Balanced Transfusion Resuscitation

Transcription

1 Transparency in Transfusion Medicine 2013 Balanced Transfusion Resuscitation HGD Hendriks MD, PhD University Medical Center Groningen

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3 Balancing Preoperative Peroperative Postoperative

4 Balanced Coagulation management is an understanding of this balance Perfect Haemostasis: No bleeding No thrombotic events - Balance the benefits of haemostatic actions against the risks - Haemostasis: platelets, coagulation proteins, fibrinolysis & endothelium - Haemostasis: monitoring - Balance in Trauma and Obstetrics

5 Benefit of Prohemostatic Actions balanced with the risk of Adverse Events Procoagulant Action FFP RBC Platelets 4FC DDAVP (Desmopressin) Lysine Analogs (Tranexamic Acid) rfviia Vitamin K Protamine sulfate Aprotinin TRALI, TACO, Allergic/anaphylactic reactions TACO,TRALI, Fever,hemolysis TRALI, fever, allergic reactions, Thrombotic complications Acute Coronary Syndrome Hyponatremia Urinary tract obstruction (Hematuria) Epileptic insult Arterial thrombotic events Anaphylactoid Reaction (IV administration) Anaphylaxis Adverse Event Renal insufficiency, Cardiovascular complications, Anaphylaxis Panday S, Vyas GN. Adverse effects of plasma transfusion. Transfusion 2012;52:65S-79S Carson JL et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2012;157:49-58 Refaai et al. Platelet transfusions: impact on haemostasis, thrombosis, inflammation and clinical outcomes. Thromb Res : M.Levi. Safety of Prohemostatic Interventions. Semin Thromb Hemost 2012;38:

6 Platelets Normal range: x 10 9 /L average life span Platelet ~ 10 days Consensus: each day x 10 9 /L new platelets Invasive procedures: 50 x 10 9 /L Neurosurgery: 100 x 10 9 /L Neuraxis Blockade: 50 x 10 9 /L Assumption: all other components of coagulation system are intact

7 Function of Platelets No clinical Test for Platelet Function Thromboelastography/metry is often used to treat and guide platelet administration but does not reflect the effect of aspirin/clopidogrel or a deficient von Willebrand factor function. Trentalange MJ. Walts LF. A comparision of thromboelastogram and template bleeding time in the evaluation of platelet function after aspirin ingestion. J Clin Anesth 1991;3(5); Mousa et al. Comparison of the effect of different platelet GPIIb/IIIa antagonists on the dynamics of platelet/fibrin-mediated clot strength induced using thromboelastography. Thromb Res 2001;104:49-56

8 Coagulation Proteins TF+VIIa Xa + Va IXa VIIIa XIa Platelet activation IIa Fibrine

9 A level of 1.5 times the upper limit of the PT and aptt is generally considered a risk for bleeding during surgery INR: Coagulation activity Reaction rate Concentration Assumption: all other components of coagulation system are intact

10 Classical Coagulation Tests PT & aptt Provide Important, but limited information These test don t predict blood loss They only measure the initial stages of fibrin formation Ungoing blood loss: retrospective analysis

11 Haemostasis in end-stage Liver Disease Platelets Thrombopenie/pathie Coagulation Proteins Factor II, V, VII, IX, X, XI Fibrinolysis tpa TAFI Platelets Von Willebrand ADAMTS-13 Coagulation Proteins FVIII Proteïne C/S, AT Fibrinolysis Plasminogen Mannucci. Abnormal hemostasis test and bleeding in chronic liver disease: are they related? No. J Thromb Haem 2006;4:

12 Liver transplant patients are in balance They fly low

13 Haemostasis in end-stage Liver Disease Platelet count PT, aptt Fibrinogen Platelets Trombopenie/pathie Coagulation Proteins Factor II, V, VII, IX, X, XI Fibrinolysis tpa TAFI Platelets Von Willebrand ADAMTS-13 Coagulation Proteins FVIII Proteïne C/S, AT Fibrinolysis Plasminogen Fibrinolysis Anti-Coagulants Interactions

