high subcutaneous fat content, such as the abdomen, thighs, breasts, and buttocks. Skin presentations can vary from dermal plaques to petechial lesions, which rapidly progress to well-demarcated, bluish-black, painful lesions and eventually to hemorrhagic bullae and necrosis.¹

At the start of warfarin therapy, the levels of protein C and factor VII (with half-lives of 5 to 8 hours) fall faster than those of other vitamin-K-dependent factors (ie, factors II, IX, and X). This causes a transient imbalance in procoagulant and anticoagulant pathways favoring thrombosis of the microvasculature, with resulting necrosis. Patients with hereditary protein C deficiency are at higher risk.⁵

Histologic review of lesions often shows venous thrombosis and diffuse necrosis of the dermis and subcutaneous tissue.²

Promptly stopping the warfarin and choosing alternative anticoagulation may help prevent further progression of this condition. Wound care, debridement, and sometimes skin grafting may be necessary, depending on the extent of the lesions. A rechallenge with warfarin is often difficult, but cases have been reported in which treatment was resumed without adverse consequences.⁶ Avoiding large loading doses of warfarin, gradually increasing doses over an extended period (about 10 days),³ and starting warfarin with a heparin bridge for at least 5 days (which was not done in this patient) would prevent the condition.

Early recognition, differentiation, and diagnosis are essential to minimize morbidity and to prevent death.

CASE CONTINUED

Warfarin was discontinued once the patient developed the skin lesions. He received vitamin K and fresh frozen plasma to normalize his INR, and he was started on a heparin infusion, after which the lesions began to heal. The patient refused a skin biopsy. Platelet counts remained stable during his hospital course. Protein C levels were not checked, given his recent use of warfarin. He was started on dabigatran (Pradaxa) and was discharged a week later.

THE OTHER DIAGNOSTIC CHOICES

Pyoderma gangrenosum is an uncommon ulcerative skin condition often associated with autoimmune disease. It usually starts at the site of a minor injury, more commonly on the legs, and gradually progresses to a painful ulcer.

Cutaneous vasculitis is an inflammation of small blood vessels characterized by palpable purpura. The lesions can resemble urticaria, petechia, or erythema multiforme. It is commonly associated with infection, drug therapy, inflammatory disease, and malignancy.

Ecthyma gangrenosum is an infection of skin caused by Pseudomonas aeruginosa. Usually, it presents as hemorrhagic pustules or infarct-like areas with surrounding erythema that evolve into necrotic ulcers surrounded by erythema.

Dermatitis herpetiformis is a chronic skin condition, presenting with fluid-filled blisters and commonly involving the neck, back, scalp, and elbows. This condition is associated with celiac disease, and the lesions are extremely pruritic.

A 75-year-old man was admitted to the hospital with new-onset atrial fibrillation. He underwent rate control, and a heparin infusion was started. Warfarin (Coumadin) 10 mg was added on the second hospital day. Two days later, the heparin infusion was discontinued when the international normalized ratio (INR) was in the therapeutic range.

Q: Which is the most likely diagnosis?

• Pyoderma gangrenosum
• Cutaneous vasculitis
• Warfarin-induced skin necrosis
• Ecthyma gangrenosum
• Dermatitis herpetiformis

A: The most likely diagnosis is warfarin-induced skin necrosis, a rare paradoxical complication that occurs in 0.01% to 0.1% of patients receiving this drug.¹ Microthrombosis leads to necrosis of the skin and subcutaneous tissues, arising within 2 to 10 days after the start of anticoagulation therapy, although in rare cases it can occur months to years later.^2,3

The most common risk factors include the unopposed use of warfarin (ie, unopposed by heparin at the start of therapy), using higher doses of warfarin during the initiation of anticoagulation, and inadequate overlap with an effective parenteral anticoagulant. Patients with protein C or S deficiency, heparin-induced thrombocytopenia,⁴ resistance to activated protein C, antithrombin deficiency, and lupus anticoagulant have also been reported to be at risk.

The most common sites affected are areas with high subcutaneous fat content, such as the abdomen, thighs, breasts, and buttocks. Skin presentations can vary from dermal plaques to petechial lesions, which rapidly progress to well-demarcated, bluish-black, painful lesions and eventually to hemorrhagic bullae and necrosis.¹

At the start of warfarin therapy, the levels of protein C and factor VII (with half-lives of 5 to 8 hours) fall faster than those of other vitamin-K-dependent factors (ie, factors II, IX, and X). This causes a transient imbalance in procoagulant and anticoagulant pathways favoring thrombosis of the microvasculature, with resulting necrosis. Patients with hereditary protein C deficiency are at higher risk.⁵

Histologic review of lesions often shows venous thrombosis and diffuse necrosis of the dermis and subcutaneous tissue.²

Promptly stopping the warfarin and choosing alternative anticoagulation may help prevent further progression of this condition. Wound care, debridement, and sometimes skin grafting may be necessary, depending on the extent of the lesions. A rechallenge with warfarin is often difficult, but cases have been reported in which treatment was resumed without adverse consequences.⁶ Avoiding large loading doses of warfarin, gradually increasing doses over an extended period (about 10 days),³ and starting warfarin with a heparin bridge for at least 5 days (which was not done in this patient) would prevent the condition.

Early recognition, differentiation, and diagnosis are essential to minimize morbidity and to prevent death.

CASE CONTINUED

Warfarin was discontinued once the patient developed the skin lesions. He received vitamin K and fresh frozen plasma to normalize his INR, and he was started on a heparin infusion, after which the lesions began to heal. The patient refused a skin biopsy. Platelet counts remained stable during his hospital course. Protein C levels were not checked, given his recent use of warfarin. He was started on dabigatran (Pradaxa) and was discharged a week later.

THE OTHER DIAGNOSTIC CHOICES

Pyoderma gangrenosum is an uncommon ulcerative skin condition often associated with autoimmune disease. It usually starts at the site of a minor injury, more commonly on the legs, and gradually progresses to a painful ulcer.

Cutaneous vasculitis is an inflammation of small blood vessels characterized by palpable purpura. The lesions can resemble urticaria, petechia, or erythema multiforme. It is commonly associated with infection, drug therapy, inflammatory disease, and malignancy.

Ecthyma gangrenosum is an infection of skin caused by Pseudomonas aeruginosa. Usually, it presents as hemorrhagic pustules or infarct-like areas with surrounding erythema that evolve into necrotic ulcers surrounded by erythema.

Dermatitis herpetiformis is a chronic skin condition, presenting with fluid-filled blisters and commonly involving the neck, back, scalp, and elbows. This condition is associated with celiac disease, and the lesions are extremely pruritic.

A 75-year-old man was admitted to the hospital with new-onset atrial fibrillation. He underwent rate control, and a heparin infusion was started. Warfarin (Coumadin) 10 mg was added on the second hospital day. Two days later, the heparin infusion was discontinued when the international normalized ratio (INR) was in the therapeutic range.

Q: Which is the most likely diagnosis?

• Pyoderma gangrenosum
• Cutaneous vasculitis
• Warfarin-induced skin necrosis
• Ecthyma gangrenosum
• Dermatitis herpetiformis

A: The most likely diagnosis is warfarin-induced skin necrosis, a rare paradoxical complication that occurs in 0.01% to 0.1% of patients receiving this drug.¹ Microthrombosis leads to necrosis of the skin and subcutaneous tissues, arising within 2 to 10 days after the start of anticoagulation therapy, although in rare cases it can occur months to years later.^2,3

The most common risk factors include the unopposed use of warfarin (ie, unopposed by heparin at the start of therapy), using higher doses of warfarin during the initiation of anticoagulation, and inadequate overlap with an effective parenteral anticoagulant. Patients with protein C or S deficiency, heparin-induced thrombocytopenia,⁴ resistance to activated protein C, antithrombin deficiency, and lupus anticoagulant have also been reported to be at risk.

