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Catastrophic antiphospholipid syndrome (CAPS)

Catastrophic antiphospholipid syndrome (CAPS)
Literature review current through: Jan 2024.
This topic last updated: Sep 15, 2023.

INTRODUCTION — Catastrophic antiphospholipid syndrome (CAPS) is a rare, life-threatening form of APS characterized by severe thrombotic complications, usually microvascular as well as large-vessel thrombosis, affecting multiple organs, that develop simultaneously or over a short period of time.

CAPS is a potentially life-threatening syndrome that requires specialized expertise and interventions such as therapeutic plasma exchange. If this expertise and capabilities are not available, the patient should be transferred urgently to a facility where they are.

The clinical presentation, diagnosis, and management of CAPS are reviewed here.

Separate topics discuss:

APS diagnosis – (See "Clinical manifestations of antiphospholipid syndrome" and "Diagnosis of antiphospholipid syndrome".)

APS treatment – (See "Management of antiphospholipid syndrome".)

APS pathogenesis – (See "Pathogenesis of antiphospholipid syndrome".)

APS in pregnancy – (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

Overview of thrombotic microangiopathies – (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

DEFINITIONS

APS – Antiphospholipid syndrome (APS) is an autoimmune syndrome characterized by arterial or venous thromboembolism and/or pregnancy morbidity with persistently positive antiphospholipid antibodies (aPL). Other clinical manifestations of APS include livedo reticularis/racemosa, thrombocytopenia, neurologic changes, kidney disease, and heart valve disease (vegetations, thickening). (See "Clinical manifestations of antiphospholipid syndrome", section on 'Clinical manifestations'.)

CAPS – Catastrophic APS (CAPS) is a life-threatening variant of APS characterized by rapid onset of symptoms, involvement of multiple organ systems, and thrombotic events that include large vessel and microvascular involvement.

Approximately 1 percent of patients with APS develop the severe clinical picture of CAPS. Approximately one-half of all patients with APS present with CAPS as their initial manifestations of APS [1,2]. (See 'Incidence' below.)

Microvascular APS – Microvascular APS is not a commonly appreciated form of APS, but we use this term to refer to individuals with APS who have predominantly microvascular involvement such as diffuse alveolar hemorrhage, aPL-nephropathy, livedoid vasculopathy, cardiac microthrombosis, or adrenal hemorrhage/infarct [3]. Individuals with microvascular APS probably have a higher risk of progression to CAPS, although this has not been formally studied.

Systemic TMA – Systemic thrombotic microangiopathy (TMA) refers to a disease process in which microvascular disease leads to thrombocytopenia, microangiopathic hemolysis (with schistocytes on the blood smear), and organ injury due to small vessel thrombosis. Several primary TMAs have been described, including thrombotic thrombocytopenic purpura (TTP), complement-mediated TMA (CM-TMA), and Shiga toxin-induced hemolytic uremic syndrome (ST-HUS).

Patient with CAPS or microvascular APS may develop systemic TMA. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Thrombotic storm – Thrombotic storm describes the dramatic clinical presentation of patients with extensive systemic thrombosis affecting multiple vascular beds [4]. Causes include CAPS and other systemic disorders such as heparin-induced thrombocytopenia (HIT), coronavirus disease 2019 (COVID-19), or Trousseau syndrome in individuals with certain cancers.

PATHOPHYSIOLOGY/MECHANISM OF THROMBOSIS — CAPS and APS are both thrombotic disorders associated with antiphospholipid antibodies (aPL). The role of aPL in APS is discussed separately. (See "Pathogenesis of antiphospholipid syndrome", section on 'Role of antiphospholipid antibodies'.)

What distinguishes CAPS from APS is the intensity and extent of the thrombotic process.

CAPS, by definition, involves multiple organs simultaneously with a diffuse, micro- or combined micro- and macrovascular process. Patients with either CAPS or APS can have a stroke, or a pulmonary embolism (PE), or a kidney infarct, but patients with CAPS also have macrovascular involvement leading to thrombosis affecting other organs. In contrast, most APS patients present with a venous thromboembolism or ischemic stroke that typically does not acutely progress when treated with appropriate anticoagulation.

The mechanism by which a "thrombotic storm" occurs (see 'Definitions' above), rather than a single clot in one vascular bed, is not well understood. Whether individuals with CAPS have aPL with different antigen specificity, avidity, titer, or other features that differ from the aPL in APS is unknown. Based on our experience, most individuals with CAPS have triple aPL positivity with high titer immunoglobulin G (IgG) anticardiolipin and anti-beta2GPI antibodies.

Activation of immune cells and coagulation factors, release of neutrophil extracellular traps (NETS) – (See "Pathogenesis of antiphospholipid syndrome", section on 'Mechanisms of thrombotic antiphospholipid syndrome' and "Overview of hemostasis", section on 'Thrombin generation'.)

Role of complement – Various preclinical studies have suggested a role of complement activation in precipitating thrombosis in APS and CAPS. Regarding CAPS:

An in vitro study using a modified HAM test (a type of hemolysis test) to identify complement C5b-9 deposition on the surface of test cells identified complement activation (C5b-9 deposition) in 86 percent of CAPS sera, compared with 36 percent of non-CAPS APS sera and only 7 percent of sera from individuals with systemic lupus erythematosus (SLE) who did not have APS [5]. (See "Pathogenesis of antiphospholipid syndrome", section on 'Complement activation'.)

The same study evaluated complement regulatory genes and found that 6 of 10 CAPS patients (60 percent) had at least one pathogenic variant in one of these genes; in comparison, only 20 to 30 percent of patients with APS, SLE, or other controls had a pathogenic variant in a complement regulatory gene [5]. (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Pathogenic sequence variants in complement genes'.)

