Antiphospholipid Syndrome

Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations of APLS. Patients with APLS are at risk for both arterial and venous thrombosis, and after a thrombotic event, patients are managed with long-term anticoagulation therapy.

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Overview

Definition

Antiphospholipid syndrome (APLS) is an autoimmune phenomenon that presents with thrombotic events and/or adverse pregnancy outcomes related to the presence of persistent antiphospholipid antibodies (aPL), which produce a hypercoagulable state. 

  • aPL: autoantibodies directed against phospholipid-binding proteins
  • Primary APLS: APLS occurring due to isolated aPLs
  • Secondary APLS: APLS occurring in the setting of underlying systemic autoimmune disease

Epidemiology

In the United States:

  • Incidence: approximately 5 cases per 100,000 persons per year
  • Prevalence: approximately 50 cases per 100,000 persons
  • Typical age affected: young to middle-aged adults
  • Gender bias: females > males
  • Associated with aPL are:
    • 6%–9% of pregnancy losses (50,000 annually)
    • 14% of strokes (110,000 annually)
    • 11% of myocardial infarctions (100,000 annually)
    • 10% of deep vein thrombosis (30,000 annually)

Classification

Patients with APLS are classified based on their clinical manifestations.

Table: Classification of APLS
ClassificationPatients present with:
Thrombotic APLSArterial or venous thrombosis
Obstetric APLSObstetric complications:
  • Recurrent pregnancy loss
  • Preterm birth associated with placental insufficiency
Catastrophic APLSLife-threatening thromboembolic events resulting in multiple end-organ damage (usually microvascular disease with acute onset)

Etiology and Pathophysiology

The prothrombotic state of APLS is related to the presence of aPL.

Etiology

  • Primary (50%):
    • Genetic predisposition to develop antibodies
    • Due to mutations in HLA-D7, DR4, DQw7, and/or C4 
  • Secondary (50%):
    • Systemic lupus erythematosus (SLE) (most common, 35%)
    • Rheumatoid arthritis (RA)
    • Sjögren syndrome (SS)
    • Immune thrombocytopenic purpura (ITP)
    • HIV
    • Hepatitis C virus (HCV)

Pathophysiology

  • Antibodies against phospholipid-binding proteins: 
    • Anticardiolipin
    • Anti-β2-glycoprotein I 
    • Lupus anticoagulant
  • Antibodies result in:
    • Activation of inflammatory cells, endothelial cells, and platelets, promoting thrombosis
    • Inactivation of anticoagulant factors (proteins C and S), promoting thrombosis
    • Increased complement activity toward the trophoblasts, resulting in recurrent pregnancy loss
  • Transient aPL are common, especially following an acute illness.
    • Diagnosis of APLS requires persistence of the antibodies.

Clinical Presentation

Antiphospholipid syndrome tends to present in young to middle-aged women with either thromboembolic events and/or pregnancy complications. Other autoimmune conditions may be present.

Thromboembolic presentations

  • Deep vein thrombosis (DVT):
    • DVTs of the lower extremities (most common DVTs):
      • Unilateral swelling and/or pain in the extremity
      • Pain with dorsiflexion of the foot
    • DVTs of the upper extremities
    • Pulmonary embolism (PE):
      • Dyspnea
      • Acute respiratory distress
      • Pulmonary hypertension
    • Cerebral sinus thrombosis
    • Hepatic and portal vein thrombosis
    • Renal vein thrombosis
    • Adrenal vein thrombosis
  • Superficial vein thrombosis
  • Arterial thrombosis:
    • Stroke (most common arterial thrombosis) and transient ischemic attacks (TIAs):
      • Focal neurologic findings
      • Cognitive deficits
    • MI:
      • Chest pain
      • Dyspnea on exertion
    • Retinal thrombosis
    • Nephropathy due to vaso-occlusion in the small renal vessels:
      • Renal failure
      • Proteinuria
      • Hypertension
  • Recurrent thromboembolic events

Obstetric presentations

  • Recurrent miscarriages
  • Preterm delivery of an anatomically normal infant < 34 weeks gestation due to either:
    • Severe preeclampsia or eclampsia
    • Features consistent with placental insufficiency:
      • Oligohydramnios (low amniotic fluid)
      • Low birth weight
      • Non-reassuring or abnormal fetal surveillance testing (e.g., non-stress tests, biophysical profile, Doppler studies)

Other findings

Some additional findings may include:

  • Hematologic findings:
    • Thrombocytopenia
    • Autoimmune hemolytic anemia (AIHA)
    • Thrombotic microangiopathic anemia
  • Cardiac findings: if present, almost always involve the valves
    • Murmurs on exam:
      • Most commonly involve the mitral and aortic valves
      • May lead to regurgitation, and less commonly stenosis
    • Thickening of the valve leaflets
    • Nodules/non-bacterial vegetations (Libman-Sacks endocarditis)
  • Dermatologic findings:
    • Livedo reticularis: a red-blue netlike, reticulated pattern occurring due to compromised blood flow in medium-sized vessels
    • Ulceration and/or gangrene of the digits
    • Splinter hemorrhages
  • Rheumatologic findings: consistent with an associated rheumatologic disorder
    • Rashes
    • Arthralgias
    • Fatigue
Livedo reticularis

Livedo reticularis

Image: “Livedo reticularis in a patient with DADA2” by Roberta Caorsi et al. License: CC BY 4.0

Diagnosis

Diagnostic criteria

To meet the diagnostic criteria for APLS, a patient must meet both clinical and laboratory criteria.

Table: Diagnostic criteria for APLS
CriteriaEvents which satisfy the criteria
Clinical criteriaNeed to have a history of at least one of the following:
  • Vascular thrombosis:
    • ≥ 1 deep vein, arterial, or small vessel thrombosis in any organ or tissue
    • Superficial venous thrombosis does not satisfy this criteria.
  • Pregnancy morbidity:
    • ≥ 3 consecutive, spontaneous pregnancy losses at < 10 weeks gestational age (WGA)
    • ≥ 1 pregnancy loss of a morphologically normal fetus at ≥ 10 WGA
    • ≥ 1 premature delivery at < 34 WGA due to severe preeclampsia/eclampsia, or placental insufficiency
Laboratory criteriaNeed at least one positive antibody finding, on at least 2 separate occasions, at least 12 weeks apart:
  • Lupus anticoagulant (positive = present)
  • Anti-cardiolipin antibodies (positive = ↑ IgG and/or IgM titers)
  • β2-glycoprotein-I antibodies (positive = ↑ IgG and/or IgM titers)

Laboratory assessment

  • Serologies and titer levels for aPL: 
    • Anticardiolipin antibodies:
      • Note: Anticardiolipin antibodies can result in a false positive test for syphilis because they react with the cardiolipin reagent in the rapid plasma reagin test.
    • Anti-β2-glycoprotein I antibodies
    • Lupus anticoagulant:
      • Note: Despite being called an “anticoagulant,” this factor is actually prothrombotic.
      • Its name comes from the fact that it functions as an anticoagulant in some lab tests.
  • CBC and coagulation studies may show:
    • Anemia (hemolytic, microangiopathic)
    • Thrombocytopenia (platelets are consumed in procoagulant states)
    • Prolonged aPTT (due to Lupus anticoagulant)
  • Complement studies: may show complement levels (e.g., C3 or C4), can be observed in both primary and secondary APLS

Other assessments

Other testing may be clinically indicated based on presentation. For example:

  • Imaging:
    • Doppler studies for a suspected DVT
    • CT for a suspected stroke
  • ECG for suspected MI
  • Thrombophilia workup (e.g., if only presenting symptom is an unprovoked DVT)
  • Rheumatologic workup (e.g., if patient has findings consistent with SLE)

Management

Management of acute thrombosis in APLS

The mainstay of therapy for both primary and secondary (i.e., associated with SLE) APLS is anticoagulation.

  • Thrombotic and obstetric APLS:
    • Initiate anticoagulation with heparin overlapped with warfarin. 
    • Low-molecular-weight heparins (LMWHs) are typically the drug of choice.
    • Heparins are continued until the INR is in the therapeutic range for 2 consecutive days. 
    • Heparins can then be discontinued, while warfarin is continued indefinitely for ongoing prophylaxis.
  • Catastrophic APLS: 
    • Anticoagulation
    • IV glucocorticoids
    • Plasmapheresis
    • IV immunoglobulins (IVIG)
  • Arterial thrombosis (e.g., MI, stroke): managed the same as patients without APLS

Prevention of thrombosis

  • Smoking cessation
  • Avoiding estrogen-containing contraceptives
  • Managing hyperlipidemia/hypertension
  • For patients who have never had a thrombotic event (i.e., primary prevention): 
    • Consider low-dose aspirin (evidence is limited; consider entire clinical picture).
    • Optimize modifiable risk factors.
  • For patients with a history of thrombosis:
    • In patients who do not desire pregnancy: warfarin therapy
    • In patients who do desire pregnancy: LMWH and aspirin (warfarin is teratogenic)
  • For patients with aPL but who do not meet diagnostic criteria for APLS, antithrombotic medication is not recommended.