The most common sites affected are areas with high subcutaneous fat content, such as the abdomen, thighs, breasts, and buttocks. Skin presentations can vary from dermal plaques to petechial lesions, which rapidly progress to well-demarcated, bluish-black, painful lesions and eventually to hemorrhagic bullae and necrosis.¹

At the start of warfarin therapy, the levels of protein C and factor VII (with half-lives of 5 to 8 hours) fall faster than those of other vitamin-K-dependent factors (ie, factors II, IX, and X). This causes a transient imbalance in procoagulant and anticoagulant pathways favoring thrombosis of the microvasculature, with resulting necrosis. Patients with hereditary protein C deficiency are at higher risk.⁵

Histologic review of lesions often shows venous thrombosis and diffuse necrosis of the dermis and subcutaneous tissue.²

Promptly stopping the warfarin and choosing alternative anticoagulation may help prevent further progression of this condition. Wound care, debridement, and sometimes skin grafting may be necessary, depending on the extent of the lesions. A rechallenge with warfarin is often difficult, but cases have been reported in which treatment was resumed without adverse consequences.⁶ Avoiding large loading doses of warfarin, gradually increasing doses over an extended period (about 10 days),³ and starting warfarin with a heparin bridge for at least 5 days (which was not done in this patient) would prevent the condition.

Early recognition, differentiation, and diagnosis are essential to minimize morbidity and to prevent death.

CASE CONTINUED

Warfarin was discontinued once the patient developed the skin lesions. He received vitamin K and fresh frozen plasma to normalize his INR, and he was started on a heparin infusion, after which the lesions began to heal. The patient refused a skin biopsy. Platelet counts remained stable during his hospital course. Protein C levels were not checked, given his recent use of warfarin. He was started on dabigatran (Pradaxa) and was discharged a week later.

THE OTHER DIAGNOSTIC CHOICES

Pyoderma gangrenosum is an uncommon ulcerative skin condition often associated with autoimmune disease. It usually starts at the site of a minor injury, more commonly on the legs, and gradually progresses to a painful ulcer.

Cutaneous vasculitis is an inflammation of small blood vessels characterized by palpable purpura. The lesions can resemble urticaria, petechia, or erythema multiforme. It is commonly associated with infection, drug therapy, inflammatory disease, and malignancy.

Ecthyma gangrenosum is an infection of skin caused by Pseudomonas aeruginosa. Usually, it presents as hemorrhagic pustules or infarct-like areas with surrounding erythema that evolve into necrotic ulcers surrounded by erythema.

Dermatitis herpetiformis is a chronic skin condition, presenting with fluid-filled blisters and commonly involving the neck, back, scalp, and elbows. This condition is associated with celiac disease, and the lesions are extremely pruritic.

We rheumatologists may have inadvertently encouraged this practice. We teach about the prevalence of specific autoantibodies in patients with specific, accurately diagnosed autoimmune disorders as opposed to that in the general population (ie, the test’s sensitivity and specificity). But that is different than using a test to diagnose a specific disease in an ill patient with a heretofore undiagnosed condition (ie, the test’s predictive value). When I ask trainees or nonrheumatologists, “Why order all those tests?” the response I often get is that they thought the rheumatologist would want them when he or she was consulted. The fact that I also see our rheumatology fellows requesting the same tests before fully evaluating the patient clinically suggests that we have not done a great job at explaining the clinical utility and limitations of these tests. A serologic test should be used to strengthen or refute the clinician’s preliminary diagnosis, depending on the test’s specificity and sensitivity. It should not be used to generate a diagnosis.

So with these concerns, why would we invite a paper encouraging the use of the relatively new anti-cyclic citrullinated peptide (anti-CCP) test to evaluate patients with possible rheumatoid arthritis (Bose and Calabrese)?

As discussed in that paper, this test has characteristics that are useful when evaluating patients with polyarthritis compatible with the diagnosis of rheumatoid arthritis. Specifically, this test, unlike the traditional test for rheumatoid factor, can help discern whether the arthritis is a reaction to an infection like hepatitis C or endocarditis. Like rheumatoid factor, anti-CCP may precede the appearance of clinically meaningful arthritis and helps to predict prognosis in established rheumatoid arthritis. But, like other serologic tests, the anti-CCP test cannot supplant the listening ears and examining fingers of the clinician in establishing the pretest likelihood of the diagnosis. Clinical evaluation must precede laboratory testing.

We rheumatologists may have inadvertently encouraged this practice. We teach about the prevalence of specific autoantibodies in patients with specific, accurately diagnosed autoimmune disorders as opposed to that in the general population (ie, the test’s sensitivity and specificity). But that is different than using a test to diagnose a specific disease in an ill patient with a heretofore undiagnosed condition (ie, the test’s predictive value). When I ask trainees or nonrheumatologists, “Why order all those tests?” the response I often get is that they thought the rheumatologist would want them when he or she was consulted. The fact that I also see our rheumatology fellows requesting the same tests before fully evaluating the patient clinically suggests that we have not done a great job at explaining the clinical utility and limitations of these tests. A serologic test should be used to strengthen or refute the clinician’s preliminary diagnosis, depending on the test’s specificity and sensitivity. It should not be used to generate a diagnosis.

So with these concerns, why would we invite a paper encouraging the use of the relatively new anti-cyclic citrullinated peptide (anti-CCP) test to evaluate patients with possible rheumatoid arthritis (Bose and Calabrese)?

As discussed in that paper, this test has characteristics that are useful when evaluating patients with polyarthritis compatible with the diagnosis of rheumatoid arthritis. Specifically, this test, unlike the traditional test for rheumatoid factor, can help discern whether the arthritis is a reaction to an infection like hepatitis C or endocarditis. Like rheumatoid factor, anti-CCP may precede the appearance of clinically meaningful arthritis and helps to predict prognosis in established rheumatoid arthritis. But, like other serologic tests, the anti-CCP test cannot supplant the listening ears and examining fingers of the clinician in establishing the pretest likelihood of the diagnosis. Clinical evaluation must precede laboratory testing.

We rheumatologists may have inadvertently encouraged this practice. We teach about the prevalence of specific autoantibodies in patients with specific, accurately diagnosed autoimmune disorders as opposed to that in the general population (ie, the test’s sensitivity and specificity). But that is different than using a test to diagnose a specific disease in an ill patient with a heretofore undiagnosed condition (ie, the test’s predictive value). When I ask trainees or nonrheumatologists, “Why order all those tests?” the response I often get is that they thought the rheumatologist would want them when he or she was consulted. The fact that I also see our rheumatology fellows requesting the same tests before fully evaluating the patient clinically suggests that we have not done a great job at explaining the clinical utility and limitations of these tests. A serologic test should be used to strengthen or refute the clinician’s preliminary diagnosis, depending on the test’s specificity and sensitivity. It should not be used to generate a diagnosis.

So with these concerns, why would we invite a paper encouraging the use of the relatively new anti-cyclic citrullinated peptide (anti-CCP) test to evaluate patients with possible rheumatoid arthritis (Bose and Calabrese)?

As discussed in that paper, this test has characteristics that are useful when evaluating patients with polyarthritis compatible with the diagnosis of rheumatoid arthritis. Specifically, this test, unlike the traditional test for rheumatoid factor, can help discern whether the arthritis is a reaction to an infection like hepatitis C or endocarditis. Like rheumatoid factor, anti-CCP may precede the appearance of clinically meaningful arthritis and helps to predict prognosis in established rheumatoid arthritis. But, like other serologic tests, the anti-CCP test cannot supplant the listening ears and examining fingers of the clinician in establishing the pretest likelihood of the diagnosis. Clinical evaluation must precede laboratory testing.

Yes. Testing for anti-cyclic citrullinated peptide (anti-CCP) antibody can help diagnose rheumatoid arthritis (RA) because it is a highly specific test.

For many years, the diagnosis of RA has been based on the presentation of symmetrical small- and large-joint polyarthritis that spares the lower spine, further supported by the presence of characteristic joint damage on radiography and an elevated rheumatoid factor while also excluding clinical mimics. However, rheumatoid factor is often not detected early in RA, and detection of rheumatoid factor is not specific for RA. Testing for anti-CCP antibody can provide additional information and, in some cases, enable earlier and more specific diagnosis.

An important advance in our understanding of the pathogenesis of RA and in improving our ability to diagnose it early is the recognition that RA patients often produce autoantibodies directed against proteins and peptides containing the amino acid citrulline. Citrulline is generated in an inflammatory environment by the modification of the amino acid arginine by the enzyme peptidylarginine deiminase. Antibodies against cyclic citrulline are generated by patients with a certain genetic makeup, although citrulline can be detected in inflammatory tissues in conditions other than RA (without the antibody).

