Recombinant Factor VIIa Research Articles

67 Clinical Outcomes of Oral Factor Xa-Inhibitor Associated Gastrointestinal Bleeds Treated with or without 4F-PCC among US Medicare Patients

Prior to the availability of a specific oral factor Xa (fXa) inhibitor reversal agent, off-label replacement agents including 4-factor prothrombin complex concentrates (4F-PCC) were used to treat life-threatening hemorrhage including gastrointestinal (GI) bleeds. We compared outcomes of US Medicare patients hospitalized for oral fXa-inhibitor associated GI bleeds treated with or without 4F-PCC. We utilized a 20% random sample of Medicare fee-for-service beneficiaries who had Part A and D (medication) coverage. We included adult (≥ 18 years) patients experiencing their first hospitalization (index event) for major GI bleeding identified via ICD9/10 codes, between 10/2013 and 9/2017. Serious GI bleeds were defined by ICD9/10 codes developed based on the Cunningham and Joos et al. algorithms. Inclusion criteria were continuous medical and prescription coverage and a claim for apixaban, edoxaban, or rivaroxaban during the 6-months prior to the index event. Patients were divided into two cohorts based on treatment with or without 4F-PCC during the index GI bleed hospitalization. Fresh frozen plasma, cryoprecipitates, packed red blood cells, activated PCC, recombinant factor VIIa, desmopressin acetate, tranexamic acid and vitamin K administration were allowed in either cohort. Use of more than one agent in either group was defined as concomitant therapy. Endpoints included the 1) intensive care unit (ICU) treatment, 2) total hospital length of stay, 3) discharge disposition and 4) 30-day readmission. Among 8,169 patients hospitalized for GI bleeding, 62 (0.75%) patients were treated with 4F-PCC. Mean age was 78.4 years and 58.8% were female. Because of the low numbers the two groups could not be propensity matched. Overall in-hospital mortality was 1.7%. Concomitant therapy was 56.5% 4F-PCC-treated vs. 45.3% non-4F-PCC patients. Incidence of ICU was 71.0% 4F-PCC vs 39.4% non-4F-PCC patients. Median (Interquartile range) hospital stay was 6 (4, 10) for 4F-PCC vs 5 (4, 6) days non-4F-PCC patients. Discharge disposition home was 45.2% for 4F-PCC vs 57.8% non-4F-PCC patients. All-cause readmission at 30 days was 18.0% for 4F-PCC vs 18.8% non-4F-PCC patients (Table 1). In a large descriptive analysis of hospitalized Medicare patients with oral fXa-inhibitor associated major GI bleeds, those treated with 4F-PCC had higher concomitant medication use, longer LOS, and lower frequency of discharge to home. Whether this is a result of off-label use of 4F-PCC or other variables in these complex patients is uncertain and deserves further study.Table 1Characteristics of US Medicare patients hospitalized for oral fXai-associated GI bleedsAll (N=8,169)4F-PCC Treated (N=62)Non-4F-PCC Treated (N=8,107)Indication for fXa inhibitors (%)Atrial fibrillation75.879.075.8Deep vein thrombosis/venous thromboembolism24.025.824.0Any concomitant medication (%)45.456.545.3Packed RBCs (%)43.853.243.7Characteristics of index hospitalizationLength of stay in days (Median; interquartile range)5.0 (4.0-6.0)6.0 (4.0-10.0)5.0 (4.0-6.0)Index hospitalization as ICU (%)39.771.039.4Discharge status (%)Home57.745.257.8Discharge to a location other than home (including in-hospital death)*42.354.842.2*Data on in-hospital death alone was not reported by treatment cohort in order to comply with the Centers for Medicare and Medicaid Services’ Cell Size Suppression Policy Open table in a new tab

Use of Low-Dose Recombinant Factor Ⅶa for Uncontrolled Perioperative Bleeding.

