ADAMTS13 Activity Research Articles

REFRACTORY THROMBOTIC THROMBOCYTOPENIC PURPURA DUE TO COVID-19

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Thrombotic Thrombocytopenic Purpura (TTP) is a hematologic emergency with a mortality of 90% if left untreated. Its is formerly characterized by a pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia (MAHA), acute kidney injury (AKI), and neurologic deficits. These were classic before the routine use of therapeutic plasma exchange (PEX) because the majority of patients developed progressive thrombotic microangiopathy(TMA) and died from untreated disease. There are multiple etiologies associated with TTP and among those rarely reported is COVID-19. SARS-CoV-2 can result in the production of platelet-rich microthrombi and decrease the level of ADAMTS13. This can precipitate TMA and rarely result in TTP. CASE PRESENTATION: A 44-year-old African-American Female with no medical history presented to our facility complaining of vomiting and diarrhea associated with bleeding gums and easy bruising. On presentation, she was calm with stable vital signs. On physical exam, she had scleral icterus and conjunctival pallor associated with petechial rash and localized ecchymosis. Initial labs were remarkable for anemia(8.6g/dL), severe thrombocytopenia(3x103/µL), AKI(creatinine 1.70mg/dL), elevated lactate-dehydrogenase(1297Units/L), and high D-dimer(636ng/mLDDU). Hemolysis workup revealed MAHA and schistocytes were confirmed on blood smear. The PCR for COVID-19 was positive. All stool studies and other workup was unremarkable. Her PLASMIC score was 6 indicating high risk for severe ADAMTS13 deficiency, and therefore she was immediately admitted to the ICU and started on steroids, rituximab, and PEX. After 5-days of PEX, her platelet count improved to 199x103/µL and was deemed responsive to initial therapy. The following day the platelet count dropped to 8x103/µL and the patient was restarted on PEX. She failed to improve despite appropriate therapy and the disease was deemed to be refractory. A multidisciplinary decision was made to initiate Caplacizumab. She completed a total of 17 PEX sessions and significant improvement in her clinical course was achieved. She was eventually discharged home in stable condition on a tapered course of steroids. DISCUSSION: When ADAMTS13 is deficient, von Willebrand factor multimers accumulate and increase platelet aggregation causing TTP. Since its activity testing has a prolonged turnaround time, the PLASMIC score is validated to identify patients at risk for severe ADAMTS13 deficiency and facilitate timely management. Our patient ADAMTS13 activity was 2.2% correlating with a severe deficiency. PEX is associated with a significant decline in mortality as it replaces the deficient ADAMTS13 and removes the inhibitory autoantibodies from the circulatory system. CONCLUSIONS: TTP is a hematologic emergency that requires prompt therapy. It's important to include COVID-19 as a potential etiology and to explore other therapeutic approaches for a refractory TTP. REFERENCE #1: Sayani, F. A., & Abrams, C. S. (2015). How I treat refractory thrombotic thrombocytopenic purpura. Blood, 125(25), 3860–3867 REFERENCE #2: Bendapudi PK, Hurwitz S, Fry A, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol 2017; 4:e157. REFERENCE #3: Sweeney, J. M., Barouqa, M., Krause, G. J., Gonzalez-Lugo, J. D., Rahman, S., & Gil, M. R. (2021). Low ADAMTS13 Activity Correlates with Increased Mortality in COVID-19 Patients. TH open : companion journal to thrombosis and haemostasis, 5(1), e89–e103 DISCLOSURES: No relevant relationships by Joel Brooks, source=Web Response No relevant relationships by Ruben Cabrera, source=Web Response No relevant relationships by Jorge Cruz, source=Web Response No relevant relationships by Nathalie De paz, source=Web Response No relevant relationships by Tarig Elhakim, source=Web Response No relevant relationships by Jose Gascon, source=Web Response No relevant relationships by Daniel Gonzalez, source=Web Response No relevant relationships by Carlos Guida, source=Web Response No relevant relationships by Robert Hernandez, source=Web Response No relevant relationships by Ilde Lee, source=Web Response No relevant relationships by Daniel Zapata, source=Web Response

