SciCombinator

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Concept: Coagulation system

214

Background Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors. Methods We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C. Results A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001). A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (P<0.001). Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injection-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombosis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies were detected. Conclusions Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

Concepts: Clinical trial, Warfarin, Pharmaceutical industry, Factor X, Coagulation system, Hoffmann–La Roche, Chugai Pharmaceutical Co., Hoffmann-La Roche

169

Development of inhibitory antibodies to coagulation factor VIII (fVIII) is the primary obstacle to the treatment of hemophilia A in the developed world. This adverse reaction occurs in 20-30% of persons with severe hemophilia A treated with fVIII-replacement products and is characterized by the development of a humoral and neutralizing immune response to fVIII. Patients with inhibitory anti-fVIII antibodies are treated with bypassing agents including recombinant factor VIIa (rfVIIa). However, some patients display poor hemostatic response to bypass therapy and improved treatment options are needed. Recently, we demonstrated that fVIII inhibitors display widely variable kinetics of inhibition that correlate with their respective target epitopes. Thus, it was hypothesized that for antibodies that display slow rates of inhibition, supplementation of rfVIIa with fVIII would result in improved thrombin generation and be predictive of clinical responses to this novel treatment regimen. In order to test this hypothesis, 10 murine monoclonal antibodies (MAbs) with non-overlapping epitopes spanning fVIII, differential inhibition titers, and inhibition kinetics were studied using a thrombin generation assay. Of the 3 MAbs with high inhibitory titers, only the one with fast and complete (classically defined as “type I”) kinetics displayed significant inhibition of thrombin generation with no improvement upon supplementation of rfVIIa with fVIII. The other two MAbs that displayed incomplete (classically defined as “type II”) inhibition did not suppress the potentiation of thrombin generation by fVIII. All antibodies that did not completely inhibit fVIII activity demonstrated potentiation of thrombin generation by the addition of fVIII as compared to rfVIIa alone. In conclusion, fVIII alone or in combination with rfVIIa corrects the thrombin generation defect produced by the majority of anti-fVIII MAbs better than single agent rfVIIa. Therefore, combined fVIII/rfVIIa therapy may provide better hemostatic control than current therapy in some patients with anti-fVIII inhibitors.

Concepts: Immune system, Coagulation, Enzyme inhibitor, Factor VIII, Protein C, Thrombin, Factor X, Coagulation system

127

ACE910 is a recombinant humanized bispecific antibody that binds to activated factor IX and factor X and mimics the cofactor function of factor VIII (FVIII). This first-in-human study examined the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ACE910 in healthy male adults. A total of 40 Japanese and 24 Caucasian subjects were randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; Caucasian: 0.1, 0.3, or 1 mg/kg; n = 6 per dose group) or placebo (n = 2 per dose group). ACE910 exhibited a linear PK profile and had a half-life of approximately 4 to 5 weeks. In FVIII-neutralized plasma, ACE910 shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. All adverse events were non-serious and did not lead to any subject’s withdrawal. Neither clinical findings nor laboratory abnormalities indicating hypercoagulability were observed. Two of 48 subjects receiving ACE910 (1 Japanese and 1 Caucasian) were positive for anti-ACE910 antibodies (anti-drug antibodies; ADA). One subject tested positive for ADA both before and after ACE910 administration, whereas the other became ADA-positive after receiving ACE910. The PK and PD profiles of ACE910 were similar in healthy Japanese and Caucasian subjects, and suggest that ACE910 will be an effective and convenient prophylactic treatment for hemophilia A. This trial was registered at http://www.clinicaltrials.jp (JapicCTI-121934).

Concepts: Pharmacology, Clinical trial, Coagulation, Factor VIII, Haemophilia B, Thrombin, Factor X, Coagulation system

28

Hemophilia A and hemophilia B are caused by congenital deficiency of factor VIII and factor IX, respectively, and may lead to recurrent, spontaneous bleeding into the muscles and joints resulting in disabling arthropathy. Effective management is available in the form of prophylactic infusions of clotting factor concentrates which have been demonstrated to prevent bleeding episodes and greatly improve the quality of life of these patients. Prophylaxis is, however, expensive. Usual dosing regimens rely on weight based calculations but dosing with an understanding of an individual’s pharmacokinetic response has been demonstrated to be more effective in predicting clotting factor levels that protect against bleeding episodes. Standard pharmacokinetic studies require a prohibitive number of time sampling points but recent population or Bayesian pharmacokinetics can be used to provide an accurate estimation of an individual’s pharmacokinetic response using a limited number of sampling time points. The use of population pharmacokinetics has the potential to greatly increase the use of pharmacokinetic dosing regimens and optimize the use of clotting factor concentrates in patients with hemophilia. Pediatr Blood Cancer 2012; 60: S27-S29. © 2012 Wiley Periodicals, Inc.