Background:Recombinant activated factor VIIa (rFVIIa) is a prohemostatic agent initially approved for use in hemophilia patients and has also been used for a diverse range of off-label indications in the context of massive uncontrolled blood loss; however, no convincing evidence exists regarding the optimal dose of rFVIIa to treat uncontrolled bleeding in surgical patients.Aim:To evaluate the effects and safety of a very low dose of rFⅦa in patients with uncontrolled perioperative bleeding in the surgical intensive care unit (ICU).Methods:55 patients from Beijing Hospital, who received rFⅦa between July 2004 and November 2018 for uncontrolled perioperative bleeding were included. The controls were matched for age, sex, severity, and operation type. The baseline demographics, survival, changes in bleeding and transfusion, coagulation parameters and complications were analyzed.Results:A low dose of rFⅦa (2.0∼3.6 mg, with a median dose of 39.02 μg/kg) appears to be effective in controlling massive hemorrhage (with an effective rate of 74.55%), and can reduce volume of red blood cell transfusion, improve coagulation status, while has a relatively low risk of thromboembolic complications (3.6%).Conclusion:In patients with uncontrolled perioperative bleeding, a low dose of rFⅦa could be used when traditional methods are ineffective.

PARTIAL SPLENIC EMBOLIZATION AS A TREATMENT FOR INTRACRANIAL HEMORRHAGE CAUSED BY IMMUNE THROMBOCYTOPENIC PURPURA

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Immune Thrombocytopenic Purpura (ITP) is a disease of immune mediated platelet destruction and decreased production. Autoimmune platelet destruction occurs in tissue macrophages, mainly in the spleen. Initial treatment for ITP includes steroids and, for patients who require quicker elevation of platelet count, intravenous immunoglobulin (IVIG). Second line treatments include rituximab and newer agents that work by thrombopoiesis stimulation. Splenectomy, also a second line treatment, is generally used only after all medical options have failed due to potential complications. We report a case of partial splenic embolization (PSE) in a patient with refractory ITP presenting with acute intracranial hemorrhage (ICH). CASE PRESENTATION: A 38-year-old male with refractory ITP, initially treated with steroids, IVIG, and maintenance eltrombopag, presented to an academic medical center with two days of headache followed by acute onset weakness and slurred speech the day of presentation. Platelet count was 6k/uL; computed tomography (CT) found a pontine hemorrhage measuring 1.8x1.9x1.7cm causing effacement of the right ambient and pre-pontine cistern. He was initially treated with 4mcg/kg romiplostim, 60g IVIG, 40mg dexamethasone, 4U platelets and intubated for airway protection. Repeat laboratory results showed platelet count of 3k/uL; repeat CT showed expanding hemorrhage with worsening mass effect. Due to his worsening condition, we administered recombinant factor VIIa and performed an emergent PSE using approximately 3 ml of 300-500 µm embospheres via a right common femoral artery approach. Within nine hours of PSE, his platelet count increased to 218k/uL. Repeat CT showed stable hemorrhage; MRI did not show an underlying cause for his bleed. His platelets continued to increase, neurologic status improved and he was extubated. When the patient’s platelet count dropped to 79k/uL 11 days post-embolization, he underwent laparoscopic splenectomy. DISCUSSION: Splenectomy used to treat ITP has a high long-term remission rate.2 While there have been small, retrospective studies in the use of PSE with promising results, we found no reports in which PSE was used in an adult with ICH. Due to this presentation’s emergent nature, an active ICH and risk of bleeding, we opted for PSE rather than splenectomy for both speed and a presumed lower immediate complication rate. The PSE stabilized the patient by stopping the ICH and raising platelet count, enabling the patient to undergo laparoscopic splenectomy at a later date. CONCLUSIONS: PSE can be a safe alternative or bridge to splenectomy in patients with acute bleed due to ITP. Reference #1: Kuwana M, et al. Splenic macrophages maintain the anti-platelet autoimmune response via uptake of opsonized platelets in patients with immune thrombocytopenic purpura. J Thromb Haemost. 2009;7(2):322-329 Reference #2: Mikhael J, Northridge K, Lindquist K, Kessler C, Deuson R, Danese M. Short-term and long-term failure of laparoscopic splenectomy in adult immune thrombocytopenic purpura patients: a systematic review. Am J Hematol. 2009;84(11):743-748. DISCLOSURES: No relevant relationships by Lewis Eisen, source=Web Response No relevant relationships by Nader Emami, source=Web Response No relevant relationships by David Hirschl, source=Web Response No relevant relationships by David Schecter, source=Web Response

Serpins, New Therapeutic Targets for Hemophilia.

