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Thromb Haemost 1992; 67(02): 264-271
DOI: 10.1055/s-0038-1648423
Original Articles
Schattauer GmbH Stuttgart

Normalization of the Haemostatic Plugs of Dogs with Haemophilia A (Factor VIII Deficiency) Following the Infusion of a Combination of Factor Xa and Phosphatidylcholine/Phosphatidylserine Vesicles

Hong yu Ni
The Departments of Pathology and Medicine, Queen’s University, Kingston, Ontario, Canada
,
Alan R Giles
The Departments of Pathology and Medicine, Queen’s University, Kingston, Ontario, Canada
› Author Affiliations
Further Information

Publication History

Received 18 December 1990

Accepted after revision 30 August 1991

Publication Date:
02 July 2018 (online)

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Summary

The bolus intravenous infusion of factor Xa in combination with phosphatidylcholine/phosphatidylserine (PCPS) vesicles, at a dose of 2.6 × 10-11 moles and 4.0 × 10-8 moles/kg body weight respectively, has previously been shown to correct the bleeding diathesis of haemophilic (factor VIII deficient) dogs (Br J Haematol 1988; 69: 491-7). The cuticle bleeding time (CBT) was used as the test to evaluate objectively this response. Transmission electron microscopy was performed to document the evolution of haemostatic plugs forming in the vascular bed of the injured cuticles of both normal and factor VIII deficient dogs with and without treatment with factor Xa/PCPS. The dosage previously shown to normalize the CBT in haemophilic and significantly shorten it in normal animals was used. Subjective and objective observations, using morphometric techniques, were made over a period of 25 min following injury induction. The administration of factor Xa/PCPS was associated with complete and sustained normalization of haemostatic plug development in the haemophiliacs including platelet recruitment, activation and compaction and subsequently fibrinous transformation. In the case of the normals, platelet activation, etc., was exaggerated and fibrinous transformation appeared to be accelerated. The haemostatic plugs forming in the treated haemophiliacs were indistinguishable from those forming in the normals and significantly different, with regard to all parameters measured, from the morphological appearances noted in the untreated haemophiliacs. These data suggest that the correction of the haemostatic defect previously observed results from the normalization of haemostatic plug formation and that this is sustained despite the promotion of systemic fibrinolysis that is also known to occur.

 

