Thrombotic Storm Research Articles

Thrombotic storm and malignancy in elderly woman: a case report

Thrombotic storm is a state of hypercoagulability of relevance in the context of neoplasias, trauma, gestation, autoimmune diseases and deficiencies of coagulation proteins. The following case brings this topic associated with weight loss and a subsequent atypical primary site of neoplasm found in postmortem biopsy. Objectives: To present an atypical case of thrombosis in several sites in elderly women in a context of consumptive syndrome without definite primary cancer site; to discuss differentials and pathophysiological processes relevant to the case. Case report: A 74-year-old female patient, previously healthy, presented a constipation associated with weakness in right superior limb, edema and weakness of left lower limb, with difficulty in gait and subsequent bed restriction. It evolved with multiple thrombotic events (axillary arterial, segmental branches of the left pulmonary artery, hepatic, renal and splenic parenchymal infarction, deep venous thrombosis in the common femoral vein, superficial femoral vein and left femoral vein, and right superficial femoral vein thrombosis). Abdominal computed tomography (CT) showed hepatic nodules suggestive of metastases and lymph node enlargement up to 2.0 cm. Hepatic biopsy was performed by interventional radiology resulting inconclusive due to extensive areas of necrosis. Laboratory tests revealed hepatic enzymes, canalicular and direct bilirubin with increased and increasing values, normochromic normocytic anemia worsening and with increasing values of RDW and platelets. Ca19.9 accounted for > 1,000 U / mL. FAN, anticardiolipin IgM and IgG, lupus anticoagulant, ANCA negative. Death verified 12 days after admission, despite intensive care. Necroscopic report showed adenocarcinoma centered in bile ducts involving gallbladder and extra and intrahepatic bile ducts with vascular dissemination (pulmonary and lymph node metastases) and extension to gastric wall and small intestine. Post-mortem diagnosis of cholangiocarcinoma was performed. Discussion: the case discusses is of multiple thrombotic events in unusual sites associated with non-specific findings at the beginning. The hypothesis of phospholipid antibody syndrome (APS) was proposed although it is unlikely in an elderly patient. Subsequent evaluation for thrombophilias was not done since weight loss and abdominal CT with multiple hepatic nodules suggested neoplasia of indeterminate site. Hence, SAF was discarded and the patient died without diagnosis of primary site due to the difficulty of the case. Conclusion: neoplasia of uncommon sites can be a disease of hard diagnosis and management especially in patients worsening in a short time. However they must be considered with proper investigation in patients with multiple thrombotic events due to the very known association with these findings.

A child of thrombotic storm controlled by rivaroxaban

A child of thrombotic storm controlled by rivaroxaban

Síndrome antifosfolípidos catastrófico. Reporte de caso y revisión bibliográfica

The present document is the report of a case of a very rare clinical entity, which presents with acute multiorganic failure after a thrombotic storm related to antiphospholipid antibodies, the so-called catastrophic antiphospholipid syndrome, which began as a recurrent picture of mesenteric thrombosis, with a previous history of venous insufficiency and distal ulcers probably associated with an unidentified antiphospholipid; deserving management in intensive care and the consultation by the world expert, Dr. Ricard Cervera who confirmed the diagnosis and recommend treating as such entity, the patient's evolution was satisfactory so far. Final recommendations for diagnosis and current treatment options such as rituximab or eculizumab are made. The present case was added to the international registry that currently houses around 500 cases worldwide (International CAPS Registry).

Catastrophic antiphospholipid syndrome (Ronald Asherson syndrome) and obstetric pathology.

Catastrophic antiphospholipid syndrome (CAPS) is an uncommon, often fatal, variant of the antiphospholipid syndrome (APS) that results in a widespread coagulopathy and high titres of antiphospholipid antibodies (aPL) and affects predominantly small vessels supplying organs with the development of multiorgan failure. It remains unclear why some patients develop the typical clinical picture of APS (thrombosis of large vessels), whereas others show the development of progressive microthrombosis, which the authors called "thrombotic storm" and multiple organ failure, that is, CAPS. Since 2001-2016, we discovered 17 patients with CAPS development. CAPS is life-threatening condition, but optimal treatment for CAPS is not developed yet and the mortality rate is as high as 30%-40%.