Once activated, complement produces C5a, a strong inflammatory mediator, and the C5b-9 complex, which attacks cell membranes [6]. C5b-9 causes hemolysis, resulting in the release of free heme that is prothrombotic. There is also damage to vascular endothelial cells that exposes subendothelial collagen and tissue factor, which can in turn activate platelets and initiate clotting. Complement attack on neutrophils may cause extrusion of DNA as NETs.

Complement dysregulation also has a pathophysiologic role in microvascular thrombosis with thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and acute kidney injury in complement-mediated thrombotic microangiopathy (CM-TMA), paroxysmal nocturnal hemoglobinuria (PNH), and other "complementopathies" [6]. (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS" and "Complement-mediated hemolytic uremic syndrome in children" and "Pathogenesis of paroxysmal nocturnal hemoglobinuria".)

It has been proposed that complement disorders may have a "two hit" mechanism in which the first hit (aPL or a complement gene abnormality) predisposes to complement dysregulation, and a second hit (infection, inflammation, pregnancy, surgery, or another stimulus) triggers complement-mediated cellular injury, with clinical manifestations of hemolysis and thrombosis [6]. Complement blockade may be effective in refractory CAPS. (See 'Eculizumab' below and "Pathogenesis of antiphospholipid syndrome".)

INCIDENCE — CAPS is rare, affecting approximately 1 percent of individuals with APS or 5 per million in the general population.

In the Euro-Phospholipid Project, which included 1000 patients with APS followed for 10 years, only nine (0.9 percent) developed CAPS [7].

In the APS Alliance for Clinical Trials and International Networking (APS ACTION) Registry, based on 804 international patients, only nine (1 percent) developed CAPS [2].

In two smaller series with nearly 300 patients total, rates of CAPS were 2 and 5 percent respectively [8,9].

Not all individuals with CAPS have a prior diagnosis of APS; in one series, approximately one-half of patients carried a prior APS diagnosis and one-half did not [1].

Overall, females are more likely to be affected than males (approximately 70 percent females and 30 percent males, more evenly distributed in patients without lupus), and the age range is broad, from children to older adults [10,11].

ADDITIONAL RISK FACTORS — Most episodes of CAPS are associated with additional thrombosis risk factors such as infection, surgical procedure, malignancy, or pregnancy, in an individual with clinically significant antiphospholipid antibodies (aPL). The diagnosis of antiphospholipid syndrome (APS) may be known at the time of presentation or may be identified during the evaluation of the acute presentation. (See 'Evaluation' below.)

In a series of 547 patients with 571 CAPS events, 68 percent had an additional thrombotic risk factor [10]:

Infection – 29 percent

Surgery – 9 percent

Cancer – 9 percent

Estrogen use – 4 percent

Pregnancy or postpartum – 3 percent

Active systemic lupus erythematosus (SLE) – 2 percent

Approximately one-half of these individuals presented with CAPS as their first manifestation of APS, and 28 percent were known to have had a prior diagnosis of SLE [10].

Inadequate anticoagulation in a patient with known APS may also increase the risk of CAPS. In a series that included 67 individuals with known APS who developed CAPS while receiving warfarin, the INR at the time CAPS developed was <2 in 72 percent [12]. These findings highlight the importance of adequate anticoagulation in individuals with APS. (See "Management of antiphospholipid syndrome", section on 'Secondary thrombosis prevention'.)

In the population of patients known to have aPL or APS, identifying and addressing additional thrombosis risk factors is important in preventing further thrombosis and possibly progression to CAPS. (See "Management of antiphospholipid syndrome", section on 'Reduction of risk factors'.)

CLINICAL MANIFESTATIONS — APS and CAPS represent a spectrum of clinical disorders. Initially it may not be clear whether an antiphospholipid antibodies (aPL)-positive individual with or without a diagnosis of APS is having isolated microvascular and/or hematologic complications of APS that will progress to a catastrophic presentation; the course may only become apparent when one or more macrovascular events has occurred. Consequently, vigilance is required to identify disease progression. Individuals who ultimately develop CAPS will typically manifest multiple thromboses, and generally, thrombocytopenia. (See 'Thrombosis and organ involvement' below and 'MAHA and thrombocytopenia' below.)

The most comprehensive information about CAPS and many of the studies cited below come from the CAPS Registry, a database with clinical information from hundreds of patients.

Thrombosis and organ involvement — Most patients have multiorgan involvement (and often multiorgan failure) on presentation [13]. Almost every organ system may be affected.

Commonly affected organ systems – In a report of 571 episodes of CAPS, the following organ systems were most likely to be affected [10]:

Kidneys – 74 percent (all with kidney failure)

Brain – 56 percent

Lungs – 55 percent

Heart – 53 percent

Skin – 45 percent

Liver – 34 percent

Peripheral vessels – 37 percent

Gastrointestinal tract – 12 percent

Extent of thrombosis – CAPS is characterized by multiple thromboses occurring in different vascular beds over a relatively short period of time (days). This contrasts with APS, in which there is typically a single, large-vessel thrombotic event (or a series of events separated in time, such as an initial pulmonary embolus [PE] followed by a deep vein thrombosis [DVT] months later in association with inadequate anticoagulation). (See "Clinical manifestations of antiphospholipid syndrome".)

Often in CAPS, thrombosis is microvascular as well as in large vessels. Large vessel thrombosis includes DVT in any vascular bed, PE, or arterial thrombosis (eg, ischemic stroke, myocardial infarction). Isolated microvascular thrombosis in a patient with APS may not indicate CAPS, but it does suggest an increased risk of progression to CAPS and implies the need for heightened vigilance.

