Introduction
Recently, we improved management of abdominal aorta anastomosis and obstructing thrombus formation [1], [2] with the stable gastric pentadecapeptide BPC 157 [1], [2].
Now, we focused on the counteraction of the effect on heparin, warfarin and aspirin in treated rats undergoing amputation, particularly the reduction of bleeding time and the lower incidence of thrombocytopenia after amputation in animals receiving the BPC 157. In addition, mortality in the BPC 157 treated animals could be reduced. As a particular anti-ulcer peptide (GEPPPGKPADDAGLV, M.W. 1419, PL-10, PLD-116, PL 14736), in trials for inflammatory bowel disease, wound treatment [1], [6] (i.e., stimulation of expression of the early growth response 1 (egr-1) gene [7]), producing no reported toxicity (LD1 could be not achieved), effective alone without carrier [1]), it has a particular effect on endothelium protection [1], [2], [8] along with prominent angiogenesis [9], [10], [11] and an effect of NO-system [12], [13], [14] and endothelin serum level [14] (that may have a particular role in bleeding disturbances [15], [16]).
Initially, we suggested from gastrointestinal tract viewpoint [1], [2] (and probably not only in theory) that these both may be implemented endothelium protection (i.e., endothelium maintains mucosal integrity [4]vs. essential role of endothelium in hemostasis and thrombosis [5]) holding stomach cytoprotection theory [3] and peptidergic anti-ulcer cytoprotection therapy with the pentadecapeptide BPC 157 [1], [2] as a novel peptidergic mediator of Robert's cytoprotection and adaptive cytoprotection [1] (providing that cytoprotective agents essentially share an endothelium protection).
Now, in addition, we specially hold that it's possible further effect to decrease bleeding follows its particular beneficial effect on wound healing [1], [2], [6], [7], [9], [10], [17], [18], [19], [20], [21], [22], [23]. Namely, the wound healing process accomplished all of 4 major events (vascular constriction, loose platelet plug, fibrin mesh to insure stability of platelet plug, dissolution of the clot) that occur in a set order following the loss of vascular integrity, and thereby, an agent implemented in wound healing, such as stable gastric pentadecapeptide BPC 157, and shown to be effective in wound healing should be effective also in bleeding disorders [1], [2], [6], [7], [9], [10], [17], [18], [19], [20], [21], [22], [23]. For instance, it may be of both theoretical and practical value that coagulation is beneficial to wound healing [24], but it also has the negative effect of compromising blood supply to the injured site [25]; in severe injury, particularly in burns, large areas of ischemic tissue may develop [25] while BPC 157 improves the healing of both simple incisional wound [17] and deep skin wound [6], [18]. Also, in advancing muscle [19], tendon [20], ligament [21] post-transection healing, BPC 157 clearly improves the stumps bridging and fulfilling of large post-transection gap of muscle [19], tendon [20] or ligament [21] that could otherwise not heal. Finally, after improved intestinal wound healing such as various intestinal anastomoses healing was verified [22], [23], final demonstration may pose the evidence in rats with abdominal aorta terminoterminal anastomosis [2]. Namely, BPC 157 application may prevent obstructive thrombus formation and rapidly destroy already formed obstructing thrombus along with the rescuing of lower leg function [2].
Thus, while a direct demonstration is still lacking (the clot itself can also play a role in wound healing by acting as conductive matrix or “scaffold” upon which cells can adhere and begin the wound healing process [26]), such an effect (obviously not procoagulant) [1], [2], [6], [7], [9], [10], [17], [18], [19], [20], [21], [22], [23], may have a more general impact on induced bleeding, i.e., bleeding time, amount of bleeding, coagulation parameters (i.e., prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen concentration (FIB)) and acute thrombocytopenia, and survival rate after amputation in normal rats, and after heparin, warfarin, aspirin challenge, regardless different pathophysiology involved. The coagulation pathway is a complex interaction of many elements – the endothelium, coagulation factors, and platelets – with ultimate goals of stemming the loss of blood at the site of injury and laying the groundwork for injury repair and healing [27]. Warfarin affects the vitamin K-dependent clotting factors (II, VII, IX, X), whereas heparin and related compounds increase the action of antithrombin on thrombin and factor Xa [28], [29], [30] (and thereby, the effect of BPC 157 on heparin activity (anti-Xa specific chromogenic substrate assay) and APTT was particularly given). Aspirin is known to inhibit localized platelet aggregation secondary to its ability to block thromboxane-A2 synthesis, and to have little effect on thrombin-induced platelet aggregation [31].
