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Antiphospholipid Syndrome - A Rare Multisystem Autoimmune Disorder

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Antiphospholipid syndrome is a rare multisystem autoimmune disorder in which autoantibody reactions lead to recurring blood clots in the vessels.

Medically reviewed by

Dr. Kaushal Bhavsar

Published At January 18, 2023
Reviewed AtMay 24, 2023

Introduction

Antiphospholipid syndrome (APLS), also known as Hughes syndrome or Lupus-anticoagulant syndrome, is a rare autoimmune thrombo-inflammatory disorder in which the body misinterprets the phospholipid-binding proteins as foreign antigens and antibody reactions are directed against it leading to recurring clots within the blood vessels. The most commonly affected regions are the lower limb and cranial vessels.

Who Are More Susceptible to Antiphospholipid Syndrome?

Antiphospholipid syndrome is found in about 1 in 20,000 individuals and is currently estimated to be the causative agent of 1% of all thromboses. About 50% of individuals below the age of 50 years presenting with a history of stroke are positive for APLS. 10 to 15 % of SLE (systemic lupus erythematosus) cases present with antiphospholipid syndrome. More than 70% of all recorded antiphospholipid syndrome cases are females presenting a probable female predilection. 10 to 15 % of females who have had multiple miscarriages tend to have antiphospholipid syndrome. Antiphospholipid syndrome is a secondary manifestation of other autoimmune syndromes in about 40% of cases.

What Are the Types of Antiphospholipid Syndrome?

Antiphospholipid syndrome is classified into three types:

  1. Primary antiphospholipid syndrome.

  2. Secondary antiphospholipid syndrome.

  3. Catastrophic antiphospholipid syndrome.

What Causes Antiphospholipid Syndrome?

Antiphospholipid syndrome can be a primary disorder or a secondary manifestation of autoimmune diseases. The condition is caused due to the formation of antiphospholipid antibodies (APLA) against the phospholipid proteins, namely lupus anticoagulant, anticardiolipin, and anti-B2 glycoprotein I. The patient may test positive for antibodies against one or more of these phospholipids. Genetic mutations to coagulation factors pose a risk for APLS. APLS has been observed to have a close association with several null alleles, namely HLA-DR7, DR4, DRw53, DQw7, and C4.

Infections from Borrelia burgdorferi, treponema, HIV (human immunodeficiency virus), and leptospira have been indicated as causative agents of APLS. Certain drugs like Chlorpromazine, Procainamide, Quinidine, and Phenytoin can also trigger APLS.

What Is the Pathophysiology of Antiphospholipid Syndrome?

It is observed that even though antiphospholipid antibodies (APLA) are the most important factors associated with venous thrombosis (clot in the veins), myocardial infarction (heart attack due to coronary artery blockage), and ischemic stroke (brain stroke due to deficient blood supply), not all patients with positive antibodies develop APLS.

Antibody profile (both type and titer) along with underlying comorbidities contribute as risk factors to APLS. Triple positive antibody results against all three associated antigen proteins are the major risk factor, while a single positive report for anticardiolipin or anti-beta-2-glycoprotein I antibodies poses a low risk of pathology. Other risk factors include patients with SLE, cardiovascular diseases, a history of recurrent thrombosis even under anticoagulant therapy, or a history of arterial thrombosis.

A “two-hit” process is hypothesized to explain thrombus formation in APLS patients where the first hit refers to an uneventful primary injury to the epithelium, and the second hit triggers the thrombus formation.

Another theory postulates that in the absence of any endothelial injury, a redox balance disturbance in the vascular beds makes the endothelium vulnerable to thrombosis. This theory is based on the study that patients with APLS often present with a decline in levels of non-immunogenic beta-2 glycoprotein I and upregulated endothelial cell surface receptor-Annexin A2 levels. Smokers with positive lupus anticoagulants present with significant endothelial injury and increased pro-thrombotic susceptibility.

There is a marked decrease in plasma nitrate levels in APLS patients. This is due to anti-beta-2-glycoprotein I antibodies, which antagonize the endothelial nitric oxide synthase enzyme, which then forms peroxynitrites and superoxides. These byproducts result in monocyte adhesion and inhibition of nitric oxide-dependent arterial relaxation.

Autoantibodies disrupt the mitochondrial function of neutrophils and monocytes and increase ROS (reactive oxygen species) levels. When anti-beta two glycoprotein-I autoantibodies bind to the monocytes' surface and endothelial cells' multiprotein complexes, they activate the tissue factors’ expression by intracellular signaling pathways, which then results in the activation of coagulation. APLA also induces thrombosis by complement activation and inhibition of fibrinolysis.

Miscarriage in pregnant women is provoked due to intraplacental thrombosis, complement pathway activation, interference with trophoblast growth and differentiation, impaired trophoblastic invasion, and hormone production.

