Microangiopathic Hemolytic Anemia Research Articles

A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome.

Recessive mutations in the genes encoding the four subunits of the tRNA splicing endonuclease complex (TSEN54, TSEN34, TSEN15, and TSEN2) cause various forms of pontocerebellar hypoplasia, a disorder characterized by hypoplasia of the cerebellum and the pons, microcephaly, dysmorphisms, and other variable clinical features. Here, we report an intronic recessive founder variant in the gene TSEN2 that results in abnormal splicing of the mRNA of this gene, in six individuals from four consanguineous families affected with microcephaly, multiple craniofacial malformations, radiological abnormalities of the central nervous system, and cognitive retardation of variable severity. Remarkably, unlike patients with previously described mutations in the components of the TSEN complex, all the individuals that we report developed atypical hemolytic uremic syndrome (aHUS) with thrombotic microangiopathy, microangiopathic hemolytic anemia, thrombocytopenia, proteinuria, severe hypertension, and end-stage kidney disease (ESKD) early in life. Bulk RNA sequencing of peripheral blood cells of four affected individuals revealed abnormal tRNA transcripts, indicating an alteration of the tRNA biogenesis. Morpholino-mediated skipping of exon 10 of tsen2 in zebrafish produced phenotypes similar to human patients. Thus, we have identified a novel syndrome accompanied by aHUS suggesting the existence of a link between tRNA biology and vascular endothelium homeostasis, which we propose to name with the acronym TRACK syndrome (TSEN2 Related Atypical hemolytic uremic syndrome, Craniofacial malformations, Kidney failure).

Congenital thrombotic thrombocytopenic purpura simulating alloimmune thrombocytopenia

Congenital thrombotic thrombocytopenic purpura (cTTP) is a thrombotic microangiopathic caused by severely reduced activity of the von Willebrand factor-cleaving protease A Disintegrin And Metalloproteinase with a Thrombospondin type 1 Motif, member 13 (ADAMTS-13), which leads to small-vessel platelet-rich thrombi, thrombocytopenia, and microangiopathic hemolytic anemia (MHA) in the absence of neutralizing antibodies. We describe a case of cTTP in a female neonate presenting initially on the 1st day of life with asymptomatic thrombocytopenia thought to be alloimmune thrombocytopenia, then progressed to severe neonatal jaundice, pallor, and MHA, in whom ADAMTS-13 levels <5%, and the anti-ADAMTS-13 antibody titer was negative confirming the diagnosis of cTTP. The patient initially received intravenous immunoglobulin infusion before documenting MHA. She received fresh frozen plasma infusions which successfully reversed the MHA (by supplying ADAMTS-13) and prevented organ damage in this patient.

Carcinocythemia-associated Microangiopathic Haemolysis

Carcinocythemia defined as the presence of circulating carcinoma cells in the peripheral blood identifiable on routine light microscopy is an extremely rare complication of widely disseminated and usually end-stage solid organ malignancies. Given the rarity of this entity, it can cause diagnostic challenges for pathologists interpreting the peripheral blood smear. Microangiopathic Haemolytic Anaemia (MAHA) has been reported in the literature in patients with carcinocythemia. The author reports a case of 57-year-old female with widely metastatic lobular breast carcinoma who presented with bleeding gums and worsening fatigue. Peripheral blood smear showed findings consistent with MAHA as well as numerous circulating adenocarcinoma cells. A bone marrow biopsy showed near-complete replacement of the marrow by metastatic carcinoma. This case brings to light the association of carcinocythemia with haemolysis. Given the high incidence of MAHA in carcinocythemia and the differential treatment, a careful screening of peripheral smears maybe warranted in patients with a known history of metastatic carcinoma and laboratory suspicion of haemolysis.

Trombotična mikroangiopatija kao prva manifestacija diseminovane maligne bolesti

Introduction: Thrombotic microangiopathies are a group of diseases characterized by disseminated intravascular thrombosis, thrombocytopenia and ischemic organ damage. This group includes thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. One of the causes of thrombotic microangiopathy, although rare, can also be malignant diseases, primarily cancers of the stomach, prostate, breast and lungs. Case report: We present a patient with thrombotic microangiopathy and disseminated malignant disease of unclear etiology. Conclusion: This clinical entity is called carcinoma-associated thrombotic microangiopathy and was first described in 1970. However, only a few dozen cases have been described to date. Considering the high mortality, it should be considered in patients with malignant disease, microangiopathic hemolytic anemia, and thrombocytopenia.

