Safety and differences between direct oral anticoagulants and vitamin K antagonists in the risk of post-traumatic intrathoracic bleeding after rib fractures in elderly patients

Closed chest traumas are frequent consequences of falls in the elderly. The presence of concomitant oral anticoagulant therapy can increase the risk of post-traumatic bleeding even in cases of trauma with non-severe dynamics. There is limited information about the differences between vitamin K antagonists and direct oral anticoagulants in the risk of post-traumatic bleeding. To assess differences in the risk of developing intra-thoracic hemorrhages after chest trauma with at least one rib fracture caused by an accidental fall in patients over 75 years of age taking oral anticoagulant therapy. This study involved data from four emergency departments over two years. All patients on oral anticoagulant therapy and over 75 years of age who reported a closed thoracic trauma with at least one rib fracture were retrospectively evaluated. Patients were divided into two study groups according their anticoagulant therapy. Of the 342 patients included in the study, 38.9% (133/342) were treated with direct oral anticoagulants and 61.1% (209/342) were treated with vitamin K antagonist. A total of 7% (24/342) of patients presented intrathoracic bleeding, while 5% (17/342) required surgery or died as a result for the trauma. Posttraumatic intrathoracic bleeding occurred in 4.5% (6/133) of patients receiving direct oral anticoagulants and 8.6% (18/209) of patients receiving vitamin K antagonist. Logistic regression analysis, revealed no difference in the risk of intrathoracic haemorrhages between the two studied groups. Direct oral anticoagulants therapy presents a risk of post-traumatic intrathoracic haemorrhage comparable to that of vitamin K antagonist therapy.

EFFICACY AND SAFETY OF MOROCTOCOG ALFA IN AN OPEN, MULTICENTER, PROSPECTIVE, CLINICAL STUDY IN CHILDREN 2 TO 6 YEARS OF AGE WITH SEVERE HEMOPHILIA A

The purpose of the study was to assess the efficacy, safety and pharmacokinetics of the moroctocog alfa (Octofactor) in children aged 2-6 with haemophilia A. Materials and methods of research : six patients between 2 and 6 years of age (average age 4.3±0.8 years) were included in the open multicenter prospective clinical trial. The efficacy of the drug was assessed against the background of the introduction of 30±10 IU/kg every 2–3 days, the safety was assessed by the frequency and causality of adverse reactions. Results: 7 post-traumatic bleeding was registered. The average prophylactic dose of the drug is 37.84±7.13 IU/kg. The dose of the drug for stopping bleeding was 1000 IU. 2 adverse events have been reported that are not related to moroсtocog alfa. Conclusion: the obtained data indicate the efficacy and safety of moroсtocog alfa in the study group of patients.

An engineered activated factor V for the prevention and treatment of acute traumatic coagulopathy and bleeding in mice

Acute traumatic coagulopathy (ATC) occurs in ≈30% of trauma patients and is associated with increased mortality. Excessive generation of activated protein C (APC) and hyperfibrinolysis are believed to be driving forces for ATC. Two mouse models were used to investigate whether an engineered activated FV variant (superFVa) that is resistant to inactivation by APC and contains a stabilizing A2-A3 domain disulfide bond, is able to reduce traumatic bleeding and normalize hemostasis parameters in ATC. First, ATC was induced by the combination of trauma and shock. ATC was characterized by APTT prolongation and reductions of FV, FVIII, and fibrinogen, but not FII and FX. Administration of superFVa normalized the APTT, returned FV and FVIII clotting activity levels to their normal range, and reduced APC and thrombin-antithrombin (TAT) levels, indicating improved hemostasis. Next, a liver laceration model was used where ATC develops as the consequence of severe bleeding. SuperFVa prophylaxis prior to liver laceration reduced bleeding, prevented APTT prolongation, depletion of FV and FVIII, and excessive generation of APC. Thus, prophylactic administration of superFVa prevented the development of ATC. SuperFVa intervention started after the development of ATC stabilized bleeding, reversed the prolonged APTT, returned FV and FVIII levels to their normal range, and reduced TAT levels that were increased by ATC. In summary, superFVa prevented ATC and traumatic bleeding when administered prophylactically, and superFVa stabilized bleeding and reversed abnormal hemostasis parameters when administered while ATC was in progress. Thus, superFVa may be an attractive strategy to intercept ATC and mitigate traumatic bleeding.

