Elsevier

Journal of Autoimmunity

Volume 92, August 2018, Pages 1-11
Journal of Autoimmunity

The diagnosis and clinical management of the catastrophic antiphospholipid syndrome: A comprehensive review

https://doi.org/10.1016/j.jaut.2018.05.007Get rights and content

Highlights

  • CAPS is characterized by the development of multiple thrombosis in a short period of time, mainly affecting small vessels.

  • Most CAPS episodes are related to a precipitating factor such as infections, surgical procedures or malignant diseases.

  • The disease usually involves the kidneys, the lungs and the heart, although any organ system can be affected.

  • Treatment is based on the administration of anticoagulants, corticosteroids, plasma exchange and/or intravenous immunoglobulins.

  • Rituximab and eculizumab have also been used in refractory cases. However, mortality is still around 30% despite treatment.

Abstract

The catastrophic antiphospholipid syndrome (CAPS) is a life-threating variant of the antiphospholipid syndrome characterized by the development of multiple thrombosis in a short period of time, usually ending up in the failure of function of several vital organs. Most CAPS episodes are related to a prothrombotic situation or precipitating factor such as infections, surgical procedures or malignant diseases. In patients with CAPS, the development of multiple thrombosis leads to an important cytokine release that worsens the already critical patient's situation. The disease usually involves the kidneys, the lungs and the heart, although any organ system can be affected. Although occasionally the disease affects large vessels, in the majority of cases it affects small vessels, leading to a disseminated microangiopathic syndrome resembling thrombotic thrombocytopenic purpura. Treatment is based on the administration of anticoagulants, corticosteroids, plasma exchange and/or intravenous immunoglobulins. Cyclophosphamide is recommended in those CAPS cases associated to systemic lupus erythematosus. Additionally, rituximab and eculizumab have been used in refractory cases. Mortality is still around 30% despite current treatment.

Introduction

The antiphospholipid syndrome (APS) is an autoimmune disorder characterized by an increased risk of thrombosis and pregnancy loss associated with antiphospholipid antibodies (aPL) [1]. Persistently positive lupus anticoagulant (LAC), moderate to high titers of anticardiolipin (aCL) or anti-β2-glycoprotein I (aβ2GPI) antibodies, in isolation or in any combination, are the aPL included in the updated revised classification criteria for APS [2].

This syndrome is currently considered the most frequent cause of acquired thrombophilia. In a recent systematic review, the frequency of aPL in young patients with cerebrovascular events was estimated at 17%, increasing to 22% for aCL in patients with stroke [3]. Regarding pregnancy morbidity, myocardial infarction, and deep venous thrombosis, the overall frequency of aPL was estimated as 6%, 11%, and 9.5%, respectively [4]. These figures are of paramount importance considering that APS is not only a frequent disorder but also an effectively treatable disease. In general, current consensus is to treat APS patients with thrombotic manifestations with long-term oral anticoagulation therapy and those with obstetric features with aspirin or the combination of aspirin and heparin [5].

Approximately 1% of APS patients develop a severe clinical picture characterized by multiple thromboses involving mainly small vessels [6]. In the first descriptions of this devastating type of APS, mortality raised to 50% of patients [7]. Due to this poor prognosis, the term “catastrophic” was introduced to describe this life-threatening form of APS [8]. Patients with catastrophic APS (CAPS) have in common: a) clinical evidence of multiple organ involvement (commonly, three or more organs) developing over a very short period of time; b) histopathological evidence of multiple small vessel occlusions, and c) laboratory confirmation of the presence of aPL, usually in high titers [9].

Therefore, although uncommon, its potentially lethal outcome emphasizes its importance in clinical medicine today. Most patients with CAPS end up in intensive care units (ICU) with multi-organ failure. Unless the condition is considered in the differential diagnosis by the attending physicians, it may be completely missed, resulting in a disastrous outcome for these patients [10].