The frontline of TMA management

Thrombotic microangiopathy (TMA) is a pathological condition characterized by platelet thrombi-induced generalized microvascular occlusion, thrombocytopenia, and microangiopathic hemolytic anemia. TMA includes the life-threatening diseases thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). TTP is different from HUS in that it has a severe deficiency in ADAMTS13 activity. Congenital TTP is caused by a lack of plasma ADAMTS13 activity caused by genetic mutations, and acquired TTP is caused by a secondary deficiency caused by autoantibodies. In Japan the only product approved for the treatment of congenital TTP is fresh frozen plasma containing ADAMTS13. Recombinant ADAMTS13 may provide a new treatment option for congenital TTP. The first-line treatment for acquired TTP is plasma exchange. Rituximab treatment should be considered for patients who are refractory or have relapsed. Caplacizumab is a nanobody that specifically targets von Willebrand factor. ISTH recently published guidelines recommending that caplacizumab be added to the initial treatment for acquired TTP. Atypical HUS (aHUS) is related with the dysregulation of the complement alternative pathway. Eculizumab, a monoclonal antibody that inhibits C5, was the first drug approved for aHUS, and it was found to be well-tolerated by patients and effective in clinical use. TMA is classified based on its etiology, and specific treatments for targeting various etiologies are now available.

Co-existence of Thrombotic Thrombocytopenic Purpura and Megaloblastic Anaemia: A Case-Based Review.

Introduction:Thrombotic thrombocytopenic purpura is a rare and fatal thrombotic microangiopathy characterised by a pentad of microangiopathic haemolytic anaemia, thrombocytopenia, renal abnormalities, neurological abnormalities, and fever. Due to ineffective erythropoiesis, vitamin-B12 deficiency may rarely present as haemolytic anaemia.Case report:We report a case of a 42-year-old vegetarian female presenting as vitamin B12 deficiency anaemia found to have concomitant TTP, responding to plasmapheresis, corticosteroids, and rituximab therapy.Discussion:In this case of vitamin B12 deficiency with co-existent TTP, we hypothesise vitamin B12 deficiency as a contributory or precipitating factor for TTP. We reviewed similar cases in the literature to support this hypothesis. Timely detection of TTP and the initiation of treatment is of utmost importance as TTP has a high mortality when left untreated. The possible relationship with Vitamin B12 deficiency needs further exploration.

Metabolism-mediated thrombotic microangiopathy and B12.

Thrombotic microangiopathies (TMAs) are a group of life-threatening conditions requiring urgent management and characterized by a clinical triad of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic tissue injury. Severe vitamin B12 (Cobalamin-Cbl) deficiency or defective cobalamin metabolism, particularly defects in intracellular B12 metabolism, may lead to a TMA-like picture. The latter has been termed metabolism-mediated TMA (MM-TMA). This confusing picture is mediated partly by ineffective erythropoiesis with significant red cell fragmentation resulting in a hemolytic pattern, coupled with reduced platelet production and endothelial injury with organ damage resulting from accumulated toxic byproducts of B12 dysmetabolism. However, unlike in classic thrombotic thrombocytopenic purpura, where therapeutic plasma exchange has to be initiated promptly, cases of MM-TMA can be treated, if diagnosed properly, with adequate B12 replacement.

Anesthetic Management in a Parturient with Thrombotic Thrombocytopenic Purpura for Cesarean Section: A Case Report and Literature Review

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia linked to disseminated microvascular platelet rich-thrombi. TTP is specifically related to a severe deficiency of ADAMTS13, a cleaving protease for von Willebrand (vWF).