Pulmonary involvement – Pulmonary involvement may progress to acute respiratory distress syndrome (ARDS) and may be complicated by PE or pulmonary hemorrhage [14]. Pulmonary microvascular involvement is generally in the form of alveolar hemorrhage, which can be asymptomatic with ground glass opacities on chest computed tomography (CT) or may present with gross hemoptysis.

Cardiac involvement – Cardiac involvement can include valve disease (mitral, aortic) or myocardial infarction.

Skin involvement – Cutaneous manifestations can include livedo reticularis/racemosa (picture 1), purpura, subungual hemorrhage, and skin necrosis [15].

Visceral and organ involvement – Abdominal pain may reflect intra-abdominal thrombotic complications affecting the vasculature of the kidneys, liver, adrenal glands, spleen, intestines, mesentery, or pancreas [16]. Other less common organ involvement includes testicular/ovarian infarction, acalculous cholecystitis, bone marrow infarction, esophageal rupture, and gastric and colonic ulcerations [16].

Kidney involvement – Individuals with kidney involvement often have fever, hypertension, proteinuria, and hematuria. A urinalysis with urine sediment may show proteinuria and hematuria.

Central nervous system (CNS) – CNS changes include acute ischemic encephalopathy with confusion, seizures, and/or focal findings.

MAHA and thrombocytopenia — Common findings on the complete blood count (CBC) and blood smear review include thrombocytopenia and schistocytes (picture 2).

Thrombocytopenia and microangiopathic hemolytic anemia (MAHA) are nonspecific features of microvascular thrombosis and are seen in other thrombotic microangiopathies (TMAs). In a series of 280 patients with CAPS, 42 (15 percent) had evidence of disseminated intravascular coagulation (DIC) [1]. DIC is a nonspecific finding, and, if severe, might suggest an alternative cause of the TMA findings. (See 'Differential diagnosis' below and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

EVALUATION

When to suspect — A high level of suspicion for CAPS should be maintained in any patient with features of multiorgan involvement (often with evidence of ischemic changes on imaging), rapid clinical deterioration, and findings suggestive of microangiopathic hemolytic anemia (MAHA) such as thrombocytopenia and schistocytes on peripheral blood smear, as illustrated in the figure (algorithm 1).

A prior diagnosis of APS or systemic lupus erythematosus (SLE) should further increase the clinical suspicion. Notably, approximately one-half of patients with CAPS do not have a known history of APS at the time of initial presentation, and the identification of APS occurs during the CAPS evaluation. (See 'Incidence' above.)

Important indicators that a patient may have CAPS rather than APS or another thrombotic disorder include rapidly progressive disease, multiorgan involvement, and a combination of large vessel and microvascular thrombosis.

Important indicators that a patient may have CAPS rather than sepsis or a primary thrombotic microangiopathy (TMA) include prior history of APS, large vessel thrombosis, and lack of known exposures associated with TMAs. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

During pregnancy, HELLP syndrome (hemolysis, elevated liver function tests, and low platelets) and CAPS may be challenging to distinguish and may coexist [17]. Patients presenting with clinical manifestations of either of these diagnoses should be cared for by experts with experience in both conditions, given the high likelihood of maternal and neonatal complications that may progress quickly. (See 'Differential diagnosis' below and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)

History and physical examination — The history and physical examination should focus on (algorithm 1):

History of APS or SLE (or findings consistent with these diagnoses) – (See "Diagnosis of antiphospholipid syndrome" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults".)

Clinical findings of large vessel or microvascular thrombosis or other manifestations – (See 'Thrombosis and organ involvement' above.)

Possible associated additional thrombosis risk factors – (See 'Additional risk factors' above.)

Alternative causes of thrombosis, MAHA, and thrombocytopenia – (See 'Differential diagnosis' below.)

These features are summarized in the table (table 1).

Laboratory testing — Some treatments, especially therapeutic plasma exchange (TPE), can obscure certain laboratory results, especially antibody levels, and it is best to obtain any laboratory testing that may be helpful before these treatments are administered (algorithm 1). (See 'Plasma exchange and/or IVIG' below.)

Laboratory evaluation includes the following, if not already done:

CAPS-associated laboratory changes:

CBC and blood smear – Complete blood count (CBC) with platelet count and blood smear review for signs of infection, MAHA, and thrombocytopenia. The blood smear should be reviewed by an experienced individual for schistocytes, manual platelet count review, and red blood cell (RBC) changes that could indicate an alternate diagnosis such as another cause of hemolytic anemia. (See "Diagnosis of hemolytic anemia in adults", section on 'CBC/blood smear review' and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Verify MAHA and thrombocytopenia'.)

Hemolysis testing – Reticulocyte count, lactate dehydrogenase (LDH), and haptoglobin can confirm hemolysis, although this testing is not needed to confirm hemolysis in patients with typical peripheral blood findings. The table summarizes typical findings (table 2).

aPL testing – Specific testing for antiphospholipid antibodies (aPL). It is generally recognized that IgG is clinically more significant than IgM.

-Anticardiolipin antibodies (aCL); IgG and IgM by enzyme-linked immunosorbent assay (ELISA)

-Anti-beta2GPI antibodies; IgG and IgM by ELISA

-Lupus anticoagulant (LA) assay – (see "Clinical use of coagulation tests", section on 'Lupus anticoagulant tests')

Criteria for APS include positive aPL testing on two occasions 12 weeks apart; if the diagnosis of APS has already been made, this testing does not need to be repeated during evaluation for CAPS. Testing for aPL and interpretation of results is presented separately. (See "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing' and "Diagnosis of antiphospholipid syndrome", section on 'Interpretation of positive results'.)

