Antiphospholipid syndrome

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

In the early 1980s, the term antiphospholipid syndrome was coined to describe a unique form of autoantibody-induced thrombophilia. In 1999, Sapporo classification criteria for APS was published. In 2006, the preliminary Sapporo criteria was revised with the inclusion of anti-β2 glycoprotein I (GPI) antibodies in the diagnostic criteria.

The historical perspective of antiphospholipid syndrome (APS) is as follows:^[1][2][3]

• In the early 1980s, the term antiphospholipid syndrome was coined to describe a unique form of autoantibody-induced thrombophilia, whose hallmarks are complications in pregnancy complications and recurrent thrombosis.
• In 1999, Sapporo classification criteria for APS were published in an international consensus statement in Sydney, Australia.

• In 2006, the preliminary Sapporo criteria was revised with the inclusion of anti-β2 glycoprotein I antibodies in the diagnostic criteria.

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

• Antiphospholipid syndrome (APS) can be divided into primary and secondary APS.

• Antiphospholipid syndrome (APS) can be divided into primary and secondary APS based on the underlying etiology. In primary APS, no underlying disease in associated with the syndrome. Whereas, secondary APS is associated with an underlying autoimmune disorder.

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

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. This syndrome can be classified into primary (no underlying disease state) and secondary (in association with an underlying disease state) types. The underlying mechanism of APS mediated by the antibodies is mainly mediated via their affect on the coagulation cascade which subsequenlty leads to increased vascular tone of thrombosis. CAPS is a subclass of APS that results in development of a catastrophic illness characterized by progressive, severe arterial and venous thrombosis in multiple organs, often leading to death.

The pathogenesis of antiphospholipid syndrome is as follows:^[1][2]

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

This type of APS has no other associated condition.

The type of APS which occurs secondary to an underlying disease. The diseases and conditions associated with APS are as follows:^[3][4][5]

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

The mechanism by which clinical manifestations occur in APS is mainly mediated by the antibodies which is as follows: ^{[9][10][11][12][13][14][15]}

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

These antibodies have the following mechanism of action:^{[16][17][18][18]}

• Anti-beta-2 glycoprotein I antibody enhances the anticoagulant function of protein S by interfering its binding to its inhibitor C4b binding protein.
• They bind negatively charged phospholipids and inhibit contact activation of the clotting cascade and platelet activation.
• Another mechanism by which antiphospholipid antibodies create a prothrombotic state is by developing acquired activated protein C resistance.

The underlying cellular mechanism involved in the pathogenesis of APS in as follows:^[19][20][21]

• Monocytes, platelets, endothelial cells and complement play an important role in induction of thrombosis and fetal death in antiphospholipid syndrome.
• APS antibodies such as anti-β2-glycoprotein-1 activate endothelial cells and monocytes.
• In turn, endothelial cells express the following adhesion molecules:
  • Intercellular cell adhesion molecule-1
  • Vascular cell adhesion molecule-1
  • E-selectin
• Both endothelial cells and monocytes upregulate the production of tissue factor which activates the coagulation pathway.
• Activated platelets increase expression of glycoprotein IIb/IIIa and synthesis of thromboxane A2.
• Nuclear factor κB (NFκB) and p38 mitogen-activated protein kinase (p38 MAPK) are important mediators of these three processes.
• Complement activation play a pivotal role in thrombosis and fetal loss induced by antiphospholipid antibodies.
• C3b fragments are deposited in the placentas of patients with antiphospholipid syndrome.

• Microparticles are found in the plasma of patients with APS in elevated levels.^[22][23]
• These are cell surface fragments released from the damaged, apoptotic and dying cells.
• They lead to cell activation and subsequently lead to a prothrombotic state in the plasma.

• CAPS is a subclass of APS that results in development of a catastrophic illness characterized by progressive, severe arterial and venous thrombosis in multiple organs, often leading to death.
• Classification criteria for CAPS is as follows:

• 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
  • Adrenal hemorrhage
  • Liver and gastrointestinal tract infarctions
  • Oliguria and rapidly deteriorating renal function.

Antiphospholipid antibody syndrome is associated with the following genetic mutations:^[24][25]

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

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

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

Antiphospholipid syndrome can occur idiopathic or due to autoimmune diseases, certain drugs, infections and malignancies.

Antiphospholipid syndrome can occur idiopathic or due to autoimmune diseases, certain drugs, infections and malignancies.

The causes of secondary antiphospholipid syndrome are as follows:

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

Antiphospholipid syndrome should be differentiated from conditions such as hemolytic uremic syndrome–thrombotic thrombocytopenic purpura (HUS-TTP), disseminated intravascular coagulation (DIC), paroxysmal nocturnal hemoglobinuria, SLE, HELLP syndrome and other myeloproliferative diseases.

• Hemolytic uremic syndrome–Thrombotic thrombocytopenic purpura (HUS-TTP)
• Disseminated Intravascular Coagulation (DIC)
• paroxysmal nocturnal hemoglobinuria
• SLE
• HELLP syndrome
• Myeloproliferative diseases

Abbreviations: ABG= Arterial blood gas, ANA= Antinuclear antibody, ANP= Atrial natriuretic peptide, ASO= Antistreptolysin O antibody, BNP= Brain natriuretic peptide, CBC= Complete blood count, COPD= Chronic obstructive pulmonary disease, CRP= C-reactive protein, CT= Computed tomography, CXR= Chest X-ray, DVT= Deep vein thrombosis, ESR= Erythrocyte sedimentation rate, HRCT= High Resolution CT, IgE= Immunoglobulin E, LDH= Lactate dehydrogenase, PCWP= Pulmonary capillary wedge pressure, PCR= Polymerase chain reaction, PFT= Pulmonary function test.