EBV-ASSOCIATED ATYPICAL HEMOLYTIC UREMIC SYNDROME PRESENTING WITH DIFFUSE ALVEOLAR HEMORRHAGE

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Atypical Hemolytic Uremic Syndrome (aHUS) is a severe form of thrombotic microangiopathy that presents with nonimmune hemolytic anemia, thrombocytopenia, and renal failure. Diffuse alveolar hemorrhage (DAH) due to disruption of alveolar-capillary basement membrane is an exceedingly rare presentation of aHUS. CASE PRESENTATION: A 19-year-old-male presented with acute respiratory distress, hemoptysis, tachypnea, tachycardia, elevated blood pressure, and oliguria. One month prior the patient was diagnosed with infectious mononucleosis associated with thrombocytopenia and splenomegaly. Initial labs demonstrated hemolytic anemia, thrombocytopenia, and acute renal failure. CT chest showed diffuse bilateral central alveolar opacities concerning for alveolar hemorrhage. Patient was stabilized with supplemental oxygen and urgent hemodialysis was initiated. Further studies revealed schistocytes on peripheral blood smear, hypocomplementemia, borderline low activity of ADAMTS-13, positive IgM/IgG to EBV nuclear antigen and a renal biopsy consistent with acute thrombotic microangiopathy affecting nearly all blood vessels and glomeruli. Serologies were negative for ANA, anti-dsDNA, ANCA, Anti-GBM ab, rheumatoid factor, HIV, HBV, and HCV. Patient was diagnosed with EBV infection associated Atypical Hemolytic Uremic Syndrome (aHUS) and received treatment with plasmapheresis and eculizumab. With this treatment, patients' respiratory distress, hemoptysis, and renal function improved, following which he was discharged with outpatient hemodialysis. He continues follow up with hematology and nephrology. DISCUSSION: aHUS is much less frequent than Shiga-toxin mediated hemolytic uremic syndrome. Endothelial injury and thrombotic microangiopathy are hallmarks of this complement mediated process. It is associated with high risk of ESRD. Recent advances in therapeutics targeted at complement regulatory proteins including Eculizumab, have offered better outcomes. DAH is a life-threatening complication that has rarely been reported with aHUS. Treatment of diffuse alveolar hemorrhage depends on etiology. In our patient, diagnosis and targeted management of aHUS helped improve hemoptysis and respiratory distress from DAH. CONCLUSIONS: Atypical HUS can present with acute onset renal failure and diffuse alveolar hemorrhage in some instances. Association with EBV infection is extremely rare. REFERENCE #1: Joseph C, Gattineni J. Complement disorders and hemolytic uremic syndrome. Curr Opin Pediatr. 2013;25(2):209-15. REFERENCE #2: Hong JY, Jung JY, Kang YA, Bae YS, Kim YS, Kim SK, et al. Delayed Hemolytic Uremic Syndrome Presenting as Diffuse Alveolar Hemorrhage. Korean J Crit Care Med. 2014;29(1):43-7 REFERENCE #3: Al-Shyoukh A, Younis M, Abughanimeh O, Tahboub M, Hamarshi MS. An Unusual Case of Diffuse Alveolar Hemorrhage as a Clinical Manifestation of Atypical Hemolytic Uremic Syndrome: A Case Report. Cureus. 2019;11(7):e5059-e. DISCLOSURES: No relevant relationships by zainub ajmal, source=Web Response No relevant relationships by Sana Ghalib, source=Web Response No relevant relationships by Boris Shkolnik, source=Web Response No relevant relationships by Fatima Tuz Zahra, source=Web Response

