Understanding the mechanism of action of normal hemostasis and how the bypassing agents recombinant activated factor VII (rFVIIa; NovoSeven) and plasma‐derived activated prothrombin complex ...concentrate (Factor Eight Inhibitor Bypassing Agent FEIBA) control abnormal bleeding is imperative for healthcare professionals who treat patients with hemophilia and other bleeding disorders. A cell‐based model has improved our understanding of in vivo mechanisms of hemostasis and the basis of the bleeding tendency in hemophilia. Bypassing agents do not restore the normal pathways of hemostasis in hemophilia, but rather boost thrombin generation in spite of a lack of platelet surface FVIIIa–FIXa (‘tenase’) activity. Thus, the common clinical laboratory coagulation assays do not reflect the clinically relevant hemostatic activity of bypassing agents, and no validated assay is available with which to measure the in vivo efficacy of these agents or predict individual patient responses to treatment. Global hemostasis assays measuring overall coagulation capacity have potential for assessment of the effects of bypassing agents. This review will focus on the mechanisms of clotting and their relationship to understanding the mechanisms of action of the bypassing agents in vivo and the methodologies that are emerging to monitor the clinical efficacy of bypassing agent therapy.
Individualized PK‐based prophylaxis in severe haemophilia Dargaud, Y.; Delavenne, X.; Hart, D.P. ...
Haemophilia : the official journal of the World Federation of Hemophilia,
March 2018, 2018-Mar, 2018-03-00, 20180301, Volume:
24, Issue:
S2
Journal Article
Peer reviewed
Summary
Over the past decades, haemophilia management has continually evolved, with prophylaxis now considered the treatment of choice. Prophylaxis primarily seeks to prevent bleeding and ...haemarthrosis episodes from occurring and avert the otherwise inevitable haemophilic arthropathy. Yet, numerous unanswered issues remain. These concern dose levels, dosing intervals, ways of integrating variability in bleeding phenotype, patient age, joint status, lifestyle, physical activity, treatment adherence and individual responses to FVIII or FIX concentrates. Individualized prophylaxis may thus be paramount. One crucial tool that may allow more accurate prophylaxis regimens to be implemented is the individual pharmacokinetic (PK) study. Therefore, physicians in charge of managing those living with haemophilia must be comfortable with PK profiling in order to be in a position to tailor patients’ treatment, taking into account PK data, while minimizing patients’ inconvenience, discomfort, as well as, possibly, treatment costs. For optimization of prophylaxis, recent development of recombinant molecules with more attractive PK properties, such as prolonged elimination half‐life, increases the choice of dosing regimens, enabling decreased frequency of dosing for some, if deemed appropriate. For each patient, PK parameters can be determined, including trough levels, AUC, and time spent under a predefined threshold, with additional pharmacodynamic (PD) parameters possibly established by means of a global coagulation test like the thrombin generation test. Most importantly, target PK/PD parameters will need to consider clinical variables like patient age, body weight, joint status, treatment adherence, number of bleeding episodes, activity index or lifestyle.
Essentials
Pregnancy is a risk factor for thrombosis.
Management of thrombosis risk in pregnancy remains a challenge.
Prophylaxis needs to be personalized.
Our score may be a helpful tool for the ...management of pregnancies at high risk of thrombosis.
Summary
Background
Patients with thrombophilia and/or a history of venous thromboembolism (VTE) are at risk of thrombosis during pregnancy. A risk score for pregnancies with an increased risk of VTE was previously described by our group (Lyon VTE score).
Objectives
The aim of this prospective study was to assess the efficacy and safety of our score‐based prophylaxis strategy in 542 pregnancies managed between 2005 and 2015 in Lyon University Hospitals.
Patients/Methods
Of 445 patients included in the study, 36 had several pregnancies during the study period. Among these 445 patients, 279 had a personal history of VTE (62.7%), 299 patients (67.2%) had a thrombophilia marker, and 131 (29.4%) thrombophilic women had a personal history of VTE. During pregnancy, patients were assigned to one of three prophylaxis strategies according to the risk scoring system.