Due to the rarity of this syndrome, an international registry of patients with CAPS was created in 2000 by the European Forum on Antiphospholipid Antibodies, a network of research groups devoted to the development of multicenter projects with large populations of APS patients [11]. This database is named “CAPS Registry” and currently documents the clinical, laboratory and therapeutic data of more than 500 patients with CAPS. The periodical analysis of these data has allowed not only the description of the clinical and laboratory characteristics of this syndrome [[12], [13], [14], [15]] but also the elaboration of diagnostic algorithms [10], classification criteria and therapeutic guidelines [9].

Section snippets

Pathogenesis

Unfortunately, the pathogenesis of the APS is not well understood. It is still unclear why some patients will develop sporadic thrombosis, often confined to a single site and mainly affecting large vessels (i.e., classic APS), while others develop rapidly recurring vascular occlusions, predominantly affecting small vessels simultaneously or over a short period of time, and at multiple sites (i.e., CAPS). The explanation of the lack of studies on the pathophysiological mechanisms of the CAPS is

Clinical features

The detailed analysis of the 500 patients included in the “CAPS Registry” [12] showed that 69% were female, with a mean age of 38 years. Sixty percent suffered from primary APS, 30% from SLE, 4% from lupus-like disease, and 6% from other autoimmune diseases. Patients may develop CAPS de novo, without any previous history of a thrombosis (46%) [26].

In general, the clinical manifestations of CAPS have been related with two factors: the extent of the thrombosis and the organs directly affected by

Laboratory features

Thrombocytopenia was detected in 67% of cases from the “CAPS Registry” [12]. One third of all the patients had evidence of hemolysis and 11% had some of the features of disseminated intravascular coagulation (DIC) [12]. Laboratory features consisting with thrombotic microangiopathic hemolytic anemia (TMHA) was present in 16% of the patients analysed in this registry. Furthermore, CAPS has been found to be the most common clinical presentation in patients with TMHA associated to aPL [28].

Classification and diagnosis

When CAPS is suspected, an aggressive treatment is required. Therefore, early diagnosis is very important to start adequate therapy and decrease the high mortality rate of these patients.

In order to facilitate the diagnosis of this severe complication, a preliminary classification criteria for CAPS were proposed during the 10th International Congress on aPL in 2002 [9] (Table 1) and later validated [29]. However, in the real-world setting, the diagnosis of CAPS may be very difficult. It is

Differential diagnosis

Thrombotic microangiopathy is a syndrome that includes several disorders characterized by localized or diffuse microvascular thrombosis [32]. As discussed above, CAPS is characterized by multiple microvascular and macrovascular occlusions in a short time and, therefore, it should be included in the differential diagnosis of thrombotic microangiopathies [33]. Therefore, diagnosis of CAPS requires excluding other entities such as TTP, hemolytic uremic syndrome (HUS), DIC in the context of

Management approach

The optimal management of CAPS has been a challenge since its description. Today, CAPS mortality continues to be extremely high despite therapy [34,[38], [39], [40]]. Due to this high mortality rate, early diagnosis and aggressive treatment are essential clues in its successful management.

The evaluation of CAPS treatment in formal prospective randomized studies is very difficult due to its low incidence. This is why, in order to improve our knowledge on this condition, the analysis of hundreds

Refractory catastrophic antiphospholipid syndrome

The term refractory CAPS refers to both patients who died despite the use of first-line therapies as well as to patients suffering recurrent episodes of CAPS [90].

Considering patients with recurrent episodes of CAPS (“relapsing” catastrophic APS), our group documented in 2008 three patients with seven episodes [91]. The median time between the episodes of CAPS was 12.5 months (range, 2.5–48). From the clinical point of view, the most significant manifestations were renal involvement (present in

Mortality and prognosis factors

Among the 500 patients analysed from the “CAPS Registry”, 37% died at the time of the CAPS event [40]. The presence of SLE was associated with a higher mortality (47%) [40]. Moreover, at the time of CAPS diagnosis, those with SLE associated had a higher risk for mortality alter adjusting for age, sex, organ involvement, and treatment [26].

The main cause of mortality was infection (20%), produced by bacterial sepsis (12%), fungal sepsis (4%), Pneumocystis jiroveci pneumonia (3%), and suppurative

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