What Is the Histopathology of Antiphospholipid Syndrome?

A tissue sample obtained from the biopsy of the kidney reveals thrombotic microangiopathy.

Skin biopsy results are often non-specific but may show occlusive vasculopathy without significant vasculitis.

What Are the Signs and Symptoms of Antiphospholipid Syndrome?

The symptoms of Antiphospholipid syndrome may vary from asymptomatic to catastrophic with or without the involvement of multiple organ systems.

Vascular Thrombosis:

  • Arterial or venous thrombosis in any organ system.

  • Recurrent thrombosis in non-thrombotic vessels like upper extremity thrombosis, Budd-Chiari syndrome, and sagittal sinus thrombosis.

  • Venous thrombosis is most common in the lower extremities and may lead to pulmonary embolism and pulmonary hypertension.

  • Other sites of venous thrombosis are pelvic, renal, mesenteric, hepatic, portal, axillary, ocular, sagittal, and inferior vena cava.

  • Arterial thrombosis is caused in organs of all sizes.

  • The most common arterial event is transient ischemic events in young individuals without evident atherosclerosis.

  • Other sites of arterial thrombosis are retinal, brachial, coronary, mesenteric, and peripheral arteries.

  • Arterial thrombosis has poor prognostic value owing to high recurrences.

Pregnancy Morbidity:

  • Miscarriage is very common in APLS mothers, often in the second or third trimester.

  • APLS is also a reason for early pregnancy loss (less than ten weeks of gestation) besides genetic and chromosomal abnormalities.

  • Pregnancy-related outcomes and miscarriages are influenced by triple positivity reports, previous miscarriages, history of thrombosis, and SLE (systemic lupus erythematosus).

  • Pre-eclampsia (very high blood pressure during pregnancy) and fetal distress.

  • Early birth, fetal growth retardation, placental insufficiency.

  • HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count).

Cutaneous Manifestations:

  • Mottled skin in a net pattern (livedo reticularis) is evident (also in several autoimmune diseases).

  • Skin ulcerations in lower extremities, in variable sizes, resembling pyoderma gangrenosum, are observed.

  • Other cutaneous manifestations of APLS are nail-fold infarcts, digital gangrene (death of tissue in the digits), superficial thrombophlebitis (blood clot in the superficial veins), and necrotizing purpura (skin bleeds and dies rapidly).

Cardiac Manifestations:

  • Cardiac involvement is seen in about 80 % of APLS patients.

  • Echocardiography (ECG) shows thickening, nodules, and vegetation on the mitral and aortic valves, which may lead to regurgitation and/or stenosis.

Hematological Manifestations:

  • In about 15% of APLS patients, thrombocytopenia is seen, but severe thrombocytopenia-induced bleeding is rare.

  • Positive Coombs test.

Neurological Manifestations:

  • Cognitive dysfunction, seizures, and multi-infarct dementia secondary to ischaemic stroke.

  • Blindness is secondary to the retinal artery or vein thrombosis.

  • Sudden deafness, secondary to sensorineural hearing loss.

Pulmonary Manifestations:

  • Pulmonary artery thromboembolism results in deep vein thrombosis and may lead to pulmonary hypertension.

  • Diffuse pulmonary hemorrhage (bleeding into the lungs' alveolar spaces) results from pulmonary capillaritis.

Renal Manifestations:

  • Thrombotic microangiopathy (blood cell destruction and formation of small clots in the small vessels) in the kidney results in hypertension, proteinuria, and renal failure.

  • Renal artery thrombosis (blood clot in the vessel supplying the kidneys) leads to refractory hypertension, fibrous intimal hyperplasia (increase in cell population within the artery wall), and focal cortical atrophy (loss of neurons).

What Is Catastrophic Antiphospholipid Syndrome?

Catastrophic antiphospholipid syndrome (CAPS) is a rare variant of antiphospholipid syndrome occurring in less than 1% of APLS patients. Patients presenting with CAPS with predisposing SLE, cardiac, pulmonary, renal, or splenic involvement report a high mortality rate of over 48 %. It is characterized by the development of multiple thromboses in medium and small-sized arteries in a very short time.

The diagnosis of CAPS is based on the fulfillment of all four criteria:

  1. Involvement of three or more organs.

  2. Development of symptoms in less than a week.

  3. Small vessel occlusion was observed histopathologically in at least one organ.

  4. Laboratory confirmation of APLAs.

How to Diagnose Antiphospholipid Syndrome?

In addition to clinical manifestations, laboratory findings are essential to confirm an APLS diagnosis. Therefore, the antibody test should be repeated after 12 weeks after the first positive report. Two separate positive reports within 12 weeks or more than five years apart give a questionable diagnosis.

