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Hematology. American Society of... Dec 2022The cloning of the factor VIII (FVIII) and factor IX (FIX) genes in the 1980s has led to a succession of clinical advances starting with the advent of molecular... (Review)
Review
The cloning of the factor VIII (FVIII) and factor IX (FIX) genes in the 1980s has led to a succession of clinical advances starting with the advent of molecular diagnostic for hemophilia, followed by the development of recombinant clotting factor replacement therapy. Now gene therapy beckons on the back of decades of research that has brought us to the final stages of the approval of 2 products in Europe and United States, thus heralding a new era in the treatment of the hemophilias. Valoctocogene roxaparvovec, the first gene therapy for treatment of hemophilia A, has been granted conditional marketing authorization in Europe. Another approach (etranacogene dezaparvovec, AMT-061) for hemophilia B is also under review by regulators. There are several other gene therapy approaches in earlier stages of development. These approaches entail a one-off infusion of a genetically modified adeno-associated virus (AAV) engineered to deliver either the FVIII or FIX gene to the liver, leading to the continuous endogenous synthesis and secretion of the missing coagulation factor into the circulation by the hepatocytes, thus preventing or reducing bleeding episodes. Ongoing observations show sustained clinical benefit of gene therapy for >5 years following a single administration of an AAV vector without long-lasting or late toxicities. An asymptomatic, self-limiting, immune-mediated rise in alanine aminotransferase is commonly observed within the first 12 months after gene transfer that has the potential to eliminate the transduced hepatocytes in the absence of treatment with immunosuppressive agents such as corticosteroids. The current state of this exciting and rapidly evolving field, as well as the challenges that need to be overcome for the widespread adaptation of this new treatment paradigm, is the subject of this review.
Topics: Humans; Genetic Vectors; Hemophilia A; Hemophilia B; Genetic Therapy; Factor VIII; Factor IX; Dependovirus; Blood Coagulation Factors
PubMed: 36485127
DOI: 10.1182/hematology.2022000388 -
Blood Reviews Mar 2021Haemostasis stops bleeding at the site of vascular injury and maintains the integrity of blood vessels through clot formation. This regulated physiological process... (Review)
Review
Haemostasis stops bleeding at the site of vascular injury and maintains the integrity of blood vessels through clot formation. This regulated physiological process consists of complex interactions between endothelial cells, platelets, von Willebrand factor and coagulation factors. Haemostasis is initiated by a damaged vessel wall, followed with a rapid adhesion, activation and aggregation of platelets to the exposed subendothelial extracellular matrix. At the same time, coagulation factors aggregate on the procoagulant surface of activated platelets to consolidate the platelet plug by forming a mesh of cross-linked fibrin. Platelets and coagulation mutually influence each other and there are strong indications that, thanks to the interplay between platelets and coagulation, haemostasis is far more effective than the two processes separately. Clinically this is relevant because impaired interaction between platelets and coagulation may result in bleeding complications, while excessive platelet-coagulation interaction induces a high thrombotic risk. In this review, platelets, coagulation factors and the complex interaction between them will be discussed in detail.
Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Disease Susceptibility; Hemostasis; Humans; Platelet Activation; Platelet Aggregation; Platelet Membrane Glycoproteins; Protein Binding
PubMed: 32682574
DOI: 10.1016/j.blre.2020.100733 -
Arteriosclerosis, Thrombosis, and... Mar 2019Activation of the intrinsic pathway of coagulation contributes to the pathogenesis of arterial and venous thrombosis. Critical insights into the involvement of intrinsic... (Review)
Review
Activation of the intrinsic pathway of coagulation contributes to the pathogenesis of arterial and venous thrombosis. Critical insights into the involvement of intrinsic pathway factors have been derived from the study of gene-specific knockout animals and targeted inhibitors. Importantly, preclinical studies have indicated that targeting components of this pathway, including FXI (factor XI), FXII, and PKK (prekallikrein), reduces thrombosis with no significant effect on protective hemostatic pathways. This review highlights the advances made from studying the intrinsic pathway using gene-specific knockout animals and inhibitors in models of arterial and venous thrombosis. Development of inhibitors of activated FXI and FXII may reduce thrombosis with minimal increases in bleeding compared with current anticoagulant drugs.