  • References

  • 1 Bloom AL. Factor VIII inhibitors revisited. Br J Haematol 1981; 49: 319-324
    CrossrefPubMedSearch in Google Scholar
  • 2 Ikkala E, Helske T, Myllyla G, Nevanlinna HR, Pitkanen P, Rasi V. Changes in the life expectancy of patients with severe haemophilia A in Finland in 1930-79. Br J Haematol 1982; 52: 7-12
    CrossrefPubMedSearch in Google Scholar
  • 3 Sjamsoedin LLJM, Heijnen L, Mauser-Bunschoten EP, Geijlswijk JLv, Houwelingen Hv, Asten Pv, Sixma JJ. The effect of activated prothrombin-complex concentrate (Feiba) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. N Engl J Med 1981; 305: 717-721
    CrossrefPubMedSearch in Google Scholar
  • 4 Lusher JM, Blatt PM, Penner JA, Aledort LM, Levine PH, White GC, Warrier AI, Whitehurst DA. Autoplex versus proplex: A controlled, double-blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII. Blood 1983; 62: 1135-1138
    PubMedSearch in Google Scholar
  • 5 Giles AR. By what mechanisms could prothrombin complex concentrates promote factor VIII bypassing activity in vivo. Transfus Med Rev 1988; 1: 131-137
    PubMedSearch in Google Scholar
  • 6 Hedner U, Kisiel WK. Use of human factor Vila in the treatment of two hemophilia A patients with high-titre inhibitors. J Clin Invest 1983; 71: 1836-1841
    CrossrefPubMedSearch in Google Scholar
  • 7 Giles AR, Mann KG, Nesheim ME. A combination of factor Xa and phosphatidylcholine-phosphatidylserine vesicles bypasses factor VIII in vivo. Br J Haematol 1988; 69: 491-497
    CrossrefPubMedSearch in Google Scholar
  • 8 Giles AR. Use of an animal model to evaluate hemophilia therapies. In: Factor VIII Inhibitors. Hoyer L. (ed). Alan R Liss, Inc.; New York: 1984. pp 265-276
    Search in Google Scholar
  • 9 Giles AR, Nesheim ME, Herring SW, Hoogendoorn H, Stump DC, Heldebrant CM. The fibrinolytic potential of the normal primate following the generation of thrombin in vivo. Thromb Haemostas 1990; 63: 476-481
    PubMedSearch in Google Scholar
  • 10 VanderVelden P, Giles AR. A detailed morphological evaluation of the evolution of the haemostatic plug in normal, factor VII and factor VIII deficient dogs. Br J Haematol 1988; 70: 345-355
    CrossrefPubMedSearch in Google Scholar
  • 11 Giles AR, Tinlin S, Greenwood R. A canine model of hemophilic (factor VIII :C deficiency) bleeding. Blood 1982; 60: 727-730
    PubMedSearch in Google Scholar
  • 12 O’Brien DP, Giles AR, Tate KM, Vehar GA. Factor VUI-bypassing activity of bovine tissue factor using the canine hemophilic model. J Clin Invest 1988; 82: 206-211
    CrossrefPubMedSearch in Google Scholar
  • 13 Mertens K, Briet E, Giles AR. The role of factor VII in haemostasis: infusion studies of factor VII a in a canine model of factor VIII deficiency. Thromb Haemostas 1990; 64: 138-144
    PubMedSearch in Google Scholar
  • 14 Giles AR, Tinin S, Hoogendoorn H, Greenwood P, Greenwood R. Development of factor VIII: C antibodies in dogs with hemophilia A (factor VIII :C deficiency). Blood 1984; 63: 451-456
    PubMedSearch in Google Scholar
  • 15 Anon Guide to the Care and Use of Experimental Animals. 2nd edn. Canadian Council on Animal Care; Ottawa, Ont: 1984
  • 16 Giles AR. Guidelines for the use of animals in biomedical research. Thromb Haemostas 1987; 58: 1078-1084
    PubMedSearch in Google Scholar
  • 17 Weibel ER. Elementary introduction to stereological principles. In: Stereological Methods Vol 1: Practical Methods for Biological Morphometry. Weibel ER. (ed). Academic Press; London: 1979. pp 9-62
    Search in Google Scholar
  • 18 Weibel ER. Point counting methods. In: Stereological Methods Vol 1: Practical Methods for Biological Morphometry. Weibel ER. (ed). Academic Press; London: 1979. pp 101-161
    Search in Google Scholar
  • 19 Chalkley HW, Cornfield J, Park H. A method for estimating volume-surface ratios. Science 1949; 110: 295-297
    CrossrefPubMedSearch in Google Scholar
  • 20 Armitage P. One-way analysis of variance. In: Statistical Methods in Medical Research. Armitage P. ed. Blackwell; Oxford: 1977. pp 189-197
    Search in Google Scholar
  • 21 Armitage P. Multiple comparisons. In: Statistical Methods in Medical Research. Armitage P. ed. Blackwell; Oxford: 1977. pp 202-207
    Search in Google Scholar
  • 22 Sixma JJ, vd Berg A. The haemostatic plug in haemophilia A: A morphological study of haemostatic plug formation in bleeding time skin wounds of patients with severe haemophilia A. Br J Haematol 1984; 58: 741-753
    CrossrefPubMedSearch in Google Scholar
  • 23 Hovig T, Rowsell HC, Dodds WJ, Jorgensen L, Mustard JF. Experimental hemostasis in normal dogs and dogs with congenital disorders of blood coagulation. Blood 1967; 30: 636-638
    PubMedSearch in Google Scholar
  • 24 Marder VJ, Sherry S. Thrombolytic therapy: Current status (Part 1). N Engl J Med 1988; 318: 1512-1520
    CrossrefPubMedSearch in Google Scholar
  • 25 Erickson LA, Ginsberg MH, Loskutoff DJ. Detection and partial characterization of an inhibitor of plasminogen activator in human platelets. J Clin Invest 1984; 74: 1465-1472
    CrossrefPubMedSearch in Google Scholar
  • 26 Kruithof EKO, Nicolosa G, Bachmann F. Plasminogen activator inhibitor 1: Development of a radioimmunoassay and observations on its plasma concentration during venous occlusion and after platelet aggregation. Blood 1987; 70: 1645-1653
    PubMedSearch in Google Scholar