ANTI PHOSPHOLIPID SYNDROME

Introduction
Background

Antiphospholipid syndrome (APS) is a disorder that manifests clinically as recurrent venous or arterial thrombosis and/or fetal loss. Characteristic laboratory abnormalities in APS include persistently elevated levels of antibodies directed against membrane anionic phospholipids (ie, anticardiolipin [aCL] antibody, antiphosphatidylserine) or their associated plasma proteins, predominantly beta-2 glycoprotein I (apolipoprotein H); or evidence of a circulating anticoagulant.

Multiple terms for APS exist. Unfortunately, some synonyms can be confusing. Lupus anticoagulant (LA) syndrome, for example, is misleading because patients with APS may not necessarily have systemic lupus erythematosus (SLE) and LA is associated with thrombotic rather than hemorrhagic complications. In an attempt to avoid further confusion, APS is currently the preferred term for the clinical syndrome (as described below).

Some patients with APS have no evidence of any definable associated disease, while, in other patients, APS occurs in association with SLE or another rheumatic or autoimmune disorder. Traditionally, these have been referred to as primary or secondary APS, respectively. Currently, however, the preferred terminology is APS with or without associated rheumatic disease. Although antiphospholipid (aPL) antibodies are clinically linked to APS, whether they are involved in the pathogenesis or are an epiphenomenon is unclear. (Up to 5% of healthy individuals are known to have aPL antibodies.)
Pathophysiology

In APS, the homeostatic regulation of blood coagulation is altered; however, the mechanisms of thrombosis are not yet defined. One hypothesis postulates a defect in cellular apoptosis, which exposes membrane phospholipids to the binding of various plasma proteins, such as beta-2 glycoprotein I. Once bound, a phospholipid-protein complex is formed and a neoepitope is uncovered, which subsequently becomes the target of autoantibodies. Recent evidence suggests that oxidized beta-2 glycoprotein I is able to bind to and activate dendritic cells in a manner similar to activation triggered by Toll-like receptor 4 (TLR-4), which could amplify the production of autoantibodies.1

Other proposed mechanisms for the hypercoagulable effect of aPL antibodies, which may or may not depend on beta-2 glycoprotein I, include the following:

* Production of antibodies against coagulation factors, including prothrombin, protein C, protein S, and annexins
* Activation of platelets to enhance endothelial adherence
* Activation of vascular endothelium, which, in turn, facilitates the binding of platelets and monocytes
* Reaction of antibodies to oxidized low-density lipoprotein, thus predisposing to atherosclerosis and myocardial infarction (MI)

Complement activation has been increasingly recognized as a possible significant role in the pathogenesis of APS. Emerging evidence from murine models suggests that APL-mediated complement activation may be a primary event in pregnancy loss.2

Clinically, the series of events that leads to hypercoagulability and recurrent thrombosis can affect virtually any organ system, including the following:

* Peripheral venous system (deep venous thrombosis [DVT])
* Central nervous system (cerebrovascular accident [CVA], sinus thrombosis)
* Hematologic (thrombocytopenia, hemolytic anemia)
* Obstetric (pregnancy loss, eclampsia)
* Pulmonary (pulmonary embolism [PE], pulmonary hypertension)
* Dermatologic (livedo reticularis, purpura, infarcts/ulceration)
* Cardiac (Libman-Sacks valvulopathy, MI)
* Ocular (amaurosis, retinal thrombosis)
* Adrenal (infarction/hemorrhage)
* Musculoskeletal (avascular necrosis of bone)

Frequency
United States

The actual frequency of APS in the general population is unknown. One to 5% of healthy individuals have aPL antibodies. aCL antibodies tend to be found more frequently in elderly persons; thus, positive titer results should be interpreted with caution in this population. aPL antibodies are found in approximately 30-40% of patients with SLE, but only about 10% have APS.3 Approximately half of APS cases are not associated with another rheumatic disease. In a study of 100 patients with confirmed venous thrombosis and no history of SLE, aCL antibodies were found in 24% and LA in 4%.
International