ACUTE SPINAL CORD INFARCTION IN THE SETTING OF HEREDITARY THROMBOTIC THROMBOCYTOPENIC PURPURA

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Thrombotic thrombocytopenic purpura (TTP) is an acquired or inherited condition characterized by platelet aggregation and thrombosis due to an accumulation of von Willebrand factor multimers caused by decreased ADAMTS13 protease activity. It usually presents with fever, microangiopathic hemolytic anemia, thrombocytopenia, neurologic findings, and renal dysfunction. Acquired TTP is due to an inhibitory autoantibody against ADAMTS13 and is treated with glucocorticoids, rituximab, plasmapheresis, and caplacizumab [1]. Hereditary TTP is due to an autosomal recessive ADAMTS13 mutation and is treated with prophylactic and therapeutic plasma infusion [2]. Despite its prothrombotic nature, active bleeding at presentation is an uncommon complication described in literature. [3] We present an unusual case of hereditary TTP that caused acute spinal cord infarction from active bleeding into the spinal canal. CASE PRESENTATION: A 33-year-old female with past medical history of systemic lupus erythematosus presented with malaise, fevers, dyspnea, vomiting, and diarrhea. She was altered and febrile upon arrival, but then developed bleeding from the vagina, rectum, and bladder. TTP was empirically diagnosed based on fever, encephalopathy, and lab work (hemolysis, kidney injury, and thrombocytopenia). Blood product transfusions and plasmapheresis were initiated. Hereditary TTP was diagnosed based on decreased ADAMTS13 activity with negative inhibitor testing, so plasma infusions were started in lieu of plasmapheresis. During her hospitalization she exhibited progressive diffuse lower extremity weakness, sensory deficits, and absent deep tendon reflexes. MRI of the brain and spinal cord showed an infarction from C5 to the conus medullaris, as well as an extra-arachnoid fluid collection/hematoma throughout the dorsal canal from C3 to T12/L1. This was diagnosed as a subdural hematoma causing severe stenosis of the proximal and mid-thoracic canal. She was not a surgical candidate, so she was treated with plasma infusions and aggressive physical therapy. DISCUSSION: This case was challenging as TTP typically leads to thrombosis rather than bleeding, and the development of a spinal cord infarction is an unusual manifestation for TTP. Despite normal coagulation studies and negative active lupus studies, the patient's clinical presentation and decreased ADAMTS13 activity confirmed TTP even in the setting of significant bleeding. With acute spinal cord dysfunction, differential includes transverse myelitis, epidural abscess, infarction, and syringomyelia. MRI of the spine is diagnostic. TTP management must include platelet transfusion in the setting of active bleeding as it can be life saving.[3] CONCLUSIONS: TTP management differs on whether it is inherited or acquired. Although TTP is usually a prothrombotic entity, clinicians must keep it in the differential for active bleeding in the critically ill patient. REFERENCE #1: Scully M, Hunt BJ, Benjamin S, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 2012; 158:323. REFERENCE #2: Hamroun A, Prouteau C, Provôt F. Hereditary Thrombotic Thrombocytopenic Purpura. N Engl J Med 2020; 382:392. REFERENCE #3: Swisher KK, Terrell DR, Vesely SK, et al. Clinical outcomes after platelet transfusions in patients with thrombotic thrombocytopenic purpura. Transfusion 2009; 49:873. DISCLOSURES: No relevant relationships by Mohamed Hajmurad, source=Web Response No relevant relationships by Jonathan Hendrie, source=Web Response No relevant relationships by Hamza Khan, source=Web Response No relevant relationships by Daniel Matthews, source=Web Response

Blood–brain barrier permeability in survivors of immune-mediated thrombotic thrombocytopenic purpura: a pilot study

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disorder of systemic microthrombosis and organ ischemia. The etiology of chronic cerebrovascular outcomes in iTTP survivors is largely unknown. In this pilot study, we measured blood–brain barrier (BBB) permeability in patients with iTTP at the start of remission and 6 months later. This prospective pilot study included 7 adult patients with incident iTTP. Eligibility criteria included ADAMTS13 activity < 10% and detectable inhibitor at diagnosis. Patients were recruited from London Health Sciences Centre in Canada (2017-2019) within 3 days of hospital admission and followed for 6 months after remission (defined as normalization of platelet count and lactate dehydrogenase with no clinical signs or symptoms of microvascular injury for more than 30 days after the last plasma exchange). All patients had cerebral computed tomography perfusion scans with BBB permeability surface product measurements. Patients (5 women, 2 men) had a mean age of 48 years (range, 21-77 years). At diagnosis, patients had a mean platelet count of 22 (standard deviation [SD], 25) × 109/L. At the start of remission, mean BBB permeability surface product was 0.91 (0.30) mL/min/100 g. Six months later, the mean permeability surface product was 0.56 (0.22) mL/min/100 g, with a mean difference of −0.312 mL/min/100 g (95% confidence interval: −0.4729 to −0.1510; P = .0032). In this pilot study of patients with iTTP, pathologically increased BBB permeability was evident, and although there was some improvement, this persisted 6 months after remission. Future work will explore the chronicity of these findings and their clinical implications.

Major adverse cardiovascular events in survivors of immune-mediated thrombotic thrombocytopenic purpura.

Cardiovascular disease is a leading cause of death in survivors of immune-mediated thrombotic thrombocytopenic purpura (iTTP), but the epidemiology of major adverse cardiovascular events (MACE) in iTTP survivors is unknown. We evaluated the prevalence and risk factors for MACE, defined as the composite of non-fatal or fatal myocardial infarction (MI), stroke, and cardiac revascularization, during clinical remission in two large iTTP cohorts (Johns Hopkins University and Ohio State University). Of 181 patients followed for ≥ 3 months after recovery from acute iTTP, 28.6% had a MACE event over a median follow up of 7.6 years. Stroke was the most common type of MACE (18.2%), followed by non-fatal MI (6.6%), cardiac revascularization (4.9%) and fatal MI (0.6%). Compared to the general United States population, iTTP survivors were younger at first stroke in remission (males [56.5 years vs. 68.6 years, p=0.031], females [49.7 years vs. 72.9 years, p < 0.001]) or MI in remission (males [56.5 years vs. 65.6 years, p < 0.001] and females [53.1 years vs. 72.0 years, p < 0.001]). Age (HR 1.03 [95% CI 1.002-1.054]), race (Black/Other vs. White) (HR 2.32 [95% CI 1.12-4.82]), and diabetes mellitus (HR 2.37 [95% CI 1.09-0.03]) were associated with MACE in a Cox regression model also adjusted for sex, hypertension, obesity, hyperlipidemia, chronic kidney disease, atrial fibrillation, autoimmune disease, and relapsing iTTP. Remission ADAMTS13 activity was not significantly associated with MACE. In conclusion, iTTP survivors experience high rates of MACE and may benefit from aggressively screening for and managing cardiovascular risk factors.

