Hematology

Antiphospholipid syndrome

Antiphospholipid syndrome

What every physician needs to know:

Antiphospholipid (antibody) syndrome (APS) is a prothrombotic condition characterized by both of the following:

  • Persistent presence of antiphospholipid antibodies

- That is, lupus anticoagulant/non-specific inhibitor, anticardiolipin antibodies, and/or anti-ß2-glycoprotein I antibodies.

  • Venous or arterial thrombosis, or pregnancy morbidity

- This is defined as unexplained death greater than or equal to 10 weeks gestation, greater than or equal to three consecutive spontaneous abortions less than 10 weeks gestation, or more than one premature birth less than 34 weeks gestation.

There is a subset of APS known as catastrophic APS (CAPS) characterized by presence of antiphospholipid antibodies in patients developing small vessel occlusions affecting multiple organ systems over a period of 7 days or less.

Are you sure your patient has antiphospholipid syndrome? What should you expect to find?

The key symptoms and signs of APS include:

  • Recurrent fetal loss

  • Thrombocytopenia

  • Livido reticularis

  • Migraine

  • Arthralgia

  • Thrombosis

- This would usually be deep vein thrombosis involving lower extremities, less commonly pulmonary embolism, superficial phlebitis, or peripheral arterial thrombosis.

  • Ischemic stroke/transient ischemic attack

  • Cardiac valvular thickening or dysfunction

Beware of other conditions that can mimic antiphospholipid syndrome:

Other conditions that can mimic antiphospholipid syndrome are as follows:

  • Disseminated intravascular coagulation

  • Infective endocarditis

  • Thrombotic thrombocytopenic purpura

  • Heparin-induced thrombocytopenia

Which individuals are most at risk for developing antiphospholipid syndrome:

APS occurs predominantly in females (80%) with mean age of disease onset, 34 years old. APS can be primary (independent of any underlying disease), or secondary (occurring in patients with connective tissue disease, mainly systemic lupus erythematosis).

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

APS is a clinical-pathological diagnosis, with criteria for "definite APS" established by an expert panel. The consensus diagnostic criteria are known as the (updated) Sapporo criteria. Patients with definite APS must have documented persistent presence of antiphospholipid antibodies, in addition to clinical manifestations (thrombosis and/or pregnancy morbidity). Antiphospholipid antibodies is a collective term for autoantibodies directed against phospholipid-binding glycoproteins. There are many types of antiphospholipid antibodies, but the three that are recognized in the Sapporo criteria are:

  • Lupus anticoagulants (LAC), also known as non-specific inhibitors

  • Anticardiolipin (aCL) antibodies

  • Anti-ß2-glycoprotein I antibodies (anti-ß2GPI)

The presence of any one or more of these antibodies, documented on two or more measurements at least 12 weeks apart, meets the laboratory (pathological) criteria for APS.

Lupus anticoagulants are reported as present (positive) or absent (negative). Screening for LAC is done using a screening and confirmatory assay with dilute and excess phospholipid. False positive LAC test results can occur in patients on vitamin K antagonists such as warfarin. As a result, it is recommended that testing for LAC be done 1 to 2 weeks after discontinuing warfarin, or when the INR (international normalized ratio) is less than 1.5.

Anticardiolipin antibodies (Ig [immunoglobulin] G and/or IgM) are reported as a titre in GPL (IgG phospholipid) or MPL (IgM phospholipid) units. The Sapporo criteria use 40 GPL or MPL units as the threshold for clinically significant titres or levels greater than 99th percentile; levels below 40 GPL or MPL do not currently meet the diagnostic criteria. Anti-ß2GPI antibodies (IgG and/or IgM) are also reported as a titre. Levels greater than 99th percentile are used as the threshold for significant titres. Therefore, patients must have two or more measurements of present (positive) LAC, aCL greater than 40 GPL/MPL units, or anti-ß2GPI greater than 99th percentile, to meet the laboratory aspect of the Sapporo criteria. There are issues with standardizing antiphospholipid antibody testing that are ongoing.

Patients with definite APS therefore have persistent presence of antiphospholipid antibodies on two or more occasions, and objectively confirmed vascular thrombosis, or pregnancy morbidity. It is recognized that there are a spectrum of patients with APS and the Sapporo criteria are an attempt to standardize the diagnosis.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of antiphospholipid syndrome?