A Battle against the Odds: Intensive Therapy in Thrombotic Storm

Thrombotic storm (TS) is a rare life-threatening entity that is characterized by multiple thrombotic events affecting diverse vascular sites occurring over a short period of time (days to weeks). We describe a case of a young boy who developed extensive and rapidly progressive thrombosis which required intensive treatment that included the use of triple antithrombotic therapy, pharmacomechanical thrombectomy, systemic thrombolytic therapy, and the combined use of plasmapheresis and immunosuppression.

Catastrophic Antiphospholipid Antibody Syndrome Presenting as Intraabdominal Abscess: An Unusual Case of Thrombotic Storm.

Catastrophic Antiphospholipid Antibody Syndrome Presenting as Intraabdominal Abscess: An Unusual Case of Thrombotic Storm.

Antiphospholipid syndrome: A review

Antiphospholipid syndrome is being increasingly recognized as a disease with a myriad of clinical manifestations ranging from recurrent thrombosis and pregnancy morbidity to valvular lesions, transverse myelitis, thrombocytopenia and hemolytic anemia. It may be primary or secondary, i.e., associated with other autoimmune diseases. The latest classification criteria (Sydney 2006) recognize just three tests to define this syndrome-lupus anticoagulant, anticardiolipin antobodies and anti β2 glycoprotein 1 antibodies. Treatment of thrombotic events involves lifelong anticoagulation with vitamin K antagonists like warfarin. Antiphospholipid antibody syndrome (APS) with only pregnancy morbidity is treated with thromboprophylaxis using heparin during pregnancy and postpartum for 6 weeks. Catastrophic APS occurs in approximately 1% of APS, and is characterized by microvascular thrombosis (thrombotic storm) and organ dysfunction. In this review we discuss the pathogenesis, diagnosis, treatment and prognosis of the APS.

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Introduction: Catastrophic Antiphospholipid Syndrome (CAPS) is characterized by multi-organ dysfunction with rapid, diffuse, small vessel thromboses. Early recognition is important to initiate rapid intervention and supportive care. Management is challenging as this condition is rare and there is limited literature available. Despite appropriate diagnosis and aggressive treatment, there remains a high mortality in CAPS. This case illustrates the severe systemic manifestations of this condition which continued despite aggressive therapy. Case Description: A 67 year old male with no prior surgical history presented to an outside facility with nausea, emesis, abdominal pain, and with an acute abdomen. He was taken for an exploratory laparotomy (ex-lap), which showed necrotic small bowel and cecum. He underwent a right hemicolectomy with colostomy and small bowel resection with ileostomy. The post-operative course was complicated by bowel perforation. Repeat ex-lap showed bowel necrosis with subsequent further small bowel resection. Imaging also revealed renal and splenic infarcts. On transfer to our ICU, he had a tense abdomen with severe diffuse generalized tenderness and absent bowel sounds. Laboratory studies showed an elevated white blood cell count, thrombocytopenia, elevated aPTT, anion gap metabolic acidosis, acute renal failure, elevated lactate, and elevated liver function tests. He was again taken to the operating room because of an increasing vasopressor requirement and increasing lactate. This revealed further necrotic small bowel that required additional resection. Due to concern for CAPS, he was given unfractionated heparin, high dose methylprednisolone, plasma exchange, and intravenous immunoglobulin (IVIG). Despite this treatment, he developed continued bowel ischemia and stroke. He showed no signs of response to therapy and ultimately expired. Discussion: This case illustrates the catastrophic nature of CAPS. There is sparse literature available due to the rarity of the disease. The 10th International Congress on Antiphospholipid Antibodies has proposed classification criteria for CAPS that includes: involvement of three or more organs/systems/tissues, developing manifestations simultaneously or in less than one week, histopathology of small vessel occlusion in at least one organ/tissue, and laboratory confirmation of antiphospholipid antibodies. Management is challenging due to multiple thrombotic events that occur simultaneously or in an evolving manner, presentation is often difficult to distinguish from other entities (e.g. disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, or systemic vasculitis), and the optimal treatment regimen is unknown. If suspected, aggressive treatment is strongly recommended without delay. However, due to variable presentation a high index of suspicion is needed. Current recommendations for treatment include effective anti-coagulation with intravenous heparin, high dose steroids, plasma exchange and/or IVIG. Unfortunately, CAPS is fatal in approximately half of patients despite treatment. Prior case series had suggested that advanced age, higher number of involved organs, thrombocytopenia, and infarcts in the spleen, heart or intestines were associated with higher mortality. However more recent & larger case series showed no difference in mortality for age, sex, precipitating factors, number of organs affected, or laboratory findings. The only factor associated with a higher mortality was the presence of lupus. In regards to this case, this patient developed severe ischemic bowel from multiple thromboses and progressive multi-organ failure which previous literature has described as an imbalance in hemostasis that leads to a "thrombotic storm." Increased awareness of this disease may lead to earlier diagnosis and provide more avenues of study on this disease.

