Antiphospholipid syndrome

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Antiphospholipid syndrome

Julia S. Lehman and Mark D.P. Davis

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Antiphospholipid syndrome (APS) is characterized by the propensity for recurrent venous and arterial thrombosis in the presence of circulating antibodies against phospholipid-binding proteins. Diagnostic criteria for APS require that patients experience vascular thrombosis (venous or arterial) or pregnancy morbidity (e.g., three or more unexplained consecutive spontaneous abortions before the 10th week of gestation with exclusion of other causes), and harbor at least one serum antiphospholipid (aPL) antibody (i.e., lupus anticoagulant, anticardiolipin, anti-β2 glycoprotein-1) on two or more occasions over a 12-week period. It is important that patients not be diagnosed with APS based on isolated laboratory test abnormalities, as no laboratory test for APS is entirely specific.

Although cutaneous manifestations of APS are not part of the diagnostic criteria, they may represent the initial presentation of APS. Cutaneous signs result from thrombo-occlusion of the cutaneous vasculature and may include livedo reticularis or racemosa, livedoid vasculopathy (atrophie blanche), superficial thrombophlebitis, or ulceration.

Management strategy

In some cases, APS may represent a primary condition. However, a search for underlying causes or other contributing factors, such as infection, prothrombotic medications (such as oral contraceptives), primary hematologic coagulopathies (e.g., factor V Leiden, prothrombin G20210A gene mutation), and connective tissue diseases (e.g., systemic lupus erythematosus, SLE), is warranted. Patients should be offered subspecialty referral, where available.

Because patients with APS are at increased risk for recurrent thromboembolism, the goal of therapy is secondary thromboprophylaxis. Non-pharmacologic interventions include reduction of other prothrombotic risk factors, such as prolonged immobility and oral contraceptive use. Pharmaceutical interventions should be guided by the patient’s age and comorbidities, pregnancy status, presence of correctable prothrombotic factors, and coagulation history. In patients with persistently elevated aPL antibodies but no history of thrombosis (thereby not meeting strict criteria for APS), aspirin has not been shown to be effective in preventing future thromboembolic events. In patients with definitive APS and a history of venous thromboembolism the mainstay of treatment is long-term warfarin therapy. The optimal duration of warfarin therapy has not been established. Based on limited available data, indefinite treatment with warfarin appears to be associated with reduced rates of recurrent thromboembolism without an elevated risk for hemorrhagic complications, compared to treatment discontinuation after 6 months. Decisions regarding termination of warfarin therapy should be individualized. Long-term heparin use is discouraged because of the risk of heparin-induced osteopenia. Inferior vena cava filters may be required in patients with recurrent venous thromboembolism to prevent pulmonary embolism.

In patients with APS who have experienced arterial thromboembolism or have developed recurrent thrombosis despite achieving target international normalized ratio (INR) on warfarin, other treatment options must be pursued. These modalities, such as rituximab, intravenous immunoglobulin, and plasmapheresis, address circulating pathogenic antibodies directly rather than the resultant coagulopathy.

In patients with SLE and APS, hydroxychloroquine has been shown to reduce aPL antibody levels and to have intrinsic anticoagulative properties. Future APS therapies may include low-dose warfarin, antiplatelet agents, and statins, although these remain to be tested in APS. Correction of reversible prothrombotic factors, such as oral contraceptive use and smoking, is advisable.

Warfarin is contraindicated in pregnancy, a particularly high-risk state for patients with APS. Women with APS should be treated with aspirin prior to conception, with the introduction of low molecular weight heparin thereafter.

In acute thrombosis, monitored intravenous unfractionated heparin or subcutaneous low molecular weight heparin with or without subsequent initiation of warfarin is standard therapy. Thrombolytic medications (e.g., streptokinase, tissue plasminogen activator, tPA) or percutaneous or surgical interventions may be necessary in life- or limb-threatening thrombotic events. Catastrophic antiphospholipid syndrome (CAPS), the development of widespread thromboses with end-organ damage, requires intensive multidisciplinary interventions to halt disease progression and to reverse end-organ damage. Plasma exchange may have a role in the treatment of CAPS.

Specific investigations

First-line therapies

image Observation (persistent aPL elevation but no thromboembolic events) A
image Long-term warfarin, target INR 2.0–3.0 A
image Correction of reversible prothrombotic factors B
image Long-term warfarin, target INR >3.0 (recurrent or arterial thrombosis) B
image Low molecular weight heparin and low-dose aspirin (pregnancy) B
image Heparin followed by warfarin (acute thrombosis) C
image Thrombolytic therapy or percutaneous/surgical intervention (critical thrombosis) E
image Reduction of prothrombotic risk factors, such as avoidance of prolonged immobilization E

Treatment of antiphospholipid antibody syndrome (APS) in pregnancy: a randomized pilot trial comparing low-molecular-weight heparin to unfractionated heparin.

Stephenson MD, Ballen PJ, Tsang P, Purkiss S, Ensworth S, Houlihan E, et al. J Obstet Gynaecol Can 2004; 26: 729–34.