  • Lupus Anticoagulant Test: This test is instrumental in detecting pregnancy-related complications associated with APLS. Around 20% of APLS patients return a positive lupus anticoagulant test indicating the presence of anticardiolipin antibodies. 80% of those positive reported patients carry anticardiolipin antibodies.

  • Anticardiolipin and Anti-beta-2-glycoprotein I Antibodies: These antibodies are isolated through ELISA (enzyme-linked immunosorbent assay). Antibody titers of more than 40 GPL (immunoglobulin G phospholipid) units are associated with thrombotic events.

  • Other Laboratory Studies: Thrombocytopenia or anemia in CBC (complete blood count), ANA (antinuclear antibody), anti-Ds-DNA (anti-double-stranded DNA (deoxyribonucleic acid)), and Anti-smith in serological studies.

Hyperhomocysteinemia, factor V Leiden and prothrombin mutations, deficiency of protein C, protein S, or antithrombin III tests should also be ordered where indicated.

How to Manage Antiphospholipid Syndrome?

The treatment of antiphospholipid syndrome is primarily based on managing thrombosis and preventing pregnancy-related complications.

1. Preventing Thrombosis: Primary thromboprophylaxis in patients with recurrent clotting, Hydroxychloroquine or low dose Aspirin to patients with underlying SLE, Warfarin with or without Aspirin is given to patients with a history of thrombosis. Newer anticoagulant drugs have not been clinically tested, but they can be used in case of Warfarin allergy.

2. Pregnancy Management: Warfarin is teratogenic, so low-molecular-weight-heparin and unfractionated Heparin, along with Aspirin, are prescribed based on the history of pregnancy and miscarriage of the mother.

3. CAPS Management: Anticoagulation and high-dose corticosteroids are used in combination with IVIG (intravenous immunoglobulin), plasmapheresis (plasma from blood to removing antibodies and then replacing them back into the bloodstream), Rituximab, Cyclophosphamide, or Eculizumab to manage CAPS. Early diagnosis is critical to CAPS management due to the high mortality rate.

4. Management of Other Manifestations:

  • Corticosteroids with or without IVIG or Rituximab to manage thrombocytopenia.

  • Splenectomy may be indicated in refractory thrombocytopenia.

  • Anticoagulation and corticosteroids are prescribed against thrombotic microangiopathy.

  • In any evidence of embolism or intracardiac thrombus, anticoagulation is recommended.

What Is the Differential Diagnosis of Antiphospholipid Syndrome?

  • Hyperhomocysteinemia (abnormally high homocysteine in blood).

  • Mutations leading to factor V Leiden and prothrombin variations.

  • Deficient protein C.

  • Deficient protein S.

  • Antithrombin III deficiency (blood clotting problem).

  • Thrombotic thrombocytopenic purpura (decreased platelet count and causing blood clots).

  • Vasculitis (inflammation of the blood vessels).

  • Hemolytic uremic syndrome (damage and inflammation of small renal vessels).

  • Malignant hypertension (rapidly developing high blood pressure).

  • Lupus nephritis (lupus autoantibodies affecting the nephrons).

What Is the Prognosis of Antiphospholipid Syndrome?

In some places, survival rates of over 90% are observed over a ten-year period. Still, APLS has reported high mortality, with 20% of patients developing permanent disability and 30% developing some kind of permanent organ damage. A worse prognosis can be expected in the presence of conditions like CAPS, pulmonary hypertension, nephropathy, CNS involvement, and gangrene of the extremities.

The secondary antiphospholipid syndrome has a higher mortality rate even though both variants carry an equally poor prognosis. Lupus patients with APLS carry a higher risk of neuropsychiatric disorders.

What Are the Complications of Antiphospholipid Syndrome?

  • Fetal loss.

  • Stroke.

  • Pulmonary embolism.

  • Pulmonary hypertension.

  • Valvular abnormality (abnormality of heart valves).

  • Acute coronary syndrome (sudden, reduced blood flow to the heart).

  • Mesenteric thrombosis (blood clot within the vessels supplying the intestines).

  • Hepatic venous-occlusive disease (blockage in the veins of the liver).

  • Perioperative complications (problems after surgery).

Conclusion

Antiphospholipid syndrome is managed by an interdisciplinary team, ideally with an early diagnosis. A team of hematologists, rheumatologists, neurologists, gynecologists, nephrologists, cardiologists, and dermatologists plays a crucial role in the diagnosis, management, and follow-up care. Although the condition is not treatable, the symptoms can be managed. The prime focus is to delay the severity and avoid any pregnancy-related complications.

Dr. Kaushal Bhavsar
Dr. Kaushal Bhavsar

Pulmonology (Asthma Doctors)

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