Monitoring Prohemostatic Treatment in Bleeding Patients

Abstract

Acutely bleeding patients are commonly found in the trauma and major surgery scenarios. They require prompt and effective treatment to restore an adequate hemostatic pattern, to avoid serious and sometimes life-threatening complications.

Different prohemostatic treatments are available, including allogeneic blood derivatives (fresh frozen plasma, platelet concentrates, and cryoprecipitates), prothrombin complex concentrates, specific coagulation factors (fibrinogen, recombinant factor XIII, recombinant activated factor VII), and drugs (protamine for patients under heparin treatment, desmopressin, antifibrinolytics).

For decades, prohemostatic treatment of the acutely bleeding patient was based on empirical strategies and clinical judgment, both in terms of a correct diagnosis of the mechanism(s) leading to bleeding, and of an assessment of the effects of the treatment. This empirical strategy may lead to excessive or unnecessary use of allogeneic blood products, as well as to an incorrect, inefficacious, or even dangerous treatment. Different monitoring devices are nowadays available for guiding the diagnostic and therapeutic decision-making process in an acutely bleeding patient. This review addresses the available tools for monitoring prohemostatic treatment of the bleeding patient, with a specific respect for point-of-care tests (thromboelastography, thromboelastometry, platelet function tests, and heparin monitoring systems) at the light of the existing evidence.

Keywords

thromboelastography - platelet function analyzers - fresh frozen plasma - coagulation factors - desmopressin

