CONTENTS

• Rapid Reference – When to consider CAPS? 🚀
• Pathophysiology
• Epidemiology & precipitating factors
• Clinical presentation
• Lab tests
  • Laboratory abnormalities seen in CAPS
  • Testing for antiphospholipid antibody syndrome
• Tissue diagnosis
• Differential diagnosis
• Diagnostic criteria
• Treatment
• Prognosis
• Podcast
• Questions & discussion
• Pitfalls

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when to consider a diagnosis of CAPS?

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epidemiological clue in ~half of patients

• Known history of antiphospholipid syndrome.
• History of connective tissue disease (especially lupus).
• History of repeated pregnancy loss, or PE/DVT.

trigger in ~half of patients

• Infection is most common.
• Surgery or trauma.
• Malignancy.
• Anticoagulation withdrawal.
• Pregnancy or initiation of oral contraception.
• Flare of autoimmune disease.

clinical presentation frequently involves:

• Multi-organ failure (kidney > lung > neuro > cardiac).
• Skin manifestations may be a clue:
  • Livedo reticularis.
  • Cutaneous necrosis, digital gangrene.

laboratory abnormalities may include:

• Thrombocytopenia (~60%).
• Mild microangiopathic hemolytic anemia (20%).
• Disseminated intravascular coagulation (25%).
• Ferritin is often >1,000 ng/ml.

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pathophysiology

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antiphospholipid syndrome

• This is a pro-coagulable condition caused by antibodies which bind to endothelial surfaces and trigger coagulation. Thrombosis may occur in arteries and/or veins.
• Antiphospholipid syndrome is more common in patients with lupus, but it can also occur on its own. It often presents with isolated large vessel vascular occlusions (e.g., DVT or PE).

catastrophic antiphospholipid syndrome (CAPS)

• CAPS is a severe manifestation of antiphospholipid syndrome that involves accelerated and widespread thrombosis, which may lead to multi-organ failure.
• CAPS appears to involve a vicious spiral of progressive complement activation, leading to microvascular thrombosis and tissue damage. Three general factors seem to be involved in generating this spiral:
  • [1] Antiphospholipid antibody.
  • [2] Genetic mutations which predispose the patient towards dysregulated complement activation. (31812994)
  • [3] Triggers that stimulate complement activation (e.g., acute infection).
• CAPS may be conceptualized roughly as a combination of a thrombotic microangiopathy plus a cytokine storm. (38320593)

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epidemiology & precipitating factors

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overall epidemiology

• CAPS is extremely rare.
• CAPS is the initial manifestation of antiphospholipid syndrome in about half of diagnosed CAPS patients. Remaining patients will carry a history of pre-existing antiphospholipid syndrome.
• Relationship to other rheumatologic disorders:
  • Most patients with CAPS have isolated antiphospholipid syndrome.
  • ~30% of patients also have lupus. (32819183)
  • Other associations include rheumatoid arthritis and other rheumatologic disorders.
• 70% of patients are women. (32819183)
• Patients are often relatively young (~40s), but there is a broad age range. (32819183)

a precipitating factor is present in about half of cases 

• Infection (49%):
  • Respiratory.
  • Urinary tract.
  • Skin.
  • Gastrointestinal tract.
• Surgery or trauma (17%):
• Malignancy (16%):
  • Especially hematologic: Hodgkin's and non-Hodgkin's lymphoma, acute lymphocytic leukemia, angiocentric lymphoma, chronic myelocytic lymphoma.
  • Solid tumors: Most often lung or colon adenocarcinoma.
• Anticoagulation withdrawal, or subtherapeutic anticoagulation (8%).
• Pregnancy complications or initiation of oral contraception (8%):
  • HELLP syndrome.
  • Placental infarction.
  • Pelvic thrombosis.
• Medications (5%).
• Flare of underlying autoimmune disease (e.g., lupus)(3%). (29779928)

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clinical presentation

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AKI (acute kidney injury; 75% of patients)

• Hypertension may result from renovascular occlusion.
• Patients with AKI usually have a very abnormal urinalysis:
  • [1] Proteinuria occurs in 97%. (32819183) The mean protein loss 3.7 grams/day, usually falling within a nephrotic range (>3 g/day).
  • [2] Hematuria is seen in 79% of patients. (32819183)
• Most patients with AKI have evidence of hemolysis.
• Histopathological lesions include mostly thrombotic microangiopathy (85%) as well as proliferative glomerulonephritis (35%). (32819183)

respiratory involvement (60% of patients)

• ARDS is a common initial presentation of CAPS (occurring in ~20% of CAPS patients overall).  ARDS may occur due to a variety of different mechanisms, including:(32252584)
  • Pneumonia may be the initial trigger of CAPS.
  • DAH (diffuse alveolar hemorrhage), which is associated with thrombotic microangiopathy. (38320593)
• Pulmonary embolism is common.

neurologic involvement (50% of patients)

• Encephalopathy, sometimes to the point of coma.  This may relate to either: (38320593)
  • i) Diffuse microangiopathy (similar to thrombotic thrombocytopenic purpura).
  • ii) Cytokine storm.
• Seizure.
• Stroke (large vessel infarction in ~10%).
• Cerebral venous occlusion.

