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Complications include maternal thrombosis (stroke, venous thromboembolism [VTE]), fetal death, preeclampsia and placental insufficiency, fetal growth retardation, and preterm birth.
Low-dose aspirin and low-molecular-weight heparin (LMWH) or unfractionated heparin are the drugs of choice in pregnancy.
Prophylactic-dose heparin is recommended in the postpartum period (unless patient is on therapeutic anticoagulation) given high risk of thrombosis during this time. With adequate treatment, >70% of patients with APS deliver viable infants.
EPIDEMIOLOGY
- The prevalence of APAs increases with age but is not necessarily associated with a higher risk of thrombosis.
- For APS, female > male
Incidence
- In patients with positive APAs without prior risk of thrombosis, the annual incident risk of thrombosis is 0-3.8%. This risk is up to 5.3% in those with triple positivity (anticardiolipin antibodies, lupus anticoagulant (LAC), and anti-β2-glycorotein-1 (GP1) antibodies positive).
- 10-15% of recurrent abortions are attributable to APS.
Prevalence
APAs are present in 1-5% of the general population and in ~40% of those with SLE. A higher prevalence is seen in those with VTE and stroke.
ETIOLOGY AND PATHOPHYSIOLOGY
- Anti-β2-GP1 antibodies play a central role in the pathogenesis of APS. The procoagulant effect is mediated by various possible mechanisms:
- Endothelial effects: inhibition of prostacyclin production and loss of annexin V cellular shield
- Platelet activation resulting in adhesion and aggregation
- Interference of innate anticoagulant pathways (such as inhibition of protein C)
- Complement activation
- Pregnancy-related complications are also a result of autoantibody-mediated effects:
- Interference with expression of trophoblastic adhesion molecules resulting in abnormal placentation and placental thrombosis
- Proposed mechanisms: excess production of natural antibodies, molecular mimicry due to infections, exposure of phospholipid antigens during platelet activation, cardiolipin peroxidation, and genetic predisposition
- A "second hit"ť by environmental factors may be required to produce thrombosis.
Genetics
Most cases of APS are acquired. There are a few studies of familial occurrence of anticardiolipin antibodies and LAC. A valine 247/leucine polymorphism in β2-GP1 could be a genetic risk for the presence of anti-β2-GP1 antibodies and APS.
RISK FACTORS
- Age >55 years in males, >65 years in females
- Cardiovascular risk factors (hypertension, diabetes, obesity, smoking, combined oral contraceptive use)
- Underlying autoimmune disease (SLE, rheumatoid arthritis, collagen vascular disease, Sj ¶gren syndrome, idiopathic thrombocytopenic purpura, Beh §et syndrome)
- Surgery, immobilization, pregnancy
GENERAL PREVENTION
Risk factor modification: Control HTN and diabetes; smoking cessation; avoidance of oral contraceptives in high-risk patients; start thromboprophylaxis in established cases.
COMMONLY ASSOCIATED CONDITIONS
- Autoimmune diseases: SLE (most common), scleroderma, Sj ¶gren syndrome, dermatomyositis, and rheumatoid arthritis
- Malignancy
- Infections: viral, bacterial, parasitic, and rickettsial
- Certain drugs associated with APA production without increased risk of thrombosis: phenothiazines, hydralazine, procainamide, and phenytoin
- Hemolysis, elevated liver enzymes, and low platelet count in association with pregnancy (HELLP) syndrome
- Sneddon syndrome (APS variant syndrome with livedo reticularis, HTN, and stroke)
DIAGNOSIS
Sapporo criteria, revised 2006:
- At least one of the following clinical criteria:
- Vascular thrombosis
- ≥1 clinical episodes of arterial, venous, or small vessel thrombosis, occurring within any tissue or organ and confirmed by unequivocal imaging studies or histopathology
- Superficial venous thrombosis does not meet the criteria for APS.