14 Liver Transplantation PT = 21 sec aptt 42 sec Platelet count 78 Hepatitis Cirrhosis Primary Biliary Cirrhosis

15 Fibrinolysis Plasminogen Plasmin FIBRIN Hyperfibrinolysis: CPB OLT Trauma Obstetrics Orthopaedic surgery

16 Intact vessel wall Breached vessel wall Vasoconstriction Intact vessel wall Thrombomodulin FVIIa FVIIa Blood flow FVIIa Thrombin Platelet activation TFPI APC Thrombomodulin APC APC tpa NO PGI 2 FVIIa ADP-ase ADP-ase NO PGI 2 b b b b TFPI AT Heparan sulfate AT AT tpa Endothelial cell Collagen (subendothelial) GPIIb/IIIa fibrinogen - GPIIb/IIIa Von Willebrand Factor (Intermediary between collagen & platelet) Tissue factor Platelet Activated platelet FVIIa = activated FVII AT = antithrombin TFPI = tissue factor pathway inhibitor APC = activated protein C tpa = tissue Plasminogen activator

17 Intact vessel wall Breached vessel wall Vasoconstriction Intact vessel wall Thrombomodulin FVIIa FVIIa Blood flow FVIIa Thrombin Platelet activation TFPI APC Thrombomodulin APC APC tpa NO PGI 2 FVIIa ADP-ase ADP-ase NO PGI 2 b b b b TFPI AT Heparan sulfate AT AT tpa Endothelial cell Collagen (subendothelial) GPIIb/IIIa fibrinogen - GPIIb/IIIa Von Willebrand Factor (Intermediary between collagen & platelet) Tissue factor Platelet Activated platelet FVIIa = activated FVII AT = antithrombin TFPI = tissue factor pathway inhibitor APC = activated protein C tpa = tissue Plasminogen activator

18 Intact vessel wall Breached vessel wall Vasoconstriction Intact vessel wall Thrombomodulin FVIIa FVIIa Blood flow FVIIa Thrombin Platelet activation TFPI APC Thrombomodulin APC APC tpa NO PGI 2 FVIIa ADP-ase ADP-ase NO PGI 2 b b b b TFPI AT Heparan sulfate AT AT tpa Endothelial cell Collagen (subendothelial) GPIIb/IIIa fibrinogen - GPIIb/IIIa Von Willebrand Factor (Intermediary between collagen & platelet) Tissue factor Platelet Activated platelet FVIIa = activated FVII AT = antithrombin TFPI = tissue factor pathway inhibitor APC = activated protein C tpa = tissue Plasminogen activator

19 Intact vessel wall Breached vessel wall Vasoconstriction Intact vessel wall Thrombomodulin FVIIa FVIIa Blood flow FVIIa Thrombin Platelet activation TFPI APC Thrombomodulin APC APC tpa NO PGI 2 FVIIa ADP-ase ADP-ase NO PGI 2 b b b b TFPI AT Heparan sulfate AT AT tpa Endothelial cell Collagen (subendothelial) GPIIb/IIIa fibrinogen - GPIIb/IIIa Von Willebrand Factor (Intermediary between collagen & platelet) Tissue factor Platelet Activated platelet FVIIa = activated FVII AT = antithrombin TFPI = tissue factor pathway inhibitor APC = activated protein C tpa = tissue Plasminogen activator

20 Endothelium Role Endothelium is Crucial There are no (clinical) tests to evaluate the function of the Endothelium Is a promising and necessary target for affecting haemostasis Jerrold H Levy et al: Multidisciplinary approach to the challenge of hemostasis. A&A 2010;110:

21 Haemostasis Platelets Coagulation Proteins Fibrinolysis Endothelium Preconditions:

22 Preconditions of Haemostasis Calcium Ca ++ : 0.9 mmol/l ph: 7.4 (Activity 50% at ph7.1) Anemia: Ht 30% Temperature: 37 C - Coagulation Protein Activity 10%/ 1 C) - Platelet function * Lier et al: Preconditions of hemostasis in trauma: a review. J Trauma 2008;65: * Kermode et al: Marked temperature dependence of the platelet calcium signal induced by human vwf. Blood 1999;94:

23 Temperature MJ Rohrer. Crit Care Med 1992;20: PT & aptt at 37 0 C

24 Platelets, Coagulation Proteins, Endothelium Fibrinolysis, ph, Temperature

25 Temperature 37 C vs 32 C ph 7.4 vs 7.1 Ramaker et al. Blood Coagul Fibrinolysis Sep;20(6): Effects of acidosis, alkalosis, hyperthermia and hypothermia on haemostasis: results of point-of-care testing with the thromboelastography analyser.