Anti-CCP antibody has been found in sera up to 10 years before the onset of joint symptoms in patients who later develop RA and may appear somewhat earlier than rheumatoid factor.¹ From 10% to 15% of RA patients remain seronegative for rheumatoid factor throughout the disease course.

INFORMAL GUIDELINES FOR ANTI-CCP ANTIBODY TESTING

The role of anti-CCP antibody testing in the management of RA is still being defined, but we suggest several informal guidelines.

Anti-CCP antibody testing can help interpret the significance of an inexplicably high rheumatoid factor titer in the absence of classic RA. In such situations, a negative anti-CCP antibody test suggests a nonrheumatic disorder such as hepatitis C virus infection or endocarditis, whereas a positive anti-CCP antibody test is more consistent with early or even preclinical RA since this test, unlike rheumatoid factor testing, is generally negative in the setting of infection.

However, in a patient who has documented RA and who is seropositive for rheumatoid factor, anti-CCP antibody testing has limited value, as the information it provides may be redundant. In a patient with a low to intermediate probability for RA and with a negative or low level of rheumatoid factor, a positive anti-CCP antibody test helps confirm the diagnosis. Rheumatoid factor positivity and anti-CCP antibody positivity are each associated with more severe RA. Neither test varies with the activity of RA.

Finally, in smokers with a particular genotype, the presence of anti-CCP antibody predicts a particularly worse course for RA.

THE ROLE OF RHEUMATOID FACTOR TESTING

Rheumatoid factor, first described in 1940,⁴ is an antibody against the Fc portion of immunoglobulin G. The cutoff value for positivity varies by laboratory but is usually greater than 45 IU/mL by enzyme-linked immunosorbent assay or laser nephelometry, or greater than 1:80 by latex fixation. However, serum titers or serum levels expressed as “IU/mL” cannot accurately be compared between laboratories; instead, when using tests for rheumatoid factor, physicians should refer to specificity and sensitivity measurements for each analyzing laboratory.

Around 50% of patients with RA become positive for rheumatoid factor in the first 6 months, and 85% become positive over the first 2 years. Also, rheumatoid factor testing suffers from low specificity, since it can be detected (although sometimes in low levels) in a variety of infectious and inflammatory conditions, such as bacterial endocarditis, malaria, tuberculosis, osteomyelitis, hepatitis C (with or without cryoglobulinemia), Sjögren syndrome, systemic lupus erythematosus, primary biliary cirrhosis, postvaccination arthropathy, and aging.

Current detection methods cannot differentiate between naturally occurring, transiently induced, and RA-associated rheumatoid factor. The levels are generally higher in RA than in many non-RA disorders, but significant overlap occurs. Rheumatoid factor positivity serves as a marker of poor prognosis, predicting generally more aggressive, erosive disease, and it is correlated with extra-articular manifestations such as rheumatoid nodules and lung involvement.

The classification criteria for RA published in 2010 by the American College of Rheumatology and the European League Against Rheumatism provide references for the measurement of rheumatoid factor: “low-level positive” refers to values less than or equal to three times the upper limit of normal for a particular laboratory; “high-level positive” refers to values more than three times the upper limit of normal.⁵ This is an attempt to provide a clinically useful benchmark for the measurement of rheumatoid factor, the values of which may vary between laboratories.

STUDIES COMPARING THE TWO TESTS

Several studies have evaluated the utility and validity of anti-CCP antibody testing vs rheumatoid factor testing.

In a study of 826 US veterans with RA,⁶ 75% tested positive for anti-CCP antibody and 80% were positive for rheumatoid factor. It was found that a higher anti-CCP antibody titer was associated with increased disease activity and inversely correlated with remission, especially in those also positive for rheumatoid factor.⁶

In another study,¹ in which blood samples from 79 patients with RA who had been blood donors were analyzed, 39 patients (49.4%) were positive for either rheumatoid factor or anti-CCP antibody, or both, a median of 4.5 years (range 0.1 to 13.8 years) before the onset of RA symptoms; 32 patients (40.5%) became positive for anti-CCP antibody before symptom onset.

Whiting et al,⁷ in a systematic review of 151 studies, showed that anti-CCP antibody testing had greater specificity than rheumatoid factor testing (96% vs 86%), with similar sensitivity (56% vs 58%)—most notably in eight cohort studies of patients with early RA.⁷ In the 15 cohort studies analyzed, the test was found to have a positive likelihood ratio of 12.7 and a negative likelihood ratio of 0.45, supporting this as a test of high positive predictive value for RA.

In view of the evidence from these studies, it is not surprising that the 2010 collaborative classification of RA of the American College of Rheumatology and the European League Against Rheumatism places equal weight on anti-CCP antibody testing and rheumatoid factor testing in the early diagnosis of RA.⁵

GENETICS AND THE PROGNOSIS OF RHEUMATOID ARTHRITIS

In recent years, there has been a growing recognition that the pathogenesis of RA in patients who are seropositive for rheumatoid factor or anti-CCP antibody is different from the pathogenesis of RA in patients who are seronegative for rheumatoid factor and anti-CCP antibody. This may help us guide therapy.

Patients positive for rheumatoid factor or anti-CCP antibody who have a specific allelic subset of a region of the immune-response gene DRB1*04 appear to be highly vulnerable to smoking as an environmental trigger or to worsening RA.⁸

Patients positive for anti-CCP antibody tend also to have severe joint destruction and, hence, have a worse prognosis. Kaltenhäuser et al⁹ found that determining the presence of the shared epitope (an RA-specific genetic marker) and positivity for anti-CCP antibody facilitates prediction of the disease course and prognosis.⁹

Studies have shown that patients with confirmed RA who test positive for anti-CCP antibody may also have more-severe extraarticular manifestations. Recent studies have found anti-CCP antibody positivity in 15.7% to 17.5% of patients with psoriatic arthritis and in 85% of patients with RA. Patients with psoriatic arthritis who were positive for anti-CCP antibody had more joints that were tender and swollen, erosive arthritis, deformities, and functional impairment of peripheral joints.^10,11

THE COST DIFFERENCE IS TRIVIAL IN THE LONG RUN

Cost is the major differentiating factor between rheumatoid factor testing and anti-CCP antibody testing. Rheumatoid factor testing costs around $43, and anti-CCP antibody testing costs $102 in the reference laboratory at Cleveland Clinic. However, the difference in cost is trivial, since this is only a one-time cost, whereas the information anti-CCP antibody testing provides can have a major impact on predicting the prognosis and determining the choice of therapy for a disease associated with high direct and indirect costs over a lifetime. Also, Medicare and other insurers would likely reimburse for anti-CCP antibody testing as long as it was associated with a related diagnosis such as arthralgia or arthritis.

Given that there will be a small number of patients with confirmed RA who will be negative for rheumatoid factor yet positive for anti-CCP antibody, one can support ordering both tests in tandem in a patient whom you strongly suspect of having RA. Or, at $100, one could make the argument that it would be cost-effective to order anti-CCP antibody testing only if rheumatoid factor testing is negative.

Testing for rheumatoid factor and anti-CCP antibody should not be done serially to assess treatment response or disease activity in these patients: these markers do not vary with inflammatory activity or disappear with clinical “remission.”

Yes. Testing for anti-cyclic citrullinated peptide (anti-CCP) antibody can help diagnose rheumatoid arthritis (RA) because it is a highly specific test.

For many years, the diagnosis of RA has been based on the presentation of symmetrical small- and large-joint polyarthritis that spares the lower spine, further supported by the presence of characteristic joint damage on radiography and an elevated rheumatoid factor while also excluding clinical mimics. However, rheumatoid factor is often not detected early in RA, and detection of rheumatoid factor is not specific for RA. Testing for anti-CCP antibody can provide additional information and, in some cases, enable earlier and more specific diagnosis.

An important advance in our understanding of the pathogenesis of RA and in improving our ability to diagnose it early is the recognition that RA patients often produce autoantibodies directed against proteins and peptides containing the amino acid citrulline. Citrulline is generated in an inflammatory environment by the modification of the amino acid arginine by the enzyme peptidylarginine deiminase. Antibodies against cyclic citrulline are generated by patients with a certain genetic makeup, although citrulline can be detected in inflammatory tissues in conditions other than RA (without the antibody).

Anti-CCP antibody has been found in sera up to 10 years before the onset of joint symptoms in patients who later develop RA and may appear somewhat earlier than rheumatoid factor.¹ From 10% to 15% of RA patients remain seronegative for rheumatoid factor throughout the disease course.