Neutrophil extracellular traps: a role in inflammation and dysregulated hemostasis as well as in patients with COVID-19 and severe obstetric pathology

Numerous studies have proven a close relationship between inflammatory diseases and the state of hypercoagulability. In fact, thromboembolic complications represent one of the main causes of disability and mortality in acute and chronic inflammatory diseases, cancer and obstetric complications. Despite this, the processes of hemostasis and immune responses have long been considered separately; currently, work is underway to identify the molecular basis for a relationship between such systems. It has been identified that various pro-inflammatory stimuli are capable of triggering a coagulation cascade, which in turn modulates inflammatory responses. Neutrophil extracellular traps (NETs) are the networks of histones of extracellular DNA generated by neutrophils in response to inflammatory stimuli. The hemostasis is activated against infection in order to minimize the spread of infection and, if possible, inactivate the infectious agent. Another molecular network is based on fibrin. Over the last 10 years, there has been accumulated a whole body of evidence that NETs and fibrin are able to form a united network within a thrombus, stabilizing each other. Similarities and molecular cross-reactions are also present in the processes of fibrinolysis and lysis of NETs. Both NETs and von Willebrand factor (vWF) are involved in thrombosis as well as inflammation. During the development of these conditions, a series of events occurs in the microvascular network, including endothelial activation, NETs formation, vWF secretion, adhesion, aggregation, and activation of blood cells. The activity of vWF multimers is regulated by the specific metalloproteinase ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). Studies have shown that interactions between NETs and vWF can lead to arterial and venous thrombosis and inflammation. In addition, the contents released from activated neutrophils or NETs result in decreased ADAMTS-13 activity, which can occur in both thrombotic microangiopathies and acute ischemic stroke. Recently, NETs have been envisioned as a cause of endothelial damage and immunothrombosis in COVID-19. In addition, vWF and ADAMTS-13 levels predict COVID-19 mortality. In this review, we summarize the biological characteristics and interactions of NETs, vWF, and ADAMTS-13, the effect of NETs on hemostasis regulation and discuss their role in thrombotic conditions, sepsis, COVID-19, and obstetric complications.

Coagulation Abnormalities in Renal Pathology of Chronic Kidney Disease: The Interplay between Blood Cells and Soluble Factors.

Coagulation abnormalities in renal pathology are associated with a high thrombotic and hemorrhagic risk. This study aims to investigate the hemostatic abnormalities that are related to the interaction between soluble coagulation factors and blood cells, and the effects of hemodialysis (HD) on it, in end stage renal disease (ESRD) patients. Thirty-two ESRD patients under HD treatment and fifteen healthy controls were included in the study. Whole blood samples from the healthy and ESRD subjects were collected before and after the HD session. Evaluation of coagulation included primary and secondary hemostasis screening tests, proteins of coagulation, fibrinolytic and inhibitory system, and ADAMTS-13 activity. Phosphatidylserine (PS) exposure and intracellular reactive oxygen species (iROS) levels were also examined in red blood cells and platelets, in addition to the platelet activation marker CD62P. Platelet function analysis showed pathological values in ESRD patients despite the increased levels of activation markers (PS, CD62P, iROS). Activities of most coagulation, fibrinolytic, and inhibitory system proteins were within the normal range, but HD triggered an increase in half of them. Additionally, the increased baseline levels of ADAMTS-13 inhibitor were further augmented by the dialysis session. Finally, pathological levels of PS and iROS were measured in red blood cells in close correlation with variations in several coagulation factors and platelet characteristics. This study provides evidence for a complex coagulation phenotype in ESRD. Signs of increased bleeding risk coexisted with prothrombotic features of soluble factors and blood cells in a general hyperfibrinolytic state. Hemodialysis seems to augment the prothrombotic potential, while the persisted platelet dysfunction might counteract the increased predisposition to thrombotic events post-dialysis. The interaction of red blood cells with platelets, the thrombus, the endothelium, the soluble components of the coagulation pathways, and the contribution of extracellular vesicles on hemostasis as well as the identification of the unknown origin ADAMTS-13 inhibitor deserve further investigation in uremia.