Topics: Animals; Anticoagulants; Bleeding Time; Blood Coagulation; Blood Coagulation Factors; Disease Models, Animal; Drug Design; Enzyme Activation; Hemorrhage; Humans; Mice, Knockout; Primates; Rabbits; Rats; Thrombosis
PubMed: 30700128
DOI: 10.1161/ATVBAHA.118.312130 -
Haematologica Mar 2020The success story of hemophilia care first began in the 1970s, when the availability of plasma-derived concentrates of coagulation factor VIII (FVIII) and factor IX... (Review)
Review
The success story of hemophilia care first began in the 1970s, when the availability of plasma-derived concentrates of coagulation factor VIII (FVIII) and factor IX (FIX) provided efficacious treatment of bleeding in patients with hemophilia A and B. This positive scenario was consolidated in terms of greater safety and availability in the 1990s, when the first recombinant coagulation factors were produced. This meant that, instead of only treating episodic bleeding events, prophylaxis regimens could be implemented as a preventive measure. Following the demonstration of its superiority in the frame of two randomized clinical trials, prophylaxis became evidence-based standard of care. In high-income countries, these achievements have led to a patients' life expectancy being extended to close to that of the general male population. Alongside this, the last decade has witnessed further spectacular therapeutic progress, such as the availability of coagulation factors with a longer plasma half-life that allow for wider intervals between treatment. Moreover, new therapeutic products based on new mechanisms other than the replacement of the deficient factor, have become available (emicizumab) or are at an advanced stage of development. This review celebrates the success story of hemophilia care, while also discussing current limitations, issues and as yet unmet needs. The prospects of cure by means of gene therapy are also outlined.
Topics: Blood Coagulation Factors; Blood Coagulation Tests; Factor IX; Factor VIII; Genetic Therapy; Hemophilia A; Humans; Male
PubMed: 32060150
DOI: 10.3324/haematol.2019.232132 -
Haemophilia : the Official Journal of... May 2022Emicizumab is a bispecific monoclonal antibody developed to address the unmet needs of clotting factor replacement therapy and has become the benchmark for optimal...
INTRODUCTION
Emicizumab is a bispecific monoclonal antibody developed to address the unmet needs of clotting factor replacement therapy and has become the benchmark for optimal prophylaxis in managing patients with haemophilia A with inhibitors. We describe the emicizumab rollout and pharmacokinetic strategies and their use in paediatric patients.
METHODS
The evolving real-world experience in using emicizumab has confirmed its safety, efficacy and pharmacokinetic profile in paediatric, adolescent and adult patients receiving emicizumab at various prophylactic dosing regimens. The emicizumab current global rollout includes over 100 countries with 29 low to middle-income countries accessing emicizumab through the World Federation of Haemophilia (WFH) Humanitarian Aid Program. The diversity of emicizumab dosing and pharmacokinetic tools such as the Calibra® and the WAPPS-Hemo platforms make it possible to achieve prophylaxis goals in line with the WFH Haemophilia treatment guidelines recommendations, with minimal drug wastage. The emerging experience from long term clinical trials and long-term real-world follow-up confirm the safety, efficacy, and pharmacokinetic profile of emicizumab in paediatric haemophilia A patients. A few questions, including inhibitor recurrence, concurrent use of emicizumab with various replacement therapies and inhibitor eradication, are being addressed through multiple ongoing clinical studies.
CONCLUSION
The current global rollout of emicizumab is remarkable, and versatile dosing regimens and evolving pharmacokinetic tools such as the Calibra® and WAPPS-Hemo platforms make it a treatment choice available also for pharmacokinetic guided personalised treatment. Data from paediatric studies are consistent with those seen in adolescent and adult Haemophilia A.
Topics: Adolescent; Adult; Antibodies, Bispecific; Antibodies, Monoclonal, Humanized; Blood Coagulation Factors; Child; Factor VIII; Hemophilia A; Humans
PubMed: 35521723
DOI: 10.1111/hae.14524 -
The New England Journal of Medicine Aug 2017Emicizumab (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... (Randomized Controlled Trial)
Randomized Controlled Trial
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 .).
Topics: Adolescent; Adult; Aged; Antibodies, Bispecific; Antibodies, Monoclonal, Humanized; Blood Coagulation Factors; Child; Drug Therapy, Combination; Factor VIII; Factor VIIa; Hemophilia A; Hemorrhage; Humans; Injections, Subcutaneous; Isoantibodies; Male; Middle Aged; Recombinant Proteins; Thrombosis; Young Adult
PubMed: 28691557
DOI: 10.1056/NEJMoa1703068 -
Journal of Thrombosis and Thrombolysis Aug 2021Blood coagulation factor X/Xa sits at a pivotal point in the coagulation cascade and has a role in each of the three major pathways (intrinsic, extrinsic and the common... (Review)
Review
Blood coagulation factor X/Xa sits at a pivotal point in the coagulation cascade and has a role in each of the three major pathways (intrinsic, extrinsic and the common pathway). Due to this central position, it is an attractive therapeutic target to either enhance or dampen thrombin generation. In this brief review, I will summarize key developments in the molecular understanding of this critical clotting factor and discuss the molecular basis of FX deficiency, highlight difficulties in expressing recombinant factor X, and detail two factor X variants evaluated clinically.
Topics: Blood Coagulation; Blood Coagulation Factors; Blood Coagulation Tests; Factor X; Factor Xa; Humans; Molecular Biology; Thrombin
PubMed: 33886037
DOI: 10.1007/s11239-021-02456-w -
BMC Medicine May 2023Endometriosis is recognized as a complex gynecological disorder that can cause severe pain and infertility, affecting 6-10% of all reproductive-aged women. Endometriosis... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Endometriosis is recognized as a complex gynecological disorder that can cause severe pain and infertility, affecting 6-10% of all reproductive-aged women. Endometriosis is a condition in which endometrial tissue, which normally lines the inside of the uterus, deposits in other tissues. The etiology and pathogenesis of endometriosis remain ambiguous. Despite debates, it is generally agreed that endometriosis is a chronic inflammatory disease, and patients with endometriosis appear to be in a hypercoagulable state. The coagulation system plays important roles in hemostasis and inflammatory responses. Therefore, the purpose of this study is to use publicly available GWAS summary statistics to examine the causal relationship between coagulation factors and the risk of endometriosis.
METHODS
To investigate the causal relationship between coagulation factors and the risk of endometriosis, a two-sample Mendelian randomization (MR) analytic framework was used. A series of quality control procedures were followed in order to select eligible instrumental variables that were strongly associated with the exposures (vWF, ADAMTS13, aPTT, FVIII, FXI, FVII, FX, ETP, PAI-1, protein C, and plasmin). Two independent cohorts of European ancestry with endometriosis GWAS summary statistics were used: UK Biobank (4354 cases and 217,500 controls) and FinnGen (8288 cases and 68,969 controls). We conducted MR analyses separately in the UK Biobank and FinnGen, followed by a meta-analysis. The Cochran's Q test, MR-Egger intercept test, and leave-one-out sensitivity analyses were used to assess the heterogeneities, horizontal pleiotropy, and stabilities of SNPs in endometriosis.
RESULTS
Our two-sample MR analysis of 11 coagulation factors in the UK Biobank suggested a reliable causal effect of genetically predicted plasma ADAMTS13 level on decreased endometriosis risk. A negative causal effect of ADAMTS13 and a positive causal effect of vWF on endometriosis were observed in the FinnGen. In the meta-analysis, the causal associations remained significant with a strong effect size. The MR analyses also identified potential causal effects of ADAMTS13 and vWF on different sub-phenotypes of endometrioses.
CONCLUSIONS
Our MR analysis based on GWAS data from large-scale population studies demonstrated the causal associations between ADAMTS13/vWF and the risk of endometriosis. These findings suggest that these coagulation factors are involved in the development of endometriosis and may represent potential therapeutic targets for the management of this complex disease.