A Study of Acute Kidney Injury among the Patients with Snakebite in a Tertiary Care Hospital

Background: The clinical presentation of a snakebite victim varies with the age and size of the patient, the species of snake, the number and location of the bites, the quantity and toxicity of the venom. The exact pathogenesis of Acute kidney injury (AKI) following snakebite is not well established, due to the lack of a reproducible animal model. The factors that may contribute are:direct cytotoxicity, bleeding, hypotension, circulatory collapse, intravascular hemolysis, disseminated intravascular coagulation and microangiopathic hemolytic anemia (MAHA). Objective:To analyze various factors, influencing the outcome in patients of snakebite with acute kidney injury. Materials and Method: The present prospective study was conducted in the Department of Emergency Medicine at M S Rammaih Medical College Bengaluru from August 2017 to September 2018. A total of 100 study subjects who met the inclusion criteria (patients with history of snakebite presenting with acute kidney injury) were included in the study. Patients underwent physical examination daily. Pulse rate, blood pressure, urine output, respiratory rate and features of envenomation were monitored daily. Blood specimen was taken every day till discharge or death to measure sodium, potassium, urea, creatinine, bleeding time, clotting time, platelets and for patients undergoing dialysis, pre-dialysis and post-dialysis urea and creatinine was measured for each cycle. Results: Age, Gender, and Presence of Cellulitis does not influence the mortality in patients with Acute Kidney Injury. Early therapy with Anti-snake venom was associated with better outcome in terms of mortality. Early institution of dialysis had definite favourable outcome in Acute Kidney Injury. All patients with Acute Kidney Injury showed autopsy findings of renal involvement. Conclusion: In the present study, viper bite accounted for definite acute kidney injury. Major risk factors linked with adverse outcome in snakebite with Acute Kidney Injury were hypotension, bleeding manifestations and delayed specific therapy with anti-snake venom.

THROMBOTIC MICROANGIOPATHIC HEMOLYTIC ANEMIA IN SYSTEMIC LUPUS ERYTHEMATOSUS IN A 25 YEARS OLD FEMALE IN CHENNAI, INDIA

Systemic lupus erythematosus (SLE) is an autoimmune condition, affecting multiple organs and tissues by autoantibodies and immune complexes. Hematologic manifestations of SLE include anemia, thrombocytopenia and leukopenia. The most common type of anemia seen in SLE is anemia of chronic disease. Thrombotic microangiopathic hemolytic anemia (TMHA) in SLE is very rare. Incidence of TMHA in children with SLE is common compared to adult cases of SLE. Manifestations of TMHA include presence of schistocytes in the peripheral smear, elevated bilirubin levels, elevated LDH and negative coombs test. This case report focuses on 25-year-old female diagnosed concomitantly with SLE and TMHA, and treated with steroids, blood transfusions, megakaryocyte growth factors and antibiotics.

Task force for the diagnosis of thrombotic microangiopathy / Força-tarefa para o diagnóstico de microangiopatia trombótica

Background: Thrombotic microangiopathy triggers microangiopathic hemolytic anemia, thrombocytopenia, and organic injuries. It is a rare and serious condition that demands specific approaches and strategies to recognize it promptly, especially in critically ill patients. The task force could be an effective model. Methods: An evaluative study of the impact of a task force in establishing a routine for the diagnosis of TMA in ICUs. A standard flowchart was used for 90 consecutive days and a low platelet count was the driver for the collection of epidemiological and laboratory data. Suspicion of typical HUS was proven after analyzing haptoglobin, LDH, creatinine, ADAMTS-13 enzyme, and Shiga toxin levels. Meetings were also held with ICU personnel and the self-explanatory flowchart was fine tuned. Results: There were 490 patients (55.9% male and 44.1% female) aged 59.5 ± 21.13 years. Forty-two percent of patients in the sample had thrombocytopenia. Out of the 42 patients, five (1.02%) had TTP, three (0.6%) were presumed to have atypical HUS, and none had typical HUS. The task force remained in touch with researchers to assess diagnoses and three other suspected cases of atypical HUS underwent specific treatment.Discussion: Only 1.62% of the sampled patients had TMA. Despite its complexity, the task force model is useful in situations in which higher technology is the norm. Conclusion: The use of a task force has proven to be effective in establishing a diagnostic practice for a health condition deemed rare or exceedingly rare.

