To the Editor: Patients with coronavirus disease 2019 have a profound hypercoagulable state, and complicating venous thrombotic events are common. [1][2][3] Abnormalities in coagulation screening measures, including a prolonged activated partial-thromboplastin time (aPTT), have been reported in patients with This finding could be seen as a reason to avoid the use of anticoagulation at both therapeutic and prophylactic doses.A prolonged aPTT may indicate a clottingfactor deficiency or the presence of an inhibitor of coagulation that is either specific (e.g., antibody to factor VIII) or nonspecific (e.g., lupus anticoagulant). Lupus anticoagulant can affect in vitro tests of blood coagulation but typically is not associated with bleeding. As part of the antiphospholipid syndrome, lupus anticoagulant is associated with a thrombotic risk. We investigated the cause of prolonged aPTT in patients with Covid-19.Blood specimens obtained from 216 patients who were positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were received for coagulation screening, and 44 (20%) were found to have a prolonged aPTT. The specimens from 9 patients were excluded, and those from 35 patients were investigated further. (Details of the methods are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.)A summary of the results is provided in Table 1. The median age was 57 years, and 24 patients were male. Pulmonary embolism was confirmed in 1 patient, and clinically suspected thrombosis was present in 1 patient. No clinically significant bleeding or arterial thromboses were reported.No patients were found to have deficiencies in factor VIII or factor IX. In 5 patients, marginal reductions in factor XI were found that were un-
Objective-To identify an appropriate diagnostic tool for the early diagnosis of Acute Traumatic Coagulopathy (ATC) and validate this modality through prediction of transfusion requirements in trauma hemorrhage. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Design-Prospective observational cohort study Setting-Level 1 trauma centre Europe PMC Funders Group Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsPatients-Adult trauma patients who met the local criteria for full trauma team activation. Exclusion criteria included emergency department (ED) arrival >2 hours after injury, >2000ml of intravenous fluid before ED arrival or transfer from another hospital. Interventions-NoneMeasurements-Blood was collected on arrival in ED and analysed with laboratory prothrombin time (PT), point of care (PoC) PT and rotational thromboelastometry (ROTEM). Prothrombin ratio (PTr) was calculated and ATC defined as laboratory PTr>1.2. Transfusion requirements were recorded for the first 12 hours following admission.Main Results-300 patients were included in the study. Laboratory PT results were available at median 78 (62-103) minutes. PoC PTr had reduced agreement with laboratory PTr in patients with ATC, with 29% false negative results. In ATC the ROTEM Clot Amplitude at 5 minutes (CA5) was diminished by 42% and this persisted throughout clot maturation. ROTEM clotting time was not significantly prolonged. A CA5 threshold ≤35mm had a detection rate of 77% for ATC with a false positive rate of 13%. Patients with CA5 ≤35mm were more likely to receive red cell (46% vs 17%, p<0.001) and plasma (37% vs 11%, p<0.001) transfusions. The CA5 could identify patients who would require massive transfusion (detection rate of 71%, vs 43% for PTr >1.2, p<0.001).Conclusions-In trauma hemorrhage PTr is not rapidly available from the laboratory and PoC devices can be inaccurate. ATC is functionally characterised by a reduction in clot strength. With a threshold of CA5 ≤35mm ROTEM can identify ATC at 5 minutes and predict the need for massive transfusion.
Summary. Background: Trauma is a global disease, with over 2.5 million deaths annually from hemorrhage and coagulopathy. Overt hyperfibrinolysis is rare in trauma, and is associated with massive fatal injuries. Paradoxically, clinical trials suggest a much broader indication for antifibrinolytics. Objective: To determine the incidence and magnitude of fibrinolytic activation in trauma patients and its relationship to clot lysis as measured by thromboelastometry. Methods: A prospective cohort study of 303 consecutive trauma patients admitted between January 2007 and June 2009 was performed. Blood was drawn on arrival for thromboelastometry (TEM) and coagulation assays. Follow‐up was until hospital discharge or death. TEM hyperfibrinolysis was defined as maximum clot lysis of > 15%. Fibrinolytic activation (FA) was deterined according to plasmin–antiplasmin (PAP) complex and D‐dimer levels. Data were collected on demographics, mechanism, severity of injury, and baseline vital signs. The primary outcome measure was 28‐day mortality. The secondary outcome measures were 28‐day ventilator‐free days and 24‐h transfusion requirement. Results: Only 5% of patients had severe fibrinolysis on TEM, but 57% of patients had evidence of ‘moderate’ fibrinolysis, with PAP complex levels elevated to over twice normal (> 1500 μg L−1) without lysis on TEM. TEM detected clot lysis only when PAP complex levels were increased to 30 times normal (P < 0.001) and antiplasmin levels were < 75% of normal. Patients with FA had increased 28‐day mortality as compared with those with no FA (12% vs. 1%, P < 0.001), fewer ventilator‐free days, and longer hospital stay. Conclusions: FA occurs in the majority of trauma patients, and the magnitude of FA correlates with poor clinical outcome. This was not detected by conventional TEM, which is an insensitive measure of endogenous fibrinolytic activity.