Involvement of von Willebrand factor and botrocetin in the thrombocytopenia induced by Bothrops jararaca snake venom.

Patients bitten by snakes consistently manifest a bleeding tendency, in which thrombocytopenia, consumption coagulopathy, mucous bleeding, and, more rarely, thrombotic microangiopathy, are observed. Von Willebrand factor (VWF) is required for primary hemostasis, and some venom proteins, such as botrocetin (a C-type lectin-like protein) and snake venom metalloproteinases (SVMP), disturb the normal interaction between platelets and VWF, possibly contributing to snakebite-induced bleedings. To understand the relationship among plasma VWF, platelets, botrocetin and SVMP from Bothrops jararaca snake venom (BjV) in the development of thrombocytopenia, we used (a) Wistar rats injected s.c. with BjV preincubated with anti-botrocetin antibodies (ABA) and/or Na2-EDTA (a SVMP inhibitor), and (b) VWF knockout mice (Vwf-/-) injected with BjV. Under all conditions, BjV induced a rapid and intense thrombocytopenia. In rats, BjV alone reduced the levels of VWF:Ag, VWF:CB, high molecular weight multimers of VWF, ADAMTS13 activity, and factor VIII. Moreover, VWF:Ag levels in rats that received BjV preincubated with Na2-EDTA and/or ABA tended to recover faster. In mice, BjV caused thrombocytopenia in both Vwf-/- and C57BL/6 (background control) strains, and VWF:Ag levels tended to decrease in C57BL/6, demonstrating that thrombocytopenia was independent of the presence of plasma VWF. These findings showed that botrocetin present in BjV failed to affect the extent or the time course of thrombocytopenia induced by envenomation, but it contributed to decrease the levels and function of plasma VWF. Thus, VWF alterations during B. jararaca envenomation are an ancillary event, and not the main mechanism leading to decreased platelet counts.

Acquired thrombotic thrombocytopenic purpura: A rare disease associated with BNT162b2 vaccine

BackgroundIn December 2020 the Israeli Health Ministry began a mass vaccination campaign with the BNT162b2 vaccine. This was an important step in overcoming the severe acute respiratory syndrome corona virus 2 (SARS‐CoV‐2) pandemic. Autoimmune phenomenon have been described after receiving vaccinations. Patients/MethodsHere we describe a case series of patients who developed acquired Thrombotic Thrombocytopenic Purpura, a rare autoimmune disease, within several days of receiving the BNT162b2 vaccine. ConclusionsA disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity should be evaluated in patients with history of aTTP before and after any vaccination, especially the SARS‐CoV‐2 vaccination, and immunosuppression treatment should be considered before vaccination in cases of low ADAMTS13 activity. Patients should be closely monitored after the vaccine for clinical situation and laboratory data. Post vaccination thrombocytopenia assessment should include immune thrombocytopenic purpura, vaccine‐induced immune thrombotic thrombocytopenia and acquired thrombotic thrombocytopenic purpura.

Cardiovascular disease is a leading cause of mortality among TTP survivors in clinical remission

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) survivors experience high rates of adverse health sequelae and increased mortality over long-term follow-up. We conducted this multicenter cohort study to evaluate long-term mortality and causes of death in iTTP survivors. Between 2003 and 2020, 222 patients were enrolled in the Ohio State University and Johns Hopkins TTP registries and followed for a median of 4.5 (interquartile range [IQR], 75 0.4-11.5) years. Nine patients died during their first iTTP episode, and 29 patients died during follow-up. Mortality rate was 1.8 times higher than expected from an age-, sex-, and race-adjusted reference population. Cardiovascular disease was a leading primary cause of death (27.6%) tied with relapsed iTTP (27.6%), followed by malignancy (20.7%), infection (13.8%), and other causes (10.3%). Male sex (hazard ratio [HR], 3.74; 95% confidence interval [CI], 1.65-8.48), increasing age (HR, 1.04; 95% CI, 1.01-1.07), and number of iTTP episodes (HR, 1.10; 95% CI, 1.01-1.20) were associated with mortality in a model adjusted for African American race (HR, 0.70; 95% CI, 0.30-1.65), hypertension (HR, 0.47; 95% CI, 0.20-1.08), chronic kidney disease (HR 1.46; 95% CI, 0.65-3.30), and site (HR, 1.46; 95% CI, 0.64–3.30). There was a trend toward shorter survival in patients with lower ADAMTS13 activity during remission (P = .078). Our study highlights the need for survivorship care and investigation focused on cardiovascular disease and early mortality in TTP survivors.