Case Report on Hemolytic Uremic Syndrome

Background: In the United States, the hemolytic–uremic syndrome of childhood typically follows gastrointestinal infection with Escherichia coli O157:H7. It is presumed that the absorption from the gastrointestinal tract of Shiga toxins 1, 2, or both (formerly called Shiga-like toxins) produced by E. coli O157:H7 causes microangiopathic hemolytic anemia as a result of endothelial-cell injury. Shiga-toxin–producing E. coli belonging to serotypes other than O157:H7 can also cause the hemolytic–uremic syndrome. However, even though such organisms have been implicated as causes of sporadic cases or outbreaks of gastroenteritis, they are not believed to be important causes of the hemolytic–uremic syndrome in this country. Hemolytic uremic syndrome (HUS) is a kidney disease characterized by damaged and inflamed small blood vessels. As a result of the damage, clots in the vessels may form. Clots impede the filtration function of the kidneys, causing renal failure, which can be deadly.&#x0D; Clinical Finding: Hemolytic uremic syndrome, nephropathy and thrombocytopenia, pallor, jaundice, edema. After eight hours of stomach and left-flank pain, vomiting, and dysuria, a previously healthy six-year-old girl was seen. The day before, an enema had been used to alleviate constipation. The child had not had diarrhoea during the two weeks before evaluation. On examination, the patient had an oral temperature of 39.8°C, a pulse rate of 120 per minute, and a blood pressure of 111/59 mm Hg. There was tenderness of the suprapubic area and left costovertebral angle. The white-cell count was 23,400 per cubic millimeter (58 percent neutrophils, 23 percent band forms, 9 percent lymphocytes, and 10 percent monocytes), the hematocrit was 40 percent, and the platelet count was 293,000 per cubic millimeter. Urine obtained by catheterization had a specific gravity of 1.028 and a ph of 5, and dipstick analysis was positive for leukocyte esterase (++), protein (++), ketones (++), and blood (+++). The urinary sediment contained 21 to 100 red cells, more than 100 white cells, 1 to 5 renal tubular cells, and 1 to 5 granular casts per high-power field. Many bacteria were observed by microscopy. The left kidney showed attenuation of fat and a possible collection of fluid on abdominal ultrasonography; the right kidney was normal. Before starting ceftriaxone medication, blood was taken for culture.&#x0D; Diagnostic Evaluation: HB-5.7 g/dL, total protein-7.4 g/dL, total Alcaline phosphatase -123 U/L , total platelet count-2,93,000 per cubic millimeter, total bilirubin-3.2 mg/dl, WBC 23400 per cubic meter, CRP 5.58 mg/L, Sodium level 136 mg/dl, potassium level 3.92mg/dl.&#x0D; Therapeutic Intervention: Tab Amlodepin 10 mg BD, Tab Prednisolone 10 mg TDS, Tab Envas 2.5 mg OD, Metropenum 340 mg BD, Inj. Pantop 20 mg OD.&#x0D; Outcome: The medication has started for thrombocytopenia, the patient is on dialysis and If is given to patient for movement of body because of patient is obese. The patient was sent home after 20 days of hospitalization. Three weeks later, a voiding cystourethrogram was normal, and six weeks later, ultrasonography revealed that the focal abnormality in the left kidney had disappeared. The patient's blood urea nitrogen and serum creatinine concentrations, iothalamate clearance, and blood pressure are all normal two years later, and her urine is protein and blood-free. She has not experienced a recurrence of a urinary tract infection or hemolytic–uremic syndrome.&#x0D; Conclusion: The atypical hemolytic uremic syndrome is an uncommon condition that must be diagnosed with a high index of suspicion. It's an exclusionary diagnosis. A better outcome will be achieved if the disease is detected early and treated promptly. In all patients with thrombotic microangiopathy, the atypical hemolytic uremic syndrome should be evaluated.

