Catastrophic antiphospholipid syndrome: a CAPS-tivating hematologic disease

Abstract

Catastrophic antiphospholipid syndrome (CAPS) is a rare but life-threatening form of antiphospholipid syndrome (APS) defined by the rapid onset of large and small vessel thrombosis occurring simultaneously across multiple sites, resulting in multiorgan dysfunction. The presence of underlying immune dysfunction causing activation of coagulation and, in many cases, abnormal complement regulation predisposes these patients to thrombotic events. CAPS is often preceded by triggering factors such as infection, surgery, trauma, anticoagulation discontinuation, and malignancy. Given the high mortality rate, which may exceed 50%, prompt recognition and initiation of management is required. The detection of antiphospholipid antibodies and the histopathologic identification of microvascular ischemia via tissue biopsy are required to diagnose CAPS. However, these patients are often too unwell to obtain results and wait for them. As such, investigations should not delay CAPS therapy, especially if there is strong clinical suspicion. Management of CAPS requires "triple therapy" with glucocorticoids, intravenous heparin, therapeutic plasma exchange, and/or intravenous immunoglobulin. Treatment for refractory disease is based on poor-quality evidence but includes anti-CD20 (rituximab) or anticomplement (eculizumab) monoclonal antibodies and other immunosuppressant agents, either alone or in combination. The rarity of this syndrome and the subsequent lack of randomized clinical trials have led to a paucity of high-quality evidence to guide management. Continued international collaboration to expand ongoing CAPS registries will allow a better understanding of the response to newer targeted therapy.

Graphical abstract

Figure 1.

The overlap of CAPS and thrombotic antiphospholipid syndrome. The presence of aPLs and complement gene abnormality fosters a procoagulant and proinflammatory environment, which increases the risk for macrovascular (venous and arterial) thrombotic events in APS. Approximately 1% of patients with APS develop a severe picture of catastrophic APS (CAPS). The “2-hit” theory suggests that the presence of additional precipitating factors (including infection, inflammation, pregnancy, surgery, trauma, etc) leads to a domino effect that results in activation of the complement system, endothelium, and coagulation cascade, as well as immune cell activation, which are key contributors to the pathogenesis of CAPS.

Figure 2.

Recommended approach to managing CAPS. The following figure outlines our recommended approach to managing patients with CAPS. If there is a strong suspicion of CAPS, including characteristic clinical features and acute onset (within 1 week), then initiation of triple therapy may be warranted prior to confirmation of CAPS with histopathological or laboratory findings (ie, antiphospholipid antibodies). Triple therapy involves management with glucocorticoids, plasma exchange, and/or IVIG, as well as anticoagulation (preferably heparin). If there is a lack of clinical response (ie, progressive multiorgan failure, additional thrombotic events, or lack of improvement in complete blood count and hemolytic markers), then consider additive therapy with second-line options, including anti-CD20 (rituximab) or anticomplement (eculizumab) therapy or other immunosuppressive agents (either alone or in combination). If the patient has systemic lupus erythematous (SLE), in addition to the standard of care with hydroxychloroquine the use adjunct therapy with cyclophosphamide could be considered. If the patient remains refractory despite second-line therapy, then experimental agents or clinical trials would be warranted.