Thrombotic Storm in a Teenager With Previously Undiagnosed Ulcerative Colitis

Venous thrombosis can complicate inflammatory bowel diseases, both in adult and pediatric patients, and a few adult cases of thrombotic storm, ie, thrombosis at multiple sites occurring over a period of a few days to a few weeks, have been described. However, venous thrombosis as the first manifestation of an inflammatory bowel disease is extremely rare. We report the case of a 14-year-old girl presenting with ascites and marked hypertransaminasemia resulting from hepatic vein occlusion (Budd-Chiari syndrome). Despite anticoagulant therapy, in the following days she developed criteria suggestive of thrombotic storm to include cerebral vein, right atrial thrombosis, and bilateral pulmonary embolism. Thrombolytic treatment with recombinant-tissue plasminogen activator was started, with resolution of all venous thromboses and without bleeding complications. Additional examinations revealed a severely active ulcerative pancolitis, which did not respond to medical treatment and required surgery. No thrombophilia abnormality nor other risk factors for thrombosis were detected. We conclude that an underlying inflammatory state, such as ulcerative colitis, should be suspected in pediatric patients with venous thrombosis storm.

Clinical causes and treatment of the thrombotic storm

Thrombotic storm represents an extreme prothrombotic phenotype, characterized by multiple thrombotic events affecting diverse vascular beds occurring over a brief period of time. Thrombotic events involve venous and arterial circulation, including unusual locations, such as cerebral sinus venous thrombosis, intra-abdominal thromboembolic occlusions and microvascular events. Some patients will have antiphospholipid antibodies, but a significant number have no identifiable hypercoagulable state. The mainstay of treatment consists of anticoagulant therapy, although some patients appear to benefit from the addition of immunomodulatory therapies. Other disorders that share this thrombotic storm phenotype include catastrophic antiphospholipid syndrome, spontaneous heparin-induced thrombocytopenia and similar aggressive clinical disorders. Ongoing studies are focused on identifying underlying genetic factors that may predispose patients to develop this extreme clinical phenotype.

Treatment, Survival, and Thromboembolic Outcomes of Thrombotic Storm in Children

To describe the course and management of thrombotic storm in 8 children. Clinical data were collected and analyzed for consecutive children diagnosed with thrombotic storm, aged 6 months to 21 years inclusive, in the context of a single-institution prospective inception cohort study. Thrombotic storm was defined as newly diagnosed multisite venous thromboembolism (VTE) with acute thrombus progression despite conventional or higher than conventional dosing of heparin or low molecular weight heparin. All evaluations and therapies were ordered by the treating physicians in the context of clinical decision making. Eight of the 178 children with VTE enrolled in the cohort between March 2006 and November 2009 were diagnosed with thrombotic storm. Antiphospholipid antibodies were acutely positive in 6 children, of whom heparin-induced thrombocytopenia was confirmed by serotonin release assay in 2 and atypical in 1. One child died. Five children received a direct thrombin inhibitor, titrated to achieve normalization of markedly elevated D-dimer levels. All children were transitioned to fondaparinux or enoxaparin before receiving extended anticoagulation with warfarin. Immunomodulatory therapy was instituted in all children. During follow-up (median duration, 3 years; range, 2-6 years), 3 of the 7 surviving children experienced recurrent VTE, and 4 children had clinically significant postthrombotic syndrome. Thrombotic storm is an infrequent but potentially fatal presentation of VTE in children. Administration of direct thrombin inhibitors and immune modulation can achieve quiescence, although long-term adverse outcomes are common.

