Effects of Bovine Polymerized Hemoglobin on Coagulation in Controlled Hemorrhagic Shock in Swine

Abstract

HBOC-201, a bovine polymerized hemoglobin, has been proposed as a novel oxygen-carrying resuscitative fluid for patients with hemorrhagic shock (HS). Herein, we evaluated the hemostatic effects of HBOC-201 in an animal model of HS. A 40% blood loss-controlled hemorrhage and soft tissue injury were performed in 24 invasively monitored Yucatan mini-pigs. Pigs were resuscitated with HBOC-201 (HBOC) or hydroxyethyl starch (HEX), or were not resuscitated (NON) based on cardiac parameters during a 4-h prehospital phase. Afterward, animals received simulated hospital care for 3 days with blood or saline transfusions. Hemostasis measurements included in vivo bleeding time (BT), thromboelastography (TEG), in vitro bleeding time (platelet function; PFA-CT), prothrombin time (PT), and partial thromboplastin time (PTT). Serum lactate was measured and lung sections were evaluated for microthrombi by electron microscopy. During the prehospital phase, BT remained unchanged in the HBOC group. TEG reaction time increased in HBOC pigs during the late prehospital phase and was greater than in NON or HEX pigs at 24 h (P = 0.03). TEG maximum amplitude was similar for the two fluid-resuscitated groups. PFA-CT increased in both resuscitated groups but less with HBOC (P = 0.02) in the prehospital phase; this effect was reversed by 24 h (P = 0.02). In the hospital phase, PT decreased (P < 0.02), whereas PTT increased above baseline (P < 0.01). Lactic acidosis in HBOC and HEX groups was similar. Aspartate aminotransferase was relatively elevated in the HBOC group at 24 h. Electron microscopy showed no evidence of platelet/fibrin clots or microthrombi in any of the animals. Twenty-four-hour group differences mainly reflected the fact that all HEX animals (8/8) received blood transfusions compared with only one HBOC animal (1/8). In swine with HS, HBOC resuscitation induced less thrombopathy than HEX during the prehospital phase. Mild delayed effects on platelet and clot formation during the hospital phase are transient and likely related to fewer blood transfusions. In swine with HS, HBOC resuscitation induced less thrombopathy than HEX during the prehospital phase but more thrombopathy in the hospital phase. The delayed effects on platelet and clot formation during the hospital phase are transient and may be related to the need for fewer blood transfusions.

Comparison of the Pharmacokinetic Properties of Hemoglobin-Based Oxygen Carriers

“…Although a number of preclinical studies of HBOC-201 have been performed and its efficacy has been demonstrated [32], to best of our knowledge, pharmacokinetic studies of HBOC-201 in preclinical trials are limited, due to the fact that the half-life of HBOC-201 is around 22 h in a 40% hemorrhagic shock model of a Yucatan mini-pig [33] (or have not been published). On the other hand, the safety and efficacy of HBOC-201 has been examined in more than 20 clinical trials [34], some in which the half-life of HBOC-201 in humans were reported (Table 2).…”

Glutaraldehyde-polymerized bovine hemoglobin and phosphodiesterase-5 inhibition*

“…Although several potential mechanisms may explain the vasoconstrictive properties of these HBOCs (10, 13, 14), nitric oxide (NO) scavenging by the HBOCs is the most likely (1, 4, 15–17). Recently, this laboratory has confirmed that glutaraldehyde-polymerized bovine HBOC infusion in animals had dire consequences on hemodynamic performance in both normoxic and hypoxic rats (18).…”

Fluid Resuscitation With Hemoglobin Vesicles in a Rabbit Model of Acute Hemorrhagic Shock

“…These findings suggest that using HbV initially might be advantageous in patients having massive hemorrhages, although they cast doubt on the coagulation influence that has been suggested previously (21). Encapsulated Hb, which is one of the next generation of HBOCs, includes some RBC enzymes (22) and is permeable to glucose and other small hydrophilic molecules.…”