cardiac involvement (50% of patients)

• Systolic heart failure may relate to a variety of causes, including:
  • Myocardial infarction.
  • Thrombotic microangiopathy causing microvascular occlusions (despite a normal-appearing cardiac catheterization).
  • Myocarditis.
  • Takotsubo cardiomyopathy.
• Noninfectious, Libman-Sacks endocarditis (especially lupus-associated CAPS). (38534211)
• Adrenal insufficiency occurs in 15%, which may contribute to shock.

skin manifestations (~45%)

• Livedo reticularis (40%).
• Cutaneous necrosis with digital gangrene (~15%).
• Purpura or splinter hemorrhages. (31677977)

gastrointestinal

• Small and/or large bowel infarction.(32252937)
• Thrombotic pancreatitis.
• Budd-Chiari syndrome (hepatic vein thrombosis).

other less common manifestations

• Infarction of testes, ovaries, or prostate.
• Adrenal infarction.

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lab tests

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The diagnostic strategy may vary somewhat, depending on whether the patient is already known to have antiphospholipid antibody syndrome.  

lab panel for investigation of possible CAPS 

• Electrolytes.
• Complete Blood Count, with blood smear examination for schistocytes.
• Urinalysis and spot urine protein/creatinine ratio.
• Coagulation studies (including INR, PTT, D-dimer).
• Lactate dehydrogenase (LDH), haptoglobin.
• Evaluation for antiphospholipid syndrome (if not already diagnosed):
  • anti-cardiolipin IgG & IgM.
  • anti-beta-2-glycoprotein type I IgG & IgM.
  • Evaluation for lupus anticoagulant: dilute Russell Viper Venom test.
  • Antinuclear Antibody (ANA).

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[#1/2] laboratory abnormalities that may be seen in CAPS

TMA (thrombotic microangiopathy) with complement activation

• Basic features of microangiopathic hemolytic anemia:
  • Thrombocytopenia (60%).
  • LDH (lactate dehydrogenase) elevation.
  • Schistocytes. However, if seen schistocytes are usually scanty (unlike the abundant numbers seen in thrombotic thrombocytopenic purpura). (29779928)
  • Low haptoglobin.
• Renal failure, often with proteinuria and hematuria.
• Hypocomplementemia (60% of patients). (38320593)
• 💡 CAPS may clinically resemble and/or overlap with complement-mediated TMA (thrombotic microangiopathy).

DIC (disseminated intravascular coagulation) (~25%)

• PTT prolongation due to lupus anticoagulant may also be seen.

systemic inflammation

• Elevated ferritin levels (>1,000 ng/ml).

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[#2/2] laboratory testing for antiphospholipid syndrome

laboratory tests

• Anti-cardiolipin antibody (IgG & IgM).
  • These are less specific (e.g., found in 1/3 of patients with heparin-induced thrombocytopenia).
• Anti-beta-2-glycoprotein type I (IgG & IgM).
• Lupus anticoagulant may be evaluated in 83% of episodes. (32819183) 🌊

test interpretation

• Nonspecific:
  • Antiphospholipid antibodies may be present in a variety of disorders, including infection, malignancy, and autoimmune disorders. (38320593) Thus, the mere presence of antiphospholipid antibodies doesn't establish the diagnosis of antiphospholipid syndrome
  • In these conditions, antiphospholipid antibodies are generally present at low levels and only transiently.
• Among CAPS patients, antibodies will usually be present in high titers. (29779928) However, it is also possible that antibodies can be consumed by thrombosis, leading to low levels.

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tissue diagnosis

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• Definitive diagnosis of CAPS requires biopsy evidence of small vessel thrombosis, but this is often not possible (due to the patient's instability and coagulation abnormalities).
• If skin lesions are present, these may be biopsied to demonstrate thrombosis.
• The risk/benefit ratio of pursuing biopsy of other organs is unknown. (29978552)

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differential diagnosis

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closest mimics of CAPS

• Microangiopathic hemolytic anemia:
  • TTP (thrombotic thrombocytopenic purpura).
  • HUS (hemolytic uremic syndrome HUS) & atypical HUS.
  • HIT (heparin induced thrombocytopenia).
  • Purpura fulminans.
  • Medication-related thrombotic microangiopathy.
  • Malignant hypertension.
  • Disseminated malignancy.
  • (Further discussion here: 📖)
• Sepsis.
• Adrenal insufficiency (note: CAPS may cause adrenal insufficiency).
• Endocarditis.
• Vasculitis.
• Cholesterol emboli. (30504326)

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diagnostic criteria

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diagnostic criteria for CAPS

1. Involvement of three or more organs, systems, and/or tissues.
2. Development of manifestations simultaneously or within 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 (i.e., lupus anticoagulant and/or anti-cardiolipin antibodies).

definition of CAPS:

• Definite CAPS requires all four criteria. Sources disagree about whether it is necessary to demonstrate that antiphospholipid antibodies persist for six weeks after the initial episode (if anti-phospholipid syndrome wasn't previously diagnosed).
• Probable CAPS may be reached in a variety of different ways:
  • All four criteria, except that only two organs/systems involved.
  • All four criteria, except for absence of laboratory confirmation due to early death of a patient never tested for antiphospholipid antibodies.
  • Criteria #1, #2, and #4 (everything except pathological confirmation).
  • Criteria #1, #3, and #4 are met, with the development of a third event within 1-4 weeks after presentation (despite anticoagulation).

