Catastrophic Antiphospholipid Syndrome

1. What is antiphospholipid syndrome (APS)?
2. What is catastrophic antiphospholipid syndrome (CAPS)?
3. How common is it?
4. Why does it occur?
5. What are its major clinical manifestations?
6. How is it classified for research purposes?
7. How is it syndrome diagnosed?
8. How is it treated?
9. What is the prognosis?
10. Can I lead a normal life?

1. What is antiphospholipid syndrome (APS)?

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder in which the patient’s immune system makes antibodies (antiphospholipid antibodies [aPL]) that increase the risk of blood clots (thickened blood) and pregnancy complications.

Antiphospholipid antibodies occur in otherwise healthy individuals or in patients with other autoimmune disorders such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA).

2. What is catastrophic antiphospholipid syndrome?

Catastrophic APS, sometimes referred to as CAPS, is the most severe form of APS and is very rare. In CAPS, multiple blood clots in small (also referred as microvascular disease or microvascular APS), medium, and/or large blood vessels occur over a short period (usually within a week), sometimes associated with thrombocytopenia, hemolytic anemia, and/or thrombotic microangiopathy (see below for the descriptions).

3. How common is catastrophic antiphospholipid syndrome?

Catastrophic APS is a rare (prevalence (rate of occurrence) of less than one in 2000) disease with approximately 600 reported cases. Catastrophic APS occurs in less than 1% of APS patients.

4. Why does catastrophic antiphospholipid syndrome occur?

Catastrophic APS generally happens when certain triggers, like infections, surgery and trauma, cancer, pregnancy complications like HELLP syndrome (which involves breaking down red blood cells, liver problems, and low platelets) and placental infarction, estrogen use, drugs, or SLE flares, cause the immune system to overreact. This overreaction makes the blood clot too easily, blocking blood vessels in multiple organs and leading to organ failure. People with underlying risk factors are more vulnerable, and missing or stopping blood-thinning medication can also trigger CAPS.2 However, sometimes there is not a clear trigger for CAPS.

Some patients with CAPS have underlying complement regulatory gene (a gene that controls immune system activity) variants that increase complement activity (immune protein system), predisposing them to widespread thrombosis (blood clotting) and multiorgan failure. These genetic changes affecting immune proteins can result in a severe clinical form of CAPS.

5. What are the major clinical manifestations of catastrophic antiphospholipid syndrome?

Individuals who develop CAPS will typically manifest multiple blood clots with or without microvascular disease and/or a systemic thrombotic microangiopathy (TMA). Multiple blood clots can result in infarction (lack of oxygen in tissues) and failure of different organs, leading to “multiple organ dysfunction” – a life-threatening condition requiring intensive care unit (ICU) management. Systemic thrombotic microangiopathy (TMA) is a condition where microvascular disease causes low platelet count, hemolysis (blood cell breakdown), and small vessel blood clots. Although any organ can be involved in catastrophic APS, the most frequently affected organs are:

• Extremities: deep vein thrombosis, usually legs.
• Lung; pulmonary embolism (lung clot) and acute respiratory distress syndrome (ARDS) (lung failure).
• Kidney; kidney failure, hypertension, proteinuria (protein in urine), and hematuria (blood in urine)
• Brain; stroke, seizures, and altered mental status.
• Heart; heart failure, heart attack, arrhythmias (irregular heartbeat), and heart valve issues.
• Skin; Livedo reticularis (skin discoloration) and digital gangrene (dead tissue).
• Bowel infarction (lack of oxygen in tissues).
• Adrenal insufficiency (low hormone production from adrenal glands).
• Hematologic: Low platelet counts and anemia.

In addition, patients can develop clots in unusual locations, such as the esophagus or ovaries, and may develop blood cell abnormalities such as low platelet counts (which can increase the risk of bleeding) and anemia.

6. How is catastrophic antiphospholipid syndrome classified for research purposes?

Catastrophic APS classification criteria are used in research to select patients with similar characteristics, helping researchers improve study results. However, these criteria do not cover all aspects of the disease and are for research only.

A patient is classified with "definite" catastrophic APS when he/she fulfills all of the following criteria:

• Evidence of blood clots in three or more organs, systems, and/or tissues.
• Simultaneous development of blood clots or development of multiple blood clots in less than a week.
• Confirmation of small vessel clots in at least one organ or tissue by biopsy.
• Laboratory confirmation of persistently positive aPL, which must be confirmed at least two times, spaced at least six weeks apart:
  • lupus anticoagulant
  • anticardiolipin antibodies
  • anti-Beta-2-glycoprotein-I (aβ2GPI) antibodies

If a patient fulfills only three of the four criteria above, then the patient is classified as "probable" catastrophic APS.

7. How is catastrophic antiphospholipid syndrome diagnosed?

Diagnostic criteria are different than classification criteria, and there are no diagnostic criteria for CAPS. (Learn more about APS classification and diagnosis.)