In a randomized trial, 28 women with APS received low-dose aspirin and either low molecular weight heparin or unfractionated heparin prior to conception or early in pregnancy. Pregnancy was successful in nine of 13 (69%) women treated with low molecular weight heparin and low-dose aspirin and in four of 13 (31%) women treated with unfractionated heparin and low-dose aspirin.

In addition, the obstetrics literature tends to favor low molecular weight over unfractionated heparin because of its superior safety profile.

Second-line therapies

image Long-term low molecular weight heparin (recurrent thrombosis) D
image Hydroxychloroquine (SLE) E
image Rituximab E
image IVIG (in pregnancy) E
image Hyperbaric oxygen therapy (livedoid vasculopathy with chronic leg ulcers) D

Third-line therapies

image Plasma exchange (pregnancy) D
image Inferior vena cava filter (refractory, recurrent venous thromboses) D

Catastrophic antiphospholipid syndrome

image Anticoagulation, systemic corticosteroids, and plasmapheresis or IVIG D

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Antiphospholipid syndrome

Julia S. Lehman and Mark D.P. Davis

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Antiphospholipid syndrome (APS) is characterized by the propensity for recurrent venous and arterial thrombosis in the presence of circulating antibodies against phospholipid-binding proteins. Diagnostic criteria for APS require that patients experience vascular thrombosis (venous or arterial) or pregnancy morbidity (e.g., three or more unexplained consecutive spontaneous abortions before the 10th week of gestation with exclusion of other causes), and harbor at least one serum antiphospholipid (aPL) antibody (i.e., lupus anticoagulant, anticardiolipin, anti-β2 glycoprotein-1) on two or more occasions over a 12-week period. It is important that patients not be diagnosed with APS based on isolated laboratory test abnormalities, as no laboratory test for APS is entirely specific.

Although cutaneous manifestations of APS are not part of the diagnostic criteria, they may represent the initial presentation of APS. Cutaneous signs result from thrombo-occlusion of the cutaneous vasculature and may include livedo reticularis or racemosa, livedoid vasculopathy (atrophie blanche), superficial thrombophlebitis, or ulceration.

Management strategy

In some cases, APS may represent a primary condition. However, a search for underlying causes or other contributing factors, such as infection, prothrombotic medications (such as oral contraceptives), primary hematologic coagulopathies (e.g., factor V Leiden, prothrombin G20210A gene mutation), and connective tissue diseases (e.g., systemic lupus erythematosus, SLE), is warranted. Patients should be offered subspecialty referral, where available.

Because patients with APS are at increased risk for recurrent thromboembolism, the goal of therapy is secondary thromboprophylaxis. Non-pharmacologic interventions include reduction of other prothrombotic risk factors, such as prolonged immobility and oral contraceptive use. Pharmaceutical interventions should be guided by the patient’s age and comorbidities, pregnancy status, presence of correctable prothrombotic factors, and coagulation history. In patients with persistently elevated aPL antibodies but no history of thrombosis (thereby not meeting strict criteria for APS), aspirin has not been shown to be effective in preventing future thromboembolic events. In patients with definitive APS and a history of venous thromboembolism the mainstay of treatment is long-term warfarin therapy. The optimal duration of warfarin therapy has not been established. Based on limited available data, indefinite treatment with warfarin appears to be associated with reduced rates of recurrent thromboembolism without an elevated risk for hemorrhagic complications, compared to treatment discontinuation after 6 months. Decisions regarding termination of warfarin therapy should be individualized. Long-term heparin use is discouraged because of the risk of heparin-induced osteopenia. Inferior vena cava filters may be required in patients with recurrent venous thromboembolism to prevent pulmonary embolism.

In patients with APS who have experienced arterial thromboembolism or have developed recurrent thrombosis despite achieving target international normalized ratio (INR) on warfarin, other treatment options must be pursued. These modalities, such as rituximab, intravenous immunoglobulin, and plasmapheresis, address circulating pathogenic antibodies directly rather than the resultant coagulopathy.

In patients with SLE and APS, hydroxychloroquine has been shown to reduce aPL antibody levels and to have intrinsic anticoagulative properties. Future APS therapies may include low-dose warfarin, antiplatelet agents, and statins, although these remain to be tested in APS. Correction of reversible prothrombotic factors, such as oral contraceptive use and smoking, is advisable.

Warfarin is contraindicated in pregnancy, a particularly high-risk state for patients with APS. Women with APS should be treated with aspirin prior to conception, with the introduction of low molecular weight heparin thereafter.

In acute thrombosis, monitored intravenous unfractionated heparin or subcutaneous low molecular weight heparin with or without subsequent initiation of warfarin is standard therapy. Thrombolytic medications (e.g., streptokinase, tissue plasminogen activator, tPA) or percutaneous or surgical interventions may be necessary in life- or limb-threatening thrombotic events. Catastrophic antiphospholipid syndrome (CAPS), the development of widespread thromboses with end-organ damage, requires intensive multidisciplinary interventions to halt disease progression and to reverse end-organ damage. Plasma exchange may have a role in the treatment of CAPS.