Complete metabolic panel – To evaluate liver or kidney injury, or other complications such as adrenal insufficiency.

Testing for possible triggering conditions – If the clinical situation warrants, test for infections, pregnancy, or to evaluate abnormalities on history or examination.

Testing to exclude alternative, overlapping, or triggering conditions:

ADAMTS13 activity for TTP – Especially if MAHA and thrombocytopenia are prominent findings, or if there is known familial thrombotic thrombocytopenic purpura (TTP). (See "Diagnosis of immune TTP", section on 'ADAMTS13 testing'.)

Anti-PF4 testing for HIT or VITT – Especially if there was recent heparin exposure or recent vaccination with an adenoviral vectored COVID-19 vaccine (or other similar vaccine). Testing can be serologic (heparin-induced thrombocytopenia enzyme linked immunosorbent assay [HIT ELISA]) or functional (serotonin release assay; may be negative in vaccine-induced immune thrombotic thrombocytopenia [VITT]). (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'HIT antibody testing' and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)", section on 'Evaluation'.)

Cultures for infection – Testing may include cultures of blood, urine, or other fluids.

Pregnancy test – Pregnancy testing (where appropriate) may identify possible trigger of CAPS or a possible pregnancy-associated syndrome.

Complement testing for complement-mediated thrombotic microangiopathy (CM-TMA) – Testing for disease variants in complement regulatory genes may be done to identify a CM-TMA, but these tests are slow to return, not diagnostic of CAPS, and are not found in all patients with clinically diagnosed CAPS. Low C3 and C4 are seen in both CAPS and CM-TMA and are relatively nonspecific [18]. (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Complement testing'.)

Imaging studies — Imaging may be needed if large vessel occlusion is suspected and/or to evaluate neurologic findings, provided the patient is stable and can tolerate the imaging procedure.

Brain imaging is especially important in individuals with neurologic symptoms prior to initiating anticoagulation, to ensure that there is no central nervous system bleeding.

Sensitive imaging techniques will identify characteristics of microvascular ischemia characteristic of these disorders.

Biopsy in selected cases — Tissue biopsy is not routinely performed in clinical practice; however, biopsy may be helpful in cases of diagnostic uncertainty, provided the patient can tolerate the procedure, bleeding risk is acceptable, and awaiting the results will not unnecessarily delay treatments.

If biopsy is pursued, it should focus on involved tissues and should consider potential complications, especially related to bleeding and thrombotic risks. The McMaster practice guideline suggests restricting biopsy to selected cases [19]. The guideline panel noted the following points: no randomized trials of biopsy have been conducted; sensitivity and specificity for CAPS is unknown; biopsy carries risks; and the results may not affect management. Tissue biopsy is included in the classification criteria for CAPS [20]. (See 'Management' below.)

There are no histologic features that distinguish CAPS from other TMAs on a biopsy specimen. Findings are consistent with CAPS or another TMA small vessel thrombosis (capillary, arteriole) with luminal shrinkage and endothelial edema [21].

Diagnosis — There are no pathognomonic findings that distinguish CAPS from other forms of thrombotic storm. Patients may have a prior diagnosis of APS, or findings consistent with APS may be identified during the evaluation, as illustrated in the figure (algorithm 1). Importantly, not all positive aPL tests indicate APS; APS requires identification of clinically significant aPL. (See "Diagnosis of antiphospholipid syndrome", section on 'Antiphospholipid antibody testing'.)

A diagnosis of suspected CAPS necessitates prompt initiation of aggressive treatment; treatment should not be delayed while awaiting the results of more extensive testing. (See 'Aggressiveness of initial therapy' below.)

Classification criteria for CAPS have been proposed by the International Congress on aPL and validated for research purposes [20]. These are research criteria and should not take the place of clinical judgment of a clinician with expertise in CAPS or individual with expertise in diagnosing thrombotic disorders. However, many clinicians refer to aspects of these criteria to guide them in making a diagnosis of CAPS.

Definite CAPS – Definite CAPS is present if all four criteria are present (table 1):

Involvement of ≥3 organs, systems, or tissues

Manifestations develop simultaneously or over <1 week

Small vessel occlusion is confirmed histologically in at least one organ or tissue

Presence of aPL (anticardiolipin antibodies, anti-beta2-glycoprotein I antibodies, and/or lupus anticoagulant) is documented twice, at least 12 weeks apart

Probable CAPS – Probable CAPS allows less stringent criteria:

Involvement of only two organs, and/or sites of tissue involvement

Manifestation of a third event develops between one week and one month after presentation, despite anticoagulation

No histologic confirmation

No laboratory confirmation of aPL

In a cohort of 220 patients and 175 controls with SLE or APS, definite CAPS classification was established in 81 CAPS patients (51 percent) and probable CAPS in an additional 70 (40 percent), for a sensitivity of 91 percent. Only one patient in the control group (0.6 percent) was classified as probable CAPS [22].

Differential diagnosis — The differential diagnosis of CAPS includes other thrombotic syndromes, especially those with venous and arterial thrombosis in multiple or unusual sites and those with microvascular thrombosis. Some of these conditions are summarized in the table (table 3).

It is important to note that there is not an either/or distinction between CAPS and these other conditions; CAPS may overlap with any of these conditions. If an individual with one of these conditions is positive for aPL, then the prognosis of the condition may be worse.

