Catastrophic antiphospholipid syndrome in a community-acquired methicillin-resistant Staphylococcus aureus infection: a review of pathogenesis with a case for molecular mimicry

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has remarkable pathogenicity and can cause severe infections, such as necrotizing pneumonia, necrotizing fasciitis, and sepsis. To our knowledge, no case of CA-MRSA resulting in catastrophic antiphospholipid syndrome (CAPS) has been reported. Furthermore, no specific pathogenic link between these two disorders has been described. Staphylococcal sequence homologies and binding capabilities to plasma protein β2-glycoprotein I (β2-GPI) may result in anti-β2-GPI antibody production. These antibodies represent the critical prothrombotic factor in pathogenesis of antiphospholipid syndrome and CAPS. However, the development of CAPS requires additional prothrombotic activities. In our case, sepsis and CA-MRSA-induced leukocytolysis likely represent the activity required to transform a hypercoagulable state into the life threatening, diffusely thrombotic CAPS. The presence of anti-β2GPI-antibodies and diffuse microvascular occlusion are characteristic of CAPS. However, other life threatening syndromes cause microvascular thrombi and multiorgan failure, and more studies are needed to determine the frequency of antiphospholipid antibodies and clinical syndromes consistent with CAPS in patients with staphylococcal infections.     

Catastrophic antiphospholipid (Asherson's) syndrome and genetic thrombophilic disorders in obstetrics

Catastrophic antiphospholipid syndrome (CAPS) (Asherson's Syndrome), is a life-threatening condition characterized by a rapidly progressive thromboses resulting in a multiorgan dysfunction syndrome (MODS), evidence of systemic inflammatory response syndrome (SIRS) in the presence of antiphospholipid antibodies. CAPS differs from the classic APS by predominantly affecting small vessels, involvement of unusual organs, rapid onset of MODS, and the development of acute respiratory distress syndrome (ARDS) in 25% of patients, which is a feature of SIRS. Obstetric-related multiorgan failure may be a feature of a subset of CAPS more frequently than was previously thought. Patients with obstetric complications should be tested for antiphospholipid antibodies and genetic thrombophilia in order to institute early prophylaxis. Low-molecular-weight heparin is the drug of choice for preventing obstetric complications and CAPS due to its anticoagulant and anti-inflammatory properties.     

All that seems sepsis is not sepsis

Catastrophic antiphospholipid antibody syndrome (CAPS) resembles severe sepsis in its acute presentation, with features of systemic inflammatory response syndrome (SIRS) leading to multiple organ dysfunction. Infections are the best known triggers of CAPS. This emphasizes the need for early diagnosis and aggressive treatment as the mortality is as high as 50%. We present a 42-year-old woman who developed SIRS postoperatively and was eventually diagnosed as CAPS.     

Current knowledge regarding Asherson’s syndrome

Catastrophic antiphospholipid (Asherson’s) syndrome (CAPS) is known to be a severe variant (1%) of antiphospholipid syndrome, with a high rate of mortality (50%). The distinguishing feature of CAPS is microvascular thromboses in the presence of antiphospholipid antibodies. Molecular mimicry between β2-glycoprotein I and infectious agents, endothelial cell activation and reduced fibrinolysis are the most frequently described pathophysiological mechanisms. Genetic risk factors have also been implicated in the onset of CAPS, although these have not yet been identified. There have been no randomized, controlled trials evaluating the efficacy of any medication on CAPS; however, when CAPS is suspected, aggressive multimodal treatment is required. Patients who receive a combination of anticoagulation therapy, glucocorticosteroids and plasma exchange with or without intravenous immunoglobulin show the best survival rates. Herein, we review the clinical and laboratory findings, diagnostic criteria, pathophysiology, treatment and prognosis of CAPS.     

The Catastrophic Antiphospholipid Syndrome in Serbia: Diagnostic and Management Problems

Antiphospholipid antibodies (aPL) are a common cause of acquired thrombophilia, termed antiphospholipid syndrome (APS, Huges syndrome). Catastrophic antiphospholipid syndrome (CAPS, Asherson’s syndrome) is an unusual form of APS characterized with multi-organ failure and high mortality. Fortunately, CAPS accounts for less than 1% of APS cases. The recurrence rate is low with a stable clinical course if these patients are treated with adequate anticoagulation therapy. Due to the rarity of the condition, an international registry of CAPS patients was created in 2000 supported by the European Forum on Antiphospholipid Antibodies held in Taormina, Italy at the Tenth International Congress on aPL. The objective of our study is to describe characteristics of 12 Serbian patients with CAPS included in the international CAPS registry.     