Results
In the antepartum period, low molecular weight heparin (LMWH) prophylaxis was prescribed to 64.5% of patients at high risk of VTE. Among them, 34.4% were treated in the third trimester only, and 30.1% were treated throughout pregnancy. During the postpartum period, all patients received LMWH for at least 6 weeks. Two antepartum‐related VTEs (0.37%; one with a score of < 3 and the other with a score of > 6) and four postpartum‐related VTEs (0.73%; three with scores of 3–5 and one with a score of > 6) occurred. No case of pulmonary embolism was observed during the study period. The rate of bleeding was 0.37%. No serious bleeding requiring transfusions or surgery occurred during the study period.
Conclusion
The use of a risk score may provide a rational decision process to implement safe and effective antepartum thromboprophylaxis in pregnant women at high risk of VTE.
Introduction
For individuals with haemophilia A, prophylaxis with factor VIII (FVIII) is typically directed towards trough activity >1 IU/dL; however, some patients still experience spontaneous ...bleeding events (sBEs).
Aim
Aims were to evaluate relationships of endogenous thrombin potential (ETP) and FVIII:C with occurrence of clinical bleeding.
Methods
GENA‐21 was a prospective, open‐label, phase IIIb study investigating the safety and efficacy of Nuwiq® (human‐cl rhFVIII) in previously treated adults with severe haemophilia A. The study included a 72‐hour pharmacokinetic (PK) evaluation phase and a 6‐month personalized prophylaxis phase in which treatment was guided by PK parameters. This subanalysis assessed FVIII:C by one‐stage assay and ETP by thrombin generation assay in blood samples.
Results
Baseline mean ETP was lower in the 7 patients who experienced sBEs during personalized prophylaxis versus 25 who did not (n = 32 with data from PK phase and prophylaxis phase; P = .0002). During personalized prophylaxis (n = 49), only patients with lower median trough ETP experienced sBEs (8/49 patients; ROC AUC = 0.9421; P < .0001); there was no significant relationship for FVIII:C in predicting sBEs (ROC AUC = 0.5838; P = .4750). Directly following infusion of human‐cl rhFVIII, ETP was lower in patients who experienced sBEs versus those who did not (P = .0002), whereas FVIII:C did not differ significantly between these groups.
Conclusions
In adults with severe haemophilia A and reduced thrombin generation, increased frequency of spontaneous bleeding was observed irrespective of trough FVIII levels. Thus, personalized prophylaxis should take into account variables other than FVIII:C. Large prospective trials are needed to verify ETP as a marker for spontaneous bleeding.
The pathogenesis of the prothrombotic state of cancer patients ismostly due to the ability of cancer cells to activate the coagulation system. There are several complex and not fully understood ...interactions between the malignant cell and the clotting system. Tumour cells possess the capacity to interact with the haemostatic system in multiple ways. The principal mechanisms include the expression of haemostatic proteins by tumour cells, the production of inflammatory cytokines and the direct adhesion of tumour cells to platelets, endothelial cells and monocytes. This paper summarizes the prothrombotic mechanisms of tumour cells and their role in both coagulation and tumour growth and metastasis.
Résumé: La pathogenèse de l’hypercoagulabilité liée aux cancers est essentiellement expliquée par la capacité des cellules tumorales à activer le système de coagulation. Il existe des interactions multiples et complexes entre les cellules néoplasiques et l’hémostase. Cet article a comme objectif de faire le point sur les interactions entre l’hémostase et le cancer responsables du risque thrombotique, de la prolifération tumorale et de la dissémination métastatique des cancers. Les cellules tumorales expriment plusieurs protéines prothrombotiques comme le facteur tissulaire. L’inflammation associée au cancer et des taux élevés de cytokines proinflammatoires constituent un autre mécanisme responsable d’hypercoagulabilité. Les interactions entre les cellules tumorales, les plaquettes, les monocytes et les cellules endothéliales favorisent la croissance tumorale, l’angiogenèse et la métastase des cellules tumorales.
There is a potential for significant paradigm shift in the assessment of haemostasis from the conventional plasma recalcification times, such as prothrombin time (PT) and activated partial ...thromboplastin time (APTT), which correspond to artificially created compartments of haemostasis to tests that assess the entire process in a more physiological and holistic manner. These include the thrombin generation test, thromboelastogram and the clot wave form analysis. While these tests have been described many years ago, there is renewed interest in their use with modified technology for assessing normal haemostasis and its disorders. Although early data suggest that they can provide much greater information regarding the overall haemostasis process and its disorders, many challenges remain. Some of them are possible only on instruments that are proprietary technology, expensive and are not widely available. Furthermore, these tests need to be standardized with regard to their reagents, methodology and interpretation, and finally, much more data need to be collected regarding clinical correlations with the parameters measured.