Purple Thrombocytopenic Thrombotic

Thrombotic thrombocytopenic purpura is a rare disease of immune origin, belonging to thrombotic microangiopathies. In most cases, it can present as microangiopathic hemolytic anemia accompanied by thrombocytopenia, neurological deficit and kidney abnormalities. The present clinical case belongs to a female patient with no significant personal or family history, who went to the doctor for a clinical picture of 2 days of evolution with hematuria, general malaise, asthenia and adynamia, on physical examination without alterations, with vital signs in ranges of normality. The diagnosis of thrombotic thrombocytopenic purpura was made due to hemolysis, elevated levels of lactate dehydrogenase and a reduction in serum haptoglobin accompanied by the presence of serum schistocytes&gt; 6% in the peripheral blood smear. Thrombocytopenic purpura is a diagnostic challenge because its clinical picture is often nonspecific, making it more difficult to start its treatment in a timely manner. Another drawback is the high costs for ADAMTS13 activity tests. Despite the fact that the treatments for this disease have low success rates, in our clinical case our patient responded favorably to the treatment instituted

Cost-effectiveness of thrombotic thrombocytopenic purpura diagnosis: a retrospective analysis in the University Hospital Center of Lyon (France).

The aim of the present study was to perform an economic evaluation of two alternative assays of ADAMTS13 activity (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats, member 13) for diagnosing thrombotic thrombocytopenic purpura (TTP) in the Hospital of Lyon (France). The study approach was more economic than clinical. We retrospectively calculated the prescription costs of ADAMST13 activity from January to December 2019 for patients depending on the assay: manual ELISA (Technozym) or automated assay (AcuStar Werfen, Instrumentation Laboratory). Then, we compared the cost of therapeutic plasma exchange (TPE) consumption awaiting ADAMTS13 activity assay results. From an economic point of view, the automated assay was more cost-effective. From a clinical one, we supposed that the faster results given by AcuStar could improve patient care by reducing the number of TPEs. Automated assay could improve patient care without increasing costs in our institution.

СИСТЕМА «АDAMTS13 – ФАКТОР ФОН ВИЛЛЕБРАНДА – ТРОМБОЦИТЫ» ПРИ АТИПИЧНОМ ГЕМОЛИТИКО- УРЕМИЧЕСКОМ СИНДРОМЕ У ДЕТЕЙ

Atypical hemolytic uremic syndrome (aHUS) is an orphan disease caused by hyperactivation of the alternative complement pathway. Objective of the study: to assess the state of the «ADAMTS13 – von Willebrand factor (vWF) – platelets» system in children with aHUS. Materials and methods of research: [by the FRET method (fluorescence resonance energy transfer) for the FRETSVWF73 (Peptide Institude, Inc., Japan)] hydrolysis of the fluorescent substrate and ADAMTS13 antigen [by ELISA using TECHNOZYM® ADAMTS13 5450551 ELISA (Technoclone GmbH, Austria)], vWF activity [for platelet agglutination (aggregation) in the presence of ristomycin (NPO Renam reagent kit for the ALAT-230LA-2 aggregometer, Russia)] and vWF antigen [by ELISA using the TECHNOZYM® vWF kit: Ag 5450201 ELISA (Technoclone GmbH , Austria)]. Results: there was a decrease in the activity and concentration of ADAMTS13 in 63% and 62% of patients, respectively. A decrease in vWF activity was noted in 44% of cases, an increase in its concentration – in 54% of children. Thrombocytopenia was diagnosed in 99% of children. Conclusion: the imbalance in the «ADAMTS13 – vWF – platelets» system supports the process of thrombus formation with the development of organ ischemia in aHUS under conditions of endothelial dysfunction. Reduced ADAMTS13 activity predicts the severity of the disease.

Post Approval Experience with Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura at a Single Institution.

Caplacizumab prevents platelet adhesion and has been approved for acquired thrombotic thrombocytopenic purpura (aTTP). This study was retrospective, including all patients diagnosed with aTTP and treated with caplacizumab since commercial availability in 2019 until 28 February 2021 at a single academic hospital with no exclusion criteria. Results used definitions for outcomes in aTTP from the International Working Group Consensus. Ten patients with aTTP received caplacizumab. The median age was 52 years. Six (60%) patients had refractory aTTP while 4 (40%) had newly diagnosed aTTP. The median laboratory values prior to therapy demonstrated: platelet count (PC) 29/uL, LDH 518 U/L (182–1850), ADAMTS13 activity 3% and ADAMTS13 inhibitor 1.4 BU. Everyone received glucocorticoids, rituximab, therapeutic plasma exchange (TPE) and caplacizumab. The median number of TPE was 12 days. Caplacizumab was started at a median of 5 days after the first TPE and the median treatment duration was 31 days. Normalization of PC, LDH and ADAMTS13 activity in days were 5, 3.5, and 32.5, respectively. Six (60%) patients achieved complete response, 3 (30%) had refractory disease and 1 (10%) had relapsed aTTP. No subject suffered abnormal bleeding, or thrombotic event. There were no deaths. Caplacizumab with TPE, glucocorticoids and rituximab was a safe and effective therapy for aTTP.