DIC – Disseminated intravascular coagulation (DIC) is a systemic condition involving widespread activation of coagulation and fibrinolysis that may occur in the setting of sepsis or malignancy. Like catastrophic APS, DIC may be associated with laboratory features including thrombocytopenia, low fibrinogen, and increased D-dimer or fibrin degradation products. Unlike CAPS, DIC is associated with an underlying systemic disorder (often infection or malignancy); and acute DIC is more likely to be associated with bleeding and increased prothrombin time (PT) and activated partial thromboplastin time (aPTT). (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

HIT and HIT variants – Heparin-induced thrombocytopenia (HIT) is an immune-mediated thrombocytopenia that occurs in the setting of heparin exposure. HIT variants including spontaneous HIT or COVID-19 VITT occur in the absence of heparin. In HIT syndromes, antibodies against platelet factor 4 (PF4) can cause platelet activation leading to potentially fatal arterial and venous thromboses. Like CAPS, HIT can cause thrombocytopenia. Unlike aPL in CAPS, HIT antibodies are directed against PF4/heparin complexes rather than platelet phospholipids. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

Primary TMAs – Thrombotic microangiopathies (TMAs) are systemic syndromes (acquired or inherited) in which small vessel platelet microthrombi form in various vascular beds, leading to thrombocytopenia, MAHA, and organ injury that may be life-threatening. Primary TMAs include TTP, CM-TMA, drug-induced TMA (DITMA), Shiga toxin-induced hemolytic uremic syndrome (ST-HUS), and others. Like CAPS, TMAs may present with unexplained severe thrombocytopenia and organ involvement. Unlike CAPS, TMAs typically do not cause large vessel thromboses (and are not treated with anticoagulation), and TMAs are generally associated with specific laboratory abnormalities related to their underlying pathophysiology, such as severe ADAMTS13 deficiency in TTP. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Vasculitis – Small-vessel vasculitis (particularly antineutrophil cytoplastic antibody [ANCA]-associated vasculitis) can manifest with multiorgan involvement (kidneys, lungs); patients may also have cutaneous lesions such as palpable purpura, petechiae, livedo reticularis, panniculitis, and ulcerations. Unlike CAPS, patients with ANCA-associated vasculitis are positive for ANCA and negative for aPL. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Cardiac involvement and vascular manifestations'.)

Sepsis – Sepsis due to overwhelming infection can cause multiorgan involvement and may be associated with coagulation abnormalities. Infection can also be a trigger for CAPS. Unlike patients with CAPS, patients with sepsis do not have positive aPL testing, and sepsis often improves with appropriate antibiotics. (See 'Additional risk factors' above and "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)

Preeclampsia or HELLP syndrome – Preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) are pregnancy-associated syndromes that can cause severe illness with thrombocytopenia and hemolytic anemia. Like CAPS, these conditions are associated with hemolysis and thrombocytopenia [23]. In persistently aPL-positive patients, these conditions can progress to CAPS. In aPL-negative patients, these disorders typically improve with delivery. (See "Preeclampsia: Clinical features and diagnosis" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)

MANAGEMENT

Aggressiveness of initial therapy — This management discussion presumes that the diagnosis of CAPS is likely, although clinical findings are a continuum, and expert input may be required to reach that conclusion. Often, treatment decisions for suspected CAPS must be made with incomplete clinical information and revised frequently as the patient's clinical status changes or new laboratory results become available, as illustrated in the figure (algorithm 2). Key diagnostic features are discussed above. (See 'When to suspect' above.)

Treatment of CAPS is much more aggressive than treatment of APS, so the implications of accurate diagnosis are large.

CAPS is typically treated with a combination of anticoagulation, glucocorticoids, and therapeutic plasma exchange (TPE) or intravenous immune globulin (IVIG), sometimes referred to as triple therapy [3].

APS is typically treated with anticoagulation.

Patients with suspected CAPS or other aggressive systemic thrombotic processes should be treated in a center with appropriate clinical expertise and therapeutic modalities, including the ability to do therapeutic plasma exchange. Multidisciplinary care is often necessary and may include involvement of hematology, rheumatology, nephrology, infectious disease, the intensive care team, and obstetrics when relevant. If this expertise and capabilities are not available, the patient should be transferred to a facility where they are available. Anticoagulation and glucocorticoids can be started before transfer.

Some treatments, especially plasma exchange, can obscure certain laboratory test results, and it is best to obtain any laboratory testing (especially antibody tests and ADAMTS13 activity) that may be helpful before these treatments are administered. (See 'Plasma exchange and/or IVIG' below.)

Rituximab or eculizumab are typically reserved for refractory disease but may occasionally be used as part of initial therapy. Their use is discussed further below. (See 'Refractory disease' below.)

Rituximab is often added for individuals with prominent microvascular involvement and/or severe thrombocytopenia, both of which are also common in thrombotic thrombocytopenic purpura (TTP), or those with progressive disease despite anticoagulation and glucocorticoids. (See 'Rituximab' below.)

Anti-complement therapy may be added for individuals with evidence of complement dysregulation, or sometimes in individuals with a prominent thrombotic microangiopathy (TMA) syndrome that continues to worsen despite other therapies. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Suspected complement-mediated TMA: Use anti-complement therapy'.)

Our approach to therapy is generally consistent with the McMaster guidelines on CAPS [19].

There are no randomized trials comparing the individual therapeutic options and this approach is largely based on observational evidence and expert opinion, including the 2018 McMaster guideline [19].

A 2018 report that included 471 patients observed that triple therapy (anticoagulation, glucocorticoids, and plasma exchange or IVIG) was associated with a higher survival rate [24]:

Triple therapy – Survival rate 71 percent

Single or combination of two therapies – Survival rate 59 percent

No therapy – Survival rate 25 percent

Another report documented a higher recovery rate was associated with triple therapy (69 percent) versus fewer than three therapies (54 percent) [1].

Anticoagulation and antiplatelet therapy — Therapeutic dose anticoagulation is required for all individuals with large vessel thrombosis (algorithm 2); this represents the majority of CAPS patients [3,19,25].