Pregnancy associated atypical hemolytic uremic syndrome triggered by massive uterine bleeding after outpatient dilatation and evacuation

Background: Atypical Hemolytic Uremic Syndrome (aHUS) is a renal threatening multi-system disorder with significant hematologic findings of microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. Early recognition and institution of late complement inhibitors can interrupt a cycle of progressive hemolysis and renal injury. Methods: We present an informative case of aHUS triggered by pregnancy termination. Diagnostic, laboratory, and treatment measures are reviewed. Results: Clinical evidence demonstrates immediate improvement in hemolysis, platelet consumption, and acute kidney injury following initiation of eculizumab. Conclusion: Pregnancy is a recognized trigger of aHUS and its proper management requires early recognition and institution of late complement blockade. Genetic testing can be sent for genetic counseling purposes, but initiation of treatment should neither await these results nor be discontinued when high-risk polymorphisms are absent.

Evaluation and Management of Thrombotic Thrombocytopenic Purpura in the Emergency Department.

Thrombotic thrombocytopenic purpura (TTP) is a dangerous condition that can be misdiagnosed in the emergency department. The purpose of this narrative review article is to provide a summary of the background, pathophysiology, diagnosis, and management of TTP, with a focus on emergency clinicians. TTP is a disorder with microangiopathic hemolytic anemia, severe thrombocytopenia, and multiorgan ischemic injury. It may be acquired or hereditary, and is caused by a reduced amount or function of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), which is an enzyme involved in cleaving von Willebrand factor. The classic presentation of TTP includes fever, neurologic abnormalities, thrombocytopenia with purpura, microangiopathic hemolytic anemia, and acute renal injury. However, < 7% of cases have all of these findings present. Testing should include a complete blood count, complete metabolic panel, blood smear, coagulation panel, fibrinogen, D-dimer, lactate dehydrogenase, ADAMTS13 level, troponin, human immunodeficiency virus assessment, urinalysis, pregnancy test as appropriate, and electrocardiogram. Management includes hematology consultation if available, plasma exchange and corticosteroids, and treatment of end-organ complications. All patients require admission for treatment and close monitoring. TTP is a potentially dangerous medical condition requiring rapid diagnosis and management. It is essential for emergency clinicians to know how to diagnose and treat this disorder.

Case series: coronavirus disease 2019 infection as a precipitant of atypical hemolytic uremic syndrome: two case reports

BackgroundAtypical hemolytic uremic syndrome is an exceedingly rare thrombotic microangiopathy caused by accelerated activation of the alternative complement pathway.Case presentationHere, we report two cases of patients presenting with suspected atypical hemolytic uremic syndrome precipitated by coronavirus disease 2019 infection. The first patient, a 25-year-old Hispanic male, had one prior episode of thrombotic microangiopathy presumed to be atypical hemolytic uremic syndrome precipitated by influenza A, and re-presented with thrombocytopenia, microangiopathic hemolytic anemia, nonoliguric renal failure, and normal ADAMTS13 activity, with confirmed coronavirus disease 2019 positivity. The second patient, a 31-year-old Caucasian female, had no personal history of thrombotic microangiopathy, though reported a family history of suspected atypical hemolytic uremic syndrome. She presented with similar laboratory derangements, oliguric renal failure requiring hemodialysis, and confirmed coronavirus disease 2019 positivity. Both patients were treated with eculizumab with complete resolution of their hematologic and renal complications.ConclusionTo our knowledge, this represents the largest case series of atypical hemolytic uremic syndrome precipitated by coronavirus disease 2019 in adults.