Global Coagulation Potentials and Breakthrough Bleeds in Emicizumab-Treated Hemophilia a Patients Were Similar to Mild Hemophilia a Patients

Emicizumab prophylaxis dramatically reduces bleeding events in severe patients with hemophilia A (PwHA) with and without FVIII inhibitors. Recently, some real-world experiences on PwHA with emicizumab prophylaxis have been reported. The effectiveness of emicizumab could be attributed to an earlier report that the coagulant potential in emicizumab at clinical dosage appeared to correspond to 10-15 IU/dL of factor VIII activity (FVIII:C) (Muto, JTH 2014), indicating that emicizumab enables to transform severe PwHA to mild PwHA. However, the comparison of coagulation potential and bleeding characteristics in PwHA receiving emicizumab (Emi-PwHA) and mild PwHA (PwMHA) remains to be investigated. Here, we examined the clinical and laboratory characteristics in Emi-PwHA and PwMHA. Clinical data of bleeding episodes and coagulation potentials were collected from 64 Emi-PwHA and 15 PwMHA (median FVIII:C 13 IU/dL [IQR 8.5-17.0]). Comprehensive coagulation function was evaluated using Ca 2+-triggered rotational thromboelastometry (ROTEM) and/or ellagic acid/tissue factor-triggered clot waveform analysis (CWA). Furthermore, we compared the features of breakthrough bleeds in two groups. We first compared with the clinical characteristics and coagulation function between the Emi-PwHA with and without the experience of breakthrough bleeds. The age, treatment period, annual bleeding rates (ABR), the percentage of inhibitor-positive, and prophylaxis regimen were not significantly different between both groups. There was no significant difference in ROTEM and CWA-based coagulation potential between Emi-PwHA with and without breakthrough bleeds (median; CT+CFT 1,703s [IQR 1,547-1,849] and 1,837s [IQR 1,671-2,216], Ad|min1| 4.92 [IQR 4.63-5.27] and 4.78 [IQR 4.4-5.11], respectively). We examined clinical data and ROTEM-based coagulation function between the Emi-PwHA and PwMHA. The age in PwMHA (median 25 years [IQR 20-49]) was older than that in Emi-PwHA (median 13 years [IQR 6-25]; p=0.004). The ABR and coagulation function in Emi-PwHA (median; ABR 0 [IQR 0-0.4], CT+CFT 1,795s [IQR 1,659-2,135]) were not significantly different from that in PwMHA (median; ABR 0.3 [IQR 0-0.49], CT+CFT 2,077s [IQR 1,627-2,449]), suggesting that the global coagulation potential in Emi-PwHA was equivalent to that in PwMHA. We next investigated bleeding features in Emi-PwHA (19 cases) and PwMHA (12 cases). Bleeding patterns of them were similar and divided into 3 groups; spontaneous, early post-traumatic (bleeding associated with trauma within 1-2 days) and late post-traumatic (bleeding involved with trauma within 1-2 weeks). Emi-PwHA experienced spontaneous (5/19), early post-traumatic (14/19) and late post-traumatic (3/19) bleedings, and PwMHA experienced spontaneous (4/12), early post-traumatic (7/12) and late post-traumatic (5/12) bleedings. Some patients of them had both spontaneous and early post-traumatic bleeding or both early and late post-traumatic bleeding. The majority of their bleedings was trauma-induced. Severe bleeding symptoms such as muscle bleeds, hemarthrosis or fracture in Emi-PwHA were required FVIII (total 60-200 IU/kg) and hospitalization for 3-5 days. In contrast, those severe breakthrough bleedings in PwMHA were required higher doses of FVIII (total 140-705 IU/kg) and hospitalization for 1-2 weeks. Although the coagulation potential in Emi-PwHA was similar to that in PwMHA, the treatment period and hospitalization for breakthrough bleeds in PwMHA appeared to be longer than those in Emi-PwHA. We speculated that this discrepancy might be due to the difference of physical activities or preventive managements for bleeding because Emi-PwHA was originally severe PwHA. In conclusion, the coagulation potential and bleeding characteristics in Emi-PwHA appeared to be similar to PwMHA, suggesting that emicizumab-mediated coagulation potential reflected the mild type in clinical severity. Disclosures Nakajima: Chugai Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical company: Research Funding. Mizumachi: Chugai Pharmaceutical Co., Ltd.: Research Funding. Shimonishi: CSL Bering: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Furukawa: Chugai Pharmaceutical Co., Ltd.: Research Funding. Ogiwara: Chugai Pharmaceutical Co., Ltd.: Research Funding. Takeyama: Chugai Pharmaceutical Co., Ltd.: Research Funding. Shima: Fujimoto Seiyaku: Consultancy, Speakers Bureau; Sanofi S.A.: Speakers Bureau; BioMarin Pharmaceutical Inc.: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk A/S: Honoraria, Speakers Bureau; Takeda: Research Funding; CSL Behring: Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies, Research Funding, Speakers Bureau. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk A/S: Honoraria, Research Funding, Speakers Bureau; Bayer AG: Honoraria, Research Funding, Speakers Bureau; Sanofi S.A.: Honoraria, Research Funding, Speakers Bureau; KM Biologics Co., Ltd.: Honoraria, Research Funding, Speakers Bureau.