The clinical criteria for APS is based on objective documentation of thrombosis. Patients with suspected deep vein thrombosis need to undergo objective testing, most commonly using compression ultrasonography. If pulmonary embolism is suspected, the most common diagnostic test performed would be computed tomography (CT) pulmonary angiography or ventilation perfusion (V/Q) scanning. Patients with stroke symptoms should undergo neuroimaging with CT or magnetic resonance imaging (MRI).

In situations where there is evidence of organ dysfunction, histopathological examination may be required (for example, renal biopsy). In these cases, thrombosis must be present without evidence of inflammation of the vessel wall.

Women who experience fetal loss greater than or equal to 10 weeks gestation should have confirmation that the fetus was morphologically normal. Women with greater than or equal to three spontaneous losses less than 10 weeks gestation need investigations to rule out maternal anatomic or hormonal abnormalities and maternal and paternal chromosomal abnormalities. Women with greater than or equal to one premature birth less than or equal to 34 weeks gestation should have the placenta examined for evidence of placental insufficiency. In the setting of fetal loss, there needs to be adequate assessment for alternate causes for pregnancy loss.

If you decide the patient has antiphospholipid syndrome, what therapies should you initiate immediately?

Patients with APS typically present with thrombotic symptoms. Therefore, the mainstay of treatment for APS is antithrombotic therapy.

Venous thromboembolism

Patients with objectively confirmed VTE (venous thromboembolism, such as deep vein thrombosis, pulmonary embolism) should be started on a parenteral anticoagulant. Therapeutic doses of subcutaneous low molecular weight heparin (LMWH), intravenous or subcutaneous unfractionated heparin, or subcutaneous fondaparinux should be started immediately.

Oral anticoagulation using a vitamin K antagonist such as warfarin can be given concurrently with the parenteral anticoagulant. Therapeutic dose LMWH is dosed according to a patient's body weight, with no maximum dose given subcutaneously. Dalteparin 200 IU/kg daily or 100 IU/kg twice daily, enoxaparin 1.5mg/kg daily or 1mg/kg twice daily, or tinzaparin 175 IU/kg daily are all reasonable options. Intravenous unfractionated heparin should be given as a bolus (80units/kg or 5,000 units) followed by a continuous infusion, to maintain the activated partial thromboplastin time (aPTT) 1.5 to 2.0 times the reference range. Subcutaneous unfractionated heparin is given as a bolus (333units/kg) followed by 250units/kg every 12 hours, with a mid-interval aPTT done at 6 hours, to ensure the aPTT is 1.5 to 2.0 times the reference range.

Subcutaneous unfractionated heparin has been used successfully without aPTT monitoring but has not been studied specifically in patients with APS. Subcutaneous fondaparinux is dosed according to a patient's body weight:

  • Less than 50kg: 5mg once daily

  • 50 to 100kg: 7.5mg once daily

  • Greater than 100kg: 10mg once daily

Note that LMWH and fondaparinux are renally eliminated, are relatively contraindicated, and must be used with caution (dose reduction or anti-Xa level monitoring) in patients with creatinine clearance less than 30ml/min.

Ischemic stroke

The optimal treatment of patients with APS who present with ischemic stroke is controversial. In a nested prospective cohort of patients with antiphospholipid antibodies (Antiphospholipid Antibodies and Stroke Study - APASS), the recurrent stroke rate was similar in patients receiving aspirin 325mg daily as it was for those receiving warfarin (target INR 1.4 to 2.8). These patients were studied within a larger randomized trial comparing aspirin with warfarin for treatment of ischemic stroke.

It is notable that patients in the prospective cohort did not meet the current revised Sapporo criteria for definite APS, having only one positive measurement of antiphospholipid antibody. Further, many of the patients were older with vascular risk factors, unlike the "typical" young patient with APS. These limitations have led some experts to continue recommending warfarin for patients with APS and ischemic stroke, and some advocate using a higher target INR (INR greater than 3.0) for these individuals. The American Heart Association/American Stroke Association recommends aspirin in patients with cryptogenic stroke with a single positive test for antiphospholipid antibodies, and warfarin (target INR 2.0 to 3.0) in patients with persistently positive measurements.