Hemostasis is a tightly regulated process characterized by a finely tuned balance between procoagulant and anticoagulant systems. Among inherited hemostatic conditions, hemophilia is one of the most well-known bleeding disorders. Hemophilia A (HA) and B (HB) are due to deficiencies in coagulation factor VIII (FVIII) or FIX, respectively, leading to unwanted bleeding. Until recently, hemophilia treatment has consisted of prophylactic replacement therapy using plasma-derived or recombinant FVIII in cases of HA or FIX in cases of HB. Because FVIII and FIX deficiencies lead to an imbalance between procoagulant and anticoagulant systems, a recent upcoming strategy implies blocking of endogenous anticoagulant proteins to compensate for the procoagulant factor deficit, thus restoring hemostatic equilibrium. Important physiological proteins of the anticoagulant pathways belong to the serpin (serine protease inhibitor) family and, recently, different experimental and clinical studies have demonstrated that targeting natural serpins could decrease bleeding in hemophilia. Here, we aim to review the different, recent studies demonstrating that blocking serpins such as antithrombin, protein Z-dependent protease inhibitor, and protease nexin-1 or modifying a serpin like α1-antitrypsin could rebalance coagulation in hemophilia. Furthermore, we underline the potential therapeutic use of serpins for the treatment of hemophilia.

Приобретенная гипопротромбинемия у пациентки с лимфопролиферативным заболеванием в сочетании с волчаночным антикоагулянтом

Введение: Приобретенная гипопротромбинемия, обусловленная циркуляцией волчаночного антикоагулянта (ВА), ассоциируется с высоким риском развития тяжелого кровотечения. Клинический случай: Описан случай приобретенного дефицита протромбина и фактора IX в сочетании с положительным ВА: у пациентки Н. была диагностирована лимфома из клеток маргинальной зоны, выявлен дефицит фактора II (21%) и фактора IX (27,1%), увеличение активированного частичного тромбопластинового времени, протромбинового времени и международного нормализованного отношения, обнаружены положительные маркеры антифосфолипидного синдрома, по данным тромбоэластографии — выраженная гипокоагуляция. Выполнена абдоминальная спленэктомия. Перед операцией пациентке был введен концентрат протромбинового комплекса (КПК) Уман Комплекс Д. И. в дозе 1500 МЕ. После введения КПК мы не достигли целевого значения активности факторов свертывания: фактор II увеличился до 49%, фактор IX — до 47%. Клинически оперативное вмешательство не сопровождалось геморрагическим синдромом. Заключение: Сочетанный приобретенный дефицит протромбина и фактора IX у пациентки Н. с лимфомой при наличии ВА существенно увеличивал риск развития тяжелого интраоперационного кровотечения. Введение КПК с адекватным мониторингом гемостаза позволило избежать развития осложнений в периоперационном периоде. Background: Acquired hypoprothrombinemia due to lupus anticoagulant presence is associated with a high risk of severe bleeding. Clinical case: The article describes the case of acquired prothrombin and factor IX defi ciency combined with a positive lupus anticoagulant (LA). The patient N. was diagnosed lymphoma from marginal zone cells. She had factor II (21%) and factor IX (27.1%) deficit, increased activated partial thromboplastin time, prothrombin time and international normalized ratio, positive markers of antiphospholipid syndrome, severe hypocoagulation according to thromboelastography. An abdominal splenectomy was performed. Before surgery, prothrombin complex concentrate (PCC) Complex DI Uman in a dose of 1500 IU was administrated. After PCC administration, we did not reach the target value of coagulation factors activity: factor II increased to 49%, factor IX — to 47%. Surgery was not associated with hemorrhagic syndrome. Conclusions: The combined acquired defi ciency of prothrombin and factor IX in patient N. with lymphoma and LA significantly increased the risk of severe intraoperative bleeding. PCC administration with adequate monitoring of hemostasis allowed to avoid the development of complications in perioperative period.