International frequency is probably similar to US frequency.
Mortality/Morbidity

* APS may contribute to an increased frequency of CVAs or MIs, especially in younger individuals. CVAs may develop secondary to in situ thrombosis or embolization that originates from the valvular lesions of Libman-Sacks (sterile) endocarditis, which may be seen in patients with APS. Cardiac valvular disease may be severe enough to require valve replacement. Recurrent pulmonary emboli or thrombosis can lead to life-threatening pulmonary hypertension.
* Catastrophic APS (CAPS) is a rare, serious, and often fatal manifestation (mortality rate of approximately 50%) characterized by multiorgan infarctions over a period of days to weeks.
* Late spontaneous fetal loss (second or third trimester) is common; however, it can occur at any time during pregnancy. Recurrent early fetal loss (<10 weeks’ gestation) is also possible. Race * No defined racial predominance for primary APS has been documented, although SLE is more common in African American and Hispanic populations. Sex * A female predominance has been documented, particularly for secondary APS. This parallels the association of APS with SLE and other connective-tissue diseases, which also have a female predominance. Age * APS is more common in young to middle-aged adults; however, it also manifests in children and elderly people. Disease onset has been reported in children as young as 8 months. In an international registry of pediatric APS cases, patients without associated rheumatic disease were younger and had a higher frequency of arterial thrombotic events, whereas patients with associated rheumatic disease were older and had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations.4 Clinical History Antiphospholipid syndrome (APS) is a heterogenous disorder in terms of clinical manifestations and range of autoantibodies. In 2006, revised criteria for the diagnosis of APS were published in an international consensus statement.5 At least one clinical criterion and one laboratory criterion (discussed further in Lab Studies) must be present for a patient to be classified as having APS. * The clinical criteria are as follows: o Vascular thrombosis + One or more clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ confirmed by findings from imaging studies, Doppler studies, or histopathology (see Histologic Findings). + Thrombosis may involve the cerebral vascular system, coronary arteries, pulmonary system (emboli or thromboses), arterial or venous system in the extremities, hepatic veins, renal veins, ocular arteries or veins, or adrenal glands. Investigation is warranted if a history of DVT, PE, acute ischemia, MI, or CVA (especially when recurrent) is present in a younger individual (males <55 y; females <65 y) or in the absence of other risk factors. o Pregnancy morbidity + One or more late-term (>10 weeks' gestation) spontaneous abortions
+ One or more premature births of a morphologically healthy neonate at or before 34 weeks’ gestation because of severe preeclampsia or eclampsia or severe placental insufficiency
+ Three or more unexplained, consecutive, spontaneous abortions before 10 weeks’ gestation
* Laboratory criteria: Patients must have (1) medium to high levels of immunoglobulin G (IgG) or immunoglobulin M (IgM) anticardiolipin (aCL), (2) anti–beta-2 glycoprotein I, or (3) LA on at least 2 occasions at least 12 weeks apart. (See also Lab Studies.)

Other antiphospholipid (aPL)–associated clinical features recognized by the 2006 consensus statement but not included in the criteria include cardiac valve disease, livedo reticularis, thrombocytopenia, nephropathy, and neurologic manifestations.

Thus, history of any of the following should raise the examiner's suspicion for APS:

* Thrombosis (eg, DVT/PE, MI, transient ischemic attack [TIA], or CVA, especially if recurrent, at an earlier age, or in the absence of other known risk factors)
* Miscarriage (especially late trimester or recurrent) or premature birth
* History of heart murmur or cardiac valvular vegetations
* History of hematologic abnormalities, such as thrombocytopenia or hemolytic anemia
* History of nephropathy
* Nonthrombotic neurologic symptoms, such as migraine headaches, chorea, seizures, transverse myelitis, Guillain-Barré syndrome, or dementia (rare)
* Unexplained adrenal insufficiency
* Avascular necrosis of bone in the absence of other risk factors
* Pulmonary hypertension

Physical

* Cutaneous
o Livedo reticularis (see image below)
+

Antiphospholipid syndrome. Livedo reticularis.
Antiphospholipid syndrome. Livedo reticularis.