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

The incidence of antiphospholipid syndrome (APS) is approximately 5 cases per 100,000 persons per year. The prevalence of APS is approximately 40-50 cases per 100,000 persons worldwide. APS due to systemic lupus erythematosus (SLE) is more commonly seen in the African American and Hispanic population. Middle aged women are more commonly affected by APS than males.

The epidemiology and demographics of antiphospholipid syndrome is as follows:^[1][2][3][4]

• The incidence of antiphospholipid syndrome (APS) is approximately 5 cases per 100,000 persons per year.

• The prevalence of APS is approximately 40-50 cases per 100,000 persons worldwide.

• The case-fatality rate/mortality rate of catastrophic APS is approximately 50%.

• The commonly affected age groups are young to middle aged adolescents.
• However, APS is also seen in children and elderly age group.

• APS due to systemic lupus erythematosus (SLE) is more commonly seen in the African American and Hispanic population.

• Middle aged women are more commonly affected by APS than males.

• There is no particular regional predilection.

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

The most common risk factors of antiphospholipid syndrome risk factors are history of autoimmune diseases like SLE, sjogren’s syndrome, infections- cytomegalovirus, human immunodeficiency virus, parvovirus B-19, hepatitis C virus, lyme’s disease, syphilis, E.coli, leptospirosis, medications such as hydralazine, quinidine, phenytoin, and amoxicillin, family history- antiphospholipid syndrome is common in patients with a family history of antiphospholipid syndrome.

The risk factors associated with antiphospholipid syndrome(APS) are as follows:^{[1][2][3][4][5]}

Common risk factors

• History of autoimmune disease:
  • SLE
  • Sjogren’s syndrome

• Infections:
  • Cytomegalovirus
  • Human Immunodeficiency Virus
  • Parvovirus B-19
  • Hepatitis C Virus
  • Lymes disease
  • Syphilis
  • E.coli
  • Leptospirosis.

• Drugs:
  • Hydralazine
  • Quinidine
  • Phenytoin
  • Amoxicillin
• Family history: Antiphospholipid syndrome is common in patients with a family history of antiphospholipid syndrome.

Less common risk factors:

• Pregnancy
• Obesity
• Hypertension
• Sedentary lifestyle
• Recent surgery
• Tobacco Smoking
• Oral contraceptives
• Estrogen therapy
• Hyperlipidemias
• Cancer

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

If left untreated, 90% of patients with antiphospholipid syndrome (APS) progress to develop recurrent thrombotic or thromboembolic events such as pulmonary embolism, Stroke, Transient ischemic attack, Deep vein thrombosis. The complications caused by APS are mainly thrombotic, neurological, obstetrical, pulmonary and ocular. APS is associated with increased morbidity and mortality. The mean age of death is 59 years.

• If left untreated, 90% of patients with antiphospholipid syndrome (APS) progress to develop recurrent thrombotic or thromboembolic events which include:
  • Pulmonary embolism
  • Stroke
  • Transient ischemic attack
  • Deep vein thrombosis
• Other patients can develop thrombocytopenia, livedo reticularis, skin ulcers, microangiopathic hemolytic anemia (MAHA).
• Obstetrical complications include premature birth, early pregnancy loss and intrauterine growth restriction.

The complications of APS are described in a systemic order which are as follows:^{[1][2][3][4][5][6][7]}

Thrombotic complications:

Thrombotic events are the hallmark of APS. They are as follows:

• Venous thrombosis is more common than arterial thrombosis. The major sites of involvement are pulmonary, pelvic, renal, hepatic, portal, axillary, subclavian, ocular, and cerebral sinuses, as well as the inferior vena cava.

Neurological complications:

Following complications are seen on neurological exam:

• Stroke
• Transient ischemic attack

Obstetrical complications:

The pregnancy related complications are as follows:

• Maternal thrombosis
• Fetal loss
• Pre-eclampsia
• Placental insufficiency
• Fetal growth restriction
• Iatrogenic preterm birth

Pulmonary complications:

Thromboembolic and non-thromboembolic complications include:

• • Diffuse alveolar hemorrhage
  • Pulmonary arterial hypertension
  • Acute respiratory distress syndrome (ARDS)
  • Pulmonary micrthrombosis

Hematological complications:

• • Autoimmune hemolytic anemia
  • Thrombocytopenia
  • Bone marrow necrosis

Cardiac involvement:

• • Valvular thickening and valve nodules also called as Libmann-Sacks endocarditis.
  • Coronary artery disease

Adrenal involvement:

• Hemorrhagic infarction of the adrenals

Ocular manifestations:

The ocular manifestations are the following:

• Anterior ischemic optic neuropathy
• Amaurosis fugax
• Retinal venous occlusion

Gastrointestinal complications:

Ischemia of the gastrointestinal tract leads to the following complications:

• Gastrointestinal bleeding
• Abdominal pain
• Esophageal necrosis with perforation
• Duodenal ulcer

The prognosis of antiphospholipid syndrome is as follows:^[8][9]

• It is associated with increased mortality and morbidity.
• The mean age of death is 59 years.
• Main causes of death in the order of percentage include the following:
  • Thrombosis (31%)
  • Sepsis (27%)
  • Malignancy (14%)
  • Hemorrhage (11%)
  • Systemic lupus erythematosus involvement (8%)
  • Catastrophic APS