Clinical case of an infant with severe hemophilia A on emicizumab

Hemophilia A is an X-linked congenital bleeding disorder caused by a deficiency or absence of coagulation factor VIII. In children who are in the first year of life, bleeding into the head accounts for 12.8–17.7 % of cases, and up to 45.5 % of them are intracranial bleeding in contrast to adult patients, in whom joints are the most frequent localization of bleeding. The first 2 years of life are the most dangerous in relation tointracranial bleeding for a child with hemophilia and the provision of full preventive treatment is extremely important for this time.Aim of the study – present the first experience of using emicizumab as primary prophylaxis in a child of the first year of life with hemophilia A. A patient born in 2020 with a severe hemophilia A had two post-traumatic bleeding that required hospitalization and replacement therapy. We decided to start primary prophylaxis with emicizumab at the age of 10 months.There were not spontaneous bleedings during 8 months of emicizumab usage. Post-traumatic bleeding did not require hospitalization and additional therapy.The clinical case demonstrates that emicizumab is effective and safe in infant who have not previously received prophylactic treatment.

Spectrum of Non-Traumatic Bleeding Complaints among women with Bleeding Disorders

Objective: To study the spectrum of bleeding complaints among women with bleeding disorders. Methodology: This observational study was done at Dept. of Pathology – Liaquat University Hospital, Hyderabad from January 2019 to July 2019 upon a sample of 121 women, selected via non-probability, consecutive sampling). Women presenting to study setting with complaints of non-traumatic bleeding were included in the study. After taking written informed consent, the data was obtained from patient interviews and laboratory investigations was. The data obtained was analyzed using SPSS v. 21.0. Results: The mean age of the women was 28.13 years (±5.21 SD). Among the 121 women studied, 73.55% hailed from urban areas, while 26.45% were from rural residential background. The most common presenting complaint was menorrhagia (30.58%), followed by bruising (17.36%) and epistaxis (15.7%). Among the underlying hemostatic pathologies, VWD was the most common (15.7%), followed by other platelet dysfunctions comprising the second most common finding (6.6%). Mean duration of presence of symptoms was 34 months (±17 SD). Conclusion: As per the findings of this study, menorrhagia, occasional bruising and epistaxis are reported to be the most common non-traumatic bleeding complaints among women with bleeding disorders. The presence of these symptoms may serve as potential indicators of the probable presence such as bleeding disorders and help in early referral, timely diagnosis and appropriate treatment. Keywords: menorrhagia, epistaxis, Hemostatic Dysfunction, Bleeding Disorder, Non traumatic bleeding complaints

