Repeated Doses of Oral and Subcutaneous Heparins Have Similar Antithrombotic Effects in a Rat Carotid Arterial Model of Thrombosis

Abstract

Although heparins are usually injected intravenously or subcutaneously, antithrombotic activity is observed in rat models following single oral heparin doses. Since repetitive dosing is usually needed for thromboprophylaxis, study objectives were to determine whether repetitive oral heparin prevented arterial thrombosis and to compare effectiveness to subcutaneous administration. Wistar rats were given subcutaneous or oral unfractionated heparin ([UFH] 1 mg/kg per 48 h), low-molecular-weight heparin ([LMWH] tinzaparin, 0.1 mg/kg per 12 h), or saline for 30 days. On the last day, thrombosis was initiated by placing 30% FeCl(3)-soaked filter paper on the distal carotid. Subsequent flow measurements, for a 60-minute period, included recorded time of initial thrombus formation (time till thrombus begins [TTB]), and time until carotid occlusion (time till occlusion [TTO]). The formed thrombus was dried and weighed. The activated partial thromboplastin time (aPTT), anti-factor Xa, and antithrombin activity were determined from the plasma. Both oral and subcutaneous heparins significantly increased TTB and TTO. Time of initial thrombus formations were 12.6 ± 1.1, 21.2 ± 2.2, 25.3 ± 3.9, 21.7 ± 3.1, and 21.3 ± 1.7 minutes and TTOs were 29.3 ± 3.6, 54.8 ± 4.0, 60.0 ± 0.3, 56.7 ± 3.3, and 58.3 ± 1.7 minutes (mean ± SEM) for control, subcutaneous UFH, oral UFH, subcutaneous LMWH, and oral LMWH, respectively. Thrombus weight was 2.52 ± 0.29 g in control and was reduced to 43%, 23%, 33%, and 28% of control weight for subcutaneous UFH, oral UFH, subcutaneous LMWH, and oral LMWH, respectively. Thrombus weight was significantly less for oral compared to subcutaneous UFH. The aPTT for oral UFH, and anti-factor Xa activity in the LMWH-treated groups were significantly greater than control (two-tailed t tests). These findings confirm that orally administered heparins are absorbed. Repeated treatment with oral heparin showed similar antithrombotic activity compared to subcutaneous heparin. Oral heparin use for arterial thromboprophylaxis should be further investigated.

Repeated Oral or Subcutaneous LMWH Has similar Antithrombotic Activity in a Rat Venous Thrombosis Model: Antithrombotic Activity Correlates With Heparin on Endothelium When Orally Administered

“…6,7,29 Repeated doses of orally administered unfractionated heparins and the LMWH tinzaparin prevented thrombosis in a rat carotid arterial model where the effects were equal or similar to SC administration. 10 The results presented here, using a rat jugular vein thrombosis model, support this observation and indicate that the LMWH tinzaparin, administered by gastric tube at 0.1 mg/kg/12 hours over a 30day period, prevents thrombosis, and the antithrombotic effect is equal to that following SC administration. This reveals that repetitive orally administered LMWH has antithrombotic effects in both arterial and venous thrombosis models.…”

“…Antithrombotic activity was similar for oral and SC administration. 10 In this study, we examine the antithrombotic effect of the LMWHs tinzaparin and reviparin, following repeated oral administration in a rat venous thrombosis model. We also determined whether an orally administered dose of LMWH repeated over 30 days had an antithrombotic effect similar to a single dose or to SC administration.…”

Timing of Heparin Administration Modulates Arterial Occlusive Thrombotic Response in Rats

“…The rat ferric chloride model has been used in a number of studies to evaluate thrombosis, particularly in the context of antithrombotic therapies. The controls (no therapy) in our study had an average TTO of~12 min; other studies using various parameters of ferric chloride concentration and time of application, as well as filter paper dimensions, have control TTO data from 7.8-8.7 min [19,20] to greater than 30 min [8,21,22], with many values between these times [23][24][25][26][27][28][29][30][31][32][33]. We selected our particular ferric chloride induction parameters to provide a moderate injury so that heparin therapy might have an influence, as was determined to be the case.…”