Clinical and Laboratory Features of the Catastrophic Antiphospholipid Syndrome

Catastrophic antiphospholipid syndrome (CAPS, Asherson’s syndrome) is an unusual form of antiphospholipid syndrome (APS) characterized by multi-organ failure and high mortality. Fortunately, CAPS accounts for less than 1% of APS cases. Due to the rarity of the condition, an international registry of CAPS patients was created in 2000 supported by the European Forum on Antiphospholipid Antibodies held in Taormina, Italy at the Tenth International Congress on Antiphospholipid Antibodies. Clinical and laboratory features are the most important in the criteria for the diagnosis of this syndrome and can affect many organ systems. The majority of patients presented with multiple organ involvement at the time of CAPS. The combination of pulmonary, cardiac, and renal involvement was most commonly seen. The organ systems most commonly involved at the onset include the cardiopulmonary system, primarily characterized by dyspnea and respiratory failure, the central nervous system, and the renal system. Laboratory criteria for the classification of CAPS include the presence of antiphospholipid antibodies—LA and/or aCL and/or β₂-GPI antibodies.     

Hypotrichosis‐lymphedema‐telangiectasia‐renal defect associated with a truncating mutation in the SOX18 gene

SOX18 mutations in humans are associated with both recessive and dominant hypotrichosis–lymphedema–telangiectasia syndrome (HLTS). We report two families with affected children carrying a SOX18 mutation: a living patient and his stillborn brother from Canada and a Belgian patient. The two living patients were diagnosed with HLTS and DNA analysis for the SOX18 gene showed that both had the identical heterozygous C > A transversion, resulting in a pre‐mature truncation of the protein, lacking the transactivation domain. Both living patients developed renal failure with severe hypertension in childhood for which both underwent renal transplantation. To our best knowledge this is the first report of renal failure associated with heterozygous mutations in the SOX18 gene. We conclude that this specific mutation results in a new, autosomal dominant condition and propose the acronym HLT‐renal defect syndrome for HLTRS.     

The catastrophic antiphospholipid (Asherson's) syndrome

The catastrophic antiphospholipid syndrome (CAPS, Asherson's syndrome) develops rapidly following an identifiable triggering factor (eg infection, trauma, inadequate coagulation neoplasia, obstetric) in antiphospholipid antibody positive patients. It is most frequently encountered in patients with a primary antiphospholipid syndrome or systemic lupus erythematosus (SLE) or "lupus-like" disease (LLD). It manifests mainly with small vessel thromboses affecting organs (gastrointestinal tract, brain, heart), large vessel occlusions in one-third, manifestations of the systemic inflammatory response syndrome (SIRS), particularly the acute respiratory distress syndrome (ARDS). The mortality is high, although with early and effective therapies, including full parenteral anticoagulation, corticosteroids, plasma exchanges and IV globulins, an improvement in this high death rate has been noted recently.     

The catastrophic antiphospholipid (Asherson's) syndrome and malignancies

The catastrophic antiphospholipid syndrome is characterised by the rapid chronological development of fulminant thrombotic complications that predominantly affect small vessels. It has been reported as frequently occurring in patients with underlying malignancies. We analysed the web site-based international registry of patients with catastrophic APS. The clinical characteristics of patients with CAPS and an underlying malignancy were evaluated. Of the 262 patients included in the CAPS registry, information on associated malignancies was available in 23 (9%) cases. Haematological malignancies were present in 6 (26%) patients. Four of the patients suffered from lung carcinoma (17%), and two patients (9%) from colon carcinoma. In most of the patients (61%), malignancy was the precipitating factor for CAPS. In 4 patients (17%), however, surgical procedures related to the carcinoma were noted as precipitating factors. In one patient CAPS occurred during allogenic stem cell transplantation after diagnosis of acute lymphoblastic leukemia (ALL). Cerebral manifestations were most common and consisted mainly of cerebral infarcts and encephalopathy. Recovery occurred in 9/23 (39%) patients. Malignancy may be an important risk factor for CAPS. 9% of patients with CAPS presented with an underlying malignancy. In most of these patients, the malignancy and/or surgical procedures were the precipitating factors for CAPS.     

Catastrophic antiphospholipid syndrome: CAPS]

Antiphospholipid syndrome (APS) is well known as an autoimmune thrombotic syndrome with recurrent thromboses. In APS, thromboses occurs both artery and vein, and from large to micro vessels. In contrast, so called catastrophic antiphospholipid syndrome, CAPS, develops multiple thromboses at microvessels mainly within a few weeks and induces to poor prognosis. CAPS often occurs in patients with SLE or primary APS after a change of antithrombotic therapy, infection, and operation. Treatments for CAPS have not established although plasma exchange is carried out usually as well as intensive anticoagulation and immunosuppressive therapy. We treated with immunoadsorption plasmapheresis (IAPP) for 5 CAPS patients and they improved their clinical symptoms and ameliorated their titers of antiphospholipid antibodies. IAPP could be an useful treatment skill for CAPS and we have started prospective study.     