• References

• 1 van Veen JJ, Gatt A, Makris M. Thrombin generation testing in routine clinical practice: are we there yet?. Br J Haematol 2008; 142 (6) 889-903
• 2 Al Dieri R, Peyvandi F, Santagostino E , et al. The thrombogram in rare inherited coagulation disorders: its relation to clinical bleeding. Thromb Haemost 2002; 88 (4) 576-582
• 3 al Dieri R, Alban S, Béguin S, Hemker HC. Thrombin generation for the control of heparin treatment, comparison with the activated partial thromboplastin time. J Thromb Haemost 2004; 2 (8) 1395-1401
• 4 Devreese K, Peerlinck K, Arnout J, Hoylaerts MF. Laboratory detection of the antiphospholipid syndrome via calibrated automated thrombography. Thromb Haemost 2009; 101 (1) 185-196
• 5 Avidan MS, Alcock EL, Da Fonseca J , et al. Comparison of structured use of routine laboratory tests or near-patient assessment with clinical judgement in the management of bleeding after cardiac surgery. Br J Anaesth 2004; 92 (2) 178-186
• 6 Shore-Lesserson L, Manspeizer HE, DePerio M, Francis S, Vela-Cantos F, Ergin MA. Thromboelastography-guided transfusion algorithm reduces transfusions in complex cardiac surgery. Anesth Analg 1999; 88 (2) 312-319
• 7 Spiess BD, Tuman KJ, McCarthy RJ, DeLaria GA, Schillo R, Ivankovich AD. Thromboelastography as an indicator of post-cardiopulmonary bypass coagulopathies. J Clin Monit 1987; 3 (1) 25-30
• 8 Cerutti E, Stratta C, Romagnoli R , et al. Thromboelastogram monitoring in the perioperative period of hepatectomy for adult living liver donation. Liver Transpl 2004; 10 (2) 289-294
• 9 Brohi K. Diagnosis and management of coagulopathy after major trauma. Br J Surg 2009; 96 (9) 963-964
• 10 Selby R, Geerts W, Ofosu FA , et al. Hypercoagulability after trauma: hemostatic changes and relationship to venous thromboembolism. Thromb Res 2009; 124 (3) 281-287
• 11 Johansson PI. Hemostatic strategies for minimizing mortality in surgery with major blood loss. Curr Opin Hematol 2009; 16 (6) 509-514
• 12 Johansson PI, Bochsen L, Stensballe J, Secher NH. Transfusion packages for massively bleeding patients: the effect on clot formation and stability as evaluated by thrombelastolastograph (TEG). Transfus Apher Sci 2008; 39: 3-8
• 13 Johansson PI, Stensballe J. Effect of Haemostatic Control Resuscitation on mortality in massively bleeding patients: a before and after study. Vox Sang 2009; 96 (2) 111-118
• 14 Schöchl H, Nienaber U, Maegele M , et al. Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy. Crit Care 2011; 15 (2) R83
• 15 Solomon C, Cadamuro J, Ziegler B , et al. A comparison of fibrinogen measurement methods with fibrin clot elasticity assessed by thromboelastometry, before and after administration of fibrinogen concentrate in cardiac surgery patients. Transfusion 2011; 51 (8) 1695-1706
• 16 Schöchl H, Posch A, Hanke A, Voelckel W, Solomon C. High-dose fibrinogen concentrate for haemostatic therapy of a major trauma patient with recent clopidogrel and aspirin intake. Scand J Clin Lab Invest 2010; 70 (6) 453-457
• 17 Lee SH, Lee SM, Kim CS , et al. Use of fibrin-based thromboelastometry for cryoprecipitate transfusion in cardiac surgery involving deep hypothermic circulatory arrest during cardiopulmonary bypass. Blood Coagul Fibrinolysis 2010; 21 (7) 687-691
• 18 Karkouti K, McCluskey SA, Syed S, Pazaratz C, Poonawala H, Crowther MA. The influence of perioperative coagulation status on postoperative blood loss in complex cardiac surgery: a prospective observational study. Anesth Analg 2010; 110 (6) 1533-1540
• 19 Takamiya O, Hando S, Tekondo M , et al. Japanese collaborative study for fibrinogen assay: variability of the fibrinogen assay between different laboratories does not improve when a common calibrator is used. Clin Lab Haematol 2005; 27 (3) 177-183
• 20 Kettner SC, Panzer OP, Kozek SA , et al. Use of abciximab-modified thrombelastography in patients undergoing cardiac surgery. Anesth Analg 1999; 89 (3) 580-584
• 21 Koster A, Kukucka M, Fischer T, Hetzer R, Kuppe H. Evaluation of post-cardiopulmonary bypass coagulation disorders by differential diagnosis with a multichannel modified thromboelastogram: a pilot investigation. J Extra Corpor Technol 2001; 33 (3) 153-158
• 22 Solomon C, Cadamuro J, Ziegler B , et al. A comparison of fibrinogen measurement methods with fibrin clot elasticity assessed by thromboelastometry, before and after administration of fibrinogen concentrate in cardiac surgery patients. Transfusion 2011; 51: 1695-1706
• 23 Lang T, Toller W, Gütl M , et al. Different effects of abciximab and cytochalasin D on clot strength in thrombelastography. J Thromb Haemost 2004; 2 (1) 147-153
• 24 Hendriks HG, Meijer K, de Wolf JT , et al. Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation: a pilot study. Transplantation 2001; 71 (3) 402-405
• 25 Karkouti K, Beattie WS, Wijeysundera DN , et al. Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis. Transfusion 2005; 45 (1) 26-34
• 26 Niemann CU, Behrends M, Quan D , et al. Recombinant factor VIIa reduces transfusion requirements in liver transplant patients with high MELD scores. Transfus Med 2006; 16 (2) 93-100