Other management points

  • Immunomodulatory agents:
    • May be considered in some patients with:
      • Recurrent thrombosis despite adequate anticoagulation
      • Hematologic manifestations (e.g., thrombocytopenia or thrombotic microangiopathies)
    • Limited evidence to guide use, though theoretically helpful because APLS is an autoimmune disease
    • Agents to consider: hydroxychloroquine, rituximab
  • Thrombocytopenia:
    • Many patients with APLS have mild thrombocytopenia.
    • Cause of the thrombocytopenia should still be investigated.
    • Anticoagulation should be continued while the platelet count is > 50,000/µL. 
  • Screening ECGs: 
    • Despite an increased risk for cardiac valvulopathies, routine ECGs are generally not recommended.
    • ECGs should be performed for new murmurs or symptoms.

Clinical Relevance

Differential diagnosis for recurrent thrombosis

Hypercoagulable states: hypercoagulable states or thrombophilias are defined by an increased risk of clot formation or thrombosis. The cause may be inherited or acquired; both lead to the production of clots that may cause occlusion of vessels in major organs, which can be fatal. Factor V Leiden is the most common inherited cause. Management usually involves the use of anticoagulants.

Table: Causes of a hypercoagulable state
TypeDiseaseDescription
Primary or inheritedFactor V Leiden
  • Autosomal dominant with incomplete penetrance
  • Most common inherited thrombophilia in caucasians
  • Caused by a point mutation substituting guanine for adenine
  • Results in resistance to factor V degradation by protein C
Prothrombin 20210A or factor II mutations
  • Autosomal dominant
  • 2nd most common inherited thrombophilia
  • Point mutation leads to ↑ prothrombin function.
Antithrombin deficiency
  • Autosomal dominant (or can be acquired)
  • Antithrombin normally inhibits thrombin and factor Xa.
  • Antithrombin deficiency leads to:
    • ↑ Thrombin and factor Xa
    • Resistance to LMWH
Protein C or S deficiency
  • Proteins C and S are vitamin K-dependent anticoagulants.
  • Deficiencies result in overactivity of factors V and VIII.
Secondary or acquiredVenous stasis
  • Immobility (cast, stroke patients, post-knee surgery, long flights)
  • Varicose veins
  • Hyperviscosity (e.g., polycythemia vera)
Endothelial injury
  • Malignancy
  • Vasculitis
  • Instrumentation
Acquired hypercoagulability
  • Oral contraceptive pills
  • Antiphospholipid syndrome
  • Nephrotic syndrome
  • Paroxysmal nocturnal hemoglobinuria
  • Inflammatory bowel disease

Common presentations of recurrent thrombosis

  • Deep vein thrombosis (DVT): thrombosis of the deep venous systems found in the lower limb. The condition is a clinical manifestation of hypercoagulable states and requires management acutely to prevent the development of pulmonary emboli. Diagnosis is typically made using Doppler ultrasonography. The condition is treated with anticoagulants.
  • Pulmonary embolism (PE): a medical emergency in which an embolus will block the pulmonary trunk/artery, resulting in acute shortness of breath and impaired ventilation/perfusion. About 30% of these patients have a concurrent DVT. Diagnosis can be made on a CT pulmonary angiography (CTPA) scan and/or a V/Q. Patients are treated with anticoagulants.

References

  1. Urkan, D, Ortel, T. (2020). Clinical manifestations of antiphospholipid syndrome. Viewed Retrieved Apr 18, 2021, from https://www.uptodate.com/contents/clinical-manifestations-of-antiphospholipid-syndrome
  2. Urkan, D, Ortel, T. (2020). Diagnosis of antiphospholipid syndrome. Retrieved Apr 18, 2021, fromhttps://www.uptodate.com/contents/diagnosis-of-antiphospholipid-syndrome 
  3. Urkan, D, Ortel, T. (2020). Treatment of antiphospholipid syndrome. Retrieved Apr 18, 2021, from https://www.uptodate.com/contents/treatment-of-antiphospholipid-syndrome
  4. Bustamante, J. (2020). Antiphospholipid syndrome. In Singhal, M. (Ed.) StatPearls. Retrieved April 23, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/17705/ 
  5. Movva, S. (2020). Antiphospholipid syndrome. In Diamond, H. (Ed.) Medscape. Retrieved April 23, 2021, from https://emedicine.medscape.com/article/333221-overview

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