Parenteral anticoagulant – The choice of initial anticoagulant is intravenous unfractionated heparin. Heparin is avoided (and a non-heparin anticoagulant used) if heparin-induced thrombocytopenia (HIT) is considered likely. If HIT is ruled out with laboratory testing, intravenous heparin should be used in preference to other anticoagulants. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'HIT antibody testing'.)

Special considerations apply to individuals with platelet counts <50,000/microL. (See 'Anticoagulation with severe thrombocytopenia' below.)

Transition to warfarin – After recovery, hemodynamically stable patients may be transitioned to warfarin, and managed with a target international normalized ratio (INR) of 2 to 3. (See "Management of antiphospholipid syndrome", section on 'Long-term anticoagulation'.)

Direct oral anticoagulants (DOACs) are generally avoided in CAPS (and APS) due to the risk of recurrent thrombosis, especially arterial (stroke, myocardial infarction). (See "Management of antiphospholipid syndrome", section on 'Limited role of alternative agents'.)

Low-dose aspirin – For most patients with CAPS, we suggest low-dose aspirin, started without delay, in addition to anticoagulation. We also use aspirin in most individuals with CAPS who cannot receive anticoagulation. However, aspirin may reasonably be withheld in patients with a high risk of bleeding [19]. We generally start once-daily low-dose aspirin 81 to 100 mg. (See "Management of antiphospholipid syndrome", section on 'Arterial thrombosis'.)

Duration of therapy – Anticoagulation and low-dose aspirin are typically continued indefinitely, similar to treatment of APS, unless the bleeding risks are considered to outweigh the benefits. (See "Management of antiphospholipid syndrome", section on 'Duration of anticoagulation'.)

Supporting evidence – Randomized trials of anticoagulation or antiplatelet therapy in CAPS have not been reported. The McMaster CAPS guideline included a meta-analysis of observational data from 325 patients that found an association between anticoagulation and reduced mortality (odds ratio [OR] 0.18, 95% CI 0.09-0.38) [19].

Glucocorticoids — For nearly all patients with CAPS, we suggest high-dose glucocorticoids (algorithm 2). A rare exception would be an individual with exclusively moderate to large vessel disease (no microvascular disease) and severe concern about glucocorticoid side effects.

A typical dose is methylprednisolone, 0.5 to 1 g intravenously, once daily for three days; however, the dose should be evaluated daily, as earlier dose reduction is possible if there is significant clinical improvement. This is followed by oral or parenteral therapy with the equivalent of 1 mg/kg of prednisone per day with a taper started once the patient is clinically improving [25]. There are no specific guidelines on the speed of the taper; four to six weeks is reasonable. It is important not to taper too rapidly.

The large majority of patients who are discharged from the hospital will be off glucocorticoids within a few weeks of discharge, unless they have another diagnosis requiring long-term immunosuppression. As glucocorticoids are withdrawn, patients should be monitored for adrenal insufficiency that has occurred as a consequence of silent adrenal hemorrhage/infarction rather than due to a hypothalamic/pituitary axis suppression due to the exogenous glucocorticoid administration.

Randomized trials of glucocorticoids in CAPS have not been reported. Use of a glucocorticoid is supported by observational evidence of benefit when combined with other therapies [24].

Plasma exchange and/or IVIG — For most patients with CAPS, we suggest therapeutic plasma exchange (TPE) or intravenous immune globulin (IVIG), but typically not both (algorithm 2), in addition to anticoagulation and glucocorticoids [19]. Occasionally patients are treated with TPE (eg, five exchanges over five days) followed by IVIG. However, these therapies may reasonably be omitted (or delayed) in some patients.

Factors that may help in deciding between TPE and IVIG include:

Severe thrombocytopenia and kidney dysfunction generally favor TPE

Vascular access is required for TPE

Major bleeding, severe thrombocytopenia, and/or full-dose anticoagulation make TPE more challenging but are not contraindications to TPE; IVIG may be reasonable in these individuals.

The timing to start TPE is individualized, typically related to the certainty that CAPS is the diagnosis. If there is high confidence that CAPS is the diagnosis (eg, patient with known APS who presents with multiorgan failure), TPE is initiated without delay.

Plasma exchange – The mechanism by which TPE acts in CAPS is not clear; it may involve removal of antiphospholipid antibodies (aPL) or complement factors that contribute to pathogenesis. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Suspected TTP: Start therapeutic plasma exchange (TPE)'.)

Exchanges are typically performed once daily for five days (longer in patients with refractory disease); the optimal number of exchanges has not been determined. In one series, five consecutive treatments resulted in 95 percent lowering of anticardiolipin antibodies [26]. Details of the procedure and complications are discussed separately. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology" and "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)

Randomized trials comparing TPE to other therapies for CAPS have not been performed. Evidence to support the use of plasma exchange comes from observational studies that suggest plasma exchange performed as a component of triple therapy is associated with improved survival [27-29]. The McMaster CAPS guideline included a meta-analysis that found a trend towards lower mortality with plasma exchange that did not reach statistical significance (OR 0.68, 95% CI 0.41-1.12) [19]. There were no specific harmful effects reported among the patients with CAPS.

Despite the lack of randomized trials, CAPS is considered a first-line indication for therapeutic plasma exchange. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'ASFA therapeutic categories'.)

IVIG – The mechanism by which IVIG acts in CAPS is not clear; it may provide immunosuppression through a variety of actions. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Suppression of inflammatory/autoimmune processes'.)

A typical dose of IVIG is in the range from 400 mg per kg daily for five days. It should be given slowly in patients with kidney disease and older individuals. Additional information on dosing and complications of IVIG is presented separately. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Dosing and administration' and "Intravenous immune globulin: Adverse effects".)

