Prothrombin complex concentrate mitigates diffuse bleeding after cardiopulmonary bypass in a porcine model

F Kaspereit, S Hoffmann, I Pragst, G Dickneite, F Kaspereit, S Hoffmann, I Pragst, G Dickneite

Abstract

Background: Extracorporeal circuit priming and intravascular volume expansion during cardiopulmonary bypass (CPB) may lead to dilutional coagulopathy and excessive diffuse postoperative bleeding. Prothrombin complex concentrate (PCC) containing clotting factors II (FII), VII (FVII), IX (FIX), and X (FX) could be of potential value in correcting dilutional coagulopathy and reducing blood loss.

Methods: Anaesthetized pigs underwent CPB with hypothermia for 2 h at 25°C followed by 1 h of normothermia. Approximately 1 h after CPB, animals randomly received either isotonic saline 1 ml kg⁻¹ or PCC 30 IU kg⁻¹ in a volume of 1 ml kg⁻¹. Diffuse coagulopathic bleeding was assessed as suture hole blood loss from a Gore-Tex patch placed over a full-thickness incision in the left carotid artery.

Results: After CPB, levels of FII, FVII, FIX, and FX declined from baseline by 32% to 48%, and PCC fully or partially reversed those deficits. Median suture hole blood loss after administration of saline placebo was 74 ml. PCC reduced suture hole bleeding by a median of 54 ml with a 95% confidence interval of 6-112 ml (P=0.026) compared with saline. PCC, but not saline, normalized skin bleeding time. Peak thrombin generation markedly decreased after CPB, but then returned in PCC-treated animals to a level higher than baseline by 28.7 nM (14.5-41.1 nM; P=0.031).

Conclusions: PCC was effective in correcting dilutional coagulopathy and reducing diffuse bleeding in an in vivo large-animal CPB model. Further research is warranted on PCC as a haemostatic agent in CPB.

Figures

Fig 1
Fig 1
Study design. CPB, cardiopulmonary bypass; PCC, prothrombin complex concentrate; SBT, skin bleeding time.
Fig 2
Fig 2
Individual animal levels of (a) FII, (b) FVII, (c) FIX, and (d) FX at baseline and after CPB and subsequent administration of PCC. Concentration values expressed as percentages of the baseline means, shown as dashed lines. CPB, cardiopulmonary bypass; FII, factor II; FVII, factor VII; FIX, factor IX; FX, factor X; PCC, prothrombin complex concentrate.
Fig 3
Fig 3
Individual animal suture hole blood losses after CPB and administration of saline or PCC in comparison with those of a control group which did not undergo CPB. Horizontal lines indicate median values. CI, 95% confidence interval; CPB, cardiopulmonary bypass; PCC, prothrombin complex concentrate.
Fig 4
Fig 4
Peak thrombin generation in individual animals at baseline and after CPB and subsequent administration of saline or PCC. Medians depicted as horizontal lines. In the table inset, grouped comparison indicated between saline and PCC; all other comparisons paired. CI, 95% confidence interval; CPB, cardiopulmonary bypass; PCC, prothrombin complex concentrate.