Background Major trauma is a leading cause of morbidity and mortality worldwide with hemorrhage accounting for 40% of deaths. Acute traumatic coagulopathy exacerbates bleeding, but controversy remains over the degree to which inhibition of procoagulant pathways (anticoagulation), fibrinogen loss, and fibrinolysis drive the pathologic process. Through a combination of experimental study in a murine model of trauma hemorrhage and human observation, the authors’ objective was to determine the predominant pathophysiology of acute traumatic coagulopathy. Methods First, a prospective cohort study of 300 trauma patients admitted to a single level 1 trauma center with blood samples collected on arrival was performed. Second, a murine model of acute traumatic coagulopathy with suppressed protein C activation via genetic mutation of thrombomodulin was used. In both studies, analysis for coagulation screen, activated protein C levels, and rotational thromboelastometry (ROTEM) was performed. Results In patients with acute traumatic coagulopathy, the authors have demonstrated elevated activated protein C levels with profound fibrinolytic activity and early depletion of fibrinogen. Procoagulant pathways were only minimally inhibited with preservation of capacity to generate thrombin. Compared to factors V and VIII, proteases that do not undergo activated protein C–mediated cleavage were reduced but maintained within normal levels. In transgenic mice with reduced capacity to activate protein C, both fibrinolysis and fibrinogen depletion were significantly attenuated. Other recognized drivers of coagulopathy were associated with less significant perturbations of coagulation. Conclusions Activated protein C–associated fibrinolysis and fibrinogenolysis, rather than inhibition of procoagulant pathways, predominate in acute traumatic coagulopathy. In combination, these findings suggest a central role for the protein C pathway in acute traumatic coagulopathy and provide new translational opportunities for management of major trauma hemorrhage.
Vaccine‐induced immune thrombocytopenia and thrombosis (VITT) following ChAdOx1 nCOV‐19 vaccine has been described, associated with unusual site thrombosis, thrombocytopenia, raised D‐dimer and high titre immunoglobulin‐G (IgG) class anti‐Platelet Factor 4 (PF4) antibodies. Enzyme linked immunosorbent assays (ELISA) have been shown to detect anti‐PF4 in patients with VITT, but chemiluminesence assays do not reliably detect them. ELISA assays are not widely available in diagnostic laboratories, and, globally, very few laboratories perform platelet activation assays. Assays which are commercially available in the United Kingdom were evaluated for their ability to identify anti‐PF4 antibodies in samples from patients with suspected VITT. Four IgG‐specific ELISAs, two polyspecific ELISAs and four rapid assays were performed on samples from 43 patients with suspected VITT from across the UK. Cases were identified after referral to the UK Expert Haematology Panel multi‐disciplinary team and categorised into unlikely, possible or probable VITT. We demonstrated that the HemosIL AcuStar HIT‐IgG, HemosIL HIT‐Ab, Diamed PaGIA gel and STic Expert assays have poor sensitivity for VITT in comparison to ELISA. Where these assays are used for heparin induced thrombocytopenia diagnosis, laboratories should ensure that requests for suspected VITT are clearly identified so that an ELISA is performed. No superiority of IgG‐ELISAs over polyspecific‐ELISAs in sensitivity to VITT could be demonstrated. No single ELISA method detected all possible/probable VITT cases; if a single ELISA test is negative, a second ELISA or a platelet activation assay should be considered where there is strong clinical suspicion.