Whole-Exome Sequencing Identifies Novel Risk Variant for Thrombotic Storm

Abstract 1229 Background:Thrombotic storm (TS) is an extremely severe clinical phenotype that occurs in a very small subset of patients with venous thromboembolic disease. It is characterized by patients who exhibit two or more of the following in a short period of time; 1) > 2 acute arterial/venous thromboemboli, and/or thrombotic microangiopathy, 2) unusual location, 3) progressive/recent unexplained recurrence, and/or 4) refractory to and/or atypical response to therapy (Kitchens et al., Am J Med, 2011). We hypothesize these patients possess an underlying prothrombotic risk factor that results in an accelerated form of thrombosis following an initial event that provokes the attack in the relevant clinical context. Methods:To identify potential genetic risk variants we performed whole-exome sequencing on a TS participant and his unaffected parents and sibling. The proband was a 14 year old male who presented with thrombosis of the sagittal, right transverse and sigmoid sinuses following a sports-related knee injury. There was no personal or family history of venous thromboembolism, and a hypercoagulable workup, including testing for antiphospholipid antibodies, was negative. His course was complicated by the development of disseminated intravascular coagulation, delaying early initiation of anticoagulant therapy. Despite aggressive supportive care, which included anticoagulation therapy, the proband did not improve and expired after severe cerebral edema with herniation was diagnosed by clinical exam and CT imaging. At autopsy, bilateral pulmonary emboli and extensive pelvic vein thrombosis were also identified. DNA was extracted from whole blood and the relevant regions were captured using the Agilent Sure Select 50mb kit. Sequencing was performed on the Illumina HiSeq2000 under the manufacturer’s recommended protocol. Alignment of reads to the reference was performed using BWA, and genotype calls were made with GATK. Variants were initially filtered based on quality (depth ≥ 8, phred-like quality ≥ 30), function (nonsense, missense, splicing), and novelty. Additional filters include inheritance mode (autosomal recessive or de novo heterozygote), conservation (phastcons score > 0.5, GERP score > 2), and damage prediction (SIFT or Polyphen). Potential variants were validated using Sanger sequencing. Results:Whole-exome sequencing identified over 127,000 variants in the nuclear family with at least one member having a high quality variant at the position. Filtering these variants based on function, novelty, and high quality in parents and affected proband reduced the list to 2,735 variants. Of these, 7 variants fit an autosomal recessive model (homozygous in the proband, heterozygous in both parents, not homozygous in the unaffected sibling); of these 7, two were at conserved sites, predicted to be damaging, and also called using SAMTOOLS. The first of the recessive variants is a nonsense variation in the EGFL8 gene (tyrosine to stop codon, at the 74th amino acid; tyr74stop), and the second is in HLA-E (gln276pro). Of the initial list of 2,735 variants there were 138 that fit a de novo heterozygous model (present in the affected proband, but not parents); of these 138, two were at a conserved site, predicted to be damaging, and were also called with SAMTOOLS. The first de novo heterozygote is in SLC26A2 (arg178stop), and the second variant is in PRMT7 (arg531trp). These four variants were resequenced using Sanger sequencing within the family. Three of the variants (EGFL8, SLC26A2, and PRMT7) were confirmed using Sanger; the fourth (HLA-E) is still being resequenced. Discussion:These variants represent excellent candidate loci for thrombotic storm risk. In particular, the EGFL8 variant is a homozygous change to a stop codon less than one quarter of the way through the open reading frame – a change that likely severely damages protein function. Additionally, EGFL8 (epidermal growth factor-like domain-containing protein 8) has two EGF domains, a common motif identified in hemostatic and fibrinolytic proteins, and is therefore potentially involved in coagulation. These variants will be further analyzed for frequency in controls and tested in animal models for functional significance. Disclosures:No relevant conflicts of interest to declare.

Thrombotic storm in Kimura disease

We report herein a patient with Kimura disease who experienced life threatening visceral venous thromboses and a clinical course fitting the description of "thrombotic storm". Kimura disease is an indolent chronic inflammatory disease common in Asians and characterized by angiolymphoid proliferation with ample eosinophil infiltration, peripheral blood eosinophilia and elevated serum immunoglobulin E levels. The clinical course of the disease is thought to be benign. Our patient experienced a major thrombotic event with a thorough evaluation revealing no evidence of inherited thrombophilia or acquired conditions associated with visceral venous thromboembolism. Despite persisting eosinophilia and other manifestations of Kimura disease there have been no recurrent thrombotic events with continuous warfarin therapy over a 4-year period. This case highlights the occurrence of hypercoagulability in association with this unusual eosinophilic disorder.