• 27 von Heymann C, Redlich U, Jain U , et al. Recombinant activated factor VII for refractory bleeding after cardiac surgery—a retrospective analysis of safety and efficacy. Crit Care Med 2005; 33 (10) 2241-2246
• 28 Friederich PW, Geerdink MG, Spataro M , et al. The effect of the administration of recombinant activated factor VII (NovoSeven) on perioperative blood loss in patients undergoing transabdominal retropubic prostatectomy: the PROSE study. Blood Coagul Fibrinolysis 2000; 11 (Suppl. 01) S129-S132
• 29 Lawson JH, Murphy MP. Challenges for providing effective hemostasis in surgery and trauma. Semin Hematol 2004; 41 (1) (Suppl. 01) 55-64
• 30 Ranucci M, Isgrò G, Soro G, Conti D, De Toffol B. Efficacy and safety of recombinant activated factor vii in major surgical procedures: systematic review and meta-analysis of randomized clinical trials. Arch Surg 2008; 143 (3) 296-304, discussion 304
• 31 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 (1) 21-27
• 32 Levi M, Peters M, Büller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. Crit Care Med 2005; 33 (4) 883-890
• 33 Carr Jr ME, Martin EJ, Kuhn JG, Ambrose H, Fern S, Bryant PC. Monitoring of hemostatic status in four patients being treated with recombinant factor VIIa. Clin Lab 2004; 50 (9-10) 529-538
• 34 Young G, Blain R, Nakagawa P, Nugent DJ. Individualization of bypassing agent treatment for haemophilic patients with inhibitors utilizing thromboelastography. Haemophilia 2006; 12 (6) 598-604
• 35 Sørensen B, Ingerslev J. Thromboelastography and recombinant factor VIIa- hemophilia and beyond. Semin Hematol 2004; 41 (Suppl. 01) 140-144
• 36 Sørensen B, Ingerslev J. Tailoring haemostatic treatment to patient requirements: an update on monitoring haemostatic response using trombelastography. Haemophilia 2005; 11 (Supp 1) 1-6
• 37 Pivalizza EG, Escobar MA. Thrombelastography-guided factor VIIa therapy in a surgical patient with severe hemophilia and factor VIII inhibitor. Anesth Analg 2008; 107 (2) 398-401
• 38 Wasowicz M, Meineri M, McCluskey SM, Mitsakakis N, Karkouti K. The utility of thromboelastography for guiding recombinant activated factor VII therapy for refractory hemorrhage after cardiac surgery. J Cardiothorac Vasc Anesth 2009; 23 (6) 828-834
• 39 Levy JH, Gill R, Nussmeier NA , et al. Repletion of factor XIII following cardiopulmonary bypass using a recombinant A-subunit homodimer. A preliminary report. Thromb Haemost 2009; 102 (4) 765-771
• 40 Jámbor C, Reul V, Schnider TW, Degiacomi P, Metzner H, Korte WC. In vitro inhibition of factor XIII retards clot formation, reduces clot firmness, and increases fibrinolytic effects in whole blood. Anesth Analg 2009; 109 (4) 1023-1028
• 41 Theusinger OM, Baulig W, Asmis LM, Seifert B, Spahn DR. In vitro factor XIII supplementation increases clot firmness in Rotation Thromboelastometry (ROTEM). Thromb Haemost 2010; 104 (2) 385-391
• 42 Khan NU, Wayne CK, Barker J, Strang T. The effects of protamine overdose on coagulation parameters as measured by the thrombelastograph. Eur J Anaesthesiol 2010; 27 (7) 624-627
• 43 McLaughlin KE, Dunning J. In patients post cardiac surgery do high doses of protamine cause increased bleeding?. Interact Cardiovasc Thorac Surg 2003; 2 (4) 424-426
• 44 Raymond PD, Ray MJ, Callen SN, Marsh NA. Heparin monitoring during cardiac surgery. Part 1: validation of whole-blood heparin concentration and activated clotting time. Perfusion 2003; 18 (5) 269-276
• 45 Giavarina D, Carta M, Fabbri A, Manfredi J, Gasparotto E, Soffiati G. Monitoring high-dose heparin levels by ACT and HMT during extracorporeal circulation: diagnostic accuracy of three compact monitors. Perfusion 2002; 17 (1) 23-26
• 46 Hashimoto K, Sasaki T, Hachiya T , et al. Real time measurement of heparin concentration during cardiopulmonary bypass. J Cardiovasc Surg (Torino) 1999; 40 (5) 645-651
• 47 Despotis GJ, Santoro SA, Spitznagel E , et al. Prospective evaluation and clinical utility of on-site monitoring of coagulation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1994; 107 (1) 271-279
• 48 Despotis GJ, Joist JH, Hogue Jr CW , et al. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thromb Haemost 1996; 76 (6) 902-908
• 49 Shore-Lesserson L, Manspeizer HE, DePerio M, Francis S, Vela-Cantos F, Ergin MA. Thromboelastography-guided transfusion algorithm reduces transfusions in complex cardiac surgery. Anesth Analg 1999; 88 (2) 312-319
• 50 Davidson SJ, McGrowder D, Roughton M, Kelleher AA. Can ROTEM thromboelastometry predict postoperative bleeding after cardiac surgery?. J Cardiothorac Vasc Anesth 2008; 22 (5) 655-661
• 51 Ak K, Isbir CS, Tetik S , et al. Thromboelastography-based transfusion algorithm reduces blood product use after elective CABG: a prospective randomized study. J Card Surg 2009; 24 (4) 404-410
• 52 Royston D, von Kier S. Reduced haemostatic factor transfusion using heparinase-modified thrombelastography during cardiopulmonary bypass. Br J Anaesth 2001; 86 (4) 575-578
