Antiphospholipid syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Feham Tariq, MD [2]

Overview

Antiphospholipid syndrome (APS) is an autoimmune disease in which antiphospholipid antibodies (anti-cardiolipin antibodies and lupus anticoagulant) react against proteins that bind to anionic phospholipids on plasma membranes. The syndrome can be divided into primary (no underlying disease state) and secondary (in association with an underlying disease state) forms.

Pathophysiology

The pathogenesis of antiphospholipid syndrome is as follows:

• It is a non-inflammatory autoimmune disease, in which antiphospholipid antibodies react against proteins that bind to anionic phospholipids on plasma membranes.
• APS is divided into two types based on the underlying cause.
  • Primary APS
  • Secondary APS

Primary APS

This type of APS has no other associated condition.

Secondary APS

The type of APS which occurs secondary to an underlying disease. The diseases associated with APS are as follows:

Autoimmune diseases	Infections	Drugs	Malignancy
Systemic lupus erythmatosus(SLE)	Bacterial infections: Leptospirosis Syphilis Lymes disease Tuberculosis Leprosy Infective endocarditis Post-streptococcal rheumatic fever Klebsiella infection Viral infections: Hepatitis A,B and C HIV Epstein Barr virus Adenovirus Rubella Parvovirus Cytomegalovirus Varicella Zoster virus Parasitic infections: Visceral leischmaniasis Pneumocysitis jiroveci Malaria	Chlorpromazine Procainamide Hydralazine Quinidine Quinine Phenytoin Alpha interferon Oral contraceptives Amoxicillin Chlorothiazide Propanolol	Tumors of the following organs can cause APS: Lung Colon Breast Cervix Ovary Cancers: Hodgkins lymphoma Non-hodgkins lymphoma Myeloid leukemia Lymphocytic leukemia Primary myelofibrosis Polycythemia vera

Types of antiphospholipid antibodies

The following antiphospholipid antibodies are found in the plasma of patients:

Antiphospholipid antibodies	Percentage
Anticardiolipin antibody	31%
Antilupus antibody	23-47%
Beta-2 glycoprotein	20%

Mechanism of action

The mechanism by which clinical manifestations occur in APS is mainly mediated by the antibodies which is as follows:

Vascular thrombosis

• Antiphospholipid antibody (aPL) affects the coagulation cascade.
• They have a procoagulant action on the following proteins and tissue factors in the plasma:
  • Protein C
  • Annexin V
  • Platelets
  • Serum proteases
  • Toll-like receptors
  • Tissue factor, and via impaired fibrinolysis
• The cumulative procoagulant effect of these, leads to vascular thrombosis.

Increased vascular tone:

Another effect of aPL is increased vascular tone which subsequently results in the following manifestations:

• Neurological abnormalities such as stroke and transient ischemic attack
• Fetal loss
• Atherosclerosis

Beta2-glycoprotein-I:

These antibodies have the following mechanism of action:

• They bind negatively charged phospholipids and inhibit contact activation of the clotting cascade and platelet activation.
• Anticardiolipin antibody

  • The antibody is directed against beta2-glycoprotein-I and cardiolipin, a phospholipid component of cell membranes, also used as an antigen in the assay for syphilis (why syphilis elicits an antibody response to cardiolipin is not clear).
  • Patients with anticardiolipin antibody are more likely to have arterial clots than those with lupus anticoagulant. These patients are also at increased risk for early coronary artery bypass graft (CABG) graft occlusion, premature coronary artery disease (CAD), and valvular heart disease.

• Lupus Anticoagulant

  • Lupus anticoagulant is a misnomer: it’s actually a pro-coagulant in vivo, and is often seen in patients without lupus. It usually (not always) elevates the lab reading of the partial thromboplastin time (PTT).
  • Lupus anticoagulant is also directed against the phospholipid membrane, and requires the cofactor prothrombin.

Catastrophic Antiphospholipid Antibody Syndrome (CAPS):

Classification criteria for CAPS is as follows:

Classification criteria for CAPS
Criteria
1. Evidence of involvement of three or more organs, systems, and/or tissues 2. Development of manifestations simultaneously or in less than a week 3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissue 4. Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, and/or anti-beta2-glycoprotein I antibodies)

• A subset of patients with antiphospholipid antibody syndrome develop a catastrophic illness characterized by progressive, severe arterial and venous thrombosis in multiple organs, often leading to death.
• Though specific diagnostic criteria have not been established, some have suggested that criteria include documented thrombosis in 3 or more organs.

  • Commonly involved organs include the central nervous system (CNS), kidney and distal extremities with acral necrosis. Hypertension is also commonly present, and may be malignant.

    • CNS manifestations may be quite heterogeneous, including confusion, focal signs, and/or seizures.
    • Acute Respiratory Distress Syndrome (ARDS) may be present
    • Signficant cardiac necrosis has been described
    • Adrenal hemorrhage has been described
    • Liver and gastrointestinal tract infarctions have been described
    • Oliguria and rapidly deteriorating renal function may be observed.

  • Histopathology shows evidence of multiple small and/or large vessel occlusions.

• Frequently no specific etiology is identifiable, and patients present quite suddenly without any obvious precipiting factors.

Genetic association

Antiphospholipid antibody syndrome is associated with the following genetic mutations:

• Factor V Leiden
• Prothrombin gene mutation
• Activated protein C resistance

Microscopic Pathology Findings

The histologic findings seen in APS are as follows: Histologic studies of skin or other involved tissues reveal the following:

• A noninflammatory bland thrombosis with no signs of perivascular inflammation or leukocytoclastic vasculitis.
• Biopsy samples from affected kidneys demonstrate glomerular and small arterial microthrombi.