IVIG is generally not used simultaneously with plasma exchange but, if both treatments are given, the IVIG should be administered after the course of plasma exchange is complete so that the exchange does not remove the immune globulins.

There is no evidence that IVIG alone improves survival, but observational studies suggest that, when given as a component of triple therapy, it is associated with improved outcomes. The McMaster CAPS guideline included a meta-analysis of six studies that found a trend toward lower mortality with IVIG that did not reach statistical significance (OR 0.86, 95% CI 0.50-1.48) [19]. Another study involving >500 patients compared relative benefits of plasma exchange and IVIG as the third component of triple therapy and did not find a statistical benefit of one over the other [24].

Refractory disease — Refractory disease is challenging to assess; it may include CAPS that does not improve (or worsens, such as progressive thrombosis) despite anticoagulation, glucocorticoids, and TPE or IVIG. In such cases, we typically add rituximab (a monoclonal antibody against the B cell antigen CD20) or eculizumab (a monoclonal antibody against the complement component C5).

The decision to use either one of these agents is individualized and based on specific patient characteristics (eg, rituximab for patients with a more TTP-like picture and less kidney involvement, eculizumab for patients with a more complement-mediated TMA-like picture with more severe kidney involvement). Information from diagnostic testing for other possible conditions may also become available and may help guide therapy.

Rituximab — A typical regimen of rituximab is 375 mg/m2 once weekly for four weeks, or 500 to 1000 mg given twice, separated by 7 or 14 days [30]. The dose has not been validated in clinical trials, and some experts use lower doses of rituximab for autoimmune disorders than are used in patients with lymphoproliferative neoplasms. (See "Immune TTP: Initial treatment", section on 'Rituximab'.)

Supportive data include small series, extrapolation from other TMAs, and a possible biologic rationale based on reduced production of aPL.

A 2013 review identified 20 patients treated with rituximab (8 for initial therapy and 12 for refractory CAPS) [30]. Of these 20 individuals treated with rituximab, 15 (75 percent) recovered, four died, and one remained in the intensive care unit at the time of publication.

Additional case reports describe successful treatment with rituximab, as part of initial therapy or for refractory disease [21,31-38]. While encouraging, causality cannot be inferred.

Eculizumab — A typical regimen is 900 mg weekly for four weeks followed by 1200 mg once every two weeks, although the dose has not been evaluated in a clinical trial [18]. The duration of therapy is unclear, however, given the enormous cost of eculizumab, it should be stopped once the patient's clinical status has returned to baseline.

Eculizumab increases risks for overwhelming sepsis from encapsulated organisms, and precautions should be used (meningococcal prophylaxis and vaccination). (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors' and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Administration and dosing'.)

Supportive data include small series, case reports, and a possible biologic rationale:

A 2022 report identified 39 patients treated with eculizumab (6 for initial treatment and 30 for refractory disease) [18]. Of these, 29 (74 percent) recovered and 9 (23 percent) worsened; five died. These 39 individuals represented 6.7 percent of 584 individuals in the Registry at the time the data were reported.

Small series (9 and 11 patients) have described mixed responses with eculizumab, with some individuals improving (78 percent in one series and 45 percent in the other) and others not [39,40]. Improvements in hematologic parameters (microangiopathic hemolytic anemia [MAHA] and thrombocytopenia) were more likely than improvements in kidney function, especially dialysis-dependent kidney disease. Individual case reports have described successful treatment with eculizumab [41-47]. While encouraging, causality cannot be inferred.

A potential role for complement dysregulation in CAPS provides a biologic rationale for anti-complement therapy. (See 'Pathophysiology/mechanism of thrombosis' above.)

Additional treatment considerations

Therapy for the triggering event — Any condition that may have triggered CAPS should be treated. (See 'Additional risk factors' above.)

Anticoagulation with severe thrombocytopenia — This subject is discussed separately. (See "Anticoagulation in individuals with thrombocytopenia".)

Pregnancy — Similar principles apply as discussed above. Time off anticoagulation should be minimized. Although usual therapies for CAPS should be used during pregnancy, the fetus should be monitored, and delivery should be considered if the mother has refractory disease or if there is evidence of fetal injury.

Anecdotal experience suggests that patients with CAPS in pregnancy have very high rates of fetal death, premature delivery, and neonatal complications.

Monitoring and follow-up — During the acute event, patients are monitored daily for clinical improvement and trends in the complete blood count (CBC) and metabolic parameters. There should be close follow-up for results of other testing to ensure that results are acted upon in a timely fashion and therapy adjusted if new information becomes available. Monitoring intervals are gradually extended as clinical status improves and continued after recovery. Monitoring the level of lactate dehydrogenase (LDH) appears particularly predictive of disease activity, presumably because it is a marker of hemolysis. (See 'Laboratory testing' above.)

Most patients are treated with long-term warfarin. (See "Management of antiphospholipid syndrome", section on 'Long-term anticoagulation' and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Outpatient management'.)

PROGNOSIS

Survival – CAPS has a high fatality rate if not treated. Even with aggressive treatment, the mortality may exceed 30 percent [10,27]. Early recognition and rapid initiation of appropriate therapies may improve survival. (See 'Aggressiveness of initial therapy' above.)

The main causes of death are cerebrovascular (stroke, intracerebral hemorrhage, encephalopathy), cardiac, and infectious, collectively accounting for two-thirds of mortality in one analysis [27]. In this study, systemic lupus erythematosus (SLE) was associated with higher mortality.