Predictive Role of Haematological Determinants on Outcomes of Critically Ill COVID-19 Patients Admitted to Intensive Care Unit.

Background: The mortality of patients admitted to the intensive care unit (ICU) with COVID-19 remains significantly high. Severe COVID-19 pneumonia is characterised by refractory hypoxemia with significant shunting due to a combination of alveolar damage, vascular vasoconstriction, and occlusion due to microthrombi. Similar pathological features are seen in extra-pulmonary organs. However, the influence of thrombotic markers on the risk of mechanical ventilation (MV) and the development of acute kidney injury (AKI) is not fully defined.Methods: This was a cross-sectional evaluation of haemostatic and thrombotic markers of COVID-19 patients admitted to the ICU to determine their predictability for the development of thromboembolism and the need for non-invasive or invasive MV, development of AKI, and mortality.Results: An extended coagulation profile was obtained in 71 SARS-CoV-2 positive patients admitted to the ICU. All patients had acute severe hypoxic respiratory failure and required non-invasive or invasive MV. There were increases in peak D-dimer (3.0 mg/L), factor VIII levels (255 IU/dL) vWF antigen (471 IU/dL) with low ADAMTS13 activity (54.7 IU/dL) compared to the reference ranges. Peak D-dimer was consistently raised in patients who developed AKI and required invasive MV. ADAMTS13/vWF/platelet axis was associated with disease severity, multi-organ dysfunction, and mortality.Conclusions: Haematological abnormalities are a common feature of severe COVID-19 pneumonia. We found peak D-dimer and vWF-ADAMTS13-platelet axis are associated with increased ICU severity and outcome in severe COVID-19 patients admitted to ICU. Larger studies are needed to evaluate this more comprehensively.

Complete ADAMTS13 remission in a patient with refractory autoimmune-mediated thrombotic thrombocytopenic purpura after infliximab

Autoimmune thrombotic thrombocytopenic purpura (aTTP) is caused by autoantibodies to the von Willebrand Factor cleaving enzyme, ADAMTS13. Despite recent advances in the treatment of acute aTTP, relapse rates remain high. Guidance for the treatment of patients in clinical remission but with persistent severe ADAMTS13 deficiency who fail to respond to rituximab remains unclear. We report a case of a 29-year-old man diagnosed with aTTP at the age of 11. Over a period of 18 years, he had five clinical relapses with persistent severe ADAMTS13 deficiency (<10%) and presence of autoantibodies during clinical remissions despite immunosuppressive therapy with rituximab, bortezomib and azathioprine. While in a clinical remission, he was diagnosed with Crohn’s disease and initially treated with adalimumab. When he subsequently developed antibodies to adalimumab, he was transitioned to infliximab. ADAMTS13 activity increased to 24% by 2 months of infliximab induction, and four months later the ADAMTS13 activity improved to 42%. This case demonstrates the importance of managing concurrent inflammatory disorders and suggests that TNF may play a role in autoantibody development and ADAMTS13 depletion.

Verification of the Role of ADAMTS13 in the Cardiovascular Disease Using Two-Sample Mendelian Randomization.

ObjectiveADAMTS13 plays a crucial role in several diseases. Many observational studies have reported the relationship between ADAMTS13 and some cardiovascular diseases but have drawn different conclusions, likely attributed to confounding factors lacking adjustment. Identifying the role of ADAMTS13 in cardiovascular diseases is pivotal for prevention as well as early intervention in patients with latent cardiovascular diseases. This study aims to estimate whether the level and activity of ADAMTS13 are causally associated with common cardiovascular diseases.MethodsWe applied a two-sample Mendelian randomization approach incorporating genome-wide association summary statistics to verify the causal association between ADAMTS13 level, as well as activity and cardiovascular diseases.ResultsLower ADAMTS13 activity was causally associated with the increased risks for coronary heart diseases (b = −0.0041, se = 0.0019, p < 0.05) as well as myocardial infarction (b = −0.0048, se = 0.0022, p < 0.05). Standard inverse-variance weighted Mendelian randomization results suggested no genetic support for a causal association between ADAMTS13 level and cardiovascular diseases including coronary heart disease, myocardial infarction, atrial fibrillation, heart failure, and venous thromboembolism (p > 0.05).ConclusionThe causal effect of lower ADAMTS13 activity on the increased odds of having cardiovascular diseases was coronary heart disease and myocardial infarction.

