eMedicine Specialties > Pediatrics: General Medicine > Rheumatology
Antiphospholipid Antibody Syndrome: Treatment & Medication
Updated: Aug 4, 2009
- Overview
- Differential Diagnoses & Workup
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Treatment
Medical Care
The following are potential therapeutic interventions for various care scenarios in patients with antiphospholipid antibody (aPL) syndrome (APS). Classes of medications are suggested below, and specific drugs are covered in Medication. See the therapeutic algorithm in Media file 5.74,75,76,77,1,25,35,39,78,79,80,81,82,83,84
One set of suggested algorithms for the workup and treatment of patients with antiphospholipid antibody syndrome. This should not be considered dogmatic because laboratory evaluation is not standardized and treatment remains empiric and controversial. Laboratory testing is not recommended in healthy asymptomatic individuals with no risk factors and a negative family history.
- In healthy patients who are asymptomatic and have no risk factors and a negative family history for arterial or venous thrombosis or fetal loss, no treatment or specific follow-up care is recommended.
- In asymptomatic patients with a family history positive for arterial or venous thrombosis or fetal loss, many physicians use antiplatelet prophylaxis, such as aspirin; however, others do not treat patients in the absence of other risk factors.
- In patients with primary antiphospholipid antibody syndrome (PAPS) with venous thrombosis, the initial treatment consists of heparin followed by warfarin (Coumadin) or low molecular weight (LMW) heparin. The highest risk for recurrence is in the first 6-12 weeks after thrombosis, but many physicians treat for at least 6 months in the absence of other risk factors. Some physicians advocate treatment for life.
- In patients with primary antiphospholipid antibody syndrome with arterial thrombosis or infarction, many physicians administer antiplatelet therapy in the absence of other risk factors, but the use of anticoagulants is controversial. Some have advocated anticoagulation for life, but the recent Antiphospholipid Antibodies in Stroke Study (APASS) did not show a statistical difference between the group treated only with aspirin versus the group treated with aspirin and warfarin (Coumadin) with regard to recurrence of stroke.85
- In patients with secondary antiphospholipid antibody syndrome with arterial or venous thrombosis, the ongoing endothelial perturbation secondary to the underlying vasculitis places these patients at continuous risk for recurrence. Antiplatelet therapy (often with combinations of aspirin, hydroxychloroquine, and pentoxifylline) plus anticoagulation (with Coumadin or LMW heparin) is indicated. If the patient has positive test results for lupus anticoagulant (LAC) and any other risk factors (eg, factor V Leiden mutation, prothrombin gene mutation, methylene tetrahydrofolate reductase mutation (MTHFR) mutation), anticoagulation therapy may be necessary for life.
- Patients with catastrophic antiphospholipid antibody syndrome
- Antiplatelet therapy, anticoagulation, corticosteroids, and immunosuppression all have been used with varied success; however, all should be considered in this potentially lethal condition.
- Consider plasmapheresis in cases of coagulopathy with an underlying vasculitis or in catastrophic antiphospholipid antibody syndrome.
- Precautions include worsening of the hypercoagulable state through the removal of coagulation control proteins such as antithrombin III. This can be ameliorated by replacement with fresh frozen plasma or concentrates instead of albumin.
- Some suggest the use of intravenous immunoglobulin (IVIG) or targeted B cell therapy (rituximab) as final replacement after pheresis to decrease B-cell immunoglobulin production.
Surgical Care
- Insertion of venous umbrella
- Thrombectomy
- Organ-specific biopsy for diagnostic purposes
- Central-line insertion for vascular access (for medications or plasmapheresis)
- Cardiac valve replacement or papillary muscle repair
Consultations
Multiple consultations may be appropriate and are dependent on the organ system involvement.
- Medical - Rheumatologist, hematologist, cardiologist, neurologist, dermatologist, ophthalmologist
- Surgical - Plastic surgeon (for peripheral vascular insults/ulcerations), cardiovascular surgeon (for valvular infarctions, papillary muscle rupture), vascular surgeon (for arterial graft/bypass, thrombus removal)
Diet
- Identification and correction of folate deficiencies, elevated homocysteine levels, or both82
- Dietary supplementation with folic acid, vitamin B-12, or both is indicated for patients with hyperhomocysteinemia.
- Dietary manipulation is indicated to decrease consumption of methionine-containing foods, which may increase homocysteine levels in patients with mutations in the gene that encodes for MTHFR.
- Dietary counseling for patients on oral anticoagulant therapy
- Patients should maintain a consistent diet of foods that contain vitamin K. Foods rich in vitamin K include asparagus, broccoli, brussel sprouts, cabbage, cauliflower, egg yolk, kale, lettuce, liver and pâtés, potatoes, spinach, turnip greens, vegetable oils, and watercress.
- Patients should avoid foods that have anticoagulant properties. Herbs with anticoagulant properties include dong quai (Angelica sinensis), fenugreek (Trigonella foenum-graecum), feverfew (Tanacetum parthenium), garlic (Allium sativum), ginger (Zingiber officinale), ginkgo (Ginkgo biloba), and ginseng (Panax ginseng).
- Dietary manipulation to prevent obesity, hyperlipidemia, and hypertension, starting at a young age, especially in patients with a family history of these problems
Activity
- Physical activity: No specific limitations on activity are needed for individuals with aPL antibodies or antiphospholipid antibody syndrome other than those imposed by residua from a thromboembolic event (eg, stroke, myocardial infarction). However, certain restrictions are prudent for individuals with anticoagulation.
- Avoid contact sports and high-impact activities.
- Use protective headgear (helmet) for sports (eg, bicycle riding, skating).
- Travel: Recent studies have demonstrated Doppler evidence of DVT after prolonged air travel. These data have stimulated discussion of possible prophylaxis for travelers with aPL antibodies.
- Antiplatelet therapy for asymptomatic individuals with antiphospholipid antibodies and additional risk factors for the duration of any prolonged travel
- Anticoagulation with LMW-heparin injections for the duration of air travel (or any travel in which the individual is cramped and stationary) longer than 6 hours if the patient has positive test results for LAC and additional risk factors
Medication
Very few studies have addressed the efficacy of any treatment protocol in antiphospholipid antibody syndrome (APS). Most are small retrospective analyses or anecdotal reports. Many prospective studies have included too few patients and have been hampered by a lack of homogeneity of test groups. The Sapporo criteria were established, in part, to ensure a uniform homogeneous test population in order to promote accurate prospective studies of treatment protocols for patients with antiphospholipid antibody syndrome.Antiplatelet agents
Aspirin inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A2. It is used in low doses to inhibit platelet aggregation and improve complications of venous stases and thrombosis. However, doses as low as 5 mg/kg appear to additionally inhibit prostacyclin, thus promoting a procoagulant state. No prevalence data on aspirin resistance in children has been reported. The effect of aspirin on platelet function can be assessed by optical platelet aggregometry or Platelet Function Analyzer (PFA-100). Ticlopidine does not inhibit cyclooxygenase and, in this way, differs from aspirin. It inhibits the primary and secondary phase of aggregation induced by adenosine 5'-diphosphate (ADP) and reduces platelet-derived growth factor. Ticlopidine may also impair platelet adhesion, resulting in prolonged bleeding time. Dipyridamole potentiates the inhibitory effects of aspirin on platelet aggregation.
Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin)
Used for antiplatelet effect. Inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A2. May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis.
Adult
1-2 mg/kg/d PO for antiplatelet effect
Pediatric
Limited comparative data regarding effective antiplatelet dose in pediatrics has been reported; 1-2 mg/kg/d PO is a typical dose
Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; 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
Documented hypersensitivity; liver damage, hypoprothrombinemia, vitamin K deficiency, bleeding disorders, asthma; because of association of aspirin with Reye syndrome, do not use in children (<16 y) with influenzalike illnesses
Pregnancy
D - Fetal risk shown in humans; use only 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, with history of blood coagulation defects, or taking anticoagulants
Ticlopidine (Ticlid)
Used for livedoid vasculitis and thromboembolic disorders. Second-line antiplatelet therapy for patients who cannot tolerate or in whom aspirin therapy has failed.
Adult
250 mg PO bid
Pediatric
Not established
Effects may decrease with coadministration of corticosteroids and antacids; toxicity increases when taken concurrently with theophylline, cimetidine, aspirin, or NSAIDs
Documented hypersensitivity; neutropenia or thrombocytopenia, liver damage, and active bleeding disorders
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Discontinue if absolute neutrophil count decreases to <1200/mcL or if platelet count falls to <80,000/mcL
Dipyridamole (Persantine)
Used for thromboembolic disorders to complement usual aspirin or warfarin therapy. Platelet adhesion inhibitor that possibly inhibits RBC uptake of adenosine, which is an inhibitor of platelet reactivity. In addition, may inhibit phosphodiesterase activity, leading to increased cyclic-3',5'-adenosine monophosphate within platelets and formation of the potent platelet-activator thromboxane A2.
Used alone or in combination with low-dose aspirin therapy as indicated above. Also used in combination with low-dose PO anticoagulant therapy (with or without aspirin) in children with mechanical prosthetic heart valves.
Adult
75-400 mg/d PO divided tid/qid
Pediatric
<12 years: 3-6 mg/kg/d PO divided tid
>12 years: Administer as in adults
Theophylline may decrease the hypotensive effects; antiplatelet activity of dipyridamole may increase heparin toxicity
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in hypotension; medication has peripheral vasodilating effects
Anticoagulants
Unfractionated intravenous heparin and fractionated LMW subcutaneous heparin are the choices for initial anticoagulation therapy. If warfarin is chosen as maintenance therapy, it is initiated and concurrently administered with heparin for several days until the international normalized ratio (INR) reaches the target range.
Heparin
Used for thromboembolic disorders. Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis. Used as a continuous infusion while initiating PO warfarin therapy.
Adult
Initial dose: 40-170 U/kg IV
Maintenance infusion: 18 U/kg/h IV
Alternatively, 50 U/kg/h IV initially, followed by continuous infusion of 15-25 U/kg/h; increase dose by 5 U/kg/h q4h prn using PTT results (PTT at 2 X baseline)
Pediatric
Initial dose: 50 U/kg IV
Maintenance infusion: 15-25 U/kg/h IV
Increase dose by 2-4 U/kg/h q6-8h prn using PTT results (PTT at 2 X baseline)
Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity
Documented hypersensitivity; subacute bacterial endocarditis, active bleeding, history of heparin-induced thrombocytopenia
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
In neonates, preservative-free heparin recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as preservative; caution in severe hypotension and shock; monitor for bleeding in peptic ulcer disease, menstruation, increased capillary permeability, and when giving IM injections
Enoxaparin (Lovenox)
Used for thromboembolic disorders. Prevents DVT, which may lead to PE in patients undergoing surgery who are at risk for thromboembolic complications.
Enhances inhibition of factor Xa (preferentially) and thrombin (factor IIa) by increasing antithrombin III activity. The ratio of antifactor Xa to antifactor IIa activity is approximately 4:1 (1:1 for unfractionated heparin)
Adult
Prophylaxis (average dose): 30 mg SC q12h
Treatment (suggested dose): 1 mg/kg/dose SC q12h
Pediatric
Not established; suggested dose for prophylaxis:
<2 months: 0.75 mg/kg/dose SC q12h
>2 months: 0.5 mg/kg/dose SC q12h
Suggested dose for treatment:
<2 months: 1.5 mg/kg/dose SC q12h
>2 months: 1 mg/kg/dose SC q12h
Adjust dose by monitoring anti–factor Xa and aPTT
Platelet inhibitors or PO anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding
Documented hypersensitivity; major bleeding, thrombocytopenia
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
If thromboembolic event occurs despite LMW-heparin prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMW heparins; 1 mg of protamine sulfate reverses effect of approximately 1 mg of enoxaparin if significant bleeding complications develop
Warfarin (Coumadin)
Used for thromboembolic disorders. Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.
Adjust dose to maintain an INR in the range of 2.5-3.5.
Adult
5-15 mg/d PO qd for 2-5 d; adjust dose according to desired INR (range 2.5-3.5)
Pediatric
Administer weight-based dose of 0.05-0.34 mg/kg/d PO; adjust dose according to desired INR (range 2.5-3.5)
Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, and sucralfate
Medications that may increase anticoagulant effects of warfarin include PO antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, gemfibrozil, acetaminophen, and sulindac
Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes mellitus; patients with protein C or protein S deficiency are at risk of developing skin necrosis; abrupt withdrawal of warfarin may result in a thrombotic event
Immunomodulators
Immune globulin is a purified preparation of gamma globulin derived from large pools of human plasma. It is composed of 4 subclasses of IgG antibodies, approximating the distribution of human serum. IgA-depleted products are also low in the IgG4 component.
Immune globulin intravenous (Sandoglobulin, Gammagard, Gamimune, Gammar-P, Gamunex)
Used for autoimmune diseases. Neutralizes circulating myelin antibodies through antiidiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).
Adult
2 g/kg IV over 2-5 d
Pediatric
Not established
Suggested dose: 1-2 g/kg IV over 2-5 d
Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)
Documented hypersensitivity; IgA deficiency; IgE/IgG anti-IgA antibodies
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Check serum IgA before IVIG administration (use IgA-depleted product [eg, Gammagard S/D]); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d)
Increases risk of renal tubular necrosis in elderly patients and in diabetes mellitus, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia
Vasodilators
These agents are used to lower elevated blood pressure, decrease vasospasm, or prevent ischemia. Niacin is also used to decrease hyperlipidemia.
Nitroglycerin ointment (Nitrol, Nitro-Bid)
Causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production. The result is a decrease in blood pressure.
Onset of action for ointment is 20-60 min. Duration of effect is 2-12 h.
Adult
2% ointment (20 mg/g): Apply 2.5-5 cm topically to chest wall or extremity with occlusive dressing (eg, Tegaderm) q8h
Adjust dose for clinical effect
Pediatric
2% ointment (20 mg/g): Apply 1-2.5 cm topically to chest wall or extremity with occlusive dressing (eg, Tegaderm) q8h
Adjust dose for clinical effect
Aspirin may increase serum nitrate concentrations; marked symptomatic orthostatic hypotension may occur with coadministration of calcium channel blockers (dose adjustment of either agent may be necessary)
Documented hypersensitivity; severe anemia, shock, postural hypotension, head trauma, closed-angle glaucoma, or cerebral hemorrhage
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in coronary artery disease and low systolic blood pressure; care must be taken to avoid placing fingers in mouth or near eyes
Niacin (Niacor, Niaspan, Nicotinex, Slo-Niacin)
Also called nicotinic acid or vitamin B-3. Component of 2 coenzymes necessary for tissue respiration, lipid metabolism, and glycogenolysis; inhibits synthesis of VLDL. Used as a dietary supplement and as adjunctive treatment of hyperlipidemias, peripheral vascular disease, circulatory disorders, and treatment of pellagra.
Onset of action within 20 min (extended release within 1 h). Duration of effect 20-60 min (extended release 8-10 h). Half-life 45 min.
Adult
50-100 mg PO tid with an upward titration until desired effect is obtained or until adverse effects are not tolerable (used in hyperlipidemia at a dosage range of 1.5-6 g/d PO divided tid)
Once dosage established, sustained-release capsule or tablet can be used
Pediatric
Not established
Suggested dose: Administer as in adults with gradual upward titration
Cutaneous vasodilation may be a problem if high dose used with peripheral dilators, such as nitroglycerin, or with adrenergic blocking agents
Taking aspirin 30-60 min before first dose of the day may help alleviate prostaglandin-mediated adverse effects of niacin (ie, flushing, itching, headache); clonidine may inhibit niacin-induced flushing
May decrease effect of PO hypoglycemic agents, may inhibit uricosuric effects of sulfinpyrazone and probenecid, and may increase risk of myopathy with lovastatin
Documented hypersensitivity; severe hypotension; arterial hemorrhage; active liver disease or unexplained significant increases in AST and ALT levels; large doses of niacin, especially when administered in a sustained-release form (associated with severe hepatotoxicity); a definite and recent history of peptic ulcer disease (can reactivate ulcers); GERD
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in patients with gallbladder disease or diabetes mellitus and in those predisposed to gout; monitor blood glucose; may elevate uric acid levels; pregnancy category C when used at doses higher than RDA; some products may contain tartrazine
Drugs with effects on vascular endothelium, platelets, red blood cells
These drugs appear to have multiple mechanisms in the prevention of thrombosis and vascular spasm. The exact mechanisms are largely unexplained, but the properties of these drugs include changes in RBC rheology, inhibition of platelet adhesiveness/activation, inhibition of TNF-alpha production, and decreases in neutrophil and endothelial cell activation.
Pentoxifylline (Trental)
Used in vascular disease. May alter rheology of RBCs, which, in turn, reduces blood viscosity. Improves peripheral perfusion and vascular spasm in Raynaud phenomenon and vasculopathy/vasculitis.
Other effects include inhibition of platelet adhesiveness/activation, inhibition of TNF-alpha production, and decrease in neutrophil and endothelial cell activation.
Adult
400 mg PO tid pc; may reduce frequency to bid if GI or CNS adverse effects occur
Pediatric
Not established
Suggested doses:
<25 kg: Not established; doses of 20 mg/kg/d PO divided tid (and higher) have been used in Kawasaki disease; doses of 30 mg/kg/d have been infused IV over 6-h periods in preterm infants; doses of 40-60 mg/kg/d have been used in peripheral vascular disease
25-40 kg: 400 mg PO bid
>40 kg: 400 mg PO tid
Decrease dose frequency if GI or CNS adverse effects occur
Coadministration with cimetidine or theophylline, increases effect/toxic potential; pentoxifylline increases effect of antihypertensives
Documented hypersensitivity; cerebral and/or retinal hemorrhage
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in renal impairment
Hydroxychloroquine (Plaquenil)
Inhibits platelets, chemotaxis of eosinophils, and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions.
Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.
Adult
310 mg (base) PO qd or bid for several wk depending on response; 155-310 mg/d for prolonged maintenance therapy
Pediatric
3-5 mg base/kg/d PO qd or divided bid; not to exceed 7 mg/kg/d
Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption
Documented hypersensitivity; psoriasis; retinal and visual field changes attributable to 4-aminoquinolones
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children (but has been used for long courses in the treatment of JRA); perform periodic (6 mo) ophthalmologic examinations especially for color and peripheral vision; test periodically for muscle weakness
Cilostazol (Pletal)
Affects vascular beds and cardiovascular function. May improve blood flow by altering rheology of RBCs. Produces nonhomogenous dilation of vascular beds, with more dilation in femoral beds than in vertebral, carotid, or superior mesenteric arteries.
Cilostazol and its metabolites are inhibitors of phosphodiesterase III and, as a result, cyclic AMP is increased, which leads to inhibition of platelet aggregation and vasodilation.
Adult
100 mg PO bid at least 30 min ac or 2 h pc
Decrease to 50 mg bid if coadministering drugs that inhibit clearance (see interactions)
Pediatric
<12 years: Not established
>12 years: Administer as in adults
Inhibitors of CYP3A4 (eg, diltiazem, erythromycin, grapefruit juice, itraconazole, ketoconazole, macrolide antibiotics) or CYP2C19 (eg, ketoconazole, omeprazole) may increase levels
Documented hypersensitivity; CHF; coadministration with grapefruit juice
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in renal impairment; do not prescribe or administer without thoroughly reading complete prescribing information
Platelet count enhancers
These agents are used to augment platelet recovery.
Vincristine (Oncovin, Vincasar PFS)
Mechanism of action for treatment of thrombocytopenia is uncertain. May involve a decrease in reticuloendothelial cell function or an increase in platelet production. However, neither of these mechanisms fully explains the effect in TTP and HUS.
Adult
0.4-1.4 mg/m2 IV; not to exceed 2 mg/dose IV push; repeat weekly prn for effect
Pediatric
1-2 mg/m2 IV; not to exceed 2 mg/dose IV push; repeat weekly prn for effect
Acute pulmonary reaction may occur when taken concurrently with mitomycin-C; asparaginase, CYP3A4 inhibitors (eg, itraconazole, quinupristin/dalfopristin, sertraline, ritonavir), GM-CSF (eg, sargramostim, filgrastim), and nifedipine increase toxicity; CYP3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects
Documented hypersensitivity; IT administration (may be fatal)
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in severe cardiopulmonary disease, hepatic impairment (adjust dose), or preexisting neuromuscular dysfunction
Danazol (Danocrine)
Synthetic steroid analog with strong antigonadotropic activity (inhibits LH and FSH) and weak androgenic action.
Increases levels of C4 component of complement and reduces attacks associated with angioedema. In hereditary angioedema, danazol increases level of deficient C1 esterase inhibitor.
Adult
200-600 mg/d PO divided bid/tid
Angioedema: 200 mg PO bid/tid; after favorable response, decrease the dosage by 50% or less at intervals of 1-3 mo or longer if the frequency of attacks dictates; if an attack occurs, increase the dosage by up to 200 mg/d
Pediatric
Not established
Decreases insulin requirements and increases effects of anticoagulants; may increase carbamazepine levels
Documented hypersensitivity; seizure disorders; hepatic, renal, or hepatic insufficiency; lactation; conditions influenced by edema; undiagnosed genital bleeding; porphyria
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Caution in seizure disorders and renal, hepatic, or cardiac insufficiency
Other therapy with multiple actions
Medications with vasodilatory and antiplatelet activity with specific usage in the treatment of pulmonary hypertension and/or healing of refractory skin ulcerations have been administered in patients with APS.78,79,80
Bosentan (Tracleer)
Endothelin-receptor antagonist indicated for the treatment of pulmonary arterial hypertension in patients with WHO class III or class IV symptoms to improve exercise ability and decrease rate of clinical worsening. Inhibits vessel constriction and elevation of blood pressure by competitively binding to the endothelin-1 (ET-1) receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to a significant increase in the cardiac index (CI) associated with significant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP). Due to teratogenic potential, can only be prescribed through the Tracleer Access Program (1-866-228-3546).
Adult
<40 kg: 62.5 mg PO bid; not to exceed 125 mg/d
>40 kg: 62.5 mg PO bid for 4 wk initially, then increase to 125 mg PO bid
Pediatric
Not established; recommended
<12 years:
10-20 kg: 31.25 mg PO qd for 4 wk initially, then increase to 31.25 mg PO bid
>20-40 kg: 31.25 mg PO bid for 4 wks initially, then increase to 62.5 mg PO bid
>40 kg: 62.5 mg PO bid for 4 wks initially, then increase to 125 mg PO bid
>12 years: Administer as in adults
Toxicity may increase when concomitantly administered with inhibitors of isoenzymes CYP450 2C9 and CYP450 3A4 (eg, ketoconazole, erythromycin, fluoxetine, sertraline, amiodarone, and cyclosporine A); induces isoenzymes CYP450 2C9 and CYP450 3A4, which cause a decrease in plasma concentrations of drugs metabolized by these enzymes, including glyburide and other hypoglycemics, cyclosporin A, warfarin, hormonal contraceptives, simvastatin, and, possibly, other statins; hepatotoxicity increases with concomitant administration of glyburide; coadministration with sildenafil increases bosentan levels by 50% and reduces sildenafil levels by 63%
Documented hypersensitivity; coadministration with cyclosporin A or glyburide
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Causes at least 3-fold elevation of liver aminotransferase levels (ie, ALT, AST) in about 11% of patients; may elevate bilirubin levels (serum aminotransferase levels must be measured prior to initiation of treatment and then monthly); caution in patients with mildly impaired liver function (avoid in patients with moderate or severe liver impairment); not recommended while breastfeeding; monitor hemoglobin levels after 1 and 3 mo of treatment and every 3 mo thereafter; exclude pregnancy before initiating treatment and prevent thereafter by use of reliable contraception (hormonal contraception may not be effective, see interactions); headache and nasopharyngitis may occur
Epoprostenol (Flolan)
Prostacyclin, PGI2 analogue that has potent vasodilatory properties. Elicits immediate onset of action. Half-life is approximately 5 min. In addition to vasodilator properties (all vascular beds), also contributes to inhibition of platelet aggregation (activates intracellular adenylate cyclase and results in increased CAMP in platelets) and plays role in inhibition of smooth muscle proliferation.
Adult
2 ng/kg/min by continuous IV infusion; increase by increments of 2 ng/kg/min q15min as tolerated (monitor adverse effects)
To decrease dose, reduce dose by 2 ng/kg/min decrements at intervals of at least 15 min
Pediatric
Not established; recommend: 1-2 ng/kg/min continuous IV infusion, then increase in increments of 1-2 ng/kg/min q15min as tolerated
Coadministration with anticoagulants may increase bleeding risk due to shared effects on platelet aggregation (although typically coadministered with anticoagulants to reduce thromboembolic risk); additional blood pressure reduction may occur with other drugs that lower blood pressure (eg, diuretics, antihypertensive agents, other vasodilators); coadministration with MAOIs may cause additive hypotensive effect; sympathomimetics antagonize hypotensive effect
Documented hypersensitivity; CHF with severe LV dysfunction; chronic use in patients that develop pulmonary edema during initiation
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Abrupt withdrawal, interruptions in delivery, or large dose reductions may precipitate rebound pulmonary hypertension; dose-limiting adverse effects include nausea, vomiting, headache, and hypotension; unless contraindicated, coadminister with anticoagulants to reduce risk of thromboembolism
Sildenafil (Viagra, Revatio)
FDA-approved for pulmonary hypertension. Promotes selective smooth muscle relaxation in lung vasculature possibly by inhibiting phosphodiesterase type 5 (PDE5). This results in subsequent reduction of blood pressure in pulmonary arteries and increase in cardiac output. Elicits vasodilation and inhibits platelet aggregation. Also aids in healing refractory skin ulcerations.
Adult
20 mg PO tid
Pediatric
Not established
CYP3A4 substrate; potentiates vasodilatory effect of NO, resulting in potentially fatal drop in blood pressure; coadministration with ketoconazole, erythromycin, or cimetidine increases plasma sildenafil concentrations; coadministration with rifampin decreases plasma levels; coadministration with bosentan increases bosentan levels by 50% and reduces sildenafil levels by 63%
Documented hypersensitivity; concurrent or intermittent using of organic nitrates in any form
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in patients with retinitis pigmentosa; a small number of patients have genetic disorders of retinal phosphodiesterases; adverse effects include headaches (16%), flushing (10%), upset stomach (7%), nasal congestion (4%), and a blue haze at the periphery of vision (3%); adverse effects occur more often in men taking the 100-mg dose; serious adverse effects occur in patients with severe heart disease and those who are taking nitrates, observed rates of MI were 1.7 vs 1.4 per 100 man-years for sildenafil vs placebo groups respectively; sudden vision loss caused by nonarteritic anterior ischemic optic neuropathy (NAION) has been associated with PDE-5 inhibitors following use for ED, analysis is ongoing to determine causality
Antilipemic Agent
Therapy for dyslipoproteinemia or hyperlipidemia may reduce vascular risk factors for thrombosis. In vitro and animal model evidence suggests decreased endothelial cell and granulocyte activation.86,83
Atorvastatin (Lipitor)
The most efficacious of the statins at high doses. Inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase), which in turn inhibits cholesterol synthesis and increases cholesterol metabolism. Reports have shown as much as a 60% reduction in LDL-C. The Atorvastatin versus Revascularization Treatment study (AVERT) compared 80 mg atorvastatin daily to standard therapy and angioplasty in patients with CHD. While events at 18 mo were the same between both groups, the length of time until the first CHD event occurred was longer with aggressive LDL-C lowering. The half-life of atorvastatin and its active metabolites is longer than that of all the other statins (ie, approximately 48 h compared to 3-4 h).
May modestly elevate HDL-C levels. Clinically, reduced levels of circulating total cholesterol, LDL-C, and serum TGs are observed.
Before initiating therapy, patients should be placed on a cholesterol-lowering diet for 3-6 mo; the diet should be continued indefinitely.
Adult
10 mg PO qd; may titrate upward, not to exceed 80 mg/d
Dosage adjustment in renal insufficiency unnecessary
Pediatric
Has been FDA-approved for familial hypercholesterolemia
<10 years: Not established
10-17 years: 10 mg PO hs initially; may increase to 20 mg PO hs if needed
>17 years: Administer as in adults
Toxicity increases when coadministered with triazole antifungals, CNS depressants, macrolide antibiotics, gemfibrozil
Documented hypersensitivity; significant hepatic impairment
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Do not exceed daily dose; caution in patients receiving drugs which prolong QRS or Q-T interval
Pravastatin (Pravachol)
Effective in reducing circulating lipid levels and improving the clinical and anatomic course of atherosclerosis.
Adult
40 mg PO hs initially; may increase if needed, not to exceed 80 mg/d
Note: Initiate with 10 mg/d in patients with severe liver or renal disease
Pediatric
<8 years: Not established
8-13 years: 20 mg PO hs
14-18 years: 40 mg PO hs
Effects increase with cholestyramine; increases toxicity of gemfibrozil, clofibrate, niacin, cyclosporine, and PO anticoagulants; itraconazole and ketoconazole increase toxicity of lovastatin; concurrent use with erythromycin, niacin, or gemfibrozil may increase risk of rhabdomyolysis
Documented hypersensitivity; active liver disease
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
May elevate aminotransferases; perform LFTs before therapy and every 4-6 wk for 12-15 mo; periodically thereafter; use a starting dose of 10 mg/d with severe renal or liver impairment
Simvastatin (Zocor)
Inhibits cholesterol synthesis and increases cholesterol metabolism.
Adult
5-80 mg/d PO hs
Pediatric
<10 years: Not established
10-17 years: 10 mg PO hs; may increase by increments of 10 mg/d q4wk according to cholesterol levels, not to exceed 40 mg/d
>17 years: Administer as in adults
Effects increase with cholestyramine; increases toxicity of gemfibrozil, clofibrate, niacin, cyclosporine, and oral anticoagulants; itraconazole and ketoconazole increase toxicity of lovastatin; concurrent use with erythromycin may increase risk of rhabdomyolysis
When coadministered with fibrates (eg, gemfibrozil), niacin (>1 g/d), or cyclosporine do not exceed 10 mg/d; when coadministered with verapamil or amiodarone do not exceed 20 mg/d
Documented hypersensitivity; active liver disease; unexplained elevation of liver enzymes
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Initiate treatment at lower dose with severe renal insufficiency and discontinue if renal function worsens; discontinue therapy if symptoms of myopathy develop; caution in history of liver disease and those who consume excessive amounts of alcohol
Biological Response Modulator
Targeted anti-B cell therapy has been used in the treatment of refractory idiopathic thrombocytopenic purpura (ITP) postsplenectomy. The use of this modality has been extrapolated to treatment protocols for antiphospholipid syndrome.87,88,89
Rituximab (Rituxan)
Indicated to reduce signs and symptoms for moderately-to-severely active rheumatoid arthritis in combination with methotrexate. For use in adults who have experienced an inadequate response to one or more TNF antagonist therapies. Antibody genetically engineered. Chimeric murine/human monoclonal antibody directed against the CD20 antigen found on surface of B-lymphocytes.
Adult
1000 mg IV infusion for 2 doses, separated by 2 wk; administer methylprednisolone 100 mg IV (or its equivalent) 30 min before each infusion to reduce infusion related reactions
Do not exceed infusion rate of 50 mg/h initially; if hypersensitivity or infusion-related reactions do not occur, may escalate infusion rate by 50 mg/h increments q30min; not to exceed 400 mg/h
Pediatric
Not established; limited data from various case reports suggest 375-1000 mg/m2/dose IV
Coadministration with cisplatin is known to cause severe renal toxicity including acute renal failure; may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 months of vaccine)
Documented hypersensitivity; IgE-mediated reaction to murine proteins
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Use with caution in patients with dormant infections such as hepatitis B, hepatitis C, or CMV due to risk of reactivation; hypotension, bronchospasm, and angioedema may occur, premedication with acetaminophen and diphenhydramine may decrease incidence; discontinue treatment if life-threatening cardiac arrhythmias occur; must administer by slow IV infusion, do not administer IV push or bolus
More on Antiphospholipid Antibody Syndrome |
| Overview: Antiphospholipid Antibody Syndrome |
| Differential Diagnoses & Workup: Antiphospholipid Antibody Syndrome |
 Treatment & Medication: Antiphospholipid Antibody Syndrome |
| Follow-up: Antiphospholipid Antibody Syndrome |
| Multimedia: Antiphospholipid Antibody Syndrome |
| References |
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Further Reading
Keywords
anti-phospholipid antibody syndrome, Hughes syndrome, Hughes' syndrome, antiphospholipid syndrome, anti-phospholipid syndrome, APS, APLS, Sneddon syndrome, Sneddon's syndrome, thrombosis, primary antiphospholipid syndrome, PAPS, secondary antiphospholipid syndrome, antiphospholipid, aPl, deep venous thrombosis, arterial occlusive events, migraine headache, Raynaud phenomenon, transient ischemic attack, TIA, systemic lupus erythematosus, SLE, lupus anticoagulant, LAC, migraine headache, peripheral vasospasm, thrombocytopenia, anticardiolipin antibody, aCL antibody, cerebrovascular accident, myocardial infarction, endocarditis, pulmonary emboli, treatment, diagnosis