Concepts: Blood, Coagulation, Pharmacokinetics, Haemophilia A, Haemophilia B, Factor X, Coagulation system, Factor IX

28

The exclusion of deep venous thrombosis (DVT) in the elderly is hampered by low specificity in clinical decision of D-dimer assays in older patients. To reduce false-positive results, we evaluated specific fibrin(ogen) degradation product assays for their contribution in the diagnosis of DVT. In a post-hoc study with outpatients suspected for DVT, we evaluated the elastase-specific fibrinogen (fibrinogen elastase degradation product, FgEDP) and D-E-specific fibrin (fibrin degradation product, FbDP) degradation product assays in relation to DVT. Results were combined with five D-dimer assays as ratio, with a specific focus on age-dependency. In 437 patients (DVT prevalence 39%), FgEDP correlated with D-dimer in DVT-negative patients (P < 0.001), but not in DVT-positive patients (P > 0.55). FbDP results correlated with D-dimer in both groups (P < 0.001). The values of the area under the curve of the receiver operating characteristic curve for both assays were lower than D-dimer. Using the ratios, only in the fourth age quartile D-dimer/FgEDP ratios had diagnostic value with lower number needed to test (1.8-12.7) as compared to D-dimer less than 500 μg/l alone (5.4-102). The D-dimer/FbDP ratios in DVT-negative elderly patients increased to a plateau by increasing D-dimer. In DVT-positive patients, these ratios were near constant for increasing values of D-dimer. In elderly patients, the D-dimer/FgEDP ratios may improve the number of patients in whom DVT could be excluded. The D-dimer/FbDP ratios showed differences in composition of fibrin degradation products between DVT-negative and DVT-positive patients and between young and old DVT-negative patients.

Concepts: Hematology, Vein, Receiver operating characteristic, Deep vein thrombosis, Deep vein, D-dimer, Coagulation system, Fibrin degradation product

27

In order to increase the yield of prothrombin complex concentrates (PCCs) and to reduce their associated thrombotic risks, the influence of washing conditions on the yield, purity, and balance of coagulation factors (FII, FVII, FIX, and FX), and inhibitor proteins (PC, PS, PZ, and AT [antithrombin]) in PCCs was investigated by orthogonal testing, in which three variables (sodium citrate, NaCl, and pH) and their three levels were selected. It was found that AT yield and purity were extraordinarily low, and at lower NaCl content, the general yield, purity, and balance were higher, lower, and better, respectively; however, the results became contrary at higher NaCl. Moreover, within the investigated levels, NaCl was the first determinant for the yield except AT and the purity except FVII, PC, PS, and AT. Sodium citrate was the first determinant for AT yield and FVII, PS, and AT purity. The yield except FII, PS, and AT decreased and the purity except PC increased with increase of sodium citrate content. Just for PC purity, pH was the first determinant. The effect with pH fluctuation on the yield and purity was characteristically unobvious. The outcome undoubtedly supplies the guidance to further improve PCCs.

Concepts: Blood, Coagulation, Warfarin, Sodium hydroxide, Thrombin, Prothrombin time, Coagulation system, Antithrombin