26 Hypothermia is synergistic with acidosis and dilution resulting in greater clinical coagulopathy than can be explained by in vitro experimentation Interactions: Crucial Howard et al: Prohemostatic interventions in trauma: resuscitation-associated coagulopathy, acute traumatic coagulopathy, hemostatic resuscitation, and other hemostatic interventions. Siminars in Thrombosis and Hemostasis 2012;38:

27 Finding the Balance in a bleeding patient: difficult Haemostasis: not entirely understood Coagulation Tests: limited value Preconditions of Haemostasis: important Influence of Interactions: crucial Evidence from Trials?

28 Trials Difficult to do research in bleeding patients Evidence from Trials are often not suitable on patients in our Clinic Lack of Standardized guidelines for administration: - Blood Products - Pharmacological Agents The balance in a patient is strongly influenced by the clinical situation: Not all massive haemorrhage is the same Balance in Trauma and Obstetrics

29 Haemorrhage Trauma: haemorrhage is the most common cause of death Obstetrics: haemorrhage is the most important cause of maternal death

30 Balance in Trauma Prior to trauma normal coagulation profile Blood loss: Haemodilution, Hypothermia, Acidosis (lethal triad) (fibrinolysis, Inflammation, infections) Trauma-Induced Coagulopathy Large amounts of crystalloids (and RBC s): iatrogenic coagulopathy, resuscitation-associated coagulopathy

31 Trauma-Induced Coagulopathy Dilution: strong correlation between fluid volume and coagulopathy 25 33% of severely trauma patients are coagulopathic upon arrival in hospital* 50% who received > 3 L prehospital fluid were coagulopathic 10% who received 500 ml showed also coagulopathy** 20 th century: FFP administration was guided by PT and aptt, PLT < 50 Interactions with hypothermia and acidosis are crucial *Frith et al. The acute coagulopathy of trauma shock: clinical relevance. Surgeon2010;8: **Maegele et al. AG Polytrauma of the German Trauma Society (DGU). Injury 2007;38:

32 Trauma-Induced Coagulopathy RBC : FFP = 4 : <1 RBC : FFP = 3 : >2 65% mortality 19% mortality Borgman et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J of Trauma 2007;63: RBC : Platelet = 2 : >1 30-d survival compared to low ratios Holcomb et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients Ann. Of Surgery 2008;248:

33 Trauma-Induced Coagulopathy Shift toward balanced ratio of blood components RBC : FFP : PLT = 1 : 1 : 1 Mortality :correction coagulation? All data retrospective. Randomized and Prospective data are lacking Survivorship bias: survivors live longer to receive the treatment Magnotti et al: improved survival after hemostatic resuscitation: does the emperor have no clothes? J trauma 2011;70:97-102

34 MTB protocol RBC FFP PLT Fibrinogen (g) : 1: < 70 2 : 1 : : 1: 0.3 <1.5 g/l : 1: : 1 : : 1 : : 1: 0.3 <1.5 g/l : 1: : 1: : 1 : : 0.6 : 0.2 2

35 Trauma-Induced Coagulopathy Therapy Transfusion Ratio: RBC : FFP : PTL = 3 : 3 : 1 Fibrinogen:? Critical value of 1 g/l* g/l** Fibrinogen: first in line for depletion. Cause? Dilution and Consumption (impaired bioavailability, impaired production, enhanced breakdown, inadequate replacement) rfviia: wide variability in timing and dosing. Effect?* Tranexamic acid (CRASH-2 Trial, decrease in mortality, but no difference in bleeding). Early administration. Dose: mg/kg Guided by TEG/ROTEM** No routine use of Desmopressine** Blood Pressure (MAP 60 mmhg) (Systolic mmHg)** Hb = 5 mmol/l * Knudson et al.trauma, transfusions, and use of rfviia. J Am Coll Surg2011;212:87-95 **Rossaint et al. Management of bleeding following major trauma: an updated European guideline. Critical Care 2010;14:R52

36 Trauma-Induced Coagulopathy Therapy Hypothermia: 0 C Hypothermia is a ominous clinical sign accompanied by high mortality * Hypothermia: cold infusion, heat loss on the street (40% in trauma patients) Mild (<36 C) and moderate (32 36 C) have already deleterious effect Smith et al: Avoiding hypothermia in the trauma patient. Curr Opin Aenesthesiol 2000;13: Direct warming up the patient, warming up fluids Acidosis: serum lactate (& base deficit) Metabolic dysfunction secondary to hypoperfusion and administration NaCl 0.9% Reversal of Acidosis does not always result in return of clotting function Mechanism? Uncertain (activation Protein C by thrombomodulin?)** *Rossaint et al. Management of bleeding following major trauma: an updated European guideline. Critical Care 2010;14:R52 ** Cohen et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection an death in trauma patients. Ann Surg 2012;255:

37 PostPartum Hemorrhage

38 Postpartum Hemorrhage Postpartum hemorrhage (PPH) has been defined as: blood loss in excess of 500 ml after a vaginal birth, 1000 ml after a cesarean delivery No factors predict PPH: every pregnancy is at risk Fibrinogen: < 2g/L positive predictor of postpartum haemorrhage* No clinical trials to guide management *Charbit et al. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost 2007;5:266-73

39 Balance in Obstetrics 40% increase in Plasma Volume 25% increase Erythrocytes Ht decrease, Platelet Count drop Platelets Thrombopenie Coagulation Proteins Unchanged: FV, FXIII Unchanged: AT Fibrinolysis tpa, Platelets VWF Coagulation Proteins FI, FVII, FVIII, Protein C/S Fibrinolysis PT and aptt: Unchanged Platelet Count TEG/ROTEM: Hypercoaguable* Lange et al. Obstetric hemorrhage and coagulation: an update. Thromboelastography, thromboelastometry, and conventional coagulation tests in the diagnosis and prediction of postpartum hemorrhage. Obstet Gynecol Surv 2012;67: Solomon et al. Haemostatic monitoring during postpartum haemorrhage and implications for management. Br J Anaest 2012;109: *Sharma et al. Thromboelastographic changes in healthy parturients and postpartum woman. Anest & Analg 1997;85:94-98

40 Balance in Obstetrics 40% increase in Plasma Volume 25% increase Erythrocytes Ht decrease, Platelet Count drop Platelets Thrombopenie Coagulation Proteins Unchanged: FV, FXIII Unchanged: AT Platelets VWF Coagulation Proteins FI, FVII, FVIII, Protein C/S Fibrinolysis Fibrinolysis tpa, PT and aptt: Unchanged Platelet Count TEG/ROTEM: Hypercoaguable* Bleeding & Medication History Lange et al. Obstetric hemorrhage and coagulation: an update. Thromboelastography, thromboelastometry, and conventional coagulation tests in the diagnosis and prediction of postpartum hemorrhage. Obstet Gynecol Surv 2012;67: Solomon et al. Haemostatic monitoring during postpartum haemorrhage and implications for management. Br J Anaest 2012;109: *Sharma et al. Thromboelastographic changes in healthy parturients and postpartum woman. Anest & Analg 1997;85:94-98

41 Balance in Obstetrics Cause of bleedig: uterine atony (oxytocin, ergometrine) Damage control: balloon tamponade, embolization, hysterectomy Dilutional Coagulopathy (and consumptive) Recommended in 20th century : PT and aptt 1.5 normal value Plasma Fibrinogen 1 g/l Platelets 50 x 10 9 /L

42 Transfusion Ratio: Balance in Obstetrics If uterotonics and sutures fail Therapy RBC : FFP = 4 : 1 or 1: 1 (extrapolating) James et al. Postpartum Hemorrhage: when uterotonics and sutures fail. Am J Hematol. 2012;87:S16-22 Have a Protocol, Evaluate Temperature, Ph, Calcium Blood Pressure (MAP 60 mmhg?) rfviia: wide variability in timing and dosing. Effect? Fibrinogen: Critical value of 1 g/l g/l Tranexamic acid: 1 gr iv * Desmopressin: (0.3 µg/kg) Small trials** Peitsidis et al. Antifibrinolytic therapy with tranexamic acid in pregnancy and postpartum. Expert Opin Pharmacother 2011;12: * Novikova et al. Tranexamic acid for preventing postpartum haemorrhage. Cochrane Database Syst Rev 2010:CD **Trigg et al. A systematic review: the use of desmopressin for treatment and prophylaxis of bleeding disorders in pregnancy. Haemophilia 2012;18:25-33

43 CONCLUSIONS

44 Conclusions Haemostatic Balance is poorly understood Limited Evidence to guide therapy PT/aPTT limited value in a bleeding patient Not all massive haemorrhage is the same

45 Conclusions Treatment is tailored: - Lab: PT, aptt, PC, Fibrinogen, lactate, TEG/ROTEM, last but not least: surgical field Have a Protocol, Evaluate Tranexamic acid (recfviia) Fibrinogen administration (< 1 gr/l? 4 gr/l?) INERACTIONS: CRUCIAL Influence on blood loss of the surgeon/lab/anaesthetist/haematologist/ TEAM WORK