INFORMAL GUIDELINES FOR ANTI-CCP ANTIBODY TESTING

The role of anti-CCP antibody testing in the management of RA is still being defined, but we suggest several informal guidelines.

Anti-CCP antibody testing can help interpret the significance of an inexplicably high rheumatoid factor titer in the absence of classic RA. In such situations, a negative anti-CCP antibody test suggests a nonrheumatic disorder such as hepatitis C virus infection or endocarditis, whereas a positive anti-CCP antibody test is more consistent with early or even preclinical RA since this test, unlike rheumatoid factor testing, is generally negative in the setting of infection.

However, in a patient who has documented RA and who is seropositive for rheumatoid factor, anti-CCP antibody testing has limited value, as the information it provides may be redundant. In a patient with a low to intermediate probability for RA and with a negative or low level of rheumatoid factor, a positive anti-CCP antibody test helps confirm the diagnosis. Rheumatoid factor positivity and anti-CCP antibody positivity are each associated with more severe RA. Neither test varies with the activity of RA.

Finally, in smokers with a particular genotype, the presence of anti-CCP antibody predicts a particularly worse course for RA.

THE ROLE OF RHEUMATOID FACTOR TESTING

Rheumatoid factor, first described in 1940,⁴ is an antibody against the Fc portion of immunoglobulin G. The cutoff value for positivity varies by laboratory but is usually greater than 45 IU/mL by enzyme-linked immunosorbent assay or laser nephelometry, or greater than 1:80 by latex fixation. However, serum titers or serum levels expressed as “IU/mL” cannot accurately be compared between laboratories; instead, when using tests for rheumatoid factor, physicians should refer to specificity and sensitivity measurements for each analyzing laboratory.

Around 50% of patients with RA become positive for rheumatoid factor in the first 6 months, and 85% become positive over the first 2 years. Also, rheumatoid factor testing suffers from low specificity, since it can be detected (although sometimes in low levels) in a variety of infectious and inflammatory conditions, such as bacterial endocarditis, malaria, tuberculosis, osteomyelitis, hepatitis C (with or without cryoglobulinemia), Sjögren syndrome, systemic lupus erythematosus, primary biliary cirrhosis, postvaccination arthropathy, and aging.

Current detection methods cannot differentiate between naturally occurring, transiently induced, and RA-associated rheumatoid factor. The levels are generally higher in RA than in many non-RA disorders, but significant overlap occurs. Rheumatoid factor positivity serves as a marker of poor prognosis, predicting generally more aggressive, erosive disease, and it is correlated with extra-articular manifestations such as rheumatoid nodules and lung involvement.

The classification criteria for RA published in 2010 by the American College of Rheumatology and the European League Against Rheumatism provide references for the measurement of rheumatoid factor: “low-level positive” refers to values less than or equal to three times the upper limit of normal for a particular laboratory; “high-level positive” refers to values more than three times the upper limit of normal.⁵ This is an attempt to provide a clinically useful benchmark for the measurement of rheumatoid factor, the values of which may vary between laboratories.

STUDIES COMPARING THE TWO TESTS

Several studies have evaluated the utility and validity of anti-CCP antibody testing vs rheumatoid factor testing.

In a study of 826 US veterans with RA,⁶ 75% tested positive for anti-CCP antibody and 80% were positive for rheumatoid factor. It was found that a higher anti-CCP antibody titer was associated with increased disease activity and inversely correlated with remission, especially in those also positive for rheumatoid factor.⁶

In another study,¹ in which blood samples from 79 patients with RA who had been blood donors were analyzed, 39 patients (49.4%) were positive for either rheumatoid factor or anti-CCP antibody, or both, a median of 4.5 years (range 0.1 to 13.8 years) before the onset of RA symptoms; 32 patients (40.5%) became positive for anti-CCP antibody before symptom onset.

Whiting et al,⁷ in a systematic review of 151 studies, showed that anti-CCP antibody testing had greater specificity than rheumatoid factor testing (96% vs 86%), with similar sensitivity (56% vs 58%)—most notably in eight cohort studies of patients with early RA.⁷ In the 15 cohort studies analyzed, the test was found to have a positive likelihood ratio of 12.7 and a negative likelihood ratio of 0.45, supporting this as a test of high positive predictive value for RA.

In view of the evidence from these studies, it is not surprising that the 2010 collaborative classification of RA of the American College of Rheumatology and the European League Against Rheumatism places equal weight on anti-CCP antibody testing and rheumatoid factor testing in the early diagnosis of RA.⁵

GENETICS AND THE PROGNOSIS OF RHEUMATOID ARTHRITIS

In recent years, there has been a growing recognition that the pathogenesis of RA in patients who are seropositive for rheumatoid factor or anti-CCP antibody is different from the pathogenesis of RA in patients who are seronegative for rheumatoid factor and anti-CCP antibody. This may help us guide therapy.

Patients positive for rheumatoid factor or anti-CCP antibody who have a specific allelic subset of a region of the immune-response gene DRB1*04 appear to be highly vulnerable to smoking as an environmental trigger or to worsening RA.⁸

Patients positive for anti-CCP antibody tend also to have severe joint destruction and, hence, have a worse prognosis. Kaltenhäuser et al⁹ found that determining the presence of the shared epitope (an RA-specific genetic marker) and positivity for anti-CCP antibody facilitates prediction of the disease course and prognosis.⁹

Studies have shown that patients with confirmed RA who test positive for anti-CCP antibody may also have more-severe extraarticular manifestations. Recent studies have found anti-CCP antibody positivity in 15.7% to 17.5% of patients with psoriatic arthritis and in 85% of patients with RA. Patients with psoriatic arthritis who were positive for anti-CCP antibody had more joints that were tender and swollen, erosive arthritis, deformities, and functional impairment of peripheral joints.^10,11

THE COST DIFFERENCE IS TRIVIAL IN THE LONG RUN

Cost is the major differentiating factor between rheumatoid factor testing and anti-CCP antibody testing. Rheumatoid factor testing costs around $43, and anti-CCP antibody testing costs $102 in the reference laboratory at Cleveland Clinic. However, the difference in cost is trivial, since this is only a one-time cost, whereas the information anti-CCP antibody testing provides can have a major impact on predicting the prognosis and determining the choice of therapy for a disease associated with high direct and indirect costs over a lifetime. Also, Medicare and other insurers would likely reimburse for anti-CCP antibody testing as long as it was associated with a related diagnosis such as arthralgia or arthritis.

Given that there will be a small number of patients with confirmed RA who will be negative for rheumatoid factor yet positive for anti-CCP antibody, one can support ordering both tests in tandem in a patient whom you strongly suspect of having RA. Or, at $100, one could make the argument that it would be cost-effective to order anti-CCP antibody testing only if rheumatoid factor testing is negative.

Testing for rheumatoid factor and anti-CCP antibody should not be done serially to assess treatment response or disease activity in these patients: these markers do not vary with inflammatory activity or disappear with clinical “remission.”

Yes. Testing for anti-cyclic citrullinated peptide (anti-CCP) antibody can help diagnose rheumatoid arthritis (RA) because it is a highly specific test.

For many years, the diagnosis of RA has been based on the presentation of symmetrical small- and large-joint polyarthritis that spares the lower spine, further supported by the presence of characteristic joint damage on radiography and an elevated rheumatoid factor while also excluding clinical mimics. However, rheumatoid factor is often not detected early in RA, and detection of rheumatoid factor is not specific for RA. Testing for anti-CCP antibody can provide additional information and, in some cases, enable earlier and more specific diagnosis.

An important advance in our understanding of the pathogenesis of RA and in improving our ability to diagnose it early is the recognition that RA patients often produce autoantibodies directed against proteins and peptides containing the amino acid citrulline. Citrulline is generated in an inflammatory environment by the modification of the amino acid arginine by the enzyme peptidylarginine deiminase. Antibodies against cyclic citrulline are generated by patients with a certain genetic makeup, although citrulline can be detected in inflammatory tissues in conditions other than RA (without the antibody).

Anti-CCP antibody has been found in sera up to 10 years before the onset of joint symptoms in patients who later develop RA and may appear somewhat earlier than rheumatoid factor.¹ From 10% to 15% of RA patients remain seronegative for rheumatoid factor throughout the disease course.