A Young Woman with Anemia and Thrombocytopenia

&lt;p&gt;本文描述一位32歲女性病患，罹患全身性紅斑性狼瘡已有11年，規則於門診追蹤，因發燒、關節痛、胸痛，實驗室檢查發現貧血、血小板低下、補體（C3）低下、高效價之抗雙股去氧核糖核酸抗體（anti-dsDNA &gt; 379 IU／mL）、尿液呈現蛋白尿，初步診斷懷疑全身性紅斑性狼瘡復發。靜脈注射高劑量methylprednisolone七天，血小板仍偏低，治療反應差。本個案實驗室檢查顯示溶血性貧血、血小板低下、週邊血液抹片顯示碎裂紅血球，確定微血管性溶血性貧血證據，且血液中ADAMTS 13嚴重缺乏其血中活性為0%，因此診斷為血栓性血小板低下紫斑症。緊急接受血漿置換術，同時持續高劑量類固醇與靜脈注射Rituximab治療，因而血小板上升、乳酸脫氫脢大幅下降、貧血改善，達到治療的成效。全身性紅斑性狼瘡同時出現血栓性血小板低下紫斑症，經緊急啟動血漿置換，會降低病人的死亡率。&lt;/p&gt; &lt;p&gt;&amp;nbsp;&lt;/p&gt;&lt;p&gt;A 32-year-old female patient in this study, who suffered from systemic lupus erythematosus (SLE) for 11 years. Upon a regular rheumatology outpatient follow-up, she presented not only with fever,arthralgia and chest pain, but also with anemia, low platelets, low complement (C3), and high titer anti-double-strand deoxyribonucleic acid antibody (anti-dsDNA &gt; 379 IU/mL) on laboratory test report,as well as proteinuria on urinalysis. Accordingly, her condition was suspected to be a relapse of SLE. Unfortunately, after treatment with high-dose intravenous methylprednisolone, the response was poor with persistent low platelet level. Besides, hemolytic anemia and thrombocytopenia were noted and peripheral blood smear examination also showed fragmented red blood cells, supporting the diagnosis of microangiopathic hemolytic anemia. Moreover, there was severe ADAMTS13 deficiency in the blood, even with 0% of activity. Therefore, the patient was finally diagnosed with thrombotic thrombocytopenic purpura and then received urgent plasmapheresis in combination with high-dose glucocorticoid and of intravenous rituximab treatment. After the treatment, the platelet level increased, lactate dehydrogenase level remarkably decreased, and anemia gradually improved. Taken together, urgent initiation of plasma exchange together with glucocorticoid and rituximab treatment for SLE patient with thrombotic thrombocytopenic purpura could lower the mortality rate.&lt;/p&gt; &lt;p&gt;&amp;nbsp;&lt;/p&gt;

Too tight for comfort – A rare case of hypertensive microangiopathic haemolytic anaemia

Too tight for comfort – A rare case of hypertensive microangiopathic haemolytic anaemia

Kasabach Merritt syndrome in a 28-year-old female: A strange case report

Kasabach Merritt syndrome (KMS) is a rare disease in which a benign vascular tumor that is hemangioma grows rapidly, entraps red blood cells, platelets, and coagulation factors leading to activation of coagulation cascade resulting in life-threatening disseminated intravascular coagulation and microangiopathic hemolytic anemia. KMS affects newborns and infants. Rarely can affect older children and adults with only a few cases reported in the existing literature. Clinically patients present with large cutaneous hemangioma usually involving the extremities however visceral organs may be involved in some cases along with anemia, thrombocytopenia, coagulopathy, and bleeding. We report a case of KMS in a 28-year-old female who presented with bilateral subdural hematoma, thrombocytopenia, and consumption coagulopathy. She was given seven days course of methylprednisolone to which she responded well.

Thrombotic thrombocytopenic purpura: An unusual presentation with intracranial bleed

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia linked to disseminated microvascular platelet-rich thrombi. We present the case of a 44-year-old lady who presented with severe thrombocytopenia and anemia that did not respond to repeated transfusions and steroids. Non-contrast computed tomography scan of the brain revealed an intracranial bleed. Schistocytes were seen on the peripheral blood smear. A provisional diagnosis of TTP was made. Plasmapheresis could not be done due to her deteriorating hemodynamic status. She succumbed to her illness in spite of the best possible efforts. This case highlights the need for keeping a high index of suspicion for TTP as early diagnosis and prompt initiation of plasmapheresis are crucial for preventing death.

Evaluation of the Safety of Emicizumab Prophylaxis in Persons with Hemophilia A: An Updated Summary of Thrombotic Events and Thrombotic Microangiopathies