ADAMTS13 testing update: Focus on laboratory aspects of difficult thrombotic thrombocytopenic purpura diagnoses and effects of new therapies

AbstractTTP is a life‐threatening disorder diagnosed using a combination of clinical information and laboratory results. ADAMTS13 activity and antibody testing represent a major advance in the field, but results can sometimes be difficult to interpret due to technical aspects of the tests and characteristics of the causative antibodies in acquired TTP. Genetic testing for ADAMTS13 mutations is also now available to assist with the diagnosis of inherited TTP. This review will focus on ADAMTS13 testing and will highlight patient and laboratory aspects that can lead to diagnostic difficulty. The effects of TTP therapies on test results will also be discussed.

Report of two unrelated cases of Familial Thrombotic Thrombocytopeic Purpura

Thrombotic Thrombocytopenic Purpura (TTP) is a rare microangiopathic disorder characterised by the pentad of microangiopathic hemolytic anemia, thrombocytopenic purpura, neurologic abnormalities, fever, and renal disease. Decreased production and/or activity of ADAMTS13 is the cause of this disorder. ADAMTS13 is a metalloproteinase which is responsible of the cleavage of high weight multimers of von Wilebrand factor. Its acquired form is usually seen in adults and is due to antibody formation against the enzyme. But even rarer familial and relapsing forms (Upshow-Scholman syndrome) are due to enzyme underproduction and can be seen in pediatric age group. Here, the authors reported two unrelated cases of familial TTP from Guilan province in the north of Iran.

Prediction of Relapse Based on Remission ADAMTS13 Activity in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura

Background: Acquired, immune-mediated thrombotic thrombocytopenic purpura (iTTP) is defined by thrombocytopenia and microangiopathic hemolytic anemia due to ADAMTS13 deficiency. After the first episode of TTP, about 30-40% of the patients will experience one or more relapse. It has been hypothesized that relapses of iTTP may be associated with severely deficient ADAMTS13 activity during remission. However, some patients with iTTP will remain on remission despite persisting severely decreased ADAMTS13 activity. Moreover, spontaneous recovery of ADAMTS13 activity has also been reported. Whether severe ADAMTS13 deficiency during remission increases risk for relapse is not certain. Therefore we have evaluated the ability of ADAMTS13 activity levels measured during clinical remission to predict relapses of iTTP.Methods: Between March 2004 and June 2017, we collected clinical data and plasma samples from patients who presented to The Ohio State University with clinical diagnosis of iTTP (defined as thrombocytopenia, microangiopathic hemolytic anemia, without an alternative explanation). The diagnosis was confirmed by severely deficient ADAMTS13 activity (<10%). All ADAMTS13 measurements in this cohort were obtained from patients in remission with a platelet count >150 x109/uL and no clinical signs of active TTP. ADAMTS13 activity was determined using a SELDI-TOF mass-spectrometer-based method. For the present study, we only included samples obtained from patients that had never received any prophylactic treatment including rituximab or cyclosporine. To determine the ability of ADAMTS13 activity to predict a relapse in the following 30 and 90 days, we calculated the sensitivity, specificity and likelihood ratio of the test when the ADAMTS13 activity was less than 10% and less than 20%.Results: A total of 557 ADAMTS13 activity measurements were drawn in 39 patients while in remission, with a median interval of 91 days between samples. The demographic characteristics of the population are shown in Table 1. Fourteen patients had no history of relapses and 25 patients had at least one prior relapse. There were 23 relapses in 13 patients during the study period. Of the 557 samples, 145 (26%) were read as less than 10%, 52 (9.4%) were between 10% and 20%, and 360 (64.6%) were >20%. Only 4 (2.78%) and 11(7.59%) of the samples with ADAMTS13 activity <10%, were followed by a relapse in the next 30 and 90 days, respectively. The details of the ADAMTS13 activity during remission are listed in Table 2. The median number of samples from each patient was 10 (range 2 to 41). The sensitivity, specificity and likelihood ratio for relapse for ADAMTS13 activity <10% and 20%, over the following 30 and 90 days are shown in Table 3.Conclusions:- There is a high variability on the ADAMTS13 activity during remission from iTTP, with 25% of the samples showing severe deficiency (<10%) and 35% with activity less than 20%.- With only a small portion of severely deficient samples leading to relapses, both for the 30 and 90-day period, an ADAMTS13 activity of <10% measured during remission does not uniformly lead to relapse.- An ADAMTS13 activity < 20% is a better marker for relapse prediction than < 10%.- These findings call for prospective, randomized studies to evaluate the best biomarker or combination of biomarkers to predict a relapse. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.