INFORMAL GUIDELINES FOR ANTI-CCP ANTIBODY TESTING

The role of anti-CCP antibody testing in the management of RA is still being defined, but we suggest several informal guidelines.

Anti-CCP antibody testing can help interpret the significance of an inexplicably high rheumatoid factor titer in the absence of classic RA. In such situations, a negative anti-CCP antibody test suggests a nonrheumatic disorder such as hepatitis C virus infection or endocarditis, whereas a positive anti-CCP antibody test is more consistent with early or even preclinical RA since this test, unlike rheumatoid factor testing, is generally negative in the setting of infection.

However, in a patient who has documented RA and who is seropositive for rheumatoid factor, anti-CCP antibody testing has limited value, as the information it provides may be redundant. In a patient with a low to intermediate probability for RA and with a negative or low level of rheumatoid factor, a positive anti-CCP antibody test helps confirm the diagnosis. Rheumatoid factor positivity and anti-CCP antibody positivity are each associated with more severe RA. Neither test varies with the activity of RA.

Finally, in smokers with a particular genotype, the presence of anti-CCP antibody predicts a particularly worse course for RA.

THE ROLE OF RHEUMATOID FACTOR TESTING

Rheumatoid factor, first described in 1940,⁴ is an antibody against the Fc portion of immunoglobulin G. The cutoff value for positivity varies by laboratory but is usually greater than 45 IU/mL by enzyme-linked immunosorbent assay or laser nephelometry, or greater than 1:80 by latex fixation. However, serum titers or serum levels expressed as “IU/mL” cannot accurately be compared between laboratories; instead, when using tests for rheumatoid factor, physicians should refer to specificity and sensitivity measurements for each analyzing laboratory.

Around 50% of patients with RA become positive for rheumatoid factor in the first 6 months, and 85% become positive over the first 2 years. Also, rheumatoid factor testing suffers from low specificity, since it can be detected (although sometimes in low levels) in a variety of infectious and inflammatory conditions, such as bacterial endocarditis, malaria, tuberculosis, osteomyelitis, hepatitis C (with or without cryoglobulinemia), Sjögren syndrome, systemic lupus erythematosus, primary biliary cirrhosis, postvaccination arthropathy, and aging.

Current detection methods cannot differentiate between naturally occurring, transiently induced, and RA-associated rheumatoid factor. The levels are generally higher in RA than in many non-RA disorders, but significant overlap occurs. Rheumatoid factor positivity serves as a marker of poor prognosis, predicting generally more aggressive, erosive disease, and it is correlated with extra-articular manifestations such as rheumatoid nodules and lung involvement.

The classification criteria for RA published in 2010 by the American College of Rheumatology and the European League Against Rheumatism provide references for the measurement of rheumatoid factor: “low-level positive” refers to values less than or equal to three times the upper limit of normal for a particular laboratory; “high-level positive” refers to values more than three times the upper limit of normal.⁵ This is an attempt to provide a clinically useful benchmark for the measurement of rheumatoid factor, the values of which may vary between laboratories.

STUDIES COMPARING THE TWO TESTS

Several studies have evaluated the utility and validity of anti-CCP antibody testing vs rheumatoid factor testing.

In a study of 826 US veterans with RA,⁶ 75% tested positive for anti-CCP antibody and 80% were positive for rheumatoid factor. It was found that a higher anti-CCP antibody titer was associated with increased disease activity and inversely correlated with remission, especially in those also positive for rheumatoid factor.⁶

In another study,¹ in which blood samples from 79 patients with RA who had been blood donors were analyzed, 39 patients (49.4%) were positive for either rheumatoid factor or anti-CCP antibody, or both, a median of 4.5 years (range 0.1 to 13.8 years) before the onset of RA symptoms; 32 patients (40.5%) became positive for anti-CCP antibody before symptom onset.

Whiting et al,⁷ in a systematic review of 151 studies, showed that anti-CCP antibody testing had greater specificity than rheumatoid factor testing (96% vs 86%), with similar sensitivity (56% vs 58%)—most notably in eight cohort studies of patients with early RA.⁷ In the 15 cohort studies analyzed, the test was found to have a positive likelihood ratio of 12.7 and a negative likelihood ratio of 0.45, supporting this as a test of high positive predictive value for RA.

In view of the evidence from these studies, it is not surprising that the 2010 collaborative classification of RA of the American College of Rheumatology and the European League Against Rheumatism places equal weight on anti-CCP antibody testing and rheumatoid factor testing in the early diagnosis of RA.⁵

GENETICS AND THE PROGNOSIS OF RHEUMATOID ARTHRITIS

In recent years, there has been a growing recognition that the pathogenesis of RA in patients who are seropositive for rheumatoid factor or anti-CCP antibody is different from the pathogenesis of RA in patients who are seronegative for rheumatoid factor and anti-CCP antibody. This may help us guide therapy.

Patients positive for rheumatoid factor or anti-CCP antibody who have a specific allelic subset of a region of the immune-response gene DRB1*04 appear to be highly vulnerable to smoking as an environmental trigger or to worsening RA.⁸

Patients positive for anti-CCP antibody tend also to have severe joint destruction and, hence, have a worse prognosis. Kaltenhäuser et al⁹ found that determining the presence of the shared epitope (an RA-specific genetic marker) and positivity for anti-CCP antibody facilitates prediction of the disease course and prognosis.⁹

Studies have shown that patients with confirmed RA who test positive for anti-CCP antibody may also have more-severe extraarticular manifestations. Recent studies have found anti-CCP antibody positivity in 15.7% to 17.5% of patients with psoriatic arthritis and in 85% of patients with RA. Patients with psoriatic arthritis who were positive for anti-CCP antibody had more joints that were tender and swollen, erosive arthritis, deformities, and functional impairment of peripheral joints.^10,11

THE COST DIFFERENCE IS TRIVIAL IN THE LONG RUN

Cost is the major differentiating factor between rheumatoid factor testing and anti-CCP antibody testing. Rheumatoid factor testing costs around $43, and anti-CCP antibody testing costs $102 in the reference laboratory at Cleveland Clinic. However, the difference in cost is trivial, since this is only a one-time cost, whereas the information anti-CCP antibody testing provides can have a major impact on predicting the prognosis and determining the choice of therapy for a disease associated with high direct and indirect costs over a lifetime. Also, Medicare and other insurers would likely reimburse for anti-CCP antibody testing as long as it was associated with a related diagnosis such as arthralgia or arthritis.

Given that there will be a small number of patients with confirmed RA who will be negative for rheumatoid factor yet positive for anti-CCP antibody, one can support ordering both tests in tandem in a patient whom you strongly suspect of having RA. Or, at $100, one could make the argument that it would be cost-effective to order anti-CCP antibody testing only if rheumatoid factor testing is negative.

Testing for rheumatoid factor and anti-CCP antibody should not be done serially to assess treatment response or disease activity in these patients: these markers do not vary with inflammatory activity or disappear with clinical “remission.”

In Reply: I thank Dr. Keller for his thoughtful comments. They are most appreciated.

It is true that with availability of generic ropinirole and pramipexole, there are now cheaper alternatives to levodopa. Nonetheless, levodopa remains the cheapest and most efficacious medication for Parkinson disease to date. Whenever levodopa is compared head-to-head with any dopamine agonist, the general results remain consistent: levodopa affords better motor improvement with lesser side effects, but is more likely to lead to motor fluctuations, specifically dyskinesias. Therefore, in general, levodopa is the first choice in elderly patients where tolerability may be an issue, whereas a dopamine agonist may be the initial treatment of choice in younger Parkinson patients, who are able to tolerate the drug better and have a higher likelihood of developing dyskinesias.

It is a tougher task to determine which among the dopamine agonists is superior. The newer dopamine agonists have not been compared head-to-head. Therefore, it is practically a “coin toss” when selecting which dopamine agonist to try. Their mechanism of action (D2 and D3 receptor agonist activity) and frequency of intake (three times per day for generics; once daily for long-acting formulations), cost, and side effect profile are nearly identical, despite minor differences in their half-lives.