Recurrence risk – Individuals who recover from an episode of CAPS can have the disease recur. In an observational study of 58 individuals with CAPS who recovered and were followed for an average of 67 months, one-third had a relapse [48]. Approximately 20 percent had recurrent APS-related events, but none had another episode of multiorgan failure. Among the recurrent thromboembolic events, 40 percent occurred in a perioperative period.

The high frequency of perioperative thromboembolic events reinforces the importance of minimizing the period without anticoagulation in these individuals when they have surgery. (See "Perioperative management of patients receiving anticoagulants".)

PREVENTION — There are no high-quality studies on prevention, but it seems likely that reducing triggers in individuals with known APS might decrease the likelihood of developing CAPS. Examples might include minimizing periods without anticoagulation, reducing procoagulant exposures such as estrogen-containing contraceptives, and treating infections rapidly. (See "Management of antiphospholipid syndrome", section on 'Reduction of risk factors' and "Management of antiphospholipid syndrome", section on 'Management during pregnancy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Antiphospholipid syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Antiphospholipid syndrome (Beyond the Basics)" and "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)" and "Patient education: Pulmonary embolism (Beyond the Basics)")

Basics topic (see "Patient education: Choosing an oral medicine for blood clots (The Basics)")

SUMMARY AND RECOMMENDATIONS

Pathophysiology – Catastrophic antiphospholipid syndrome (CAPS) is a rapid-onset multiorgan syndrome with multiple vascular occlusions, often microvascular, occurring in individuals with persistently positive antiphospholipid antibodies (aPL), laboratory criteria for APS. A triggering factor for CAPS is often identified (infection, surgery, cancer, pregnancy, medications). Activation of complement may exacerbate thrombosis. (See 'Definitions' above and 'Pathophysiology/mechanism of thrombosis' above.)

Incidence – CAPS is rare, affecting approximately 1 percent of individuals with APS or 5 per million in the general population. Approximately one-half of individuals with CAPS have a prior known diagnosis of APS. (See 'Incidence' above.)

Clinical findings – CAPS is not merely severe APS. Most patients have multiorgan involvement (and often multiorgan failure). Kidneys, brain, lung, and heart are most frequently affected. Large vessel thrombosis as well as microvascular involvement, with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, are often seen. (See 'Clinical manifestations' above.)

Evaluation – A high level of suspicion should be maintained in patients with multiorgan failure, MAHA, thrombocytopenia, or a history of APS, who have rapid clinical deterioration (algorithm 1). The evaluation focuses on identifying thrombosis, aPL, and triggering factors. The differential diagnosis includes other thrombotic microangiopathies (TMAs), disseminated intravascular coagulation (DIC), heparin-induced thrombocytopenia (HIT) and HIT variants, TMAs such as thrombotic thrombocytopenic purpura (TTP), sepsis, vasculitis, and pregnancy complications. (See 'Evaluation' above and 'Differential diagnosis' above.)

Laboratory testing includes:

Complete blood count (CBC) and blood smear review

aPL testing

Metabolic panel and kidney function

Testing for triggering conditions (blood cultures for fever, pregnancy test for some females)

ADAMTS13 activity, anti-PF4 antibodies, and/or complement testing in the appropriate clinical setting

Diagnosis – The diagnosis is based on clinical features defined in the classification criteria (table 1). These criteria can support the diagnosis of definite or probable CAPS but should not take the place of clinical judgment (algorithm 1). Features supporting the diagnosis of CAPS rather than APS or another thrombotic disorder include rapidly progressive disease, multiorgan involvement, and a combination of large vessel and microvascular thrombosis. (See 'Diagnosis' above.)

Management – CAPS (or strongly suspected CAPS) is treated with anticoagulation, glucocorticoids, and therapeutic plasma exchange (TPE) or intravenous immune globulin (IVIG), sometimes referred to as triple therapy (algorithm 2). Patients should be treated in a center with appropriate clinical expertise and the ability to perform TPE. (See 'Management' above.)

Anticoagulation/antiplatelet therapy – Therapeutic dose anticoagulation is required for all individuals with a large vessel thrombosis. Unfractionated heparin is typically used unless there is high suspicion for HIT (in which case a non-heparin parenteral agent is used) or unless bleeding risk is considered too great.

We also suggest low-dose aspirin for all patients with CAPS unless there is a high risk of bleeding (Grade 2C). (See 'Anticoagulation and antiplatelet therapy' above.)

Glucocorticoids – For nearly all patients with CAPS, we suggest high-dose glucocorticoids (Grade 2C). Methylprednisolone is given once daily for three days (typical dose, 0.5 to 1 g intravenously per day), followed by oral or parenteral therapy (equivalent to prednisone 1 mg/kg daily). (See 'Glucocorticoids' above.)

TPE or IVIG – For most patients with CAPS, we also suggest TPE or IVIG (Grade 2C). This may require transfer to another facility. It may be reasonable to omit or delay these therapies in some patients. TPE is generally favored in patients with TTP-like presentations; IVIG may be used in preference to TPE when there is thrombocytopenia without other TMA features. TPE and IVIG are usually not combined. (See 'Plasma exchange and/or IVIG' above.)

Refractory disease – We often reserve rituximab and eculizumab for refractory disease, although these may be used initially in selected cases (rituximab for TTP-like presentations [severe thrombocytopenia and microvascular thrombosis without kidney injury], eculizumab for suspected complement-mediated TMA with acute kidney injury). (See 'Refractory disease' above.)

Recovery – Mortality is >30 percent despite treatment. Most deaths are due to multiorgan failure or cerebrovascular, cardiac, or infectious complications. Recurrences occur in approximately one-third of patients. Close attention to anticoagulation and avoidance of triggers are key to prevention. (See 'Prognosis' above and "Management of antiphospholipid syndrome", section on 'Reduction of risk factors'.)

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