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Thromb Haemost 2003; 89(05): 803-811
DOI: 10.1055/s-0037-1613465
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Effects of recombinant factor VIIa on platelet function and clot structure in blood with deficient prothrombin conversion

Marcus E. Carr Jr.
1   Coagulation Special Studies Laboratory, Departments of Medicine and pathology, Virginia, USA
6   Richmond Veterans Administration Medical Center Richmond, Virginia, USA
,
Erika J. Martin
1   Coagulation Special Studies Laboratory, Departments of Medicine and pathology, Virginia, USA
3   Pathology College of Virginia Virginia Commonwealth University, Virginia, USA
4   Medical College of Virginia Virginia Commonwealth University, Virginia, USA
,
Jan G. Kuhn
3   Pathology College of Virginia Virginia Commonwealth University, Virginia, USA
5   Central Virginia Center for Coagulation Disorders of MCV Hospitals and
,
Stephanie V. Seremetis
7   Novo Nordisk BioPharmaceuticals Princeton, New Jersey, USA
› Institutsangaben
Financial support: This study was supported in part by research funding from Novo Nordisk A/S, Copenhagen, Denmark
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Publikationsverlauf

Received 07. Oktober 2002

Accepted after revision 26. Februar 2003

Publikationsdatum:
09. Dezember 2017 (online)

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Summary

While recombinant factor VIIa (rFVIIa) shows promise as a broad-spectrum hemostatic agent, questions remain regarding the most appropriate dose and the best way to monitor its effects. In this study we tested the sensitivity of a thrombin dependent platelet assay, platelet contractile force, to the effects of rFVIIa in normal, factor-deficient, and inhibitor-containing blood samples. Dose dependent effects of rFVIIa on platelet contractile force (PCF) and clot elastic modulus (CEM) were measured in all blood samples.

rFVIIa minimally affected PCF and CEM in normal blood clotted with thrombin or batroxobin. While rFVIIa minimally altered PCF and CEM in factor VIII (FVIII) deficient blood clotted with thrombin, rFVIIa increased PCF and CEM and shortened the lag phase in a dose dependent manner in batroxobin-induced clots. The effects of rFVIIa in factor IX (FIX) deficient blood mirrored the effects seen in FVIII deficient samples. Whether clotted with thrombin or batroxobin, baseline PCF and CEM were abnormally low in FVIII deficient samples containing FVIII inhibitors. In such samples, rFVIIa caused dose dependent improvement of PCF, CEM, and lag phases. In one patient with a spontaneous inhibitor, rFVIIa caused dose dependent increases in PCF and CEM in blood clotted with either enzyme.

rFVIIa corrects the deficient thrombin generation seen in FVIII and FIX deficiency, and in blood containing FVIII inhibitors. As a consequence, platelet function is improved and clot structure is enhanced. Platelet contractile force and clot elastic modulus measurements are sensitive to the dose dependent effects of rFVIIa.

Keywords

Recombinant FVIIa - hemophilia - platelet contractile force - clot elastic modulus - thrombin generation
 