Regarding putative neuroprotective agents in Parkinson disease, indeed, isradipine is one of the medications currently undergoing investigation for its potential neuroprotective effect. While I personally have no objection to using it for a Parkinson disease patient who also happens to need an antihypertensive agent, I am more cautious about endorsing it as a neuroprotective agent until results of clinical trials have been released. Similarly, while a large epidemiologic study has shown that people who take ibuprofen are less likely to develop Parkinson disease, there has been no robust human trial that has shown the drug to slow the progression of Parkinson disease among patients who are already suffering from the disorder. Therefore, the current use of ibuprofen in Parkinson disease should be based more on its anti-inflammatory indications rather than its possible neuroprotective effect. Finally, we have shown, in a large, multicenter, global randomized controlled trial with a delayed-start design, that pramipexole is unlikely to possess any meaningful neuroprotective effect. Therefore, I am personally not that optimistic that dexpramipexole would demonstrate such an effect.

While in theory combining the use of catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) type B inhibitors can synergistically work to inhibit the breakdown of other catecholamines and lead to adrenergic crisis when taken concomitantly, this has not been our experience. Perhaps it is because at recommended doses, the MAO inhibition is selective to type B (where receptors are more confined to the brain) and not type A (where receptors are more distributed throughout blood vessels, thereby having a higher likelihood of causing a hypertensive crisis as is seen in the use of nonselective MAO inhibitors). Therefore, at our center, we routinely use the two classes of agents concomitantly with minimal safety concerns.

In Reply: I thank Dr. Keller for his thoughtful comments. They are most appreciated.

It is true that with availability of generic ropinirole and pramipexole, there are now cheaper alternatives to levodopa. Nonetheless, levodopa remains the cheapest and most efficacious medication for Parkinson disease to date. Whenever levodopa is compared head-to-head with any dopamine agonist, the general results remain consistent: levodopa affords better motor improvement with lesser side effects, but is more likely to lead to motor fluctuations, specifically dyskinesias. Therefore, in general, levodopa is the first choice in elderly patients where tolerability may be an issue, whereas a dopamine agonist may be the initial treatment of choice in younger Parkinson patients, who are able to tolerate the drug better and have a higher likelihood of developing dyskinesias.

It is a tougher task to determine which among the dopamine agonists is superior. The newer dopamine agonists have not been compared head-to-head. Therefore, it is practically a “coin toss” when selecting which dopamine agonist to try. Their mechanism of action (D2 and D3 receptor agonist activity) and frequency of intake (three times per day for generics; once daily for long-acting formulations), cost, and side effect profile are nearly identical, despite minor differences in their half-lives.

Regarding putative neuroprotective agents in Parkinson disease, indeed, isradipine is one of the medications currently undergoing investigation for its potential neuroprotective effect. While I personally have no objection to using it for a Parkinson disease patient who also happens to need an antihypertensive agent, I am more cautious about endorsing it as a neuroprotective agent until results of clinical trials have been released. Similarly, while a large epidemiologic study has shown that people who take ibuprofen are less likely to develop Parkinson disease, there has been no robust human trial that has shown the drug to slow the progression of Parkinson disease among patients who are already suffering from the disorder. Therefore, the current use of ibuprofen in Parkinson disease should be based more on its anti-inflammatory indications rather than its possible neuroprotective effect. Finally, we have shown, in a large, multicenter, global randomized controlled trial with a delayed-start design, that pramipexole is unlikely to possess any meaningful neuroprotective effect. Therefore, I am personally not that optimistic that dexpramipexole would demonstrate such an effect.

While in theory combining the use of catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) type B inhibitors can synergistically work to inhibit the breakdown of other catecholamines and lead to adrenergic crisis when taken concomitantly, this has not been our experience. Perhaps it is because at recommended doses, the MAO inhibition is selective to type B (where receptors are more confined to the brain) and not type A (where receptors are more distributed throughout blood vessels, thereby having a higher likelihood of causing a hypertensive crisis as is seen in the use of nonselective MAO inhibitors). Therefore, at our center, we routinely use the two classes of agents concomitantly with minimal safety concerns.

In Reply: I thank Dr. Keller for his thoughtful comments. They are most appreciated.

It is true that with availability of generic ropinirole and pramipexole, there are now cheaper alternatives to levodopa. Nonetheless, levodopa remains the cheapest and most efficacious medication for Parkinson disease to date. Whenever levodopa is compared head-to-head with any dopamine agonist, the general results remain consistent: levodopa affords better motor improvement with lesser side effects, but is more likely to lead to motor fluctuations, specifically dyskinesias. Therefore, in general, levodopa is the first choice in elderly patients where tolerability may be an issue, whereas a dopamine agonist may be the initial treatment of choice in younger Parkinson patients, who are able to tolerate the drug better and have a higher likelihood of developing dyskinesias.

It is a tougher task to determine which among the dopamine agonists is superior. The newer dopamine agonists have not been compared head-to-head. Therefore, it is practically a “coin toss” when selecting which dopamine agonist to try. Their mechanism of action (D2 and D3 receptor agonist activity) and frequency of intake (three times per day for generics; once daily for long-acting formulations), cost, and side effect profile are nearly identical, despite minor differences in their half-lives.

Regarding putative neuroprotective agents in Parkinson disease, indeed, isradipine is one of the medications currently undergoing investigation for its potential neuroprotective effect. While I personally have no objection to using it for a Parkinson disease patient who also happens to need an antihypertensive agent, I am more cautious about endorsing it as a neuroprotective agent until results of clinical trials have been released. Similarly, while a large epidemiologic study has shown that people who take ibuprofen are less likely to develop Parkinson disease, there has been no robust human trial that has shown the drug to slow the progression of Parkinson disease among patients who are already suffering from the disorder. Therefore, the current use of ibuprofen in Parkinson disease should be based more on its anti-inflammatory indications rather than its possible neuroprotective effect. Finally, we have shown, in a large, multicenter, global randomized controlled trial with a delayed-start design, that pramipexole is unlikely to possess any meaningful neuroprotective effect. Therefore, I am personally not that optimistic that dexpramipexole would demonstrate such an effect.

While in theory combining the use of catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) type B inhibitors can synergistically work to inhibit the breakdown of other catecholamines and lead to adrenergic crisis when taken concomitantly, this has not been our experience. Perhaps it is because at recommended doses, the MAO inhibition is selective to type B (where receptors are more confined to the brain) and not type A (where receptors are more distributed throughout blood vessels, thereby having a higher likelihood of causing a hypertensive crisis as is seen in the use of nonselective MAO inhibitors). Therefore, at our center, we routinely use the two classes of agents concomitantly with minimal safety concerns.

To the Editor: I have the following comments and questions regarding the excellent Medical Grand Rounds article on Parkinson disease by Dr. Fernandez in your January 2012 issue.¹

The author mentions that when “cost may be of concern, levodopa is the preferred starting drug.”¹ Generic versions of pramipexole and ropinirole are now available and have made these medications more affordable. For example, the cash price of generic ropinirole 5 mg was recently $66 for 100 tablets, comparable with generic carbidopa/levodopa (25/100 mg priced at $46 for 100 tablets.² And even though the price of generic pramipexole was $240 for 90 tablets, seniors with Medicare Part D drug coverage can usually get any generic medication for a low copay.

When choosing a dopamine agonist, how does Dr. Fernandez decide between ropinirole and pramipexole (aside from the price difference noted above)? Pramipexole has a longer elimination half-life (8 to 12 hours) compared with ropinirole (6 hours).³ Does this imply a significantly longer effective dosing interval for pramipexole? Are there other significant clinical differences between these agents?

Isradipine (DynaCirc CR), a dihydropyridine calcium channel blocker, has shown promise as a neuroprotective agent for slowing the progression of Parkinson disease in epidemiologic and laboratory studies, as noted by the author. In addition, immediate-release isradipine, with its relatively short elimination half-life of 8 hours,³ may be well suited for treating Parkinson patients whose essential hypertension is complicated by episodes of orthostatic hypotension. It should be noted that dihydropyridines that do not cross the blood-brain barrier (such as amlodipine [Norvasc]) have shown no evidence of neuroprotection.

Ibuprofen is another drug that has fairly strong epidemiologic and laboratory evidence that it might be neuroprotective,⁴ although the other nonsteroidal anti-inflammatory drugs (NSAIDs) have proven disappointing as a class.⁵ Lacking any prospective randomized trials, the evidence is not strong enough to recommend ibuprofen solely for neuroprotection. Does Dr. Fernandez, however, consider it reasonable to suggest ibuprofen to Parkinson patients who need to take an NSAID for an approved indication (such as pain)?