Evaluation of thrombocytopenia: A single-center experience

To evaluate the common etiologies and bleeding manifestations in patients of thrombocytopenia and its clinical presentation, methods of investigation, and impact of various modes of management. Total 104 patients with platelet count less than l00,000 per cu.mm. with age, more than 12 years admitted to hospital between January 2010 to October 2011 were included in this study. Platelet count on automated cell counter less than 100,000 per cu.mm. and confirmed in peripheral smear were included in the study. All EDTA samples were processed in Abacus junior 5 hematology Analyser. Peripheral blood smear review was done for all cases. Clinical history and physical examination were collected from patients and medical record files.The present study included 56 male patients and 48 female patients. The most common bleeding manifestation was petechial rash 8.6%, hemoptysis and traumatic bleeding account for 1.9 % each, whereas 74% of patients did not present with any bleeding issues. Total 66 patients presented with symptoms of fever, 73 had signs of pallor, 22 patients had splenomegaly, 16 patients had hepatomegaly. Total 37.5% of patients were diagnosed with malaria and 1 patient (0.96%) was diagnosed with plasma cell leukemia. Chronic liver disease, megaloblastic anaemia, ITP (Idiopathic thrombocytopenia) and chronic renal failure account for 9.6%, 13.4%, 5.7% and 3.8% respectively. Total 16 patients had platelet counts less than 20000/cu.mm. and 37 patients had platelet count between 60000-80000/cu.mm. Malaria (39 patients) was the major cause of thrombocytopenia. Out of 39 patients with malaria 10 patients had P. Falciparum, 27 had P. Vivax and 2 patients had both. Patients with a platelet count less than 100,000/cu.mm have very high chances of bleeding manifestation. Cutaneous bleed is the most common manifestation. Malaria can be present with signs of thrombocytopenia. Timely and accurate diagnosis is the key to the management of thrombocytopenia.

Optimized outcome of pregnancy in a woman with Glanzmann thrombasthenia with multidisciplinary approach

Glanzmann thrombasthenia (GT), an autosomal recessive disorder of defective platelet aggregation due to abnormalities of platelet receptor GPIIb/IIIa, can result in complication of bleeding during pregnancy. We report multidisciplinary management of a case with optimized outcome. 23 years old short statured (142 cm) primigravida was referred for contracted pelvis at term in labour. She was diagnosed with GT at 12 years of age during evaluation of gum bleeding, easy bruising, and prolonged post traumatic bleeding. She was born of a second-degree consanguineous marriage. At admission she was hemodynamically stable but moderately pale. Her hemoglobin was 8.7 g%, with 4.6 lacs platelets and clotting time of 15 minutes. Multidisciplinary team of hematologist, transfusionist and anesthetist was activated. Arranging single donor platelets in a short notice was challenging. Emergency cesarean section under general anesthesia was performed after transfusing two units packed red blood cell and 2 single donor platelets to deliver an alive male baby of 3.3 kg. Hemostasis was secured with cautery and ligatures. Tranexamic acid infusion and sublingual misoprostol was given prophylactically. she was transfused another 4 random donor platelets during operation and postoperatively. The case details will be presented. GT have normal to high platelet counts though they are normal morphologically, they are dysfunctional. This fact needs to be recognized and referred early to equipped centres. We used component transfusion, active management of third stage and tranexamic acid for optimizing outcome due to haemorrhage. At present, there is lack of consensus regarding optimum treatment of post-partum hemorrhage in patients with GT.

Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage

Background and Purpose: Andexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH). Methods: ANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days. Results: A total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population). Conclusions: Andexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02329327.