  • References

  • 1 Kristensen J, Killander A, Hippe E.. et al. Clinical experience with recombinant factor VIIa in patients with thrombocytopenia. Haemostasis 1996; 26 (Suppl. 01) Suppl 159-64.
    PubMedSuche in Google Scholar
  • 2 Vlot JA, Ton E, Machaag AJC, Kramer MHH, Gaillard CAJM.. Treatment of a severely bleeding patient without preexisting coagulopathy with activated recombinant factor VIIa. Am J Med 2000; 108: 421-2.
    CrossrefPubMedSuche in Google Scholar
  • 3 Kenet G, Walden R, Eldad A, Martinowitz U.. Treatment of traumatic bleeding with recombinant factor VIIa. Lancet 1999; 354: 1879.
    CrossrefPubMedSuche in Google Scholar
  • 4 Monroe DM, Hoffman M, Allen GA, Roberts HR.. The factor VII-platelet interplay: effectiveness of recombinant factor VIIa in the treatment of bleeding in severe thrombocytopathia. Semin Thromb Hemost 2000; 26: 373-7.
    Thieme ConnectPubMedSuche in Google Scholar
  • 5 Kjalke M, Ezban M, Monroe DM, Hoffman M, Roberts HR, Hedner U.. High-dose factor VIIa increases initial thrombin generation and mediates faster platelet activation in thrombocytopenia-like conditions in a cell-based model system. Br J Haematol 2001; 114: 114-20.
    CrossrefPubMedSuche in Google Scholar
  • 6 Carr ME, Shen LL, Hermans J.. Mass-Length Ratio of Fibrin Fibers from Gel Permeation and Light Scattering. Biopolymers 1977; 16: 1-15.
    CrossrefPubMedSuche in Google Scholar
  • 7 Carr Jr ME, Hermans J.. Size and density of fibrin fibers from turbidity. Macromolecules 1978; 11: 46-50.
    CrossrefPubMedSuche in Google Scholar
  • 8 Blomback B, Carlsson K, Hessel B, Liljeborg A, Procyk R, Aslund N.. Native fibrin gel networks observed by 3D microscopy, permeation and turbidity. Biochim Biophys Acta 1989; 997: 96-110.
    CrossrefPubMedSuche in Google Scholar
  • 9 Bale MD, Ferry JD.. Strain enhancement of elastic modulus in fine fibrin clots. Thromb Res 1988; 52: 565-72.
    CrossrefPubMedSuche in Google Scholar
  • 10 Carr Jr ME, Zekert SL.. Abnormal clot retraction, altered fibrin structure, and normal platelet function in multiple myeloma. Am J Physiol 1994; 266: H1195-201.
    PubMedSuche in Google Scholar
  • 11 Gabriel DA, Muga K, Boothroyd EM.. The effect of fibrin structure on fibrinolysis. J Biol Chem 1992; 267: 24259-63.
    PubMedSuche in Google Scholar
  • 12 Carr Jr ME, Dent RM, Carr SL.. Abnormal fibrin structure and inhibition of fibrinolysis in patients with multiple myeloma. J Lab Clin Med 1996; 128: 83-8.
    CrossrefPubMedSuche in Google Scholar
  • 13 Collet JP, Park D, Lesty C, Soria J, Soria C, Montalescot G, Weisel JW.. Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol 2000; 20: 1354-61.
    CrossrefPubMedSuche in Google Scholar
  • 14 Mullin JL, Norfolk SE, Weisel JW, Lord ST.. Clot lysis of variant recombinant fibrinogens confirms that fiber diameter is a major determinant of lysis rate. Ann N Y Acad Sci 2001; 936: 331-4.
    PubMedSuche in Google Scholar
  • 15 Hemker HC, Giesen PL, Ramjee M, Wagenvoord R, Beguin S.. The thrombogram: monitoring thrombin generation in platelet-rich plasma. Thromb Haemost 2000; 83: 589-91.
    Thieme ConnectPubMedSuche in Google Scholar
  • 16 Carr ME, Carr SL, Greilich PE.. Heparin ablates force development during platelet mediated clot retraction. Thromb Haemost 1996; 75: 674-8.
    Thieme ConnectPubMedSuche in Google Scholar
  • 17 Carr ME, Carr SL.. At high heparin concentrations, protamine concentrations which reverse anticoagulant effects are insufficient to reverse heparin antiplatelet effects. Thromb Res 1994; 75: 617-30.
    CrossrefPubMedSuche in Google Scholar
  • 18 Carr ME, Zekert SL.. Measurement of platelet-mediated force development during plasma clot formation. Am J Med Sci 1991; 302: 13-8.
    CrossrefPubMedSuche in Google Scholar
  • 19 Carr ME, Hines S, Carr SL, Todd WM, Taylor TL, Mohanty L.. Storage pool disease in chronic lymphocytic leukemia: abnormal aggregation and secretion without bleeding. Am J Med Sci 1997; 313: 176-81.
    PubMedSuche in Google Scholar
  • 20 de Gaetano G, Bottecchia D, Vermylen J.. Retraction of reptilase-clots in the presence of agents inducing or inhibiting the platelet adhesion-aggregation reaction. Thromb Res 1973; 2: 71-84.
    CrossrefPubMedSuche in Google Scholar
  • 21 de Gaetano G, Franco R, Donati MB, Bonaccorsi A, Garattini S.. Mechanical recording of reptilase-clot retraction: effect of adeno-sine-5’-diphosphate and prostaglandin E1 . Thromb Res 1974; 4: 189-92.
    CrossrefPubMedSuche in Google Scholar
  • 22 Sabovic M, Blinc A.. Biochemical and biophysical conditions for blood clot lysis. Pflugers Arch 2000; 440 (Suppl. 05) (Suppl) R134-6.
    CrossrefPubMedSuche in Google Scholar
  • 23 Roberts HR, Monroe DM, Oliver JA, Chang JY, Hoffman M.. Newer concepts of blood coagulation. Haemophilia 1998; 4: 331-4.
    CrossrefPubMedSuche in Google Scholar
  • 24 Kjalke M, Ezban M, Monroe DM, Hoffman M, Roberts HR, Hedner U.. High-dose factor rVIIa increases initial thrombin generation and mediates faster platelet activation in thrombocytopenia-like conditions in a cell-based model system. Br J Haematol 2001; 114: 114-20.
    CrossrefPubMedSuche in Google Scholar
  • 25 Hoffman M, Monroe DM.. The action of high-dose factor VIIa (FVIIa) in a cell-based model of hemostasis. Semin Hematol 2001; 38: 6-9.
    PubMedSuche in Google Scholar
  • 26 Butenas S, Brummel KE, Branda RF, Paradis SG, Mann KG.. Mechanism of factor VIIa-dependent coagulation in hemophilia blood. Blood 2002; 99: 923-30.
    CrossrefPubMedSuche in Google Scholar
  • 27 Carr ME, Carr SL.. Fibrin structure and concentration alter clot elastic modulus but do not alter platelet mediated force development. Blood Coagul Fibrinolysis 1995; 6: 79-86.
    CrossrefPubMedSuche in Google Scholar
  • 28 Greilich PE, Carr ME, Zekert SL, Dent RM.. Quantitative Assessment of Platelet Function and Clot Structure in Patients with Severe Coronary Artery Disease. Am J Med Sci 1994; 307: 15-20.
    CrossrefPubMedSuche in Google Scholar
  • 29 Krishnaswami A, Carr Jr ME, Jesse RL, Kontos MC, Minisi AJ, Ornato JP, Vetrovec GW, Martin EJ.. Patients with coronary artery disease who present with chest pain have significantly elevated platelet contractile force and clot elastic modulus. Thromb Haemost 2002; 88: 739-44.
    Thieme ConnectPubMedSuche in Google Scholar