Background and Objectives Total knee replacement (TKR) is the treatment of choice in case of end‐stage knee arthropathy, the main complication of haemophilia. We report here a retrospective ...evaluation of 72 total knee replacement in 51 haemophilia A and B patients using continuous infusion of factor concentrates (CIFC).
Materials and Methods Patients were evaluated on the basis of the following efficacy and safety criteria: range of motion, surgery‐related blood loss by three different methods, factor consumption and occurrence of short and long term complications.
Results Kaplan–Meier analysis showed a removal‐free survival of TKRs of 88.4% 10 years after surgery. Most patients were satisfied with their prosthesis and described pain relief and improved mobility and better quality of life after surgery. The long term follow‐up showed a mean range of motion at 86° with a flexion deformity of 4°. The blood loss differed significantly according to the method used for measurement. No life‐threatening bleeding occurred. Twenty six haematomas (36.1%) and 2 haemarthroses (2.7%) occurred in 38.8% of cases during the first three postoperative weeks, with no significant impact on the orthopaedic outcome. The average factor consumption during hospitalization was 79 IU/kg/day for patients with haemophilia A and 99 IU/kg/day for patients with haemophilia B. Infections occurred in 4.1% of patients. One patient with severe haemophilia A developed an inhibitor.
Conclusions The multidisciplinary approach and the homogeneous management of our large cohort allowed the achievement of excellent functional results. Our results confirmed previously reported data on the safety and efficacy of CIFC in situations requiring intensive factor replacement, such as TKR surgery.
Summary
Thirty per cent of patients with mild haemophilia A (MHA) present markedly different FVIII: C level when assayed by one‐stage clotting and two‐stage chromogenic assays. It is, therefore, a ...real clinical challenge to predict the individual bleeding risk of these patients. The aim of the present work was to study the relationship between the bleeding tendency of these patients with the results of a panel of phenotypic and genotypic tools. Thirty‐six patients with MHA were included in this multicentre prospective clinical study. The severity of bleeding symptoms was evaluated using the ISTH/SSC score. FVIII:C levels were measured using an activated partial thromboplastin time‐based one‐stage FVIII assay (FVIII: C1) and three commercial chromogenic kits (FVIII:CR). FVIII antigen levels, thrombin generation measurement and FVIII gene mutation analysis were also performed. Our results showed that a one‐stage FVIII: C assay cannot rule out the diagnosis of MHA, a combined use of FVIII:C1 with a FVIII:CR is suitable for detecting MHA. We observed that FVIII:CR results better reflected the clinical bleeding tendency of patients compared to FVIII:C1. We also observed a relationship between thrombin generation (TG) capacity and FVIII:CR of these patients. FVIII gene mutation analysis showed mutations previously reported in MHA patients with discrepant FVIII:C measurements, but with no predictive value of the individual bleeding phenotype of patients. Overall, we observed a relationship between chromogenic FVIII:C results, TG assay and bleeding tendency of patients with discrepant FVIII:C measurements, while FVIII:C1 was not well correlated with clinical bleeding phenotype in this particular population.
Haemophilia comprehensive care centres (HCCC) were first created more than 50 years ago. Their first objective was educating the patient and healthcare professionals in the management of bleeding. ...Today HCCCs are centres of excellence with multidisciplinary specialists, which continue to provide essential services that are continually reassessed in light of new scientific information. In addition, HCCCs make significant research contributions by studying new methods to improve the well‐being of patients with haemophilia. Laboratory expertise is one of the central pillars of HCCCs with a direct impact on diagnosis and management of the haemophilia disease. Vast efforts have been made for the standardization of factor VIII (FVIII) and FIX measurements and inhibitor detection. Molecular biology has improved diagnostics and made it possible to develop new, more secure FVIII and FIX concentrates for replacement therapy. However, phenotyping of each haemophilia patient with an accurate prediction of the individual bleeding risk and also the individual response of patients to antihaemophilic treatment still remains a challenge. In the last 5 years, an expanding interest of haematologists for thrombin generation testing (TGT) reflects the need for new laboratory tools able to evaluate the overall coagulating capacity of patients. This study will review unmet laboratory needs in haemophilia and the potential applications of TGT in the management of haemophiliacs. Furthermore, technical and standardization issues of the method will be discussed.
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