Diagnosing CAPS can be difficult and requires careful assessment of the situation. This condition involves dangerous blood clots and rapid organ failure, so quick diagnosis and treatment are crucial. Suspicion for CAPS is based on a combination of:

• Multiple blood clots forming in different parts of the body.
• Multiorgan failure.
• Rapid clinical deterioration.
• Schistocytes (which are damaged red blood cells) found in a blood test.
• Low platelet counts.
• Blockages in small blood vessels, either confirmed through a microscope or strongly suspected.
• Persistent aPL positivity.

While diagnosing CAPS early can improve outcomes, it’s challenging because:

• Half of CAPS patients don't have a history of APS or aPL.
• Other conditions, such as severe infections, can look like CAPS.
• Antiphospholipid antibody test results may not be available at the early stage of the disease or may be unreliable if the patient has an infection or is on blood thinners.
• In critically ill patients, it is often difficult to perform an organ biopsy to confirm small vessel involvement.
• During pregnancy, CAPS can be mistaken for HELLP syndrome (which also involves blood clots, liver problems, and low platelets). Both conditions pose serious risks to both mother and baby, so care from specialists is vital.

In summary, CAPS is a serious condition, and its diagnosis requires careful evaluation. If your doctor suspects CAPS, they will likely start treatment even before confirming the diagnosis to prevent life-threatening complications.

8. How is catastrophic antiphospholipid syndrome treated?

Catastrophic APS is a serious condition, and the diagnosis requires careful evaluation. If your doctor suspects CAPS, they will likely start treatment even before confirming the diagnosis to prevent life-threatening complications. Current treatment recommendations for catastrophic APS have three clear goals:

• to treat any “trigger” factors (for example, early antibiotics if infection is suspected)
• to prevent and to treat existing blood clots
• to suppress excessive inflammation

If catastrophic APS is suspected, aggressive treatment should be started without delay. For the first-line treatment of CAPS patients, based on the McMaster RARE-Best Practices Clinical Practice Guideline, a combination therapy with heparin, glucocorticoids, and either intravenous immunoglobulin (IVIG) or plasma exchange is recommended over single agents or other combinations of therapies.

• Heparin, and once stabilized, patients are transitioned to long-term anticoagulation with warfarin. Heparin and warfarin are anticoagulants, blood thinners that inhibits blood clot formation and dissolves existing clots.
• High dose corticosteroids as an anti-inflammatory agent may also suppress the negative effects of aPL.
• Plasma exchange may temporarily remove both aPL and certain proteins that cause inflammation from the blood.
• Intravenous gamma globulin blocks autoantibodies and helps modulate inflammation.

Some of the additional medications that can be considered in CAPS patients include hydroxychloroquine, statins (cholesterol lowering medications), cyclophosphamide, rituximab, and eculizumab.

• Based on animal models, hydroxychloroquine, reduces blood clot formation, prevents harmful platelet activity, improves blood flow, and protects cells from damage caused by aPL. Based on animal models and a limited number of human studies, statins reduce inflammation, lowers harmful molecule production, and prevent immune cells from sticking to blood vessels, helping to reduce clotting risks associated with aPL. Thus, both hydroxychloroquine and statins care sometimes used in difficult-to-treat APS patients.
• Rituximab, an immunosuppressive drug that targets the inflammatory cells that secrete aPL, has been used in a limited number of catastrophic APS patients, especially in those with low platelet counts and microvascular disease.
• Cyclophosphamide, an immunosuppressive drug, may be helpful in patients who also have lupus and experience a lupus flare in addition to catastrophic APS.
• Eculizumab is also an immunosuppressive drug and has demonstrated promise in treating severe, therapy resistant cases of CAPS, especially in the presence of systemic thrombotic microangiopathy (TMA).

Patients with severe complications may need special treatments to support their organs:

• Dialysis helps if the kidneys fail.
• Mechanical ventilation assists breathing in cases of lung failure or serious complications.
• Vasopressors are used to raise blood pressure and ensure blood flow to organs during shock or very low blood pressure.

9. What is the prognosis of catastrophic antiphospholipid syndrome?

Short Term: Analysis of the published catastrophic APS case reports shows that mortality from this condition has been decreasing since the year 2000. This is probably due to the increased recognition and early treatment of the disease. However, catastrophic APS remains a very serious life-threatening condition. In addition to the specific manifestations of catastrophic APS, patients may develop other complications during the acute period – such as infections or bleeding – which directly affect the prognosis.

Long Term: Based on one retrospective (looking back at collected data) study that analyzed long-term outcomes (up to six years) in catastrophic APS patients, approximately 70% of the patients who survived the initial catastrophic APS event and took warfarin (a blood thinner), remained free of blood clots. CAPS can cause serious complications, leading to long-term disability. It progresses quickly, often damaging organs like the kidneys, brain, and lungs. Many survivors develop chronic kidney disease, cognitive problems, motor issues, or pulmonary hypertension due to blood clots and organ damage. Immediate medical treatment is essential to limit these effects.

10. Can I lead a normal life after catastrophic antiphospholipid syndrome?

Following a catastrophic APS event, permanent damage may occur; the extent of this damage depends on the type and severity of the organs involved. After an acute event, catastrophic APS patients receive long term anticoagulation therapy. Patients should discuss the need for other medications with their physicians and follow important precautions to reduce the risk of a new clot.

Updated: 12/30/2024

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References

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