Antiphospholipid syndrome

In antiphospholipid syndrome, individuals produce antiphospholipid antibodies, which attack the phospholipids in the cell membrane of their own cells, or attack proteins that are bound to those phospholipids.

So antiphospholipid syndrome, or APS, is an autoimmune disease.

Antiphospholipid syndrome can be primary or secondary. Primary antiphospholipid syndrome occurs by itself, whereas secondary antiphospholipid syndrome occurs with other autoimmune diseases, especially systemic lupus erythematosus.

And just like most autoimmune diseases, antiphospholipid syndrome is more common in young females.

The exact cause of antiphospholipid syndrome isn’t known, but there are some known genetic and environmental factors.

For instance, the HLA-DR7 gene encodes a specific type of a protein called major histocompatibility complex or MHC class II, which sits on the surface of the B cell.

These surface proteins help activate B cells so that they can start producing antibodies.

Now, having a mutated HLA-DR7 gene predisposes individuals to activate B cell production of antiphospholipid antibodies.

But the presence of the mutated HLA-DR7 gene alone isn’t enough to develop antiphospholipid syndrome - an environmental trigger must also be present.

There’s a variety of potential triggers - some common ones include infections - like syphilis, hepatitis C, HIV, and malaria - drugs, like some cardiovascular drugs - including procainamide, quinidine, propranolol, and hydralazine - or antipsychotic drugs like phenytoin and chlorpromazine.

The main antiphospholipid antibody is anti-beta2-glycoprotein I, which targets the protein beta2-glycoprotein I, also called apolipoprotein H.

This protein binds to phospholipids and inhibits agglutination which is when platelets clump together to form blood clots.

So when anti-beta2-glycoprotein I binds beta2-glycoprotein I, it’s not free to do its job, and that leads to clot formation.

Another antiphospholipid antibody is anti-cardiolipin, which targets a lipid in the inner mitochondrial membrane called cardiolipin which binds beta2-glycoprotein I.

Anti-cardiolipin antibodies are also present in syphilis, and that can cause a false-positive test for syphilis.

Autoantibodies might also target blood components.

If platelets are targeted, it can lead to thrombocytopenia, and if red blood cells are targeted it can lead to anemia.

So the antiphospholipid antibodies lead to a hypercoagulable state, meaning that they cause thrombosis or blood clots to form within arteries and veins.

Arterial thrombosis is more common in males, and can cause a heart attack, stroke, or limb ischemia.

In addition, individuals might develop Libman-Sacks endocarditis, which is where vegetations form, which are a mixture of immune cells and blood clots - usually on the mitral valve.

Venous thrombosis is more common in females, and typically presents as a deep vein thrombosis.

Sometimes, a part of the main clot may break free and become an embolus, which is where a blood clot travels downstream.

Since lung capillaries are very small, this embolus could get stuck, causing a pulmonary embolism.

This is a life-threatening situation because it literally blocks blood from getting into the lungs to pick up oxygen.

Another organ with very small capillaries is the kidneys, so individuals might develop renal failure.

A typical skin finding in antiphospholipid syndrome is livedo reticularis, which is caused by swelling of the venules due to clots obstructing them, and appears as a mottled purplish discoloration of the skin.

Women affected by antiphospholipid syndrome tend to have pregnancy-related complications that can lead to a miscarriage.

This can occur due to thrombosis leading to placental infarction.

For reasons that aren’t completely understood, antiphospholipid antibodies are thought to cause neurologic symptoms like headaches and seizures.

In rare cases, antiphospholipid syndrome leads to rapid organ failure due to generalized thrombosis; this is called catastrophic antiphospholipid syndrome and can lead to death.

Diagnosing antiphospholipid syndrome requires meeting at least one clinical and one laboratory diagnostic criteria.

The two clinical criteria are history of thrombosis, and pregnancy complications.

While the three laboratory criteria are presence of anticardiolipin, anti-beta2 glycoprotein antibodies, or lupus anticoagulant in the blood.

Now, lupus anticoagulant assay is a funny name, but it has an explanation.

It’s called “lupus” because it was initially found in people affected by systemic lupus erythematosus.

And it’s called “anticoagulant,” because it acts as an anticoagulant in vitro, even though it’s a procoagulant in vivo.

This is because phospholipid-rich platelets, which are only found in vivo, are needed to activate coagulation factors and cause a clot.

In vitro, which is tested using the lupus anticoagulant assay, the individual’s plasma is mixed with normal pooled plasma and clotting time is assessed.

The pooled plasma doesn’t have many phospholipid-rich platelets, so individuals with antiphospholipid antibodies end up prolonging the clotting time.

In vivo, there are plenty of phospholipid-rich platelets around, so the effect is excess clotting.

Treatment of antiphospholipid syndrome is aimed at preventing thrombosis with aspirin to inhibit platelet activation, and avoiding risk factors, like smoking and oral contraceptives.

People that have had a blood clot should also take warfarin as oral anticoagulant therapy.

During pregnancy, warfarin can cross the placenta and have a toxic effect on the fetus, so it must be replaced by low molecular weight heparin up until six weeks after delivery.

In people with non-thrombotic manifestations or other associated autoimmune diseases, corticosteroids may be used to help limit the immune response, and finally, if symptoms are really severe, certain immunosuppressive drugs might be used.

Summary

All right, as a quick recap, antiphospholipid syndrome is caused by antibodies, which target the phospholipids in the cell membrane.

The three laboratory criteria are presence of anticardiolipin, anti-beta2 glycoprotein antibodies, or lupus anticoagulant in the blood.

Individuals affected are at higher risk of thrombosis and pregnancy-related complications.

Treatment involves avoiding other risk factors for thrombosis, as well as taking lifelong aspirin sometimes as prevention of thrombosis.

People that have had thrombotic symptoms should also take warfarin, and during pregnancy, warfarin must be replaced by low molecular weight heparin.