The Influence of Infusions of 1-Desamino-8-D-Arginine Vasopressin (DDAVP) In Vivo on Thrombin Generation In Vitro

Abstract

SummaryTo investigate the effect of increasing FVIII:C in-vivo on coagulation ex-vivo, DDAVP was infused over 15 min in 10 volunteers and in-vitro thrombin generation measured. FVIII:C rose from 0.42 and 0.43 IU/ml before DDAVP to 1.38, 1.73 and 1.78 IU/ml at 15, 30 and 60 min respectively (p <0.001).A computer-assisted thrombin generation test was performed in defibrinated plasma using chromogenic substrate, S2238. Time to reach 50% maximal thrombin activity (T50/s) and lag phase of thrombin generation (lag/s) were measured. Lag shortened from 75 and 60 s before to 45 s during and after infusion (p <0.001). T50 shortened from 78.5 and 76.0 to 62.5, 60.0 and 58.5 s at times 15 (p <0.01), 30 (p <0.001) and 60 (p <0.001) min. FVIII:C correlated inversely with lag and T50 (r = –0.847, p <0.001, r = –0.826, p <0.001, n = 10) respectively.These findings show that acute elevations of FVIII:C in-vivo accelerate in-vitro thrombin production. This work suggests that elevated FVIII:C levels in-vivo may be important in thrombo-occlusive disease.

Epidemiology of Coagulation Factors, Inhibitors and Activation Markers: The Third Glasgow Monica Survey I. Illustrative Reference Ranges by Age, Sex and Hormone Use

“…Although these correlations are modest (r < 0·21), this may reflect the short plasma half-lives of F1, 2 (90 min) and TAT (15 min) (Bauer & Rosenberg, 1994) compared to those of coagulation factors or inhibitors, as well as the many other variables which affect both activation markers and coagulation factors or inhibitors . Furthermore, these associations are consistent with each other; with previous reports that factor VII is associated with FpA (Lowe et al, 1991) and with F1, 2 in population samples; with elevations in F1, 2 and TAT following intravenous infusions of prothrombin complex concentrates (Mannucci et al, 1990;Hampton et al, 1993) or recombinant factor VIIa ; with increased generation of thrombin in vitro after elevation of factor VIII by desmopressin infusion (Ibbotson et al, 1992); and by increased levels of F1, 2 and FpA in heterozygous protein C deficiency (Bauer et al, 1988;Mannucci et al, 1992).…”

Desmopressin (DDAVP) in the treatment of bleeding disorders: the first twenty years

“…A puzzling, unresolved question is how desmopressin is efficacious in bleeding disorders other than haemophilia and vWD, in patients who have normal or even high levels of factor VIII and vWF. The favourable effects of the compound may be mediated by increased platelet adhesion to the vessel wall [18, 19], due not only to the rise of plasma vWF but also to the abluminal secretion of the protein toward the subendothelium [22]; by heightened coagulability, due to supranormal levels of factor VIII, a rate‐accelerating factor in the process of fibrin formation [27]; and by the fresh appearance in plasma of ultralarge vWF multimers [28]. These are haemostatically very effective because they support to a higher degree platelet adhesion to the vascular subendothelium and induce platelet aggregation under conditions of high shear [29].…”

Clotting Factor XIII and desmopressin improve hemostasis in uncontrolled bleeding

“…Additionally, DDAVP reduces the lag phase of thrombin generation by increasing FVIII, von Willebrand factor, and platelet organelle calcium (Ca 2+ ) 23 . Therefore, more thrombin is available to activate both FXIII and platelets, and to initiate fibrin polymerization from fibrinopeptide cleavage 24 .…”