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Antiphospholipid syndrome. Livedo reticularis.

Antiphospholipid syndrome. Livedo reticularis.
o Superficial thrombophlebitis
o Leg ulcers
o Painful purpura
o Splinter hemorrhages
* Venous thrombosis
o Leg swelling (DVT)
o Ascites (Budd-Chiari syndrome)
o Tachypnea (PE)
o Peripheral edema (renal vein thrombosis)
o Abnormal funduscopic examination results (retinal vein thrombosis)
* Arterial thrombosis
o Abnormal neurologic examination results (eg, CVA)
o Digital ulcers
o Gangrene of distal extremities (see image below)
+

Antiphospholipid syndrome. Arterial thrombosis re...
Antiphospholipid syndrome. Arterial thrombosis resulting in ischemia and necrosis of the foot.

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Antiphospholipid syndrome. Arterial thrombosis re...

Antiphospholipid syndrome. Arterial thrombosis resulting in ischemia and necrosis of the foot.
o Signs of MI
o Heart murmur (frequently aortic) or mitral insufficiency (Libman-Sacks endocarditis)
o Abnormal funduscopic examination results (retinal artery occlusion)

Causes

APS is an autoimmune disorder of unknown cause. The search for possible triggers has uncovered a wide array of associated autoimmune or rheumatic diseases, infections, and drugs that are associated with the LA or aCL antibodies. These associations may ultimately provide a clue to the etiology of APS. A considerable percentage of persons with certain autoimmune or rheumatic diseases also have aPL antibodies. Note that these represent percentages of patients with aPL antibodies, rather than the clinical syndrome of APS.

* Common autoimmune or rheumatic diseases and the percentage of affected patients with aPL antibodies
o SLE - 25-50%
o Sjögren syndrome - 42%
o Rheumatoid arthritis - 33%
o Autoimmune thrombocytopenic purpura - 30%
o Autoimmune hemolytic anemia - Unknown
o Psoriatic arthritis - 28%
o Systemic sclerosis - 25%
o Mixed connective-tissue disease - 22%
o Polymyalgia rheumatica or giant cell arteritis - 20%
o Behçet syndrome - 20%
* Infections
o Syphilis
o Hepatitis C infection
o HIV infection
o Human T-cell lymphotrophic virus type 1 infection
o Malaria
o Bacterial septicemia
* Drugs
o Cardiac - Procainamide, quinidine, propranolol, hydralazine
o Neuroleptic or psychiatric - Phenytoin, chlorpromazine
o Other - Interferon alfa, quinine, amoxicillin
* Genetic predisposition
o Familial association: Relatives of persons with known APS are more likely to have aPL antibodies. One study showed a 33% frequency.
o HLA associations: Recent studies have revealed an association between aCL antibody and groups of individuals who carry certain HLA genes, including DRw53, DR7 (mostly people of Hispanic origin), and DR4 (mostly whites).Differential Diagnoses

Disseminated Intravascular Coagulation
Infective Endocarditis
Thrombotic Thrombocytopenic Purpura
Other Problems to Be Considered

Hypercoagulable state: Malignancy, oral contraceptive use and hormone replacement therapy, homocystinemia, antithrombin III deficiency, protein C or S deficiency, factor V Leiden mutation, prothrombin A20210 mutation, antiprothrombin antibodies
Atherosclerotic vascular disease, including multiple cholesterol emboli syndrome
Systemic necrotizing vasculitis
Workup
Laboratory Studies

The hallmark result from laboratory tests that defines antiphospholipid syndrome (APS) is the presence of antiphospholipid (aPL) antibodies or abnormalities in phospholipid-dependent tests of coagulation. In addition to the clinical criteria listed in History, at least one of the following laboratory criteria is necessary for the classification of APS:

* Presence of LA in plasma on 2 or more occasions at least 12 weeks apart (see below)
* Presence of moderate to high levels of anticardiolipin (aCL) (IgG or IgM) in serum or plasma (ie, >40 IgG phospholipid units (GPL)/mL or IgM phospholipid units (MPL)/mL or >99th percentile) on 2 or more occasions at least 12 weeks apart
* Presence of moderate to high levels of anti–beta-2 glycoprotein I antibodies (IgG or IgM) in serum or plasma (>99th percentile) on 2 or more occasions at least 12 weeks apart

aCL antibodies react primarily to membrane phospholipids, such as cardiolipin and phosphatidylserine. Of the 3 known isotypes of aCL (ie, IgG, IgM, immunoglobulin A [IgA]), IgG correlates most strongly with thrombotic events. Cardiolipin is the dominant antigen used in most serologic tests for syphilis; consequently, these patients may have a false-positive test result for syphilis.

Recent literature suggests that an abnormal LA finding is the laboratory test result that confers the strongest risk for thrombosis.6 LA is directed against plasma coagulation molecules. In vitro, this interaction results in the paradoxical prolongation of clotting assays, such as activated partial thromboplastin time (aPTT), kaolin clotting time, and dilute Russell viper venom time (DRVVT). The presence of LA is confirmed by mixing normal platelet-poor plasma with the patient's plasma. If a clotting factor is deficient, the addition of normal plasma corrects the prolonged clotting time. If the clotting time does not normalize during mixing studies, an inhibitor is present; the absence of a specific clotting factor inhibitor confirms that a LA is present.

Patients with APS may have one or more abnormal results from these laboratory tests; the following laboratory tests should be considered in a patient suspected of having APS:

* aCL antibodies (IgG, IgM)
* Anti–beta-2 glycoprotein I antibodies (IgG, IgM)
* Activated partial thromboplastin time (aPTT)
* LA tests such as DRVVT (A threshold of approximately 1.6 for the DRVVT ratio has been recommended for helping discriminate APS from non-APS.7 )
* Serologic test for syphilis (false-positive result)
* CBC count (thrombocytopenia, hemolytic anemia)

Thrombocytopenia is fairly common in persons with APS (22% at presentation, 30% cumulatively) and is therefore associated with paradoxical thrombosis. However, patients with platelet counts of less than 50,000/µL may have an increased risk of bleeding. Hemolytic anemia has been well described in patients with APS and is associated with the presence of IgM aCL antibodies.

A low antinuclear antibody level may be present and does not necessarily imply coexisting SLE.

Additional antibodies directed against phospholipid/phospholipid-protein complexes that may be useful in selected cases include the following:

* IgA aCL
* IgA beta-2 glycoprotein I
* anti-phosphatidylserine antibodies
* anti-phosphatidylethanolamine antibodies
* anti-prothrombin antibodies
* antibodies against the phosphatidylserine-prothrombin complex

Imaging Studies

* Imaging studies are helpful for confirming a thrombotic event. A good example is the use of CT scanning or MRI of the brain (CVA), chest (PE), or abdomen (Budd-Chiari syndrome).
* Doppler ultrasound studies are recommended for possible detection of DVT.
* Two-dimensional echocardiography findings may demonstrate asymptomatic valve thickening, vegetations, or valvular insufficiency; aortic or mitral insufficiency is the most common valvular defect found in persons with Libman-Sacks endocarditis.

Procedures

* Individualize appropriate procedures to evaluate specific thrombotic events.

Histologic Findings
Unlike inflammatory autoimmune diseases, histologic studies of skin or other involved tissue reveal a noninflammatory bland thrombosis with no signs of perivascular inflammation or leukocytoclastic vasculitis. Similarly, biopsy samples from affected kidneys demonstrate glomerular and small arterial microthrombi.Treatment
Medical Care

Patients with antiphospholipid syndrome (APS) may be evaluated in an outpatient setting. Inpatient evaluation is required if the patient presents with a significant clinical event. Patients with CAPS require intense observation and treatment, often in an intensive care unit.

In general, treatment regimens for APS must be individualized according to the patient's current clinical status and history of thrombotic events. Asymptomatic individuals in whom blood test findings are positive do not require specific treatment.

* Prophylactic therapy
o Eliminate other risk factors, such as oral contraceptives, smoking, hypertension, or hyperlipidemia.
o Low-dose aspirin is used widely in this setting; however, the effectiveness of low-dose aspirin as primary prevention for APS remains unproven. Clopidogrel has anecdotally been reported to be helpful in persons with APS and may be useful in patients allergic to aspirin.
o In patients with SLE, consider hydroxychloroquine, which may have intrinsic antithrombotic properties.
o Consider the use of statins, especially in patients with hyperlipidemia.
* Thrombosis
o Perform full anticoagulation with intravenous or subcutaneous heparin followed by warfarin therapy.
o Based on the most recent evidence, a reasonable target for the international normalized ratio (INR) is 2.0-3.0 for venous thrombosis and 3.0 for arterial thrombosis. Patients with recurrent thrombotic events, while well maintained on the above regimens, may require an INR of 3.0-4.0. For severe or refractory cases, a combination of warfarin and aspirin may be used. Treatment for significant thrombotic events in patients with APS is generally lifelong.
* Obstetric considerations
o Guidelines from the American College of Obstetricians and Gynecologists (based primarily on consensus and expert opinion [level C]) regarding prenatal and postpartum care for women with APS recommend prophylaxis for those with no history of thrombosis and full anticoagulation for those with a history of thrombosis.8
o Patients with pregnancy loss receive prophylactic subcutaneous heparin (preferably low–molecular-weight heparin [LMWH]) and low-dose aspirin. Therapy is withheld at the time of delivery and is restarted after delivery, continuing for 6-12 weeks postpartum. Warfarin (Coumadin) is contraindicated in pregnancy.
o Patients with a history of thrombosis receive therapeutic doses of heparin during pregnancy; long-term anticoagulation is then continued postpartum.
o Corticosteroids have not been proven effective for persons with primary APS, and they have been shown to increase maternal morbidity and fetal prematurity rates.
o Breastfeeding women may use heparin and warfarin.
* CAPS
o These patients are generally very ill, often with active SLE.
o Treatment with intensive anticoagulation, plasma exchange, and corticosteroids appears beneficial, but no controlled trials have been performed. Intravenous immunoglobulin may be of some benefit and cyclophosphamide may be considered in selected cases, especially in SLE-associated CAPS.

Surgical Care

Recurrent DVT may necessitate placement of an inferior vena cava filter.
Consultations

* Rheumatologist
* Hematologist
* Neurologist, cardiologist, pulmonologist, hepatologist, ophthalmologist (depending on clinical presentation)
* Obstetrician with experience in high-risk pregnancies

Diet

* If warfarin therapy is instituted, instruct the patient to avoid excessive consumption of foods that contain vitamin K.

Activity

* No specific limitations on activity are necessary.
* Individualize the activity according to the clinical setting.
* Instruct the patient to avoid sports with excessive contact if taking warfarin.
* Limit activity in patients with acute DVT.
* Instruct the patient to avoid prolonged immobilization.

Medication

Therapeutic agents are based on anticoagulant properties, and benefits are weighed carefully against their significant risks. Life-long treatment with warfarin (see Treatment) is standard for recurrent thrombotic events.

For obstetric patients with antiphospholipid syndrome (APS) (see Obstetric considerations), the standard therapy is subcutaneous LMWH and low-dose aspirin.

Heparin therapy may be administered in several regimens, as follows:

* Thrombotic events are initially treated with intravenous infusion of unfractionated heparin or therapeutic doses of LMWH.
* Subcutaneous LMWH (enoxaparin [Lovenox]) may also be used for obstetric or thrombosis prophylaxis. Lower doses (20-40 mg/d SC) are used to prevent fetal loss, while higher doses (1 mg/kg q12h or 1.5 mg/kg/d) are used for thrombosis prophylaxis in patients (pregnant or nonpregnant) who have had prior thrombotic events.

Patients who require heparin administration throughout pregnancy should receive calcium and vitamin D supplementation to help avoid heparin-induced osteoporosis. When monitoring heparin therapy, note that the aPTT may be unreliable in the presence of circulating LA with a baseline elevated aPTT. In this case, factor Xa may be helpful.

Recent studies have begun to cast doubt on the value of heparin therapy in pregnancy, however. Canadian investigators conducted a randomized, controlled trial comparing LMWH plus aspirin with aspirin alone in women with recurrent pregnancy loss, almost half of whom had antiphospholipid (aPL) antibodies; the trial was halted when interim analysis showed that women receiving aspirin alone had the same rate of live births and a lower rate of pregnancy loss compared with those who also received LMWH.9

The antithrombotic properties of hydroxychloroquine have long been recognized and may be considered in the prophylactic treatment of a patient with SLE and a positive aPL antibody test result. Case reports suggest that clopidogrel may be effective because of its antiplatelet effect. Recently, statins have been suggested to have potential antithrombotic effects. In addition to full anticoagulation, plasma exchange and corticosteroids are generally used in the treatment of CAPS. Intravenous immunoglobulin or cyclophosphamide may also be considered in selected patients with CAPS. For example, a recent retrospective study reported a decrease in late pregnancy complications in women with APS who received 0.2 g/kg of intravenous immunoglobulin.10

Rituximab has shown promise in the treatment of APS.11,12 Trials of rituximab for APS are in progress.12
Anticoagulants

Standard therapy for thrombosis commonly consists of intravenous heparin followed by warfarin. Treatment of a pregnant patient with a history of recurrent fetal loss is controversial but generally includes subcutaneous heparin and aspirin.

Warfarin (Coumadin)

Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Long-term warfarin is DOC for APS in patients with recurrent thrombotic events. Titrated dose suggested to maintain INR in therapeutic range (see above).

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Individualized to achieve target INR
Pediatric

Individualized to achieve target INR

* Dosing
* Interactions
* Contraindications
* Precautions

Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate
Drugs that may increase anticoagulant effects include oral antibiotics, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, gemfibrozil, and acetaminophen
Drugs that may enhance bleeding diathesis when coadministered include aspirin, most NSAIDs (eg, ibuprofen, indomethacin, naproxen), ticlopidine, and clopidogrel

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; active bleeding or hemorrhage; malignant hypertension; severe liver or kidney disease; pregnancy; neurologic, ophthalmologic, or traumatic surgery

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk
Precautions

Monitor PT and INR; hepatic or renal insufficiency; elderly or debilitated patients or those prone to falls; do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis

Enoxaparin (Lovenox)

LMWH. Most experience; other LMWH preparations available.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Low dose: 20-40 mg/d SC
High (adjusted dose): 1 mg/kg SC bid; alternatively, 1.5 mg/kg SC qd
See above
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Drugs that inhibit platelet activation (eg, aspirin, NSAIDs, dipyridamole, sulfinpyrazone, ticlopidine, clopidogrel) may increase risk of bleeding

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; major bleeding; thrombocytopenia (see information for heparin)

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Monitor platelets, hematocrit, and stool for occult blood; active or recent GI bleed or hemorrhagic CVA; severe hypertension; recent brain, spinal, or eye surgery; heparin-induced thrombocytopenia; heparin-induced osteoporosis; elderly or debilitated patients

Unfractionated heparin

Used in inpatient settings as continuous infusion during conversion to warfarin therapy until a therapeutic INR is achieved. May be administered SC as substitute for warfarin during attempted pregnancy or for temporary anticoagulation during warfarin loading in outpatient setting.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

SC: 5000-10,000 U q12h
IV standard dosing
Initial: 5000 U
Maintenance: 1000-2000 U/h
Weight-based dosing
Initial: 80 U/kg IV
Maintenance: 18 U/kg/h IV
IV: Titrate infusion to aPTT; aPTT of 2-times baseline is considered therapeutic (if baseline is within reference range)
Pediatric

Use weight-based dosing as described for adults

* Dosing
* Interactions
* Contraindications
* Precautions

Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; aspirin, NSAIDs, ticlopidine, clopidogrel dextran, dipyridamole, sulfinpyrazone, and hydroxychloroquine may increase toxicity

* Dosing
* Interactions
* Contraindications
* Precautions

Severe thrombocytopenia; uncontrollable active bleeding; when monitoring is not possible; documented hypersensitivity; subacute bacterial endocarditis; history of heparin-induced thrombocytopenia

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus
Precautions

Monitor platelets, hematocrit, and stool for occult blood; active or recent GI bleed or hemorrhagic CVA; severe hypertension; recent brain, spinal, or eye surgery; heparin resistance; heparin-induced osteoporosis; in neonates, preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) from benzyl alcohol, which is used as preservative; caution in severe hypotension, shock, or elderly or debilitated patients

Aspirin (Anacin 81, Ascriptin, Bayer Aspirin)

Although not proven effective when used alone, most clinicians use aspirin with SC heparin in pregnant patients with APS. Begin aspirin as soon as conception is attempted.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

81 mg PO qd
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Effects may decrease with antacids and urinary alkalinizers; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; aspirin-sensitive asthma; because of association of aspirin with Reye syndrome, do not use in children (<16 y) with influenza or varicella infections

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus
Precautions

May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, in those with a history of blood coagulation defects, or those taking anticoagulants
Antimalarials

As prophylactic therapy, these agents may have an additional anticoagulant effect in patients with SLE.

Hydroxychloroquine (Plaquenil)

Most common antimalarial used in APS, mostly because of excellent safety profile.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

6-7 mg/kg/d; usually 200-400 mg/d PO qd or divided doses
Pediatric

6-7 mg/kg/d PO

* Dosing
* Interactions
* Contraindications
* Precautions

Hepatotoxic or dermotoxic drugs may increase toxicity; serum levels increase with cimetidine; choline magnesium trisalicylate may decrease absorption

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; retinal and visual-field changes attributable to 4-aminoquinolones

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus
Precautions

Perform periodic ophthalmologic examinations (q6-12mo); hepatic disease, G-6-PD deficiency, psoriasis, and porphyria
Immunosuppressive agents

Consider immunosuppressive agents in select cases (eg, refractory APS, CAPS).

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As an alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Has not been shown to be effective in APS.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

0.5-1 g/m2 IVPB single dose
2-3 mg/kg/d PO single morning dose
Pediatric

Dosing by weight; administer as in adults

* Dosing
* Interactions
* Contraindications
* Precautions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; infection; severely depressed bone marrow function; severe cytopenias

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Leukopenia and thrombocytopenia; monitor CBC and platelet counts and perform urinalysis q1-2wk with any change in dosing; perform urinalysis with cytology q6-12mo after cessation of drug (especially with PO regimen)
Corticosteroids

In selected cases with specific nonthrombotic autoimmune manifestations (eg, clinically significant thrombocytopenia), corticosteroids may be considered.

Prednisone (Deltasone, Orasone, Sterapred)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Useful in treating cytopenias.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Individualize dosing depending on clinical setting and specific manifestation being treated
Pediatric

Individualize dose as in adults; high dose is 1-2 mg/kg/d PO

* Dosing
* Interactions
* Contraindications
* Precautions

May cause water and salt retention, exacerbating hypertension and increasing requirement for antihypertensive drugs in patients with hypertension; may aggravate hyperglycemia, increasing requirement for hypoglycemic agents in patients with diabetes; metabolism may be increased by drugs that induce hepatic microsomal enzymes, including phenytoin, phenobarbital, carbamazepine, and rifampin, thus increasing corticosteroid requirements

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; no absolute contraindications; use caution in severe bacterial, viral, or fungal infection; active peptic ulcer disease; uncontrolled diabetes mellitus

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Toxicities include weight gain, dyspepsia, mood changes, infection, peptic ulcer disease, hypertension, diabetes mellitus, osteoporosis, avascular necrosis, cataracts, glaucoma, myopathy, and skin changes; growth retardation in children; abrupt discontinuation may result in adrenal crisis
Immunomodulatory therapy agents

These agents interfere with processes that promote immune reactions resulting from diverse stimuli.

Intravenous immune globulins, 5% (Gammagard, Gamimune)

Following features may be relevant to efficacy: neutralization of circulating myelin antibodies through antiidiotypic antibodies, down-regulation of proinflammatory cytokines (including IFN-gamma), blockade of Fc receptors on macrophages, suppression of helper/inducer T and B cells and augmentation of suppressor T cells, blockade of the complement cascade, promotion of remyelination, and 10% increase in CSF IgG. May be effective in APS.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

400 mg/kg/d IV for 5 d; alternatively, 1000 mg/kg/d for 1-2 consecutive days
Pediatric

Administer as in adultsFollow-up
Further Inpatient Care

* Intensive observation is warranted for patients with CAPS.

Further Outpatient Care

* Carefully monitor medication doses and the INR if applicable.
* Closely observe the patient for clinical events.
* Ensure the care of any underlying connective-tissue disease.

Inpatient & Outpatient Medications

* The suggested medications include heparin, warfarin, aspirin, and, in selected cases, hydroxychloroquine, intravenous immunoglobulin, and corticosteroids.
* Corticosteroids are rarely used for the treatment of recurrent fetal loss because of the increased risk of maternal morbidity. Generally, the use of corticosteroids is reserved for specific nonthrombotic manifestations, such as associated thrombocytopenia, autoimmune hemolytic anemia, or the treatment of an underlying connective-tissue disease.
* Prescribe antihypertensive drugs when necessary.
* Administer antihyperlipidemic agents including statins when appropriate.

Transfer

* When treating seriously ill patients with CAPS, transfer the patient to a setting where plasma exchange can be performed or where intravenous immunoglobulin or cyclophosphamide can be administered if needed.

Deterrence/Prevention

* Instruct the patient to avoid smoking.
* Inform the patient to avoid oral contraceptives or estrogen replacement therapy.
* Ensure that the patient avoids any prolonged immobilization.

Complications

* Permanent functional disability or death can occur at a relatively young age. Complications may include the following:
o Cerebrovascular accident
o MI
o Pulmonary hypertension
o Renal failure13

Prognosis

* With appropriate medication and lifestyle modifications, most individuals with primary antiphospholipid syndrome (APS) lead normal healthy lives. However, subsets of patients continue to have thrombotic events despite aggressive therapies. In these patients and in patients with CAPS, the disease course can be devastating, often leading to significant morbidity or early death.
* A retrospective study suggested that hypertension or medium-to-high titers of IgG anticardiolipin antibody are risk factors for a first thrombotic event in asymptomatic patients with antiphospholipid (aPL) antibodies.14 Primary prophylaxis against thrombosis appears to offer significant protection in such cases.
* Patients with secondary APS carry a prognosis similar to that of patients with primary APS; in the former, however, morbidity and mortality may also be influenced by these patients' underlying autoimmune or rheumatic condition. In patients with SLE and APS, aPL antibodies have been associated with neuropsychiatric disease and have been recognized as a major predictor of irreversible organ damage.
* Women with aPL antibodies who experience recurrent miscarriages may have favorable prognoses in subsequent pregnancies if treated with aspirin and heparin.

Patient Education

* Stress the importance of early recognition of a possible clinical event.
* Educate the patient about anticoagulation therapy.
* Discuss the importance of planned pregnancies so that long-term warfarin can be switched to aspirin and heparin before pregnancy is attempted.
* For excellent patient education resources, visit eMedicine's Circulatory Problems Center. Also, see eMedicine's patient education article Blood Clot in the Legs.

Miscellaneous
Medicolegal Pitfalls

* Failure to recognize antiphospholipid syndrome (APS) when suggested by history or clinical examination findings, especially thrombosis in a relatively young individual
* Failure to warn female patients about potential complications with pregnancy
* Failure to discourage continuation of oral contraceptives or other estrogen preparations

Special Concerns

* No specific treatment is required in a patient with antibodies or other laboratory evidence of APS who lacks the clinical manifestations of APS.