Rapidly developing multiorgan failure in a young patient is, fortunately, a rare event that is usually secondary to sepsis or exposure to chemical toxins. Recently, a new etiology for this medical emergency has been described -- the catastrophic antiphospholipid antibody syndrome (CAPS). Since this syndrome will not respond to antibiotics or dialysis, but may respond to intensive immunosuppressive and anticoagulant therapy, it seems important for clinicians to be aware of CAPS and know how to diagnose it.

The antiphospholipid syndrome (APLS) consists of recurrent venous and arterial thromboses, thrombocytopenia and recurrent abortion in association with antiphospholipid (APL) antibodies. The APL antibodies can be detected as anti-cardiolipin antibodies or as immunoglobulins that prolong the activated partial thromboplastin time (lupus anticoagulants). More recently, an association between antibodies to beta-2-glycoprotein 1, a serum inhibitor of coagulation, and APLS has also been described.

APLS usually occurs in SLE patients but may also occur in patients with no known underlying connective tissue disease. In these latter patients, the condition is referred to as the primary APLS. A subset of patients with APL antibodies develop a fulminating and frequently life threatening coagulopathy. This latter syndrome is referred to as the catastrophic antiphospholipid syndrome (CAPS).

CAPS differs from APLS both clinically and pathologically, although the APL antibodies in both conditions appear to be qualitatively similar. Clinically, CAPS is characterized by the rapid development of failure/dysfunction of three or more organs as described below. The patients may or may not have prior manifestations of the APL syndrome or a previous diagnosis of SLE. When patients have underlying SLE, it is typically inactive lupus or overlap/lupus-like syndromes which have apparently been well-controlled either without therapy, or with minimal treatment up to the time of illness.

Like many autoimmune disorders, CAPS is more common in females in a ratio of approximately 2:1 and presents most frequently in young adults. In one recent study, the mean age at presentation was 38±14 years, though it may occur at any age. In about one-fifth of the patients, a triggering factor can be identified. The most common triggering factors are infections, drugs, especially anticoagulants, minor surgical procedures and hysterectomy. Late term pregnancy appears to be another precipitating event.

Pathologically, CAPS is characterized by a widespread thrombotic microangiopathy, as opposed to the scattered large arterial or venous thromboses seen in APLS. High titers of anti-cardiolipin antibodies, predominantly of the IgG isotype, and/or antibodies to beta-2-glycoprotein-1 of the IgG or IgA isotype, as well as the lupus anticoagulant, are present in the serum of patients with CAPS.

Clinical Profile

Renal. The kidney is the most commonly involved organ. Patients may present with oliguria and rapidly deteriorating renal function, usually with accompanying hypertension, which may be of the "malignant" type. Proteinuria may be seen but hematuria and cellular casts have not been reported. Renal biopsy shows diffuse thromboses of the glomerular capillaries with necrosis of the glomeruli in the majority of cases.

CNS. Most of the patients reported in the literature with CAPS have had significant changes in cognitive function ranging from confusion to coma. A number of the patients have presented with seizures including status epilepticus. Changes in behavior and emotional instability are common. Cortical blindness has also been seen. A rapidly progressive peripheral neuropathy has also been described. The MRI of the brain may show multiple areas of infarction that often do not correspond to the neurological findings. Numerous microinfarctions too small to be detected by MRI secondary to the small vessel microangiopathy have been seen in autopsy specimens.

Respiratory system. Approximately 25% of reported cases of CAPS have had significant hypoxemia accompanied by bilateral interstitial infiltrates. These patients complain of dyspnea and nonproductive cough. The pulmonary function tests and lung histology are consistent with adult respiratory distress syndrome (ARDS).

Cardiovascular system. In contrast to patients with APLS who may develop thromboses of major coronary arteries resulting in macroscopic myocardial infarction, patients with CAPS may develop acute left ventricular failure from microvascular occlusions. Accelerated hypertension with cerebral hemorrhages and papilloedema have complicated the course of CAPS. This hypertension results from increased peripheral vascular resistance secondary to either diffuse microangiopathy or excessive renin release from renal ischemia.

Other. As might be expected with widespread microvascular coagulation, a number of other organ systems may be involved in individual patients. These include:

• Adrenal and pituitary gland infarction leading to hypotension and electrolyte disturbances;
• Bone marrow infarction manifesting as severe hypoplastic anemia thrombocytopenia and neutropenia;
• Digital cyanosis and gangrene, as well as prominent and widespread livedo reticularis and ischemic ulcerations;
• Abnormal liver function, manifested by elevations of hepatic transaminases secondary to hepatic infarctions, may occur. Bowel involvement presenting as severe abdominal pain from intestinal ischemia, splenic vessel thrombosis and pancreatic involvement can be seen.

CAPS has also been seen in association with the HELLP syndrome (Hemolysis, Elevated Liver enzymes and Low Platelets) occurring in the last trimester of pregnancy.(3)

Investigations

Thrombocytopenia is common, sometimes severe. It is often associated with leucocytosis and elevated ESR. The serological profile will show antiphosopholipid antibodies, usually in high titres and predominantly of IgG isotype. The test for lupus anticoagulant is positive more often than not. The ANA test, if positive, is usually in low titre; other serologies specific to lupus may be found in low titres but only if the patient has concomitant lupus. The chest X-ray may show typical ARDS changes with increased bibasilar markings and/or evidence of CHF when the condition is advanced and severe hypertension is present. The EKG may be normal or show generalized ST depressions.

Differential Diagnosis

Most patients with CAPS have been febrile and the possibility of disseminated intravascular coagulation (DIC), secondary to sepsis, is always a primary consideration. However, in CAPS as opposed to DIC, the level of fibrin split products is normal and blood cultures are negative, while the antiphospholipid antibody tests are positive, in contrast to DIC.

Thrombotic thrombocytopenic purpura (TTP) is another microangiopathy which can also resemble CAPS. In TTP, numerous schistocytes are seen in the peripheral blood smear, though these mechanically damaged red blood cells have not been a prominent feature of CAPS. Moreover, in TTP, large multimers of von Willebrand's factor are found in the plasma secondary to an autoantibody to a metalloprotease that cleaves these marcomolecules. In CAPS, these multimers have not been reported.

One must also keep in mind the extensive vasculitis in various organ systems, which presents as sudden multiorgan failure, especially when antiphospholipid antibodies are associated with SLE. The markers of active lupus-like complements would, however, be low in these cases, though the ultimate differential diagnosis would need to be determined by biopsy.

Treatment

Treatment of CAPS is not currently standardized. A combination of anticoagulation + steroids + plasmapheresis with replacement with soluble IVIg was seen to have the highest survival in an extended series of 50 patients. The rationale for plasmapheresis using fresh frozen plasma is that it contains protein C, protein S and antithrombin III and, therefore, replenishes the natural anticoagulants depleted during the clotting process. Plasmapheresis may also help in CAPS by removing the antiphospholipid antibodies. Soluble IVIg should be used with caution, keeping in mind the potential risk of renal failure. Anecdotal reports have appeared indicating response to ancrod (a Malaysian pit viper venom extract), defibrotide (alkali metal salt of DNA fraction) and even cyclophosphamide.

Conclusion

Catastrophic antiphosopholipid syndrome is an uncommon and potentially life-endangering condition that requires a high degree of clinical awareness by the clinician. The majority manifest microangiopathic occlusive disease affecting small vessels, though a minority may experience the typical large vessel occlusions seen in uncomplicated APLS.