▪Background: Emicizumab is indicated for routine prophylaxis in persons with congenital hemophilia A (PwcHA) with/without factor (F)VIII inhibitors in >100 and >80 countries, respectively. Emicizumab has been used by >11,400 persons across the globe (data cut-off 15 May 2021). The pivotal HAVEN 1-4 trials established the efficacy and safety of emicizumab prophylaxis; however, the HAVEN 1 trial identified an increased risk of thrombotic events (TEs) and thrombotic microangiopathies (TMAs) when used in conjunction with >100 U/kg/24 hours activated prothrombin complex concentrate (aPCC) for ≥24 hours (Oldenburg, et al. New Engl J Med 2017). Here we report an updated safety evaluation of emicizumab prophylaxis focusing on TEs and TMAs.Methods: All individual safety reports for emicizumab from clinical trials, registries, expanded access programs, compassionate use and the post-marketing setting were collated with a cut-off date of 15 May 2021 and analyzed for TEs and TMAs. Number of TEs/TMAs, clinical factors (indication, age, FVIII inhibitor status, comorbidities) and drug factors (co-exposure to medications affecting coagulation) are presented in aggregate. Individual case reports (cases) were reviewed to exclude non-TEs and any duplicate reports. TEs were identified using the Medical Dictionary for Regulatory Activities (MedDRA) search strategy: ‘Embolic and Thrombotic Events’ Standardized Medical Query ([SMQ] Wide) and Preferred Term ‘Acute Coronary Syndrome’. TMAs were defined as hemolytic uremic syndrome, microangiopathic hemolytic anemia, microangiopathy, thrombotic microangiopathy and thrombotic thrombocytopenic purpura.Results: In total, 52 cases (56 events) meeting the search criteria were identified on the Roche Global Safety Database as of 15 May 2021 (Figure). After review, 39 cases were reported in PwcHA and 10 cases were determined to be off-label (acquired hemophilia A, n=7; or unknown indication, n=3). Two additional cases were determined to be duplicates. One case of ‘hemiparesis’ was identified through SMQ review, but did not fit the clinical definition of a true TE. Six cases occurred with concomitant aPCC use, of which four were TMAs. In total, 33 cases were not associated with concomitant aPCC use, and these comprised 37 TEs and no TMAs in PwcHA. No new TEs or TMAs associated with aPCC were reported since the last update (Lee, et al. Haemophilia 2020).For the 37 TEs reported in PwcHA and not associated with aPCC, the median age (range) at time of event was 49 years (0.42-84) and the median (range) emicizumab treatment duration at time of event was 330 days (0-1076). In total, 36 (97.3%) TEs were medically confirmed and one (2.7%) was patient reported. Seventeen (45.9%) TEs occurred in PwcHA with FVIII inhibitors. Seven (18.9%) TEs were associated with central venous access devices (CVADs), of which four were reported to be resolving/recovering at last report. All except for two (with limited information) non-aPCC associated TEs in PwcHA were associated with ≥1 cardiovascular (CV) risk factors (e.g. previous myocardial infarction, ischemic heart disease, coronary artery disease, hypertension, hyperlipidemia, smoking, advanced age) or other risk factors for thrombosis (e.g. sepsis/bacteremia, device use, coinciding injury, hepatitis C).Of the non-aPCC and non-CVAD associated events reported, six (20.0%) TEs led to the discontinuation of emicizumab. Across all non-aPCC associated events, an evaluation of latency or duration of treatment did not reveal any patterns or trends. In total, four TEs were fatal: two myocardial infarctions, both in medically complex patients; and two disseminated intravascular coagulation events in patients >70 years of age with pneumonia. Where reported, 20/31 (64.5%) TEs were recovered/resolving at the time of this analysis, with the majority of these cases reporting no change to emicizumab prophylaxis as a result of the event.Conclusions: The reporting rate for TEs without concomitant aPCC remains low as exposure increases. Notably, all cases with adequate information available were associated with CV risk factors and/or risk factors for thrombosis. All TMAs were associated with concomitant use of aPCC. This post-marketing analysis does not support TEs and TMAs without concomitant aPCC as an identified risk for PwcHA receiving emicizumab prophylaxis. The risk-benefit profile of emicizumab remains unchanged. [Display omitted] DisclosuresHoward: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. McKinley: Pro Unlimited: Current Employment. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Ko: Genentech, Inc.: Current Employment; Genentech, Inc.-Roche: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Nissen: Novartis: Consultancy; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company. OffLabel Disclosure:The enclosed analysis of the Roche Hemlibra internal database was produced by submitted safety reports, including reports of off-label use. These data will be discussed in aggregate, and not individually described.