Thus, providing the initial hemostatic plug, composed primarily of platelets [26], stabilized further by a fibrin mesh generated in secondary hemostasis, the arrest of bleeding in a superficial wound, such as the bleeding time wound, almost exclusively from the primary hemostatic plug - the effect on platelets, the preserved platelet count, and counteraction (or at least attenuation) of acute thrombocytopenia that may arise in excessively bleeding rats [29], may be the prime target for BPC 157 effect. To accentuate this point, hematocrit (HCT) values will be made available as well.
To emphasize practical significance, BPC 157 counteracting regimens (intravenous, intraperitoneal, intragastrical (highly stable in human gastric juice for at least 24 hours [1])) correspondingly follow the route of heparin (intravenous), warfarin (intragastrical) and aspirin (intraperitoneal or intragastrical) application.
Access through your organization
Check access to the full text by signing in through your organization.Access through your organization
Section snippets
Animals
Male Albino Wistar rats were used in all of the experiments (10 rats per experimental group and interval). Experiments were approved by the Local Ethics Committee and assessed by observers unaware of the given treatment. The values PT ratio 1.25-1.45, APTT ratio 0.38-0.51, TT 30–50 sec, FIB 1.5-2.0 g/L, PLT 650–1100 x109/L, HTC 0.38-0.49 L/L, anti-Xa 0.0 IU/ml, were established as normal.
Drugs
Medication, without carrier or peptidase inhibitor, included stable gastric pentadecapeptide BPC 157 (a partial
Amputation only
Controls spontaneously bleed close to 20 minutes and appear with less platelets count. On the other hand, such post-amputation bleeding did not produce any failure of coagulation parameters. BPC 157, 10 μg/kg, 10 ng/kg regimens markedly reduced the bleeding time and blood loss and also counteracted acute thrombocytopenia (Table 1, Table 2, Table 3, Table 5, Table 6).
Heparin administration. Amputation associated with heparin administration
BPC 157 markedly attenuated the acute thrombocytopenia associated with heparin application only, before bleeding induction.
Discussion
As it was initially predicted from preventing obstructing clot formation and rapidly destroying already formed obstructing clot by pentadecapeptide BPC 157 [2], after amputation, and after administration of heparin, warfarin, aspirin, and after amputation associated with heparin, warfarin, aspirin administration the main findings are the reduction of bleeding time and the markedly counteracted thrombocytopenia in all animals receiving the BPC 157.In addition, mortality in the BPC 157 treated
Conflict of interest
Authors have no conflict of interest.
Cited by (69)
Rat inferior caval vein (ICV) ligature and particular new insights with the stable gastric pentadecapeptide BPC 157
2018, Vascular Pharmacology
As previously described [12,34,35], medication without carrier or peptidase inhibitor, included stable gastric pentadecapeptide BPC 157 (a partial sequence of the human gastric juice protein BPC, freely soluble in water at pH 7.0 and in saline). It was prepared as a peptide with 99% (HPLC) purity (1-des-Gly peptide was the main impurity; manufactured by Diagen, Ljubljana, Slovenia, GEPPPGKPADDAGLV, M.W. 1419) (in dose and application regimens as described before) [12,34,35]. In deeply anesthetized rats, the ICV was exposed via a midline laparotomy, dissected at the level of the right ovarian vein, and then ligated up to the right ovarian vein.
Mortal hyperkalemia disturbances in rats are NO-system related. The life saving effect of pentadecapeptide BPC 157
2013, Regulatory Peptides
This was, along with neuroprotective capabilities, also shown in brain trauma [21] or peripheral nerve transection (without or with nerve anastomosis) [22]. In addition, from the viewpoint of BPC 157 and counteraction of hyperkalemia consequences, we should also appreciate the beneficial counteracting effect of BPC 157 in other conditions that may be commonly associated with hyperkalemia (i.e., NSAIDs-toxicity [5], heparin over-toxicity [42]). Finally, cell membrane potential may also in turn alter the reaction to hyperkalemia after potassium chloride-overdose. View all citing articles on Scopus
Copyright © 2011 Elsevier Ltd. All rights reserved.