References

    1. Frankel TL, Stamou SC, Lowery RC, et al. Risk factors for hemorrhage-related reexploration and blood transfusion after conventional versus coronary revascularization without cardiopulmonary bypass. Eur J Cardiothorac Surg. 2005;27:494–500. .
    1. Choong CK, Gerrard C, Goldsmith KA, Dunningham H, Vuylsteke A. Delayed re-exploration for bleeding after coronary artery bypass surgery results in adverse outcomes. Eur J Cardiothorac Surg. 2007;31:834–8. .
    1. Salis S, Mazzanti VV, Merli G, et al. Cardiopulmonary bypass duration is an independent predictor of morbidity and mortality after cardiac surgery. J Cardiothorac Vasc Anesth. 2008;22:814–22. .
    1. Mehta RH, Sheng S, O'Brien SM, et al. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: incidence, risk factors, time trends, and outcomes. Circ Cardiovasc Qual Outcomes. 2009;2:583–90. .
    1. Bull BS, Hay KL, Herrmann PC. Postoperative bypass bleeding: a bypass-associated dilutional (BAD) coagulopathy? Blood Cells Mol Dis. 2009;43:256–9. .
    1. Schick KS, Fertmann JM, Jauch K-W, Hoffmann JN. Prothrombin complex concentrate in surgical patients: retrospective evaluation of vitamin K antagonist reversal and treatment of severe bleeding. Crit Care. 2009;13:R191. .
    1. Römisch J, Gröner A, Bernhardt D, et al. Nanofiltration bei der Herstellung von Beriplex® P/N: Erhöhung der Kapazität zur Viruseliminierung unter Beibehaltung der Produktqualität. Beitr Infusionsther Transfusionsmed. 1996;33:220–4.
    1. Stuklis RG, O'Shaughnessy DF, Ohri SK. Novel approach to bleeding in patients undergoing cardiac surgery with liver dysfunction. Eur J Cardiothorac Surg. 2001;19:219–20. .
    1. Bruce D, Nokes TJ. Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital. Crit Care. 2008;12:R105. .
    1. Demeyere R, Gillardin S, Arnout J, Strengers PFW. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. Vox Sang. .
    1. Weimer T, Streichert S, Watson C, Gröner A. High-titer screening PCR: a successful strategy for reducing the parvovirus B19 load in plasma pools for fractionation. Transfusion. 2001;41:1500–4. .
    1. Ostermann H, Haertel S, Knaub S, Kalina U, Jung K, Pabinger I. Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers. Thromb Haemost. 2007;98:790–7.
    1. Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H. Prothrombin complex concentrate (Beriplex® P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008;6:622–31. .
    1. Dickneite G, Pragst I. Prothrombin complex concentrate vs fresh frozen plasma for reversal of dilutional coagulopathy in a porcine trauma model. Br J Anaesth. 2009;102:345–54. .
    1. Wilkes MM, Navickis RJ, Sibbald WJ. Albumin versus hydroxyethyl starch in cardiopulmonary bypass surgery: a meta-analysis of postoperative bleeding. Ann Thorac Surg. 2001;72:527–33. .
    1. Canver CC, Nichols RD. Use of intraoperative hetastarch priming during coronary bypass. Chest. 2000;118:1616–20. .
    1. Wiesen P, Canivet JL, Ledoux D, Roediger L, Damas P. Effect of hydroxyethylstarch on renal function in cardiac surgery: a large scale retrospective study. Acta Anaesthesiol Belg. 2005;56:257–63.
    1. Glickman M, Gheissari A, Money S, Martin J, Ballard JL. A polymeric sealant inhibits anastomotic suture hole bleeding more rapidly than gelfoam/thrombin: results of a randomized controlled trial. Arch Surg. 2002;137:326–31.
    1. Dickneite G, Metzner H, Nicolay U. Prevention of suture hole bleeding using fibrin sealant: benefits of factor XIII. J Surg Res. 2000;93:201–5. .
    1. McLoughlin TM, Fontana JL, Alving B, Mongan PD, Bünger R. Profound normovolemic hemodilution: hemostatic effects in patients and in a porcine model. Anesth Analg. 1996;83:459–65. .
    1. Dickneite G, Doerr B, Kaspereit F. Characterization of the coagulation deficit in porcine dilutional coagulopathy and substitution with a prothrombin complex concentrate. Anesth Analg. 2008;106:1070–7. .
    1. Dickneite G, Dörr B, Kaspereit F, Tanaka KA. Prothrombin complex concentrate versus recombinant factor VIIa for reversal of hemodilutional coagulopathy in a porcine trauma model. J Trauma. 2010;68:1151–7. .
    1. Hemker HC, Giesen P, Al Dieri R, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb. 2003;33:4–15. .
    1. Staudinger T, Frass M, Rintelen C, et al. Influence of prothrombin complex concentrates on plasma coagulation in critically ill patients. Intensive Care Med. 1999;25:1105–10. .
    1. Preston FE, Laidlaw ST, Sampson B, Kitchen S. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. Br J Haematol. 2002;116:619–24. .
    1. Lorenz R, Kienast J, Otto U, et al. Efficacy and safety of a prothrombin complex concentrate with two virus-inactivation steps in patients with severe liver damage. Eur J Gastroenterol Hepatol. 2003;15:15–20. .
    1. Fries D, Haas T, Klingler A, et al. Efficacy of fibrinogen and prothrombin complex concentrate used to reverse dilutional coagulopathy—a porcine model. Br J Anaesth. 2006;97:460–7. .
    1. Pragst I, Kaspereit F, Dörr B, Dickneite G. Prothrombin complex concentrate (Beriplex P/N) for control of bleeding after kidney trauma in a rabbit dilutional coagulopathy model. Thromb Res. 2010;125:272–7. .
    1. Rodewald L, Scharrer I. Protein chemical investigation of 30 consecutive lots of double-virus eliminated PCC (Beriplex P/N) and summary of safety data. Hämostaseologie. 2004;24:A46.
    1. Gill R, Herbertson M, Vuylsteke A, et al. Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery. Circulation. 2009;120:21–7. .
    1. Martinowitz U, Holcomb JB, Pusateri AE, et al. Intravenous rFVIIa administered for hemorrhage control in hypothermic coagulopathic swine with grade V liver injuries. J Trauma. 2001;50:721–9. .
    1. Jeroukhimov I, Jewelewicz D, Zaias J, et al. Early injection of high-dose recombinant factor VIIa decreases blood loss and prolongs time from injury to death in experimental liver injury. J Trauma. 2002;53:1053–7. .
    1. Lynn M, Jerokhimov I, Jewelewicz D, et al. Early use of recombinant factor VIIa improves mean arterial pressure and may potentially decrease mortality in experimental hemorrhagic shock: a pilot study. J Trauma. 2002;52:703–7. .
    1. Schreiber MA, Holcomb JB, Hedner U, Brundage SI, Macaitis JM, Hoots K. The effect of recombinant factor VIIa on coagulopathic pigs with grade V liver injuries. J Trauma. 2002;53:252–7. .
    1. Sondeen JL, Pusateri AE, Hedner U, Yantis LD, Holcomb JB. Recombinant factor VIIa increases the pressure at which rebleeding occurs in porcine uncontrolled aortic hemorrhage model. Shock. 2004;22:163–8. .
    1. Klemcke HG, Delgado A, Holcomb JB, et al. Effect of recombinant FVIIa in hypothermic, coagulopathic pigs with liver injuries. J Trauma. 2005;59:155–61. .
    1. Pusateri AE, Ryan KL, Delgado AV, et al. Effects of increasing doses of activated recombinant factor VII on haemostatic parameters in swine. Thromb Haemost. 2005;93:275–83.
    1. Howes DW, Stratford A, Stirling M, Ferri CC, Bardell T. Administration of recombinant factor VIIa decreases blood loss after blunt trauma in noncoagulopathic pigs. J Trauma. 2007;62:311–5. .
    1. Martini WZ, Pusateri AE, Uscilowicz JM, Delgado AV, Holcomb JB. Independent contributions of hypothermia and acidosis to coagulopathy in swine. J Trauma. 2005;58:1002–9. .

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner