James A. Obester, David M. Sibell

Basics

Description: Antiphospholipid Syndrome (APS/Hughes syndrome) is an autoimmune, hypercoagulable state caused by antibodies against cell-membrane phospholipids. The most common of these antibodies, lupus anticoagulant (LA) and anticardiolipin antibodies (aCL), are the basis of laboratory diagnosis. Primary Antiphospholipid Syndrome - thrombosis or multiple pregnancy loss with the laboratory findings of persistent paradoxical prolongation of activated partial thromboplastin time (aPTT) or high titers of aCL antibodies. Secondary Antiphospholipid Syndrome: associated with other autoimmune diseases, infection, drugs, and malignancy. Primary and secondary APS can result in venous or arterial thrombosis in virtually any location; lower extremity deep vein thrombosis (DVT) is the most common presentation. Thrombotic stroke/transient ischemic attack (TIA) is the leading arterial manifestation of APS. Up to 46% of stroke patients <50 years old have antiphospholipid antibodies.

Coronary artery involvement: can present as ischemia or infarction in patients with no other risk factors. Another common cardiac finding is valvular involvement with noninfectious vegetations on the mitral or aortic valves.

System(s) affected:

• Hematologic
• Reproductive
• Nervous
• Cardiovascular
• Renal
• Hepatic
• Endocrine
• Skin
• Gastrointestinal

A severe form of APS has been reported involving multiple organ systems-catastrophic antiphospholipid syndrome (CAPS) - that results in a mortality rate of 50% (!).

Prevalence in the United States: Primary prevalence of APS is unknown, whilst secondary is up to 50% of those with systemic lupus erythematosus (SLE).

Geriatric Considerations: increased incidence in elderly with chronic disease

Pediatric Considerations: uncommon

Pregnancy Considerations:

✓ APS is the leading treatable cause of recurrent pregnancy losses and should be high on the differential list, especially in women with multiple spontaneous abortions in the fetal period (beyond 10 weeks of gestation).

✓ Fetal loss rate is 50% to 75% if untreated; reduced to ~30% on anticoagulation treatment.

✓ Preeclampsia, HELLP syndrome (hemolysis, elevated liver enzyme levels and a low platelet count), and interuterine growth restriction (IUGR), leads to 43% of infants delivered prematurely.

Coordination between obstetrician and anesthesia provider is recommended regarding options for labor analgesia/anesthesia if cesarean delivery becomes necessary.

Predominant age: presents in young to middle-age adults. Increased incidence occurs in elderly with chronic diseases.

Predominant sex: secondary APS (SLE and connective tissue disorders) occurs more often in females than in males.

Primary Risk Factors: genetic markers: HLA-DR7

Secondary Risk Factors:

✎ Above-mentioned causes plus SLE

✎ Genetic markers: HLA-B8, HLA-DR2, HLA-DR3

✎ Race: Blacks, Hispanics, Asians, and Native Americans

Genetic Markers: HLA-DR7 for Primary APS and HLA-B8, HLA-DR2, HLA-DR3 as markers of SLE for Secondary APS

Etiology of Primary APS: antiphospholipid antibodies not related to other autoimmune disorders, infections, drugs, or malignancy

Etiology of Secondary APS: other autoimmune diseases (SLE, scleroderma, vasculitis), infections (mycoplasma, rubella, varicella, mumps HIV, hepatitis, and Lyme disease), drugs (quinidine, hydralazine, procainamide, phenytoin, interferon, cocaine, and propranolol), neoplasms

General Prevention: avoid conditions that contribute to hypercoagulability, such as prolonged immobility, smoking, and estrogen therapy. Discontinuing warfarin is associated with an increased risk in thrombosis and episodes of catastrophic APS.

Associated Conditions:

• SLE
• Rheumatoid arthritis
• Scleroderma
• Behcet's syndrome
• Temporal arteritis
• Sjögren's syndrome

Diagnosis

Signs and Symptoms:

• Homan's sign (DVT): Leg warmth and pain with dorsiflexion of foot
• Pulmonary embolism: dyspnea, anxiety, hypotension
• Stroke/TIA
• Cardiac ischemia/infarct without other risk factors
• Livido reticularis
• Recurrent pregnancy loss, especially those >10 weeks gestation.
  Intrauterine growth retardation
• Preterm birth
• Pre-eclampsia/HELLP syndrome

Lab Tests: Anticardiolipin IgG or IgM is present in moderate to high titers. Lupus anticoagulant antibodies are detected by prolongation of phospholipids-dependent coagulation tests (aPTT, dilute Russell viper venom time, kaolin clotting time) and are not corrected by mixing with normal sera. Confirmed by correction with addition of phospholipid. Thrombocytopenia and hemolytic anemia can also be revealed.

Alert:

★ Venereal Disease Research Laboratory test: False positive.

★ Drugs that may alter lab results:

★ Heparin: Prolongation of aPTT

★ Disorders that may alter lab results:

★ Clotting factor deficiency: APTT will correct when mixed with normal sera (remains prolonged if LA present).

Imaging:

➲ Duplex ultrasound for DVT

➲ CT or V/Q lung scan for pulmonary embolism (PE)

➲ Head MRI or cerebral angiography for stroke/TIA

➲ Transesophageal echocardiogram (TEE) for valve vegetation

➲ Renal artery scan for refractory hypertension

Diagnostic Procedures/Surgery: based on at least one clinical and one laboratory criteria.
Clinical criteria are:
⇨ Vascular thrombosis: one or more episode of arterial or venous thrombosis
⇨ Complications of pregnancy: one or more unexplained deaths of morphologically normal fetuses at or after the 10th week of gestation, or one or more premature births of morphologically normal neonates at or before 34 weeks of gestation
Laboratory criteria:
⇨ Anticardiolipin (aCL) antibodies: ACL IgG or IgM in moderate to high levels on two or more occasions at least 6 weeks apart
⇨ Lupus anticoagulant (LA) antibodies: Detected by prolongation of phospholipids-dependent coagulation tests (activated partial thromboplastin time, dilute Russell viper venom time, kaolin clotting time) on two or more occasions at least 6 weeks apart

Pathological Findings: Arterial and venous thrombosis can occur in virtually all blood vessels and is not associated with vasculitis. CNS involvement is due to thrombosis or embolic events from aortic or mitral valve vegetations. Vegetations consist of platelets and fibrin. Coronary blood vessel thrombus may be present, in the absence of significant atherosclerotic disease. Pulmonary pathology includes PE from DVT as well as primary thrombi in pulmonary vessels. Thrombosis in the GI tract can lead to intestinal/colonic infarction, Budd-Chiari syndrome, and acalculous cholecystitis. Renal artery thrombosis may be found in APS patients with intractable hypertension. Livido reticularis results from stasis in the skin due to capillary thrombosis.

Differential Diagnosis:

✓ Factor V Leiden

✓ Deficiencies in:

• Protein C
• Protein S
• Antithrombin III
• Plasminogen
• Tissue plasminogen activator

✓ Conditions leading to stasis or hyperviscosity

✓ Homocystinemia

✓ Heparin-induced thrombocytopenia

Treatment

Appropriate health care: inpatient for initial evaluation and treatment if severity dictates, otherwise, outpatient with regular monitoring.

General measures: avoid venous stasis and hypovolemia. For inpatients, observe for signs of PE, stroke, or other organ system involvement.

Medication (Drugs)

First Line: Treatment for new thrombosis is full anticoagulation using heparin, 80 U/kg IV bolus followed by an infusion at 18 U/kg/hour infusion. Adjust heparin dose to achieve three times the normal aPTT (may require monitoring heparin levels in those with an elevated aPTT due to LA). Warfarin, 5 to 10 mg/day is started 1 to 3 days later, and heparin is continued until the INR reaches 2 to 3. Some patients require high-dose treatment with an INR of 3 or higher. Anticoagulation should be continued indefinitely due to a high rate of recurrence (up to 78%).

During pregnancy, management includes daily aspirin and low-dose heparin (5,000 units b.i.d.) or enoxaparin 40 mg daily for those with a history of pregnancy loss but no history of thrombosis. With history of thrombosis, heparin is given at 15,000 to 20,000 U/day or enoxaparin 1 mg/kg every 12 hours (target anti-factor Xa level of 0.2 to 0.6 U/mL). Duration of treatment is controversial given the risk of thrombosis during pregnancy. One option is continuing until the patient is in labor, then discontinuing and restarting 8 hours after uncomplicated vaginal delivery or 24 hours after cesarean section.

Rare cases of CAPS have been treated with full anticoagulation, steroids, plasmapheresis, and cyclophosphamide. For pain management, follow opioid protocol.

Regional and neuraxial (spinal and epidural) analgesia are contraindicated when patients are fully anticoagulated. The placement of labor epidurals in APS patients is also controversial. Consider discontinuing low-molecular-weight heparin at 39 weeks, and continuing with heparin until the patient is in labor. After labor starts, heparin is discontinued and aPTT (or plasma heparin) is monitored. Once levels are back to normal and no evidence of coagulation abnormalities is present, an epidural or spinal can be performed. If an epidural catheter is placed, it should be removed as soon as possible after delivery in case of urgent need for anticoagulation; anticoagulation must wait 4 hours after removal to avoid epidural hematoma.

Contraindications for anticoagulants:

✱ Active bleeding, recent neurosurgical procedure, or previous adverse reactions

✱ Warfarin is contraindicated during pregnancy.

✱ History of recent severe hemorrhage, nonembolic stroke, or surgery

Precautions:

① Heparin-induced thrombocytopenia

② Warfarin necrosis

③ If neuraxial analgesia is used, monitor for signs and symptoms of epidural hematoma.

Significant possible interactions:

Increased anticoagulation due to cimetidine, alcohol, amiodarone, NSAIDs, sulfonamides, thyroid hormones

Decreased anticoagulation effects: estrogen, carbamazepine, glucocorticoids, and cholestyramine

Surgery: vena cava filters for those presenting with DVT and contraindications for anticoagulation. APS patients undergoing surgical procedures are at increased risk of thrombotic events after discontinuing warfarin perioperatively.

Follow-Up

Prognosis: long-term prognosis for APS is poor, with recurrent thrombosis in up to 29% of patients, despite antithrombotic therapy. During an 8-year follow-up of 354 patients, 37 had died and 125 new thromboses had occurred.

Complications:

☞ Recurrence of thrombosis in untreated or inadequately treated patients
☞ CAPS:

• Multiple concurrent thrombi
• Exacerbated by infection, surgical procedures, drugs

☞ Hemorrhage as a result of chronic anticoagulation, especially in those requiring a therapeutic INR greater than 3

Patient Monitoring:

aPTT or anti-factor Xa levels until heparin dose is stabilized. Platelets should be monitored and heparin discontinued if thrombocytopenia develops. Starting warfarin, monitor INR daily until therapeutic (INR 2 to 3), then weekly. Once stable, INR can be monitored monthly. Patient should watch for signs of bleeding while on anticoagulation therapy.

References:

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