Recurrent pregnancy loss

Women who meet the Sapporo criteria for APS based on pregnancy morbidity (and have no history of venous or arterial thrombosis) and who are pregnant, are treated with combination subcutaneous heparin (5,000 to 7,500 units every 12 hours) or LMWH (standard prophylactic doses) and low-dose aspirin (81mg/daily) to prevent further pregnancy loss.

Other arterial thromboses

The optimal treatment of patients with thrombosis other than ischemic stroke is unclear. There are no clinical trials that can guide treatment, so recommendations are based on expert opinion. Patients with APS may manifest white matter lesions on MRI. Expert opinion recommendations suggest aspirin as first line treatment, with warfarin if patients continue to experience cognitive decline or progression of white matter lesions while on aspirin. Patients with APS who develop myocardial infarction/acute coronary syndromes should receive heparin followed by warfarin.

Catastrophic antiphospholipid (antibody) syndrome

Patients with CAPS are treated with a combination of anticoagulation (usually intravenous unfractionated heparin), high-dose corticosteroids (for example, methylprednisolone 1g intravenously daily for 3 days, followed by tapering doses), plasma exchange +/- intravenous immunoglobulin (IVIG) (1g/kg/d for 2 days, or 400mg/kg/d for 5 days). The frequency and number of plasma exchanges that should be given remains uncertain.

More definitive therapies?

Venous thromboembolism

In patients with VTE, treatment with the parenteral anticoagulant (usually heparin) should continue for at least 5 days. At that time there should be significant inhibition of thrombin activity with the vitamin K antagonist, as indicated by the international normalized ratio (INR) being greater than 2.0 on two sequential measurements. The vitamin K antagonist (warfarin) is continued for a minimum of 3 months, with a target INR of 2.0 to 3.0. However, given the high rate of thrombotic recurrence in patients with APS, long-term (indefinite) therapy is recommended in patients if there are no bleeding complications on warfarin therapy.

This recommendation assumes patients place a high value on preventing recurrent thrombosis over the burden of long-term anticoagulant therapy. Direct thrombin inhibitors such as dabigatran or direct factor Xa inhibitors such as rivaroxaban have not been specifically studied for VTE treatment in these patients, and have not yet received regulatory approval in the United States of America for this indication.

Ischemic stroke

Patients with antiphospholipid antibodies and ischemic stroke are usually treated with either aspirin (doses ranging from 80mg to 325mg) or warfarin (target INR usually 2.0 to 3.0, although the APASS study used a target INR of 1.4 to 2.8) indefinitely. This is based on data suggesting that patients with APS have a higher rate of stroke recurrence in the absence of anticoagulation.

Other arterial thromboses

Patients with other arterial thromboses (white matter lesions, myocardial infarction) are treated using antithrombotic agents indefinitely, based on expert opinion. Patients with white matter lesions receive antiplatelet therapy indefinitely. If there is progression of white matter lesions, anticoagulation with warfarin or LMWH has been used, based on expert opinion. In patients with myocardial infarction, long-term treatment with warfarin is recommended. The target INR remains uncertain, with some experts recommending standard intensity (INR 2.0 to 3.0) and others recommending higher intensity (INR 3.0 to 4.0) or combined antithrombotic treatment.

Catastrophic APS

In the long-term, patients with CAPS are treated with vitamin K antagonists (warfarin) with target INR 2.0 to 3.0, based on expert opinion.

What other therapies are helpful for reducing complications?

Preventing recurrent thrombotic events is important in patients with APS. In most situations, patients receive long-term (indefinite) anticoagulation. Ensuring that patients are compliant with antiplatelet agents and ensuring that patients on warfarin have routine INR monitoring with their INR in the therapeutic range (INR 2.0 to 3.0) can help reduce thrombotic recurrences.

Patients who have antiphospholipid antibodies but have no history of thrombosis (and therefore do not meet the diagnostic criteria for APS) have a low risk of thrombosis and should be offered low-dose aspirin or no treatment. This recommendation is based on a small randomized, double-blind, placebo-controlled trial, where aspirin 81mg/day was compared to placebo in patients with persistently positive antiphospholipid antibodies. There was no difference in the rates of arterial or venous thrombosis in patients receiving aspirin or placebo, although the study was underpowered to detect a possible benefit for aspirin. In patients who have systemic lupus erythematosis (SLE) and antiphospholipid antibodies with no history of thrombosis, observational data suggest low-dose aspirin (81mg daily) and hydroxychloroquine may reduce thrombotic complications.

Women who have antiphospholipid antibodies with recurrent pregnancy loss, no history of thrombosis, and are not currently pregnant can be offered low-dose aspirin or no treatment to prevent thrombotic complications. This recommendation is based on data suggesting there is an increased risk of thrombosis compared to women with antiphospholipid antibodies with no history of pregnancy loss.

Patients with antiphospholipid antibodies but no history of thrombosis are at risk of developing thrombosis if additional risk factors are present.Therefore, expert opinion recommendations include aggressive thromboprophylaxis for all patients with antiphospholipid antibodies in high-risk situations (major medical illness with immobilization, orthopedic procedures, surgery), avoidance of hormone-containing medications (oral contraceptive pills, hormone replacement therapy), and addressing vascular risk factors (smoking cessation, treatment of hypertension and hyperlipidemia, optimal glycemic control in patients with diabetes).

What should you tell the patient and the family about prognosis?

Treatment goals in APS are to reduce the rate of recurrent thrombotic events. Patients with APS are at high risk of recurrent thrombosis if antithrombotic therapy is discontinued, based on observational data. As a result, it is recommended that patients receive indefinite antithrombotic therapy. While patients with APS can develop recurrent thrombosis while on antithrombotic therapy, this is uncommon if patients are compliant with therapy and their INR is in the target therapeutic range.

Patients with CAPS have a poor prognosis if untreated. Combination treatment with anticoagulants, high-dose corticosteroids, plasma exchange +/- IVIG, results in recovery rates of approximately 50 to 80%. In a series of 250 patients with CAPS, the main causes of death included stroke, cerebral hemorrhage, and encephalopathy.

What if scenarios.

Inconclusive diagnostic testing

One of the common misconceptions about APS is diagnosing patients as having APS based on a single positive measurement of antiphospholipid antibody. These patients do not meet Sapporo criteria for definite APS. It is possible these patients have APS but need a repeat measurement of antiphospholipid antibody. Positive measurements for antiphospholipid antibodies can occur if measured close to the time of a thrombotic event, and many of these positive measurements revert to negative months later. False positive LAC can result if measured while patients are on warfarin therapy.

Recurrent venous thromboembolism

A common unresolved clinical question is the management of recurrent VTE in patients with APS. Unfortunately there is no data to guide optimal practice. Patients who were not on anticoagulants at the time of their recurrence should be restarted on anticoagulation, and this should be continued indefinitely. Patients with suspected recurrent VTE while on anticoagulants should be assessed for anticoagulant compliance and recent INRs should be examined to ensure patients have not been subtherapeutic. If patients are compliant, their INR has been in the therapeutic range, and there is no alternate explanation for the recurrence, experts recommend one or more of the following:

  • Aiming for a higher target INR (INR 3.0 to 4.0)

  • Switching from warfarin to therapeutic-dose LMWH

  • Adding an antiplatelet agent (low-dose aspirin)

Pathophysiology

The pathophysiological mechanisms resulting in thrombosis in APS is incompletely understood. Endothelial cells, monocytes, platelets, and the complement system all appear to be involved in the underlying mechanism. Antiphospholipid antibodies with specificity for ß2-GPI activate endothelial cells and monocytes, resulting in expression of adhesion molecules on endothelial cell surfaces and upregulation of tissue factor on endothelial cells and monocytes. Platelet activation also occurs, with increased expression of surface glycoproteins and production of thromboxane A2. Activation of the complement cascade by antiphospholipid antibodies has been linked to pregnancy loss, thrombosis, and fetal growth restriction.

Antiphospholipid antibodies are recognized to bind other proteins, including prothrombin, protein C, and plasmin and in turn, prevent inhibition of procoagulant factors or inhibit fibrinolysis. Binding to annexin A5, a natural anticoagulant, can also result in thrombosis and fetal loss. There are likely multiple mechanisms which result in the thrombotic complications observed in APS.