A 34-year-old Japanese patient exhibiting NBAS deficiency with a novel mutation and extended phenotypic variation

Biallelic neuroblastoma amplified sequence (NBAS) gene mutations have recently been identified to cause a reduction in its protein expression and a broad phenotypic spectrum, from isolated short stature, optic nerve atrophy, and Pelger–Huët anomaly (SOPH) syndrome or infantile liver failure syndrome 2 to a combined, multi-systemic disease including skeletal dysplasia and immunological and neurological abnormalities. Herein, we report a 34-year-old patient with a range of phenotypes for NBAS deficiency due to compound heterozygous variants; one is a SOPH-specific variant, p.Arg1914His, and the other is a novel splice site variant, c.6433-2A>G. The patient experienced recurrent acute liver failure until early childhood. Hypogammaglobulinemia, a decrease in natural killer cells, and optic nerve atrophy were evident from infancy to childhood. In adulthood, the patient exhibited novel phenotypic features such as hepatic cirrhosis complicated by portal hypertension and autoimmune hemolytic anemia. The patient also suffered from childhood-onset insulin-requiring diabetes with progressive beta cell dysfunction. The patient had severe short stature and exhibited dysmorphic features compatible with SOPH, intellectual disability, and epilepsy. NBAS protein expression in the patient's fibroblasts was severely low. RNA expression analysis for the c.6433-2A>G variant showed that this variant activated two cryptic splice sites in intron 49 and exon 50, for which the predicted consequences at the protein level were an in-frame deletion/insertion, p.(Ile2199_Asn2202delins16), and a premature termination codon, p.(Ile2199Tyrfs*17), respectively. These findings indicate that NBAS deficiency is a multi-systemic progressive disease. The results of this study extend the spectrum of clinical and genetic findings related to NBAS deficiency.     

Therapeutic and prognostic considerations in catastrophic antiphospholipid syndrome

Catastrophic antiphospholipid syndrome (CAPS) is a rapidly progressive life-threatening disease that causes multiple organ thromboses in the presence of antiphospholipid antibodies. High index of clinical suspicion and careful investigation are required to make an early diagnosis so that treatment with anticoagulation, corticosteroids, and plasma exchange or intravenous immunoglobulins can be initiated. Despite this multi-modal treatment, CAPS is associated with high mortality; evidence-based management recommendations do not exist due to the rarity of the condition and the lack of controlled studies. This article reviews the therapeutic and prognostic controversies that were addressed during the 1st International Symposium on CAPS.     

Glucose metabolism and insulin secretion in a patient with ABCC8 mutation and Fanconi-Bickel syndrome caused by maternal isodisomy of chromosome 3

Fanconi-Bickel syndrome (FBS) is a rare disorder of glucose transport caused by autosomal recessive mutations in GLUT2. Clinically, FBS results in growth failure, hepatomegaly, renal Fanconi syndrome, and abnormal glucose homeostasis. We report a 23 month old female with FBS characterized by more severe and refractory hypoglycemia than typically seen in this disorder. Although previous reports indicate that FBS patients have diminished insulin secretion, our patient showed evidence of hyperinsulinism (HI). Sequence analysis showed that the patient was homozygous for a known null mutation in GLUT2, confirming the clinical diagnosis of FBS. Parental genotyping showed that the mother was heterozygous for the GLUT2 mutation, while the father was wild type. Tandem repeat marker analysis showed that the patient inherited the GLUT2 mutation via maternal isodisomy of chromosome 3. Further molecular testing showed that the patient was heterozygous for a mutation in ABCC8, a known cause of congenital HI. We discuss the patient's biochemical responses in light of the molecular findings.     

Eculizumab in refractory catastrophic antiphospholipid syndrome: a case report and systematic review of the literature

Clinical and Experimental Medicine - Catastrophic antiphospholipid syndrome (CAPS) is a rare disorder, characterized by the development of multiple vascular thrombosis over a short period of time,...     

