Targeting TFPI for hemophilia treatment

Peterson, Julie A.; Maroney, Susan A.; Mast, Alan E.

doi:10.1016/s0049-3848(16)30359-0

Cited by 39 publications

(40 citation statements)

References 50 publications

(56 reference statements)

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“…24 These murine experiments, along with the biochemical data uncovering the inhibition of prothrombinase by TFPIα, 25 have implicated the inhibition of platelet TFPI anticoagulant activity as a potential therapeutic target for haemophilia. 26 …”

Section: | Introductionmentioning

confidence: 99%

Correlates of plasma and platelet tissue factor pathway inhibitor, factor V, and Protein S

Ellery

Hilden

Sejling

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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SummaryBackgroundPlasma Tissue Factor Pathway Inhibitor (TFPI) circulates bound to factor V (fV) and Protein S (PS). Estrogen therapy decreases plasma TFPI and PS. TFPI, fV, and PS circulate within platelets, and are released upon activation to modulate thrombus formation.ObjectiveIdentify factors affecting the concentrations of plasma and platelet TFPI, fV, and PS.MethodsBlood samples were obtained from 435 healthy individuals. Plasma total TFPI, TFPIɑ, fV, and PS, and platelet TFPI, fV, and PS were quantified. Correlations between these protein concentrations and age, gender, race, and estrogen use were established.ResultsIn males, only plasma fV increased with age, while in females, all plasma analytes increased with age. Males had higher plasma total TFPI, TFPIα, and PS than females. The platelet proteins in either sex remained relatively stable with increasing age. Platelet TFPI and PS were comparable in both sexes, while platelet fV was higher in females. Estrogen use was associated with decreased plasma total TFPI and TFPIα, and platelet PS, but not with platelet TFPI concentration. Racial differences in plasma and platelet proteins were observed, some of which were larger than inter-individual differences observed within racial groups. TFPI, fV and PS concentrations correlated in plasma, while only fV and PS correlated in platelets.ConclusionsPlasma and platelet TFPI, fV and PS differ in their: (i) in vivo association; (ii) demographic correlates; and (iii) alteration by estrogen therapies. Therefore, the plasma and platelet pools of these proteins may modulate hemostasis and thrombosis via different biochemical pathways.

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Section: | Introductionmentioning

confidence: 99%

Correlates of plasma and platelet tissue factor pathway inhibitor, factor V, and Protein S

Ellery

Hilden

Sejling

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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“…The first such agent, emicizumab, is a novel bispecific antibody, replacing the FVIII scaffold effect. [86][87][88] Currently indicated for once-weekly prophylactic dosing in HA inhibitor patients, it is being investigated in HA without inhibitors, administered as either weekly, every other week or monthly subcutaneous injections.…”

Section: Transformative Productsmentioning

confidence: 99%

“…Other agents targeting different factors in the coagulation cascade are being developed, including fitusiran (antithrombin), TFPI inhibitors, APC inhibitors, Super FVa and long-acting and/or more potent rFVIIa variants(Table 2) [86][87][88][102][103][104]. TFPI can also directly inactivate FXa.…”

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confidence: 99%

Optimizing bleed prevention throughout the lifespan: Womb to Tomb

Gupta

Shapiro

2018

Haemophilia

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The focus of care providers, patients and families is the ability to tailor care for persons with haemophilia (PWH) across the lifespan. Care requires knowledge of the bleeding disorder and age-related complications, risk of therapeutic interventions, and evaluation of individual characteristics that contribute to outcomes. The ultimate goal is to live a normal life without the burden of bleeding, for PWH and carriers. A wide range of therapeutic options is required to achieve personalized care. Over the last decade, substantial therapeutic advantages have been achieved in the treatment of haemophilia that include the development of a robust array of factor concentrates, novel haemostatic agents, and increased knowledge and awareness of disease associated outcomes and risk factors. Significant strides on the road to accessible gene therapy have been realized. This increased range of therapeutic modalities provides options for development and implementation of care plans for each patient at each stage of life that are more flexible compared to prior care regimens. Paradigms for management of haemophilia are changing. As a community, we must work together to use these resources wisely, to learn from outcomes with new therapies and diagnostic tools, to assure all patients can achieve improved care and outcomes regardless of disease state or country of origin.

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“…A bispecific antibody specifically binding factor IX and X and mimicking the cofactor activity of FVIII (ACE910) has been produced and is injected subcutaneously [62]. Other approaches exploit the inhibition of natural anticoagulants [55,63,64], for instance via a monoclonal antibody (mAb) targeting tissue factor pathway inhibitor (TFPI) [65], a mAb blocking the interaction between FX and TFPI [66], or RNA interference therapeutic targeting antithrombin [67]. These technologies may prevent inhibitor development, and provide a mechanism for reducing or eliminating exposure to the deficient factor.…”

Section: Alternative Therapeutic Strategiesmentioning

confidence: 99%

The current state of adverse event reporting in hemophilia

Vulpen

Saccullo

Iorio

et al. 2016

Expert Review of Hematology

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Text word count: 3827; abstract word count: 187; number of tables: 5; number of references: 73.2 Abstract Introduction: Replacement of the missing clotting factor is the mainstay of haemophilia treatment. Whilst historically many haemophilia patients were infected with blood-borne viruses transmitted via plasma-derived products, nowadays the formation of alloantibodies against the missing clotting factor is the main adverse event of treatment.Areas covered: This paper provides an overview of the current national and international adverse event reporting systems, what these surveillance schemes taught us about side effects of the products presently in use, and elaborates on how to adapt these systems to the challenges we face with the changing treatment landscape.Expert commentary: Treatment of inherited bleeding disorders was accompanied by severe complications in the past, resulting in major morbidity and mortality. Current products are much safer, but still require monitoring via efficient safety surveillance systems. Adverse events are reported in national and international systems. With many new products entering the market, as well as non-factor replacement therapies, new safety issues may arise. It is important to identify potential adverse events early by making surveillance systems suitable to pick up unknown or unexpected effects, and to recognize and communicate patterns of adverse events rapidly.

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Targeting TFPI for hemophilia treatment

Cited by 39 publications

References 50 publications

Correlates of plasma and platelet tissue factor pathway inhibitor, factor V, and Protein S

Correlates of plasma and platelet tissue factor pathway inhibitor, factor V, and Protein S

Optimizing bleed prevention throughout the lifespan: Womb to Tomb

The current state of adverse event reporting in hemophilia

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