Direct comparison of two extended half-life PEGylated recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A

An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC0–tlast, primary parameter), dose-normalized AUC (AUCnorm), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUCnorm was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 (ClinicalTrials.gov identifier). Date of registration: July 9, 2019

Gene Therapy for Hemophilia A: Where We Stand.

Hemophilia A (HA) is a hereditary hemorrhagic disease caused by a deficiency of coagulation factor VIII (FVIII) in blood plasma. Patients with HA usually suffer from spontaneous and recurrent bleeding in joints and muscles, or even intracerebral hemorrhage, which might lead to disability or death. Although the disease is currently manageable via delivery of plasma-derived or recombinant FVIII, this approach is costly, and neutralizing antibodies may be generated in a large portion of patients, which render the regimens ineffective and inaccessible. Given the monogenic nature of HA and that a slight increase in FVIII can remarkably alleviate the phenotypes, HA has been considered to be a suitable target disease for gene therapy. Consequently, the introduction of a functional F8 gene copy into the appropriate target cells via viral or nonviral delivery vectors, including gene correction through genome editing approaches, could ultimately provide an effective therapeutic method for HA patients. In this review, we discuss the recent progress of gene therapy for HA with viral and nonviral delivery vectors, including piggyBac, lentiviral and adeno-associated viral vectors, as well as new raising issues involving liver toxicity, pre-existing neutralizing antibodies of viral approach, and the selection of the target cell type for nonviral delivery.

Critical Bleeding in Acquired Hemophilia A: Bypassing Agents or Recombinant Porcine Factor VIII?

Acquired hemophilia A (AHA) is caused by autoantibodies neutralizing coagulation factor VIII (FVIII). In the presence of inhibitors against FVIII, acute bleeds can be managed with bypassing agents, including recombinant factor VIIa (eptacog alfa activated, NovoSeven) and activated prothrombin complex concentrate (FEIBA), as well as recombinant porcine FVIII (susoctocog alfa, Obizur). Studies comparing these agents directly are not available, and indirect evidence suggests an overall similar efficacy. Selecting an agent in clinical practice therefore depends on (1) availability of agent, (2) safety profile, (3) monitoring requirements, (4) cost, and (5) personal experience. This review examines available data and collects additional considerations to support decision making for bleeding emergencies in AHA.

Emicizumab Augments Thrombus Formation in Whole Blood from Patients with Hemophilia A under High Shear Flow Conditions.

Emicizumab is a bispecific antibody to factor (F) IXa and FX that mimics the FVIIIa cofactor function. Emicizumab prophylaxis markedly decreases bleeding episodes in patients with hemophilia A (PwHAs), irrespective of the presence of FVIII inhibitors. However, thrombotic microangiopathy (TMA) was reported when repeated high doses of activated prothrombin complex concentrates (aPCC) were concomitantly used with emicizumab. Although bypassing agents (BPAs) are vital in the hemostatic treatment for PwHAs with inhibitors, the mechanism of emicizumab-related TMA remains unclear. To assess the risk of excessive thrombus formation associated with BPAs and emicizumab under high shear conditions. Perfusion flow-chamber experiments under high shear conditions were performed using whole blood from PwHAs in the presence of emicizumab without or together with FVIII or BPAs ex vivo. Emicizumab (100 μg/mL) added ex vivo to whole blood from PwHAs improved defective thrombus formation in a similar manner to that observed with the addition of recombinant FVIII at the early phase, while FVIII continued to be important at the later stages. aPCC (1.2 U/mL equivalent to 100 U/kg) or recombinant FVIIa (1.1 µg/mL; equivalent to 90 µg/kg) together with emicizumab further promoted platelet interactions and fibrin formation ex vivo but did not induce excessive thrombus formation. Emicizumab enhanced thrombin generation at local sites and improved defective hemostasis in whole blood from PwHAs under high shear conditions. Simple concomitant use of BPAs with emicizumab did not mediate excessive thrombus formation and remains an option for hemostatic management of emicizumab-treated PwHAs with inhibitors.

Diffuse Alveolar Hemorrhage After Pediatric Hematopoietic Stem Cell Transplantation.