New subsets of the antiphospholipid syndrome in 2006: "PRE-APS" (probable APS) and microangiopathic antiphospholipid syndromes ("MAPS")

The concept of "probable" antiphospholipid syndrome (APS) is almost identical with several conditions which may presage the development of the APS with its major complications of large vessel thromboses resulting in deep vein occlusions in the lower limbs (DVT) particularly and strokes. These conditions comprising livedo reticularis, chorea, thrombocytopenia, fetal loss and valve lesions. These conditions, comprising livedo reticularis, chorea, thrombocytopenia, fetal loss and valve lesions may be followed, often years later by diagnosable APS. The issue whether these patients should be more aggressively treated on presentation in order to prevent the thrombotic complications. A new subset of the APS is proposed viz. microangiopathic antiphospholipid syndrome ("MAPS") comprising those patients presenting with thrombotic microangiopathy and demonstrable antiphospholipid antibodies who may share common although not identical provoking factors (e.g. infections, drugs), clinical manifestations and haematological manifestations (severe thrombocytopenia, hemolytic anaemia) and treatments viz. plasma exchange. Patients without large vessel occlusions may be included in the MAPS subset. These conditions include thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and the HELLP syndrome. Patients with catastrophic antiphospholipid syndrome (CAPS) who do not demonstrate large vessel occlusions also fall into this group. Disseminated intravascular coagulation (DIC) has also been reported with demonstrable antiphospholipid antibodies and also manifests severe thrombocytopenia and small vessel occlusions. It may cause problems in differential diagnosis.     

Kidney disease in antiphospholipid antibody syndrome: Risk factors,pathophysiology and management

Antiphospholipid antibody syndrome (APLS) is a rare autoimmune disease characterized by recurrent arterial and venous thromboembolic events, pregnancy related complications as well as the persistent detection of antiphospholipid antibodies at a 12 week interval. Renal complications tend to occur in 3% of APLS patients, with renal artery stenosis being the most common kidney related complication. Renal pathology may be subdivided into macro as well as microvascular thrombotic complications with stenosis, thrombosis and infarction representing the principle macrovascular events and APLS nephropathy representing the predominant microvascular complication. APLS related kidney disease may present with an array of heterogenous manifestations ranging from hematuria and non-nephrotic range proteinuria to hypertension or as part of a severe, life threatening and fulminant multiorgan failure disorder known as catastrophic antiphospholipid antibody syndrome (CAPS). Management of APLS related renal complications depends on the site of vascular injury, the thromboembolic risk profile based on the subtype, isotype and titer of the autoantibodies as well as the severity of the injury. Primary prophylaxis in these patients primarily revolves around the use of low dose aspirin, with prophylactic anticoagulation during events that increase thromboembolic like surgery and hospitalization. Anticoagulation is the cornerstone of treatment of APLS related kidney disease with INR targets varying depending on the associated venous or arterial thrombosis. Immunosuppression with the likes of rituximab, mTOR inhibitors, eculizumab and belimumab have been used with some success, but lack randomized control trial validation for their use. Pulsed corticosteroids with Plasmapheresis and intravenous immunoglobulins is the recommended treatment for CAPS.     

ARDS in fulminant ornithosis and treatment with extracorporeal lung assist

We report a 47-year-old male patient with fulminant ornithosis who developed severe respiratory failure leading to acute respiratory distress syndrome (ARDS) complicated by gastrointestinal, neurological and renal symptoms. ARDS was successfully treated by extracorporeal lung assist. As leukocytosis is typically absent in ornithosis, C-reactive protein, interleukin 6 and procalcitonin were used as infection parameters in order to monitor clinical development. The English-language literature on severe cases of ornithosis requiring respiratory support over the past 30 years is reviewed.     

Catastrophic secondary antiphospholipid syndrome with peripheral nervous system involvement: a case report

A 34-year-old woman was admitted to our emergency room with a high fever, abdominal pain, dyspnea and confusion. High fever and abdominal pain had first occured after a cystocele operation 5 months earlier. Later, congestive heart failure with mural thrombus formation, peripheral polyneuropathy and ischemic cerebrovascular accident were identified in clinical follow-ups, and multiple arterial and venous thromboses were seen on cranial and abdominal magnetic resonance imaging angiography. The patient's symptoms improved with anticoagulant treatment. Antiphospholipid syndrome with elevated serum anticardiolipin IgG levels was diagnosed, and ischemic peripheral polyneuropathy with axonal degeneration was determined by sural nerve biopsy. In antiphospholipid syndrome, elevated anticardiolipin antibodies appear to be the most common acquired blood protein defect causing thrombosis. Disseminated vascular thrombosis in catastrophic antiphospholipid syndrome can result in multiorgan failure with increased morbidity and mortality. It rarely occurs secondary to various infections as in the case of our patient, who suffered postoperative intraabdominal infection. It is important to note that peripheral nervous system involvement is rare in antiphospholipid syndrome.