- Complications of pregnancy (any one of the following):
- ≥3 consecutive spontaneous abortions before the 10th week of pregnancy, unexplained by maternal/paternal chromosomal abnormalities or maternal anatomic/hormonal causes
- ≥1 unexplained deaths of morphologically normal fetuses (documented by ultrasonography or by direct examination) at ≥10th week of gestation
- ≥1 premature births of morphologically normal newborn babies at ≤34th week of pregnancy due to severe preeclampsia, eclampsia, or placental insufficiency
- AND the presence of at least one of three laboratory findings (confirmed on ≥2 occasions at least 12 weeks apart):
- LAC detected in blood
- Anticardiolipin IgG and/or IgM antibodies present at moderate or high levels in the blood (>40 GPL or MPL or >99th percentile) via a standardized ELISA
- Anti-β2-GP1 IgG and/or IgM antibodies in blood at a titer >99th percentile by standardized ELISA
HISTORY
- History of VTE or arterial thrombosis (stroke, MI)
- History of fetal loss or other obstetric complications
- Bleeding from thrombocytopenia if severe or acquired factor II deficiency
- Personal or family history of autoimmune disease
PHYSICAL EXAM
- Signs of venous thrombosis in extremities
- Skin manifestations, including a vasculitic rash in the form of palpable purpura or livedo reticularis or lower extremity ulcers
- Livedo reticularis
- Cardiac murmurs
- Focal neurologic or cognitive deficits
DIFFERENTIAL DIAGNOSIS
- Thrombophilic conditions
- Inherited: deficiency of protein C, protein S, antithrombin III; mutation of factor V Leiden, prothrombin gene mutation
- Acquired: neoplastic and myeloproliferative disorders, hyperviscosity syndromes, nephrotic syndrome
- Embolic disease secondary to atrial fibrillation, LV dysfunction, endocarditis, cholesterol emboli
- Heparin-induced thrombocytopenia
- Atherosclerosis
- CAPS: hemolytic-uremic syndrome, TTP, or malignant hypertension
DIAGNOSTIC TESTS & INTERPRETATION
- LAC assay and IgG and IGM anticardiolipin antibodies by ELISA, and anti-β2-GP1 IgG and IgM antibodies are diagnostic tests of choice.
- The LAC assay combines at least two out of three screening tests (prolongation of aPTT, dilute Russell viper venom time [dRVVT], and kaolin clotting) with two confirmatory tests.
- Anti-β2-GP1 antibodies are important in the pathogenesis of thrombosis. A positive LAC assay recognizes antibodies against β2-GP1 and prothrombin.
- The clinical significance of other autoantibodies (annexin V, phosphatidylserine, and phosphatidylinositol) remains unclear.
Initial Tests (lab, imaging)
- CBC, PT/INR, aPTT, LAC, anticardiolipin antibodies, anti-β2-GP1 antibodies (1)[B]
- Further testing for secondary causes such as SLE when clinically suspected
- Imaging is based on clinical picture, suspected sites of thrombosis, and organ involvement.
Follow-Up Tests & Special Considerations
- The results of LAC are difficult to interpret in patients treated with warfarin. Unfractionated heparin or LMWH and fondaparinux do not affect the LAC assay.
- Repeat testing at 12 weeks for persistence of APA.
Diagnostic Procedures/Other
Biopsy of the affected organ system may be necessary to distinguish from vasculitis.
Test Interpretation
Usual finding is thrombosis and minimal vascular or perivascular inflammation:
- Acute changes: capillary congestion and noninflammatory fibrin thrombi
- Chronic changes: ischemic hypoperfusion, atrophy, and fibrosis
TREATMENT
MEDICATION
First Line
- Primary thromboprophylaxis: Low-dose aspirin is indicated in asymptomatic carriers of APAs with SLE and in pregnancy. It may be considered in other asymptomatic carriers. Hydroxychloroquine is recommended in all antiphospholipid-positive SLE patients.
- Secondary thromboprophylaxis: All symptomatic, nonpregnant patients with APS need indefinite anticoagulation. The target INR depends on the severity and type of thrombosis:
- Venous thrombosis (first episode): warfarin with target INR of 2.0 to 3.0
- Arterial thrombosis or recurrent venous thrombosis despite anticoagulation: warfarin with target INR 3.0 to 4.0
- LMWH and fondaparinux are alternatives.
- New oral anticoagulants such as rivaroxaban, apixaban, and dabigatran; all have been approved for treatment of DVT/PE; studies in APS are lacking; a prospective randomized controlled trial of warfarin versus rivaroxaban in patients with thrombotic APS and with a target INR or 2.5 is underway.
- Rituximab may be an option in severe cases, possibly in those with hematologic and microthrombotic/microangiopathic manifestations (2,3)[B].
- Danaparoid, fondaparinux, and argatroban can be considered in APS patients with heparin-induced thrombocytopenia.
- Newer oral anticoagulants (dabigatran, apixaban, and rivaroxaban) may be alternatives to warfarin with few drug interactions and no need for monitoring. The presence of APA interferes with hemostatic mechanisms and can interfere with anticoagulants. Ongoing phase III trials will help evaluate the role of new oral anticoagulants.
- Statins can decrease proinflammatory and prothrombotic state in APS. At this time, although they are not recommended in the absence of hyperlipidemia, APA-positive patients with recurrent thrombosis while adequately anticoagulated may benefit from statin therapy.
- B-cell inhibition may help in recalcitrant APS cases.
- Complement inhibition may be useful in cases refractory to anticoagulation, but further evaluation is needed.
- Peptide therapy may be a future treatment for APA-positive patients.
- Autologous hematopoietic stem cell transplantation may be an effective option for patients with concurrent complicated SLE and APS (4).
- Vitamin D deficiency/insufficiency should be corrected in all APA-positive patients, but its role in APS needs further study.
