Coagulation factor VIIa: prohemostatic drug and biomarker for thrombosis

Anne Marieke Schut

Coagulation factor VIIa: prohemostatic drug and biomarker for thrombosis

Anne Marieke Schut

Groningen Institute for Organ Transplantation (GIOT)

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Stollingsfactor VIIa: prohemostatisch medicijn en biomarker voor trombose

Fysiologische activatie van de bloedstolling begint met de activatie van stollings factor VII tot factor VIIa. Een recombinante vorm van factor VIIa (rFVIIa) is ontwikkeld als medicijn om bloedstolling te stimuleren in patiënten met een bloedingsneiging. rFVIIa is effectief in het behandelen én voorkomen van bloedingen in patiënten met hemofilie die door remmende antistoffen niet meer met suppletie van factor VIII of IX behandeld kunnen worden. Het effect van rFVIIa op het voorkomen van bloedingen is lastig te verklaren, omdat de halfwaardetijd van rFVIIa ongeveer 2 uur is terwijl langere klinische effecten worden gezien bij een toediening van het medicijn 1x per dag. In het eerste deel van deze thesis hebben we onderzoek gedaan naar mogelijke mechanismes die het pro-hemostatische effect van rFVIIa kunnen verklaren. Onze studies suggereren dat het profylactische effect van rFVIIa verklaard kan worden door langdurige aanwezigheid van lage spiegels rFVIIa in plasma en door de aanwezigheid van lage concentraties rFVIIa in bloedplaatjes.

Veneuze trombose is een complexe ziekte waar vele risicofactoren voor zijn vastgesteld. Het reizen per vliegtuig is bijvoorbeeld geassocieerd met een 2-4 keer verhoogde kans op het krijgen van veneuze trombose. Het is echter nog onbekend hoe stolselvorming wordt geactiveerd in het ontstaan van een veneuze trombose. Wij tonen aan dat activatie van de stolling tijdens een vliegreis waarschijnlijk niet, en activatie van de stolling in patiënten met een acute veneuze trombose waarschijnlijk wel, verlopen via de extrinsieke (FVIIa-gemedieerde) stollingsroute.

Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Lisman, Ton, Supervisor de Groot, Ph. G., Supervisor, Externe Persoon
Datum van toekenning	8-jun.-2016
Plaats van publicatie	[Groningen]
Uitgever	Rijksuniversiteit Groningen
Gedrukte ISBN's	978-90-367-8842-7
Elektronische ISBN's	978-90-367-8837-3
Status	Published - 2016

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Title and contents Final publisher's version, 498 KB
Chapter 1 Final publisher's version, 1,29 MB
Chapter 2 Final publisher's version, 588 KB
Chapter 3 Final publisher's version, 2,16 MB
Chapter 4 Final publisher's version, 640 KB
Chapter 5 Final publisher's version, 578 KB
Chapter 6 Final publisher's version, 499 KB
Chapter 7 Final publisher's version, 487 KB
Chapter 8 Final publisher's version, 509 KB
Complete thesisFinal publisher's version, 3,8 MB
PropositionsFinal publisher's version, 424 KB

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title = "Coagulation factor VIIa: prohemostatic drug and biomarker for thrombosis",

abstract = "Physiological activation of blood coagulation is initiated by activation of coagulation factor VII to VIIa. A recombinant version of coagulation factor VIIa (rFVIIa) has been developed to treat patients with hemophilia. rFVIIa is effective in the treatment and prevention of bleeding in hemophilia patients who have inhibitory antibodies and therefore cannot be treated anymore by supplementation of the missing coagulation factors FVIII or FIX. The effectiveness of rFVIIa prophylaxis is difficult to explain, because the half-life of rFVIIa is about 2 hours while clinical effects were seen at a once daily administration of the drug. In the first part of this thesis we have investigated possible mechanisms that could explain the pro-hemostatic effect of rFVIIa. Our studies suggest that the prophylactic effect of rFVIIa can be explained by the prolonged presence of low levels rFVIIa in plasma, and by the presence of low concentrations rFVIIa in platelets.Venous thrombosis is a complex disease for which many risk factors have been identified. For example, traveling by air travel is associated with a 2-4 fold increased risk of developing venous thrombosis. The initiating trigger in the development of a venous thrombus is, however, at present still not known. We show that activation of coagulation during travelling by air probably not, and activation of coagulation in patients with acute venous thrombosis probably are initiated via the extrinsic (FVIIa-mediated) pathway.",

author = "Schut, {Anne Marieke}",

year = "2016",

language = "English",

isbn = "978-90-367-8842-7",

publisher = "Rijksuniversiteit Groningen",

school = "University of Groningen",

}

TY - BOOK

T1 - Coagulation factor VIIa: prohemostatic drug and biomarker for thrombosis

AU - Schut, Anne Marieke

PY - 2016

Y1 - 2016

N2 - Physiological activation of blood coagulation is initiated by activation of coagulation factor VII to VIIa. A recombinant version of coagulation factor VIIa (rFVIIa) has been developed to treat patients with hemophilia. rFVIIa is effective in the treatment and prevention of bleeding in hemophilia patients who have inhibitory antibodies and therefore cannot be treated anymore by supplementation of the missing coagulation factors FVIII or FIX. The effectiveness of rFVIIa prophylaxis is difficult to explain, because the half-life of rFVIIa is about 2 hours while clinical effects were seen at a once daily administration of the drug. In the first part of this thesis we have investigated possible mechanisms that could explain the pro-hemostatic effect of rFVIIa. Our studies suggest that the prophylactic effect of rFVIIa can be explained by the prolonged presence of low levels rFVIIa in plasma, and by the presence of low concentrations rFVIIa in platelets.Venous thrombosis is a complex disease for which many risk factors have been identified. For example, traveling by air travel is associated with a 2-4 fold increased risk of developing venous thrombosis. The initiating trigger in the development of a venous thrombus is, however, at present still not known. We show that activation of coagulation during travelling by air probably not, and activation of coagulation in patients with acute venous thrombosis probably are initiated via the extrinsic (FVIIa-mediated) pathway.

AB - Physiological activation of blood coagulation is initiated by activation of coagulation factor VII to VIIa. A recombinant version of coagulation factor VIIa (rFVIIa) has been developed to treat patients with hemophilia. rFVIIa is effective in the treatment and prevention of bleeding in hemophilia patients who have inhibitory antibodies and therefore cannot be treated anymore by supplementation of the missing coagulation factors FVIII or FIX. The effectiveness of rFVIIa prophylaxis is difficult to explain, because the half-life of rFVIIa is about 2 hours while clinical effects were seen at a once daily administration of the drug. In the first part of this thesis we have investigated possible mechanisms that could explain the pro-hemostatic effect of rFVIIa. Our studies suggest that the prophylactic effect of rFVIIa can be explained by the prolonged presence of low levels rFVIIa in plasma, and by the presence of low concentrations rFVIIa in platelets.Venous thrombosis is a complex disease for which many risk factors have been identified. For example, traveling by air travel is associated with a 2-4 fold increased risk of developing venous thrombosis. The initiating trigger in the development of a venous thrombus is, however, at present still not known. We show that activation of coagulation during travelling by air probably not, and activation of coagulation in patients with acute venous thrombosis probably are initiated via the extrinsic (FVIIa-mediated) pathway.

M3 - Thesis fully internal (DIV)

SN - 978-90-367-8842-7

PB - Rijksuniversiteit Groningen

CY - [Groningen]

ER -

Coagulation factor VIIa: prohemostatic drug and biomarker for thrombosis

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