Topics: Female; Humans; Endometriosis; Mendelian Randomization Analysis; von Willebrand Factor; Blood Coagulation Factors; Blood Coagulation
PubMed: 37226166
DOI: 10.1186/s12916-023-02881-z -
Medicina Intensiva 2016Massive obstetric hemorrhage is a major cause of maternal mortality and morbidity worldwide. It is defined (among others) as the loss of>2,500ml of blood, and is... (Review)
Review
Massive obstetric hemorrhage is a major cause of maternal mortality and morbidity worldwide. It is defined (among others) as the loss of>2,500ml of blood, and is associated to a need for admission to critical care and/or hysterectomy. The relative hemodilution and high cardiac output found in normal pregnancy allows substantial bleeding before a drop in hemoglobin and/or hematocrit can be identified. Some comorbidities associated with pregnancy can contribute to the occurrence of catastrophic bleeding with consumption coagulopathy, which makes the situation even worse. Optimization, preparation, rational use of resources and protocolization of actions are often useful to improve outcomes in patients with postpartum hemorrhage. Using massive obstetric hemorrhage protocols is useful for facilitating rapid transfusion if needed, and can also be cost-effective. If hypofibrinogenemia during the bleeding episode is identified, early fibrinogen administration can be very useful. Other coagulation factors in addition to fibrinogen may be necessary during postpartum hemorrhage replacement measures in order to effectively correct coagulopathy. A hysterectomy is recommended if the medical and surgical measures prove ineffective.
Topics: Blood Coagulation Factors; Blood Coagulation Tests; Blood Transfusion; Cesarean Section; Critical Care; Disease Management; Disseminated Intravascular Coagulation; Embolization, Therapeutic; Ergot Alkaloids; Female; Fibrinogen; Fluid Therapy; Hemorrhagic Disorders; Hemostatic Techniques; Hemostatics; Humans; Hysterectomy; Oxytocin; Postoperative Hemorrhage; Postpartum Hemorrhage; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Cardiovascular; Uterine Hemorrhage; Uterine Inertia
PubMed: 27184441
DOI: 10.1016/j.medin.2016.02.010 -
JAMA Apr 2023Optimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion: The PROCOAG Randomized Clinical Trial.
IMPORTANCE
Optimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood product consumption.
OBJECTIVE
To investigate the efficacy and safety of 4F-PCC administration in patients at risk of massive transfusion.
DESIGN, SETTING, AND PARTICIPANTS
Double-blind, randomized, placebo-controlled superiority trial in 12 French designated level I trauma centers from December 29, 2017, to August 31, 2021, involving consecutive patients with trauma at risk of massive transfusion. Follow-up was completed on August 31, 2021.
INTERVENTIONS
Intravenous administration of 1 mL/kg of 4F-PCC (25 IU of factor IX/kg) vs 1 mL/kg of saline solution (placebo). Patients, investigators, and data analysts were blinded to treatment assignment. All patients received early ratio-based transfusion (packed red blood cells:fresh frozen plasma ratio of 1:1 to 2:1) and were treated according to European traumatic hemorrhage guidelines.
MAIN OUTCOMES AND MEASURES
The primary outcome was 24-hour all blood product consumption (efficacy); arterial or venous thromboembolic events were a secondary outcome (safety).
RESULTS
Of 4313 patients with the highest trauma level activation, 350 were eligible for emergency inclusion, 327 were randomized, and 324 were analyzed (164 in the 4F-PCC group and 160 in the placebo group). The median (IQR) age of participants was 39 (27-56) years, Injury Severity Score was 36 (26-50 [major trauma]), and admission blood lactate level was 4.6 (2.8-7.4) mmol/L; prehospital arterial systolic blood pressure was less than 90 mm Hg in 179 of 324 patients (59%), 233 patients (73%) were men, and 226 (69%) required expedient hemorrhage control. There was no statistically or clinically significant between-group difference in median (IQR) total 24-hour blood product consumption (12 [5-19] U in the 4F-PCC group vs 11 [6-19] U in the placebo group; absolute difference, 0.2 U [95% CI, -2.99 to 3.33]; P = .72). In the 4F-PCC group, 56 patients (35%) presented with at least 1 thromboembolic event vs 37 patients (24%) in the placebo group (absolute difference, 11% [95% CI, 1%-21%]; relative risk, 1.48 [95% CI, 1.04-2.10]; P = .03).
CONCLUSIONS AND RELEVANCE
Among patients with trauma at risk of massive transfusion, there was no significant reduction of 24-hour blood product consumption after administration of 4F-PCC, but thromboembolic events were more common. These findings do not support systematic use of 4F-PCC in patients at risk of massive transfusion.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03218722.
Topics: Adult; Female; Humans; Male; Middle Aged; Blood Coagulation Factors; Blood Transfusion; Factor IX; Hemorrhage; Retrospective Studies; Thromboembolism; Treatment Outcome; Wounds and Injuries; Double-Blind Method; Administration, Intravenous
PubMed: 36942533
DOI: 10.1001/jama.2023.4080