Dexpramipexole has recently demonstrated great promise in a phase 3 clinical trial as a neuroprotective agent in amyotrophic lateral sclerosis.⁶ How does this compound relate to pramipexole, and does the author believe it may offer neuroprotection in other neurodegenerative diseases like Parkinson disease?

The author discusses the use of catechol-O-methyltransferase (COMT) inhibitors (such as Comtan and Tasmar) and the monoamine oxidase (MAO) type-B inhibitors rasagiline (Azilect) and selegiline (Eldepryl, Zelapar) for prolonging the effects of levodopa by slowing the breakdown of dopamine. However, it is important to note that it is contraindicated to prescribe both a COMT inhibitor and an MAO-B inhibitor, because these agents also inhibit the breakdown of other catecholamines and can lead to adrenergic crisis when taken concomitantly.

To the Editor: I have the following comments and questions regarding the excellent Medical Grand Rounds article on Parkinson disease by Dr. Fernandez in your January 2012 issue.¹

The author mentions that when “cost may be of concern, levodopa is the preferred starting drug.”¹ Generic versions of pramipexole and ropinirole are now available and have made these medications more affordable. For example, the cash price of generic ropinirole 5 mg was recently $66 for 100 tablets, comparable with generic carbidopa/levodopa (25/100 mg priced at $46 for 100 tablets.² And even though the price of generic pramipexole was $240 for 90 tablets, seniors with Medicare Part D drug coverage can usually get any generic medication for a low copay.

When choosing a dopamine agonist, how does Dr. Fernandez decide between ropinirole and pramipexole (aside from the price difference noted above)? Pramipexole has a longer elimination half-life (8 to 12 hours) compared with ropinirole (6 hours).³ Does this imply a significantly longer effective dosing interval for pramipexole? Are there other significant clinical differences between these agents?

Isradipine (DynaCirc CR), a dihydropyridine calcium channel blocker, has shown promise as a neuroprotective agent for slowing the progression of Parkinson disease in epidemiologic and laboratory studies, as noted by the author. In addition, immediate-release isradipine, with its relatively short elimination half-life of 8 hours,³ may be well suited for treating Parkinson patients whose essential hypertension is complicated by episodes of orthostatic hypotension. It should be noted that dihydropyridines that do not cross the blood-brain barrier (such as amlodipine [Norvasc]) have shown no evidence of neuroprotection.

Ibuprofen is another drug that has fairly strong epidemiologic and laboratory evidence that it might be neuroprotective,⁴ although the other nonsteroidal anti-inflammatory drugs (NSAIDs) have proven disappointing as a class.⁵ Lacking any prospective randomized trials, the evidence is not strong enough to recommend ibuprofen solely for neuroprotection. Does Dr. Fernandez, however, consider it reasonable to suggest ibuprofen to Parkinson patients who need to take an NSAID for an approved indication (such as pain)?

Dexpramipexole has recently demonstrated great promise in a phase 3 clinical trial as a neuroprotective agent in amyotrophic lateral sclerosis.⁶ How does this compound relate to pramipexole, and does the author believe it may offer neuroprotection in other neurodegenerative diseases like Parkinson disease?

The author discusses the use of catechol-O-methyltransferase (COMT) inhibitors (such as Comtan and Tasmar) and the monoamine oxidase (MAO) type-B inhibitors rasagiline (Azilect) and selegiline (Eldepryl, Zelapar) for prolonging the effects of levodopa by slowing the breakdown of dopamine. However, it is important to note that it is contraindicated to prescribe both a COMT inhibitor and an MAO-B inhibitor, because these agents also inhibit the breakdown of other catecholamines and can lead to adrenergic crisis when taken concomitantly.

To the Editor: I have the following comments and questions regarding the excellent Medical Grand Rounds article on Parkinson disease by Dr. Fernandez in your January 2012 issue.¹

The author mentions that when “cost may be of concern, levodopa is the preferred starting drug.”¹ Generic versions of pramipexole and ropinirole are now available and have made these medications more affordable. For example, the cash price of generic ropinirole 5 mg was recently $66 for 100 tablets, comparable with generic carbidopa/levodopa (25/100 mg priced at $46 for 100 tablets.² And even though the price of generic pramipexole was $240 for 90 tablets, seniors with Medicare Part D drug coverage can usually get any generic medication for a low copay.

When choosing a dopamine agonist, how does Dr. Fernandez decide between ropinirole and pramipexole (aside from the price difference noted above)? Pramipexole has a longer elimination half-life (8 to 12 hours) compared with ropinirole (6 hours).³ Does this imply a significantly longer effective dosing interval for pramipexole? Are there other significant clinical differences between these agents?

Isradipine (DynaCirc CR), a dihydropyridine calcium channel blocker, has shown promise as a neuroprotective agent for slowing the progression of Parkinson disease in epidemiologic and laboratory studies, as noted by the author. In addition, immediate-release isradipine, with its relatively short elimination half-life of 8 hours,³ may be well suited for treating Parkinson patients whose essential hypertension is complicated by episodes of orthostatic hypotension. It should be noted that dihydropyridines that do not cross the blood-brain barrier (such as amlodipine [Norvasc]) have shown no evidence of neuroprotection.

Ibuprofen is another drug that has fairly strong epidemiologic and laboratory evidence that it might be neuroprotective,⁴ although the other nonsteroidal anti-inflammatory drugs (NSAIDs) have proven disappointing as a class.⁵ Lacking any prospective randomized trials, the evidence is not strong enough to recommend ibuprofen solely for neuroprotection. Does Dr. Fernandez, however, consider it reasonable to suggest ibuprofen to Parkinson patients who need to take an NSAID for an approved indication (such as pain)?

Dexpramipexole has recently demonstrated great promise in a phase 3 clinical trial as a neuroprotective agent in amyotrophic lateral sclerosis.⁶ How does this compound relate to pramipexole, and does the author believe it may offer neuroprotection in other neurodegenerative diseases like Parkinson disease?

The author discusses the use of catechol-O-methyltransferase (COMT) inhibitors (such as Comtan and Tasmar) and the monoamine oxidase (MAO) type-B inhibitors rasagiline (Azilect) and selegiline (Eldepryl, Zelapar) for prolonging the effects of levodopa by slowing the breakdown of dopamine. However, it is important to note that it is contraindicated to prescribe both a COMT inhibitor and an MAO-B inhibitor, because these agents also inhibit the breakdown of other catecholamines and can lead to adrenergic crisis when taken concomitantly.

In Reply: We agree and thank Dr. Keller for raising this valid point. The two classes of calcium channel blockers are distinct in their actions, and the warning about not combining a calcium channel blocker with a beta-blocker because of the increased risk of developing significant bradycardia applies only to the nondihydropyridine class.

In Reply: We agree and thank Dr. Keller for raising this valid point. The two classes of calcium channel blockers are distinct in their actions, and the warning about not combining a calcium channel blocker with a beta-blocker because of the increased risk of developing significant bradycardia applies only to the nondihydropyridine class.

In Reply: We agree and thank Dr. Keller for raising this valid point. The two classes of calcium channel blockers are distinct in their actions, and the warning about not combining a calcium channel blocker with a beta-blocker because of the increased risk of developing significant bradycardia applies only to the nondihydropyridine class.

To the Editor: In their thorough review of essential tremor,¹Drs. Abboud, Ahmed, and Fernandez make a statement that needs clarification. In their list of absolute contraindications to propranolol (Inderal), the authors include “concurrent use of a calcium channel blocker.” This warning applies only to the nondihydropyridine calcium channel blockers, which are diltiazem (Cardizem) and verapamil (Calan). These two medications slow the heart rate and generally should not be combined with beta-blockers such as propranolol unless the patient requires this combination to control tachycardia. Most calcium channel blockers are dihydropyridines, which include amlodipine (Norvasc), nifedipine (Procardia), felodipine (Plendil), nisoldipine (Sular), isradipine (DynaCirc CR), and nicardipine (Cardene). These agents do not slow the heart rate significantly and therefore can be used freely in combination with propranolol. Of course, the dose of the calcium channel blocker may need to be decreased because of the antihypertensive effect of propranolol.