27

PURPOSE OF REVIEW: On the one hand, cardiac and aortic surgery is associated with a high rate of allogeneic blood transfusion. On the other hand, both bleeding and allogeneic blood transfusion is associated with increased morbidity, mortality, and hospital costs in cardiac and aortic surgery. This article reviews the current literature between 1995 and 2012 dealing with transfusion protocols in cardiovascular surgery. The 16 studies fitting these search criteria have evaluated the impact of the implementation of ROTEM/TEG based coagulation management algorithms on transfusion requirement and outcome in overall 8507 cardiovascular surgical patients. RECENT FINDINGS: The use of point-of-care (POC) transfusion and coagulation management algorithms based on viscoelastic tests such as thromboelastometry (ROTEM) and thrombelastography (TEG) in combination with POC platelet function tests such as whole blood impedance aggregometry (Multiplate) have been shown to be associated with reduced allogeneic blood transfusion requirements, reduced incidence of thrombotic/thromboembolic and transfusion-related adverse events, and improved outcomes in cardiac surgery. SUMMARY: Implementation of POC algorithms including a comprehensive bundle of POC diagnostics (thromboelastometry and whole blood impedance aggregometry) in combination with first-line therapy using immediately available specific coagulation factor concentrates (fibrinogen and prothrombin complex concentrate) and defining strict indications, calculated dosages, and clear sequences for each haemostatic intervention seems to be complex but most effective in reducing perioperative transfusion requirements and has been shown to be associated with a decreased incidence of thrombotic/thromboembolic events, transfusion-related adverse events, as well as with improved patients' outcomes including 6-month mortality.

Concepts: Blood, Surgery, Coagulation, Platelet, Warfarin, Hemostasis, Blood transfusion, Coagulation system

25

In patients with cirrhosis, decreased rotational thromboelastometry (ROTEM) parameters suggest hypocoagulability secondary to liver dysfunction. However, observed normal or increased thrombin generation suggests preserved haemostasis and/or a procoagulant state. The correlated levels of both coagulation factors and inhibitors also support preserved haemostasis.

Concepts: Coagulation, Fibrin, Platelet, Warfarin, Hemostasis, Factor X, Coagulation system, Antithrombin

24

Assessment of plasma concentration/effect of edoxaban may be useful in some situations. Also, clinicians need to know how routine coagulation assays are influenced. It was our aim to determine coagulation tests useful for the assessment of edoxaban’s pharmacodynamics and provide recommendations for the interpretation of haemostasis diagnostic tests. Edoxaban was spiked at concentrations ranging from 0 to 1,000 ng/ml in platelet-poor plasma which covers the on-therapy range (from ± 25 ng/ml at Ctrough to ± 170 ng/ml at Cmax). aPTT, PT, dRVVT, chromogenic anti-Xa assays, TGA and a large panel of haemostasis diagnostic tests were performed using several reagents. A concentration-dependent prolongation of aPTT, PT and dRVVT was observed. The effect was dependent on the reagents. FXa chromogenic assays showed high sensitivity and a linear correlation depending on the methodology. TGA may be useful to assess the pharmacodynamics of edoxaban but its turnaround time and the lack of standardisation are limitations. Edoxaban impairs the assessment of lupus anticoagulant, protein S (clotting method), APC-R, antithrombin (FXa-based assay) and measurement of clotting factor activity. Immunological assays and assays acting below the FXa are not influenced by edoxaban. In conclusion, some PT reagents could be used to estimate edoxaban activity. Chromogenic anti-Xa assays are required to assess the plasma concentration. TGA may be useful but requires standardisation. In case of thrombophilia or in the exploration of a haemorrhagic event, immunological assays should be recommended, when applicable. Standardisation of the time between the last intake and the sampling is mandatory to provide a proper assessment of the result.

Concepts: Blood, Coagulation, Platelet, Warfarin, Hemostasis, Prothrombin time, Factor X, Coagulation system

23

The plasma contact system sits atop the intrinsic coagulation cascade and plasma kallikrein-kinin pathway, and in vivo its activation contributes, respectively, to coagulation and inflammation mainly via two downstream pathways. This system has been widely investigated, its activation mechanisms by negatively charged surfaces and the interactions within its components, factor XII, prekallikrein and high molecular weight kininogen are well understood at the biochemical level. However, as most of the activators that have been discovered by in vitro experiments are exogenous, the physiological activators and roles of the contact system have remained unclear and controversial. In the last two decades, several physiological activators have been identified, and a better understanding of its roles and its connection with other signaling pathways has been obtained from in vivo studies. In this article, we present an overview of the contact pathway with a focus on the activation mechanisms, natural stimuli, possible physiological roles, potential risks of its excessive activation, remaining questions and future prospects.

Concepts: Electric charge, Molecule, Coagulation, In vivo, In vitro, Factor XII, Coagulation system, High-molecular-weight kininogen