• 53 Ranucci M, Castelvecchio S, Romitti F, Isgrò G, Ballotta A, Conti D. Living without aprotinin: the results of a 5-year blood saving program in cardiac surgery. Acta Anaesthesiol Scand 2009; 53 (5) 573-580
• 54 British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of platelet transfusions. Br J Haematol 2003; 122 (1) 10-23
• 55 Rebulla P. Revisitation of the clinical indications for the transfusion of platelet concentrates. Rev Clin Exp Hematol 2001; 5 (3) 288-310, discussion 311–312
• 56 Rebulla P. Platelet transfusion trigger in difficult patients. Transfus Clin Biol 2001; 8 (3) 249-254
• 57 Ferraris VA, Brown JR, Despotis GJ , et al; Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion; International Consortium for Evidence Based Perfusion. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011; 91 (3) 944-982
• 58 Cattaneo M, Hayward CP, Moffat KA, Pugliano MT, Liu Y, Michelson AD. Results of a worldwide survey on the assessment of platelet function by light transmission aggregometry: a report from the platelet physiology subcommittee of the SSC of the ISTH. J Thromb Haemost 2009; 7 (6) 1029
• 59 Peterson P, Hayes TE, Arkin CF , et al. The preoperative bleeding time test lacks clinical benefit: College of American Pathologists' and American Society of Clinical Pathologists' position article. Arch Surg 1998; 133: 134-139
• 60 Homoncik M, Jilma B, Hergovich N, Stohlawetz P, Panzer S, Speiser W. Monitoring of aspirin (ASA) pharmacodynamics with the platelet function analyzer PFA-100. Thromb Haemost 2000; 83 (2) 316-321
• 61 Koessler J, Kobsar AL, Rajkovic MS , et al. The new INNOVANCE^® PFA P2Y cartridge is sensitive to the detection of the P2Y₁₂ receptor inhibition. Platelets 2011; 22 (1) 19-25
• 62 Raman S, Silverman NA. Clinical utility of the platelet function analyzer (PFA-100) in cardiothoracic procedures involving extracorporeal circulation. J Thorac Cardiovasc Surg 2001; 122 (1) 190-191
• 63 Jámbor C, Weber CF, Gerhardt K , et al. Whole blood multiple electrode aggregometry is a reliable point-of-care test of aspirin-induced platelet dysfunction. Anesth Analg 2009; 109 (1) 25-31
• 64 Sibbing D, Schulz S, Braun S , et al. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 2010; 8 (2) 250-256
• 65 Ranucci M, Baryshnikova E, Soro G, Ballotta A, De Benedetti D, Conti D ; Surgical and Clinical Outcome Research (SCORE) Group. Multiple electrode whole-blood aggregometry and bleeding in cardiac surgery patients receiving thienopyridines. Ann Thorac Surg 2011; 91 (1) 123-129
• 66 Collyer TC, Gray DJ, Sandhu R, Berridge J, Lyons G. Assessment of platelet inhibition secondary to clopidogrel and aspirin therapy in preoperative acute surgical patients measured by Thrombelastography Platelet Mapping. Br J Anaesth 2009; 102 (4) 492-498
• 67 Agarwal S, Coakley M, Reddy K, Riddell A, Mallett S. Quantifying the effect of antiplatelet therapy: a comparison of the platelet function analyzer (PFA-100) and modified thromboelastography (mTEG) with light transmission platelet aggregometry. Anesthesiology 2006; 105 (6) 1287
• 68 Preisman S, Kogan A, Itzkovsky K, Leikin G, Raanani E. Modified thromboelastography evaluation of platelet dysfunction in patients undergoing coronary artery surgery. Eur J Cardiothorac Surg 2010; 37 (6) 1367-1374
• 69 Steinlechner B, Zeidler P, Base E , et al. Patients with severe aortic valve stenosis and impaired platelet function benefit from preoperative desmopressin infusion. Ann Thorac Surg 2011; 91 (5) 1420-1426
• 70 Ying CL, Tsang SF, Ng KF. The potential use of desmopressin to correct hypothermia-induced impairment of primary haemostasis—an in vitro study using PFA-100. Resuscitation 2008; 76 (1) 129-133
• 71 Weber CF, Dietrich W, Spannagl M, Hofstetter C, Jámbor C. A point-of-care assessment of the effects of desmopressin on impaired platelet function using multiple electrode whole-blood aggregometry in patients after cardiac surgery. Anesth Analg 2010; 110 (3) 702-707
• 72 Ranucci M, Nano G, Pazzaglia A, Bianchi P, Casana R, Tealdi DG. Platelet mapping and desmopressin reversal of platelet inhibition during emergency carotid endarterectomy. J Cardiothorac Vasc Anesth 2007; 21 (6) 851-854
• 73 Hunt BJ, Segal H. Hyperfibrinolysis. J Clin Pathol 1996; 49 (12) 958
• 74 Johansson PI, Stissing T, Bochsen L, Ostrowski SR. Thrombelastography and tromboelastometry in assessing coagulopathy in trauma. Scand J Trauma Resusc Emerg Med 2009; 17: 45
• 75 Segal HC, Hunt BJ, Cottam S , et al. Fibrinolytic activity during orthotopic liver transplantation with and without aprotinin. Transplantation 1994; 58 (12) 1356-1360
• 76 Royston D. High-dose aprotinin therapy: a review of the first five years' experience. J Cardiothorac Vasc Anesth 1992; 6 (1) 76-100
• 77 Levrat A, Gros A, Rugeri L , et al. Evaluation of rotation thrombelastography for the diagnosis of hyperfibrinolysis in trauma patients. Br J Anaesth 2008; 100 (6) 792-797
• 78 Murkin JM, Falter F, Granton J, Young B, Burt C, Chu M. High-dose tranexamic acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg 2010; 110 (2) 350-353