Effects of a Low Molecular Weight Heparin (Fragmin®) and of Unfractionated Heparin on Coagulation Activation at the Site of Plug Formation In Vivo

Abstract

SummaryThe clinical benefits of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) have been shown in many trials. However, the mode of action of heparin has not been fully elucidated. Thus, we wanted to study the effects of UFH and LMWH in vivo by measuring coagulation activation markers in blood obtained directly from a vascular injury site. In a double-blind, randomized, 3-way, cross-over study 18 healthy volunteers were given UFH (150 U/kg s.c.) and 2 doses of LMWH [35 U/kg s.c. (low dose, Id), 75 U/kg s.c. (high dose, hd)]. Prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and fibrinopeptide A (FPA) were measured in bleeding time blood and in venous blood before and after drug application. In addition, the effects of UFH and LMWH on in vitro coagulation tests were studied. Compared to base line, UFH and both IdLMWH and hdLMWH caused significant reductions of F1+2, TAT and FPA in bleeding time blood at 2 h. A marked effect of UFH and of hdLMWH was also seen at 5 h. The inhibition of FPA generation was more pronounced after hdLMWH compared to IdLMWH. In venous blood, UFH and LMWH caused reductions of F1+2, but not of TAT and FPA. In vitro, UFH predominantly affected the anti-IIa assays (activated partial thromboplastin time, thrombin time) and LMWH mainly the anti-Xa test system. Using a technique that investigates the activated coagulation system in vivo, a time- and dose dependent inhibitory effect of heparin on coagulation activation was detectable. Therefore, in our experimental setting a preferential inhibition of a particular portion of the coagulation system by one of the two heparin preparations was not detectable.

Blood coagulation at the site of microvascular injury: effects of low-dose aspirin

“…Previous studies on blood coagulation at sites of hemostatic plug formation, however, have been limited to measurements of FPA, TAT, or F1.2 by commercially available ELISAs. [18][19][20] In the present study, we have extended these observations to the determination of the kinetics of prothrombin, FV, and FXIII activation as well as Fbg consumption and inactivation of FVa using quantitative immunochemical techniques.…”

“…Previous studies on blood coagulation at sites of hemostatic plug formation, however, have been limited to measurements of FPA, TAT, or F1.2 by commercially available ELISAs. [18][19][20] In the present study, we have extended these observations to the determination of the kinetics of prothrombin, FV, and FXIII activation as well as Fbg consumption and inactivation of FVa using quantitative immunochemical techniques.The principal conclusions from our analyses, performed in bleeding-time blood, are the following: (1) Prothrombin is rapidly and almost completely removed at 3 to 4 minutes of bleeding.(2) Thrombin B chain and prethrombin 2 appear at 60 to 120 seconds of bleeding and are produced in similar amounts. Their maximum concentrations reach approximately 35 to 40 nM at the end of bleeding.…”

“…Previous studies undertaken to quantitate thrombin generation in bleeding-time blood focused on the measurement of FPA, thrombin-antithrombin III complexes (TAT), and prothrombin fragment 1.2 (F1.2) concentrations. [17][18][19][20] We wondered whether the model of microvascular injury could also be used to monitor other coagulant reactions that regulate thrombin formation, or are catalyzed by this enzyme (ie, activation of FV and FXIII or inactivation of FVa).…”

Systemic blood coagulation activation in acute coronary syndromes

“…These findings are in line with the previous study on healthy volunteers. 63 It is worth noting that low-molecularweight heparin suppresses thrombin generation similarly to unfractionated heparin, 63 suggesting that our observations may be extrapolated to ACS patients receiving the former.…”

“…These findings are in line with the previous study on healthy volunteers. 63 It is worth noting that low-molecularweight heparin suppresses thrombin generation similarly to unfractionated heparin, 63 suggesting that our observations may be extrapolated to ACS patients receiving the former.The number of the patients enrolled in this study was limited; however, patient selection resulted in a reasonably homogenous population, which together with well-matched controls, mitigate against significant recruitment bias. Further, patients with unstable angina, who represent a large percentage of ACS patients, were not participants in this study.…”