Pulmonary complications are common following hematopoietic cell transplantation (HCT) and contribute significantly to its morbidity and mortality. Diffuse alveolar hemorrhage is a devastating non-infectious complication that occurs in up to 5% of patients post-HCT. Historically, it carries a high mortality burden of 60–100%. The etiology remains ill-defined but is thought to be due to lung injury from conditioning regimens, total body irradiation, occult infections, and other comorbidities such as graft vs. host disease, thrombotic microangiopathy, and subsequent cytokine release and inflammation. Clinically, patients present with hypoxemia, dyspnea, and diffuse opacities consistent with an alveolar disease process on chest radiography. Diagnosis is most commonly confirmed with bronchoscopy findings of progressively bloodier bronchoalveolar lavage or the presence of hemosiderin-laden macrophages on microscopy. Treatment with glucocorticoids is common though dosing and duration of therapy remains variable. Other agents, such as aminocaproic acid, tranexamic acid, and activated recombinant factor VIIa have also been tried with mixed results. We present a review of diffuse alveolar hemorrhage with a focus on its pathogenesis and treatment options.

Successful Desensitization Protocol in an Infant Following Anaphylaxis Secondary to Recombinant Factor VIIa.

Background: Recombinant factor VIIa (rFVIIa) is a highly purified recombinant protein. It is approved for the treatment and prevention of bleeding episodes associated with congenital factor VII deficiency, congenital hemophilia with inhibitors, and Glanzmann's thrombasthenia. The most commonly reported adverse events are thrombolytic in nature. In this report, we present a successful desensitization protocol administered to an infant with a history of anaphylaxis to rFVIIa. Case: A male infant with a history of gingival bleeding at the age of 6 months was diagnosed with factor VII deficiency with a factor VII level of 1%. His sister also had diagnosis of factor VII deficiency. Our patient was hospitalized at 10 months of age with generalized petechiae and bloody stools. Twenty minutes after administration of rFVIIa, he developed anaphylaxis that responded to epinephrine and supportive care. Subsequently he was evaluated at the allergy clinic, where a skin prick test with rFVIIa was negative. However, the intradermal skin test, applied with 1/1,000 (1 μg/1 mL, 0.1 mL) dilution of rFVIIa, showed induration of 8 mm (positive reaction). Because there is no alternative treatment for factor VII deficiency, we developed a successful 13-step desensitization protocol with rFVIIa (NovoSeven®). Desensitization was performed an additional 2 times using the same protocol, one of which was for a head injury and the other for a swollen knee since the period between the doses was ∼3 months. Conclusion: Allergic reactions, such as anaphylaxis can occur without prior exposure. This can be due to the high molecular weight and structural property of the biological agent. In this report, we present an effective desensitization protocol for an infant with a history of anaphylaxis to rFVIIa. Desensitization protocols in this age group should be carried out in a medical facility and with specialized staff and equipment prepared to care for anaphylaxis.

Perioperative application of recombinant human coagulation factor Ⅶa combined with prothrombin complex in two hemophilia A patients with high titer inhibitor

Perioperative application of recombinant human coagulation factor Ⅶa combined with prothrombin complex in two hemophilia A patients with high titer inhibitor

Therapeutic doses of recombinant factor VIIa in hemophilia generates thrombin in platelet‐dependent and ‐independent mechanisms

BackgroundIn hemophilia bypass therapy, a platelet‐dependent mechanism is believed to be primarily responsible for recombinant factor VIIa (rFVIIa)’s hemostatic effect. rFVIIa may also possibly interact with other cells through its binding to endothelial cell protein C receptor (EPCR) or cell surface phospholipids. ObjectivesWe aim to investigate the relative contribution of platelet‐dependent and platelet‐independent mechanisms in rFVIIa‐mediated thrombin generation in hemophilic conditions at the injury site. MethodsPlatelets were depleted in acquired and genetic hemophilia mice using anti‐platelet antibodies. The mice were subjected to the saphenous vein injury, and the hemostatic effect of pharmacological concentrations of rFVIIa was evaluated by measuring thrombin generation at the injury site. ResultsAdministration of anti‐mouse CD42 antibodies to mice depleted platelets by more than 95%. As expected, hemophilia mice, compared with wild‐type mice, generated only a small fraction of thrombin at the injury site. The depletion of platelets in hemophilia mice further reduced thrombin generation. However, when pharmacological doses of rFVIIa were administered to hemophilia mice, substantial amounts of thrombin were generated even in the platelet‐depleted hemophilia mice. No differences in thrombin generation were detected among FVIII−/−, EPCR‐deficient FVIII−/−, and EPCR‐overexpressing FVIII−/− mice depleted of platelets or not. Evaluation of platelets by flow cytometry as well as immunoblot analysis showed no detectable expression of EPCR. ConclusionsOur data suggest that pharmacological concentrations of rFVIIa generate thrombin in hemophilia in both platelet‐dependent and platelet‐independent mechanisms.