Introduction Direct oral anticoagulants (DOACs) require no laboratory monitoring, but they interfere with almost all clotting tests to a varying degree, depending on the DOAC, assay principles and reagents used. DOAC Stop (Haematex Research, Sydney, Australia) has recently been shown to adsorb DOACs from spiked and patient plasmas. The aim of our work was to investigate the DOAC Stop effect on a range of haemostasis assays on plasmas collected from patients on rivaroxaban or apixaban, to see whether it removes the effect of these drugs to enable more accurate interpretation of coagulation assays. Methods Samples from patients anticoagulated with either rivaroxaban, apixaban or no anticoagulant were tested for prothrombin time (PT), activated partial thromboplastin time (APTT), DOAC‐specific anti‐Xa assay, factor VIII (one‐stage and chromogenic assay) and DRVVT (low and high phospholipid) before and after sample treatment with DOAC‐Stop. Results DOAC Stop significantly removed the effects of rivaroxaban and apixaban on PT, APTT, anti‐Xa activity, factor VIII (one‐stage and chromogenic assays), and DRVVT (low and high phospholipid reagents), and reduced the number of false positive of lupus anticoagulant interpretations in patients on rivaroxaban. There was no effect on the results from patients that were not anticoagulated. Conclusion This small study suggests that it is likely that DOAC Stop can be used in laboratories to screen for coagulopathy or lupus anticoagulants in samples containing rivaroxaban or apixaban. Care should be taken in the interpretation of results since complete reversal of the anti‐Xa effect did not occur in every sample.
| INTRODUC TI ONThe recent development of emicizumab (Hemlibra, also previously referred to as ACE910; Hoffman-la Roche) extends treatment options for haemophilia A patients, with and without anti-Factor (F) VIII inhibitors, and provides an alternative to FVIII replacement therapy for patients with severe haemophilia A. 1,2 The novel nature and mode of action of the molecule have implications for the laboratory testing of coagulation parameters in patients receiving this treatment. | WHAT IS EMI CIZUMAB AND HOW DOE S IT WORK?Emicizumab is an engineered IgG4 bispecific antibody that binds both factor IXa (FIXa) and its substrate factor X (FX). This interaction colocalises the components of the intrinsic tenase complex and improves Abstract Introduction: The factor VIII mimetic emicizumab (Hemlibra, Hoffman-la Roche, Basel, Switzerland) has a novel mode of action that affects the laboratory monitoring of patients receiving this treatment. Aim: This guideline from the United Kingdom Haemophilia Centre Doctors Organisation(UKHCDO) aims to provide advice for clinical and laboratory staff on appropriate use of laboratory assays in patients with Haemophilia A treated with emicizumab. Results:The guideline describes the effect of emicizumab on commonly used coagulations tests and provides recommendations on the use of assays for measurement of factor VIII and factor VIII inhibitor in the presence of emicizumab. The guideline also provides recommendations on measurement of emicizumab. Conclusion:Knowledge of the effect of emicizumab on coagulation tests and factor assays is required to ensure appropriate testing and monitoring of therapy in patients receiving this drug. K E Y W O R D Sbispecific antibody, chromogenic factor VIII assay, emicizumab, factor VIII assay, haemophilia, Hemlibra
Laboratory monitoring of factor (F) VIII or FIX replacement therapy for treatment of haemophilia A or B is performed to ensure optimal therapy. A wide variety of commercially available one-stage clotting assays or chromogenic assays of FVIII and FIX is used for this purpose. Discrepancies between results obtained using the different assays have been described in hereditary haemophilia A 1,2 and haemophilia B, 3,4 in the absence of replacement therapy, and after gene therapy for both haemophilia A and B. 5,6 Although discrepancies after infusion of FVIII have been recognized since the advent of recombinant FVIII over 20 years ago, 7,8 this guideline will highlight recent studies of enhanced half-life FVIII and FIX products which demonstrate discrepancies in results both between chromogenic and one-stage clotting assays, and within assay type. There is currently no published consensus or guidance on what magnitude of discrepancy after concentrate infusion is acceptable for clinical use, and this may vary according to the factor level and the clinical AbstractAssay discrepancies can occur with laboratory monitoring of FVIII and FIX replacement therapy, particularly for the extended half-life products. This guideline collates current published data and provides advice on appropriate choice of assays for laboratory measurement of replacement therapy for patients with Haemophilia A and B without inhibitors. It is recommended that each haemophilia centre should ensure that appropriate laboratory assays are available for FVIII and FIX products in local clinical use. Patient samples should be assayed against calibrators traceable to WHO Plasma International Standards. Assay discrepancies are common especially for the extended half-life FVIII and FIX products, and assays of these products may need to be verified with the specific CFC being used. K E Y W O R D Schromogenic assay, extended half-life, factor concentrate, haemophilia, laboratory monitoring
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