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treatment

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Treatment for CAPS is poorly defined, due to the rarity of this condition (no RCT-level evidence exists). To make matters more confusing, treatment often needs to be started before the diagnosis is entirely certain.

general measures

• Identify and treat any underlying cause, e.g.:
  • Treat any underlying infection.
• Aggressive antihypertensive therapy (uncontrolled hypertension may worsen intravascular hemolysis).
• Avoid intravascular catheters (especially arterial lines), as these tend to clot off.

heparin anticoagulation

• Heparin is probably the most important treatment (correlating most strongly with good outcomes in retrospective series). Heparin may exert some anti-inflammatory and complement-inhibitory effects. (38534211)
• Heparin infusion is used initially, although low molecular weight heparin also seems to work.
  • Ideally, heparin infusions should be titrated against anti-Xa level (because many patients will have lupus anticoagulant, which artificially increases the PTT).
• Eventually, heparin should be transitioned to oral anticoagulation with warfarin (DOACs are inferior to warfarin among patients with antiphospholipid antibody syndrome). (38534211)
• If heparin is contraindicated for reasons other than bleeding, antiplatelet agents as an alternative strategy are recommended. (38534211)

steroid

• Rationales for steroid use:
  • CAPS typically involves a pro-inflammatory state.
  • Steroid could treat some underlying rheumatological disorders (e.g., lupus), potentially decreasing the production of anti-phospholipid antibodies.
• The CAPS registry shows that steroid was used in 99% of cases. Unfortunately, there is no high-quality data to support steroid use.
• The optimal steroid dose and duration are unknown.
  • [1] Traditionally a pulse of methylprednisolone is used (e.g., 1,000 mg/day for 3-5 days), but it's dubious whether such a high dose is actually needed. For example, 250-750 mg methylprednisolone daily for three days could be sufficient. (29779928)
  • [2] This is followed by a steroid taper to achieve short treatment duration (typically 4-6 weeks). (38534211)
• The McMaster guidelines recommended against steroid monotherapy, but did recommend steroid in combination with heparin and IVIG or plasmapheresis. (29978552)

plasmapheresis and/or intravenous immunoglobulin

• These are both nonspecific therapies aimed at reducing the activity of anti-phospholipid antibodies. Plasmapheresis removes antibodies directly, whereas intravenous immunoglobulin may increase antibody turnover.
• Where these therapies should fit within an overall treatment strategy remains unclear. To date, retrospective case series suggest the best outcomes occur when treatment includes steroid, heparin, and either plasmapheresis or IVIG. (29779928, 29978552) Available retrospective data doesn't show any mortality difference between plasmapheresis versus IVIG. (38320593)
• Plasmapheresis:
  • Plasmapheresis might be preferred over IVIG in patients with microangiopathic hemolytic anemia or renal dysfunction (given the risk of kidney injury with IVIG). (29978552)
• IVIG:
  • IVIG might be preferred over plasmapheresis in CAPS patients with immune thrombocytopenia, given evidence of benefit in that condition. (29978552)
  • Typical regimens include 0.4 g/kg/day for five days or 1 g/kg/day for two days.

eculizumab

• Eculizumab is a monoclonal antibody that binds and inhibits complement protein C5.
• Traditionally eculizumab has been reserved for more refractory cases. However, increasing insight into the pathophysiology suggests that complement activation is a primary driver of the illness, suggesting that eculizumab may be beneficial if initiated earlier. (31812994)
• Eculizumab may be especially useful in patients with prominent features of thrombotic microangiopathy. (38320593) There may be significant clinicopathological overlap between CAPS and complement-mediated hemolytic uremic syndrome. 
• Several case reports describe efficacy at initial doses of ~900 mg weekly (analogous to the regimen of eculizumab for atypical hemolytic uremic syndrome). (32252584)
• Eculizumab increases the risk of meningococcal meningitis by ~1,000-fold, so meningococcal vaccines and antibiotic prophylaxis should be considered.

additional immunosuppression

• Rituximab:
  • B-cell suppression may be a rational strategy, with a goal of reducing anti-phospholipid antibody production. Rituximab causes elimination of anti-phospholipid antibodies in half of patients. (32252937) 
  • Rituximab may be considered for refractory cases. (29978552)
• Cyclophosphamide is considered for patients with CAPS in the context of lupus. (32252937)  

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prognosis

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• Mortality is 40%. (38534211)
  • Lupus-associated CAPS has a higher mortality (~50%). (38534211)
• Recurrence can occur, but is rare (<5%). (38534211)

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podcast

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Failure to consider CAPS as a competing diagnosis, in a patient with multi-organ failure who has been labeled as having septic shock.
• Delaying therapy for CAPS pending arrival at a definitive diagnosis.

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