Commentary on “Therapeutic doses of recombinant factor VIIa in hemophilia generates thrombin in platelet‐dependent and ‐independent mechanisms”

Commentary on “Therapeutic doses of recombinant factor VIIa in hemophilia generates thrombin in platelet‐dependent and ‐independent mechanisms”

Common Genetic Variants in ABO and CLEC4M Modulate the Pharmacokinetics of Recombinant FVIII in Severe Hemophilia A Patients.

The pharmacokinetic (PK) response of severe hemophilia A (HA) patients to infused factor VIII (FVIII) shows substantial variability. Several environmental and genetic factors are associated with changes in FVIII plasma levels and infused FVIII PK. Based on the hypothesis that factors influencing endogenous FVIII can affect FVIII PK, the contribution of single-nucleotide variants (SNVs) in candidate genes was investigated in 51 severe HA patients. The effects of blood group, F8 variant type, von Willebrand factor antigen and activity levels, age, and weight were also explored. The myPKFiT device was used to estimate individual PK parameters, and SNVs and clinically reportable F8 variants were simultaneously analyzed in an Illumina MiSeq instrument, using the microfluidics-based Fluidigm Access Array system. The contribution of SNVs to FVIII half-life and clearance was addressed by robust regression modeling, taking into account other modulators. In line with previous studies, we provide robust evidence that age, body weight, and blood group, as well as SNVs in ABO and CLEC4M, participate in the variability of FVIII PK in HA patients. Main results: each copy of the rs7853989 (ABO) allele increases FVIII half-life by 1.4 hours (p = 0.0131) and decreases clearance by 0.5 mL/h/kg (p = 5.57E-03), whereas each additional rs868875 (CLEC4M) allele reduces FVIII half-life by 1.1 hours (p = 2.90E-05) and increases clearance by 0.3 mL/h/kg (p = 1.01E-03). These results contribute to advancing efforts to improve FVIII replacement therapies by adjusting to each patient's PK profile based on pharmacogenomic data. This personalized medicine will decrease the burden of treatment and maximize the benefits obtained.

Reversal Agents for the Direct Factor Xa Inhibitors: Biochemical Mechanisms of Current and Newly Emerging Therapies.

The direct oral anticoagulants targeting coagulation factor Xa or thrombin are widely used as alternatives to vitamin K antagonists in the management of venous thromboembolism and nonvalvular atrial fibrillation. In case of bleeding or emergency surgery, reversal agents are helpful to counteract the anticoagulant therapy and restore hemostasis. While idarucizumab has been established as an antidote for the direct thrombin inhibitor dabigatran, reversal strategies for the direct factor Xa inhibitors have been a focal point in clinical care over the past years. In the absence of specific reversal agents, the off-label use of (activated) prothrombin complex concentrate and recombinant factor VIIa have been suggested as effective treatment options during inhibitor-induced bleeding complications. Meanwhile, several specific reversal agents have been developed. In this review, an overview of the current state of nonspecific and specific reversal agents for the direct factor Xa inhibitors is provided, focusing on the biochemistry and mechanism of action and the preclinical assessment of newly emerging therapies.

Characterization of the von Willebrand factor/factor VIII complex produced by a novel purification process.

Factor VIII (FVIII) is a blood coagulation protein that circulates as a complex with von Willebrand factor (vWF) in the plasma. In the survey of inhibitors in plasma product exposed toddlers (SIPPET) study, plasma-derived FVIII containing vWF was less immunogenic in hemophilia A patients than products with only high-purity FVIII only or recombinant FVIII. The FVIII purified by the conventional purification process using anion-exchange (AEX) chromatography had a low vWF content. In this study, purified vWF was added to the purified FVIII to increase the vWF content. The purified vWF was recovered from the discarded washing solution of the AEX chromatography using cation-exchange (CEX) chromatography. The vWF/FVIII complex had an abundance of high molecular weight vWF similar to the normal plasma, and a low reactivity of FVIII inhibitors. Furthermore, its efficacy was observed in a mouse model of hemophilia A. Therefore, the vWF/FVIII complex produced by our new purification method could be an effective and less immunogenic therapeutic agent for the hemophilia A and von Willebrand disease.

Biological mechanisms underlying inter-individual variation in factor VIII clearance in haemophilia.

Previous studies have highlighted marked inter‐individual variations in factor VIII (FVIII) clearance between patients with haemophilia (PWH). The half‐life of infused FVIII has been reported to vary from as little as 5.3 hours in some adult PWH, up to as long as 28.8 hours in other individuals. These differences in clearance kinetics have been consistently observed using a number of different plasma‐derived and recombinant FVIII products. Furthermore, recent studies have demonstrated that half‐life for extended half‐life (EHL‐) FVIII products also demonstrates significant inter‐patient variation. Since time spent with FVIII trough levels <1% has been shown to be associated with increased bleeding risk in PWH on prophylaxis therapy, this variability in FVIII clearance clearly has major clinical significance. Recent studies have provided significant novel insights into the cellular basis underlying FVIII clearance pathways. In addition, accumulating data have shown that endogenous plasma VWF levels, ABO blood group and age, all play important roles in regulating FVIII half‐life in PWH. Indeed, multiple regression analysis suggests that together these factors account for approximately 34% of the total inter‐individual variation in FVIII clearance observed between subjects with severe haemophilia A. In this review, we consider these and other putative modulators of FVIII half‐life, and discuss the biological mechanisms through which these factors impact upon FVIII clearance in vivo.

The consistent use of recombinant and plasma coagulation factors in the intensive care of massive obstetric hemorrhage

Massive obstetric hemorrhage is one of the most threatening complications of pregnancy, delivery and early postpartum period, which are part of the triad of leading causes of maternal mortality both in the world and in the Russian Federation. In recent years, to stop coagulopathy, which is one of the clinical manifestations of massive obstetric hemorrhage, recombinant and plasma factors of the blood coagulation system are successfully used, which include a concentrate of prothrombin complex and activated coagulation factor VII (eptacog alfa activated). The authors present results of successful consistent use of the blood coagulation system factors within comprehensive intensive care of coagulopathy in a patient with massive obstetric hemorrhage.

The impact of blood product ratio and procoagulant therapy on the development of thromboembolic events in severely injured hemorrhaging trauma patients.

INTRODUCTIONTransfusion therapy in hemorrhaging trauma patients is associated with the development of thromboembolic events. It is unknown whether current resuscitation strategies, including large volumes of plasma and early administration of procoagulant therapy, increases this risk.METHODSA systematic search was conducted in MEDLINE, PubMed, and Embase. Studies were screened by two independent reviewers and included if they reported on thromboembolic events in patients with severe trauma (injury severity score ≥16) who received transfusion of at least 1 unit of red blood cells. The ratio by which blood products were transfused, as well as use of procoagulant or antifibrinolytic medication, was recorded.RESULTSA total of 40 studies with 11.074 bleeding trauma patients were included, in which 1.145 thromboembolic events were reported, yielding an incidence of 10% thromboembolic events. In studies performing routine screening for thromboembolic complications, the incidence ranged from 12% to 23%. The risk of thromboembolic events was increased after administration of tranexamic acid (TXA; odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7‐4.1; p < 0.001) and fibrinogen concentrate (OR, 2.1; 95% CI, 1.0‐4.2; p = 0.04). Blood product ratio, the use of prothrombin complex concentrate or recombinant factor VIIa were not associated with thromboembolic events.CONCLUSIONThis systematic review identified an incidence of thromboembolic events of 10% in severely injured bleeding trauma patients. The use of TXA and fibrinogen concentrate was associated with the development of thromboembolic complications.