- Low-dose aspirin is superior to low-dose aspirin with low-dose warfarin due to decreased bleeding risk with no differences in number of thrombosis (5).
- CAPS: Anticoagulants and high-dose steroids may suffice in less severe cases. Aggressive treatment with either IVIG or plasmapheresis is often required in this life-threatening condition. These measures have improved survival to 66%.
- Treatment in pregnancy are as follows:
- For women with no prior history of thrombosis and ≥2 early miscarriages, either 81 mg ASA alone or in combination with unfractionated heparin (5,000 to 10,000 units SC q12h) or LMWH (prophylactic dose). In those with a previous late pregnancy loss (>10 weeks' gestation) or preterm (<34 weeks) delivery due to severe preeclampsia, a combination of ASA and heparin is recommended.
- In those with a history of thrombosis, low-dose ASA plus either therapeutic low-dose heparin (dosed every 8 to 12 hours to maintain mid-interval aPTT or factor Xa levels) or LMWH (therapeutic dose)
- Refractory cases: Up to 30% of patients have recurrent pregnancy loss despite the use of ASA and heparin. There is no role for warfarin due to risk of teratogenicity (early pregnancy) and fetal bleeding (late pregnancy). Such cases are best managed in consultation with a maternal-fetal medicine specialist.
SURGERY/OTHER PROCEDURES
Patients with thrombosis may require thrombectomy or an IVC filter (depending on site) when anticoagulation is contraindicated.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Standard guidelines for monitoring to maintain INR at goal with warfarin therapy
- Close monitoring is required during pregnancy.
DIET
Heart-healthy diet. Patients on warfarin should avoid foods rich in vitamin K (kale, spinach, sprouts, greens).
PATIENT EDUCATION
- Compliance with warfarin therapy to keep INR at goal
- Awareness of drug and diet interactions with warfarin
- Avoid oral hormonal contraceptives.
PROGNOSIS
- Pulmonary HTN, neurologic involvement, myocardial ischemia, nephropathy, gangrene of extremities, and catastrophic APS are associated with a worse prognosis.
- 30% risk of recurrent thrombosis in the absence of adequate anticoagulation
COMPLICATIONS
- Pregnancy complications and pulmonary HTN are associated with higher morbidity and mortality.
- Thrombotic complications are the most common cause of death.
REFERENCES
11 Giannakopoulos B, Passam F, Ioannou Y, et al. How we diagnose the antiphospholipid syndrome. Blood. 2009;113(5):985-994.22 Arachchillage DJ, Cohen H. Use of new oral anticoagulants in antiphospholipid syndrome. Curr Rheumatol Rep. 2013;15(6):331.33 Erkan D, Aguiar CL, Andrade D, et al. 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev. 2014;13(6):685-696.44 Statkute L, Traynor A, Oyama Y, et al. Antiphospholipid syndrome in patients with systemic lupus erythematosus treated by autologous hematopoietic stem cell transplantation. Blood. 2005;106:2700-2709.55 Cuadrado MJ, Bertolaccini ML, Seed PT, et al. Low-dose aspirin vs low-dose aspirin plus low-intensity warfarin in thromboprophylaxis: a prospective, multicentre, randomized, open, controlled trial in patients positive for antiphospholipid antibodies (ALIWAPAS). Rheumatology (Oxford). 2014;53(2):275-284.
ADDITIONAL READING
- Baker WFJr, Bick RL, Fareed J. Controversies and unresolved issues in antiphospholipid syndrome pathogenesis and management. Hematol Oncol Clin North Am. 2008;22(1):155-174.
- Bramham K, Thomas M, Nelson-Piercy C, et al. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood. 2011;117(25):6948-6951.
- Branch D, Holmgren C, Goldberg J. Practice bulletin no. 132: Antiphospholipid syndrome. Obstet Gynecol. 2012;120(6):1514-1521.
- Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295-306.
- Ruiz-Irastorza G, Crowther M, Branch W, et al. Antiphospholipid syndrome. Lancet. 2010;376(9751):1498-1509.
CODES
ICD10
- D68.61 Antiphospholipid syndrome
- D68.69 Other thrombophilia
- D68.62 Lupus anticoagulant syndrome
ICD9
- 289.81 Primary hypercoagulable state
- 289.82 Secondary hypercoagulable state
SNOMED
- 26843008 antiphospholipid syndrome (disorder)
- 239892009 Primary antiphospholipid syndrome
- 239895006 Secondary antiphospholipid syndrome
CLINICAL PEARLS
- APS can be either primary, secondary, or present as a severe microvascular disease known as CAPS.
- Both clinical and laboratory criteria are required for diagnosis. The latter must be confirmed on two separate occasions at least 12 weeks apart.
- Thrombotic manifestations of APS can be either venous or arterial. Patients require lifelong anticoagulation.