To the Editor: In their thorough review of essential tremor,¹Drs. Abboud, Ahmed, and Fernandez make a statement that needs clarification. In their list of absolute contraindications to propranolol (Inderal), the authors include “concurrent use of a calcium channel blocker.” This warning applies only to the nondihydropyridine calcium channel blockers, which are diltiazem (Cardizem) and verapamil (Calan). These two medications slow the heart rate and generally should not be combined with beta-blockers such as propranolol unless the patient requires this combination to control tachycardia. Most calcium channel blockers are dihydropyridines, which include amlodipine (Norvasc), nifedipine (Procardia), felodipine (Plendil), nisoldipine (Sular), isradipine (DynaCirc CR), and nicardipine (Cardene). These agents do not slow the heart rate significantly and therefore can be used freely in combination with propranolol. Of course, the dose of the calcium channel blocker may need to be decreased because of the antihypertensive effect of propranolol.

To the Editor: In their thorough review of essential tremor,¹Drs. Abboud, Ahmed, and Fernandez make a statement that needs clarification. In their list of absolute contraindications to propranolol (Inderal), the authors include “concurrent use of a calcium channel blocker.” This warning applies only to the nondihydropyridine calcium channel blockers, which are diltiazem (Cardizem) and verapamil (Calan). These two medications slow the heart rate and generally should not be combined with beta-blockers such as propranolol unless the patient requires this combination to control tachycardia. Most calcium channel blockers are dihydropyridines, which include amlodipine (Norvasc), nifedipine (Procardia), felodipine (Plendil), nisoldipine (Sular), isradipine (DynaCirc CR), and nicardipine (Cardene). These agents do not slow the heart rate significantly and therefore can be used freely in combination with propranolol. Of course, the dose of the calcium channel blocker may need to be decreased because of the antihypertensive effect of propranolol.

In Reply: We thank Drs. Rodríguez-Gutiérrez and Gonzálvez-Gonzálvez and Dr. Keller for their thoughtful comments.

In our paper, we did not elaborate on the low-dose cosyntropin stimulation test. The 1-μg test, in particular, has been shown to have similar or better sensitivity, with similar or lower specificity, compared with the 250-μg dose, depending on the study design. Unfortunately, the administration of the 1-μg dose presents more technical difficulty than the 250-μg dose, thus limiting its use. Cosyntropin (used in the United States) comes in a vial with 250 μg of powder. This must be reconstituted with 250 mL of normal saline, and only 1 mL is to be given. Adherence to the plastic tubing may occur, and more precise timing is needed as the cortisol levels may decrease.^1–3

Responding to Dr. Keller, we were unable to find any systematic reviews comparing inhaled corticosteroids that have a “higher therapeutic index” as a class vs older inhaled corticosteroids. There are several studies, however, comparing individual inhaled corticosteroid preparations with each other in terms of adrenal effects, and we feel that it is beyond the scope of this response to perform a systematic analysis. In addition, the determination of adrenal function used in studies comparing one inhaled corticosteroid with another were varied, including cosyntropin stimulation tests and surrogates such as the urinary cortisolcreatinine ratio, a morning plasma cortisol level less than 5 μg/L, and serum cortisol concentration curves, preventing more definitive conclusions even if the data were to be pooled.^4–6 A double-blind, randomized study comparing the adrenal effects of ciclesonide and fluticasone showed a smaller reduction in the peak serum cortisol level achieved with ciclesonide compared with fluticasone, in both low-dose and high-dose cosyntropin stimulation tests, with the results in the ciclesonide group being similar to placebo.⁷ However, the mean peak serum cortisol levels after exposure to these inhaled corticosteroids were not presented in table format, and the results have to be inferred from the figures and the narrative description of the baseline mean peak cortisol levels⁸ (ie, before exposure to these inhaled corticosteroids). Case reports have suggested that changing the inhaled corticostseroid formulation from fluticasone to ciclesonide allowed for improvement of adrenal function.⁸ The purported mechanism of decreased adrenal effects of ciclesonide is its greater deposition in the lungs and, hence, less entry into the systemic circulation and fewer systemic adverse effects.⁹

In Reply: We thank Drs. Rodríguez-Gutiérrez and Gonzálvez-Gonzálvez and Dr. Keller for their thoughtful comments.

In our paper, we did not elaborate on the low-dose cosyntropin stimulation test. The 1-μg test, in particular, has been shown to have similar or better sensitivity, with similar or lower specificity, compared with the 250-μg dose, depending on the study design. Unfortunately, the administration of the 1-μg dose presents more technical difficulty than the 250-μg dose, thus limiting its use. Cosyntropin (used in the United States) comes in a vial with 250 μg of powder. This must be reconstituted with 250 mL of normal saline, and only 1 mL is to be given. Adherence to the plastic tubing may occur, and more precise timing is needed as the cortisol levels may decrease.^1–3

Responding to Dr. Keller, we were unable to find any systematic reviews comparing inhaled corticosteroids that have a “higher therapeutic index” as a class vs older inhaled corticosteroids. There are several studies, however, comparing individual inhaled corticosteroid preparations with each other in terms of adrenal effects, and we feel that it is beyond the scope of this response to perform a systematic analysis. In addition, the determination of adrenal function used in studies comparing one inhaled corticosteroid with another were varied, including cosyntropin stimulation tests and surrogates such as the urinary cortisolcreatinine ratio, a morning plasma cortisol level less than 5 μg/L, and serum cortisol concentration curves, preventing more definitive conclusions even if the data were to be pooled.^4–6 A double-blind, randomized study comparing the adrenal effects of ciclesonide and fluticasone showed a smaller reduction in the peak serum cortisol level achieved with ciclesonide compared with fluticasone, in both low-dose and high-dose cosyntropin stimulation tests, with the results in the ciclesonide group being similar to placebo.⁷ However, the mean peak serum cortisol levels after exposure to these inhaled corticosteroids were not presented in table format, and the results have to be inferred from the figures and the narrative description of the baseline mean peak cortisol levels⁸ (ie, before exposure to these inhaled corticosteroids). Case reports have suggested that changing the inhaled corticostseroid formulation from fluticasone to ciclesonide allowed for improvement of adrenal function.⁸ The purported mechanism of decreased adrenal effects of ciclesonide is its greater deposition in the lungs and, hence, less entry into the systemic circulation and fewer systemic adverse effects.⁹

In Reply: We thank Drs. Rodríguez-Gutiérrez and Gonzálvez-Gonzálvez and Dr. Keller for their thoughtful comments.

In our paper, we did not elaborate on the low-dose cosyntropin stimulation test. The 1-μg test, in particular, has been shown to have similar or better sensitivity, with similar or lower specificity, compared with the 250-μg dose, depending on the study design. Unfortunately, the administration of the 1-μg dose presents more technical difficulty than the 250-μg dose, thus limiting its use. Cosyntropin (used in the United States) comes in a vial with 250 μg of powder. This must be reconstituted with 250 mL of normal saline, and only 1 mL is to be given. Adherence to the plastic tubing may occur, and more precise timing is needed as the cortisol levels may decrease.^1–3

Responding to Dr. Keller, we were unable to find any systematic reviews comparing inhaled corticosteroids that have a “higher therapeutic index” as a class vs older inhaled corticosteroids. There are several studies, however, comparing individual inhaled corticosteroid preparations with each other in terms of adrenal effects, and we feel that it is beyond the scope of this response to perform a systematic analysis. In addition, the determination of adrenal function used in studies comparing one inhaled corticosteroid with another were varied, including cosyntropin stimulation tests and surrogates such as the urinary cortisolcreatinine ratio, a morning plasma cortisol level less than 5 μg/L, and serum cortisol concentration curves, preventing more definitive conclusions even if the data were to be pooled.^4–6 A double-blind, randomized study comparing the adrenal effects of ciclesonide and fluticasone showed a smaller reduction in the peak serum cortisol level achieved with ciclesonide compared with fluticasone, in both low-dose and high-dose cosyntropin stimulation tests, with the results in the ciclesonide group being similar to placebo.⁷ However, the mean peak serum cortisol levels after exposure to these inhaled corticosteroids were not presented in table format, and the results have to be inferred from the figures and the narrative description of the baseline mean peak cortisol levels⁸ (ie, before exposure to these inhaled corticosteroids). Case reports have suggested that changing the inhaled corticostseroid formulation from fluticasone to ciclesonide allowed for improvement of adrenal function.⁸ The purported mechanism of decreased adrenal effects of ciclesonide is its greater deposition in the lungs and, hence, less entry into the systemic circulation and fewer systemic adverse effects.⁹