What other clinical manifestations may help me to diagnose antiphospholipid syndrome?

Questions to ask on history

  • Have you ever been diagnosed with a blood clot within veins (deep vein thrombosis or pulmonary embolism) or arteries (heart attack, stroke, peripheral arterial disease)?

  • (In women) Have you experienced any spontaneous pregnancy losses (miscarriages)? How many, and at how many weeks gestation did this occur?

  • Have you been diagnosed with lupus or other autoimmune disorder?

  • Have you ever developed a lace-like, purple-coloured rash or discoloration, usually on the legs (livedo reticularis)?

  • Do you have problems with easy bruising or bleeding, or have you noticed small red spots on your skin (petechiae)? Screening for thrombocytopenia required.

  • Do you have a history of migraines?

  • Have you noticed a decline in your memory? Screening for white matter lesions required.

Signs or findings on physical examination

  • Lower extremities

- Examination of the lower extremities for evidence of new or old deep vein thrombosis (asymmetry of the calf diameter, presence of unilateral enlarged superficial veins).

  • Skin

- Examination of the skin for evidence of livedo reticularis, petechiae or purpura (seen with thrombocytopenia) or rashes seen in SLE (malar rash, discoid rash).

What other additional laboratory studies may be ordered?

In patients with signs or symptoms of SLE (for example, fatigue, arthralgia, photosensitive rash), screening with antinuclear antibodies (ANA), anti-double stranded DNA antibodies and anti-Smith (Sm) antibodies can be ordered. Referral to a rheumatologist would be warranted if patients have positive serology.

Additional blood work to rule out similar disorders can be considered. A complete blood count (CBC) can identify thrombocytopenia (frequently seen in APS, but is also seen in DIC [disseminated intravascular coagulation], TTP [thrombotic thrombocytopenic purpura], and HIT [heparin-induced thrombocytopenia]). Low fibrinogen levels may point towards evidence of coagulation activation seen in DIC or liver disease. A peripheral blood smear can identify schistocytes (red blood cell fragments) seen in patients with TTP, along with evidence of hemolysis (increased LDH [lactate dehydrogenase], increased reticulocyte count, decreased haptoglobin). Testing for the HIT antibody can be done using the gold standard serotonin release assay or less sensitive enzyme linked immunosorbent assay. Blood cultures and echocardiogram can be performed in patients with suspected infective endocarditis.

What’s the evidence?

[Explains that APS occurs predominantly in females (80%) with mean age of disease onset 34 years old, plus or minus 13 years (range 0 to 81 years).]

[Discusses APS as a clinical-pathological diagnosis, with criteria for "definite APS" established by an expert panel. The consensus diagnostic criteria are known as the (updated) Sapporo criteria.]

[Lupus anticoagulants are reported as present (positive) or absent (negative). Screening for LAC is done using a screening and confirmatory assay with dilute and excess phospholipid.]

[False positive LAC test results can occur in patients on vitamin K antagonists such as warfarin. As a result, it is recommended that testing for LAC be done 1 to 2 weeks after discontinuing warfarin, or when the INR (international normalized ratio) is less than 1.5.]

[Discusses the issues with standardizing antiphospholipid antibody testing that are ongoing.]

[Some experts continue to recommend warfarin for patients with APS and ischemic stroke, and some advocate using a higher target INR (INR greater than 3.0) for these individuals.]

[The American Heart Association/American Stroke Association recommends aspirin in patients with cryptogenic stroke with a single positive test for antiphospholipid antibodies, and warfarin (target INR 2.0 to 3.0) in patients with persistently positive measurements.]

[Patients with CAPS are treated with a combination of anticoagulation (usually intravenous unfractionated heparin), high-dose corticosteroids, plasma exchange +/- intravenous immunoglobulin.]

[Given the high rate of thrombotic recurrence in patients with APS, long-term (indefinite) therapy is recommended in patients if there are no bleeding complications on warfarin therapy.]

[Details a small randomized, double-blind, placebo-controlled trial, where aspirin 81mg/day was compared to placebo in patients with persistently positive antiphospholipid antibodies.]
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