1. Basic Clinician Training Module 4 Special circumstances: Distinguishing between different causes of bleeding

2. Bleeding: special circumstances Hemodilution vs. Hypothermia von Willebrand factor deficiency vs. Surgical bleeding Protamine overdose

3. Hemodilution vs. Hypothermia

4. Hemodilution Implementation Hematocrit < 25% Circumstances: of blood conservation techniques  Blood volume expansion  Cardiopulmonary bypass Likely to affect factors and platelets the same. Hypothermia Core temperature <34°C Circumstances:  Exposure to the cold  Induced for clinical purposes  Administration of large volume of fluids that are cold or at room temperature May not demonstrate same effect on factors and platelets, depends on temperature.

5. Hemodilution Reduction in the concentration of hemostatic factors and cellular hemostatic components. Hypothermia At 33°C the likely cause of bleeding is a reduction in platelet aggregation and adhesion. At < 33°C the likely cause of bleeding also includes reduced enzymatic function and platelet activation Hemodilution vs. Hypothermia Mechanisms of Coagulapathy [Wolberg AS, et. al. J Trauma. 2004;56:1221.]

6. Hemodilution vs. Hypothermia Differentiation and Treatments Hemodilution Identification: low HCT, normal temperature Common treatment:  Hemoconcentration, if possible  FFP for factor deficiency  Platelet transfusion for platelet deficiency Hypothermia Identification: Core temperature < 34°C, normal or low HCT. Common treatment:  Warm patient to > 36 ° C  Treat factor deficiency or platelet dysfunction if required (i.e. abnormal TEG tracing at normal temperature setting (37 ° C)).

7. Run blood sample on two channels simultaneously  Channel 1: cup temperature set at 37°C  Channel 2: adjust cup temperature to patient core temperature Results:  If Channel 1 (37°C) sample is normal and Channel 2 abnormal, bleeding is due to hypothermia and should subside with rewarming.  If both Channel 1 (37°C) and Channel 2 samples demonstrate a coagulapathy, treat with appropriate blood products or hemostatic agents until the 37°C sample is normalized. Hypothermia: Determining impact on coagulation

8. Black : cup temperature 37°C Green : cup temperature set at patient temperature (33°C) Patient bleeding likely due to hypothermia

9. Hemodilution vs. Hypothermia TEG analysis Patient status: bleeding Hemodilution vs. Hypothermia? A single TEG tracing cannot distinguish. If patient temperature is > 35°C and HCT < 25%, bleeding is likely due to hemo- dilution. Treat accordingly. If patient temperature is < 34°C, bleeding is likely due to hypothermia. Compare TEGs run at patient temperature and at 37°C. Treat accordingly.

10. Hemodilution vs. Hypothermia? TEG analysis Cup temperature: 37°C Patient status: bleeding Probable cause(s): Hemodilution +/or Factor deficiency +/or Platelet deficiency/dysfunction

11. Hemodilution vs. Hypothermia? TEG analysis Cup temperature: 33.4°C Patient status: bleeding Probable cause(s): Hypothermia +/or Factor deficiency +/or Platelet deficiency/dysfunction

12. vWF deficiency vs. Surgical bleeding

13. von Willebrand factor (vWF) deficiency vWF  Deficiency is associated with a FVIIIc deficiency  Required for platelet adhesion to vessel wall via the GP1b receptor. Circumstances:  Congential  Acquired Cardiopulmonary bypass Chronic aortic stenosis Malignancy Coagulapathy is due to reduced platelet adhesion to vessel wall, manifested as microvascular bleeding.

14. vWF deficiency: TEG analysis Patient status: bleeding Since vWF deficiency results in a platelet adhesion defect, the TEG tracing will be normal. Other possible causes of bleeding: Presence of platelet inhibitor Vessel injury

15. vWF deficiency: TEG analysis Patient status: bleeding Probable causes  Common treatments vWF deficiency  DDAVP Presence of platelet inhibitor  Platelet transfusion Vessel injury  Suture

16. vWF deficiency vs. Surgical bleeding? Both cases: TEG tracing is normal but patient is bleeding Distinguishing vWF deficiency from surgical bleeding:  vWF deficiency: appears microvascular in nature  Surgical bleeding: generally more profuse and localized Common treatments  vWF deficiency Consider treatment with DDAVP –Diminished bleeding post treatment suggestive of vWF deficiency Consider cryoprecipitate  Surgical bleeding: bleeding from small surgical sites May diminish with time May respond to continuous product transfusion

17. Protamine overdose

18. Protamine Neutralizes heparin via an ionic interaction  1 mg protamine neutralizes 1 mg heparin Protamine administration protocols vary. Typical range:  1.0 – 1.3 mg/ 100 units heparin  0.5 – 1.0 mg/kg body wt Protamine alone, or not bound to heparin, has a mild anticoagulant effect

19. Possible mechanisms of protamine anticoagulant effect. Inhibits the proteolytic activity of thrombin in a dose-dependent and reversible manner Decreases platelet count Impairs in vitro response to ADP, epinephrine, and thrombin Also releases tPA from endothelial cells Speiss, BD et al. Perioperative Transfusion Medicine. 1998.

20. Protamine anticoagulation effect Protamine doses > 2.0 mg/100 units heparin could cause bleeding  Clinical significance of protamine anticoagulation effect is debatable Protamine doses between 1.3 – 1.5 mg/100 units heparin may result in an in vitro, but not an in vivo anticoagulant effect.  If the patient is bleeding, this in vitro effect could mask the true cause of bleeding as indicated by TEG analysis. Prudent to avoid administration of protamine doses beyond the amount required neutralize heparin.  TEG analysis can demonstrate heparin reversal by protamine

21. In vitro protamine effect TEG analysis Post protamine Patient status: not bleeding Protamine dose > 1.3 mg/100 units heparin In vitro effect demonstrated in both Kaolin and Kaolin with heparinase samples

22. In vitro protamine effect TEG analysis Black: 1 hr post-op Green: post-protamine A TEG was repeated 1 hr post-op in the ICU. The in vitro protamine effect was no demonstrated.

23. Interpretation Exercises Hemorrhage – Special Cases

24. Exercise 1: Trauma patient in ER Black: cup temperature @ 37.1°C Green: cup temperature @ patient temperature (32.9°C) Using the TEG Decision Tree, what is (are) the possible cause(s) of bleeding in this patient? [Select all that apply] a. Factor deficiency b. Platelet deficiency or dysfunction c. Hypothermia d. Hemodilution e. Anticoagulant effect Answer Next

25. Exercise 2: Trauma patient in the ER The above patient came into the ER with a core temperature of 35.8°C. The patient has received 2.5 L of crystalloid volume. The patient is now hemodynamically stable, but his core temperature is 34.3°C and he has started to bleed. What would be the best treatment option for this patient at this time to stop the bleeding? a. Lasix b. FFP c. Platelets d. Warm patient to > 35.5°C e. DDAVP What additional information would help you with your decision? Answer Next

26. Exercise 3 Post-protamine The above 47 yr patient (male, aortic valve replacement) is bleeding after administration of protamine. All suture sites appear to be intact. What is (are) the most likely cause(s) of bleeding in this patient? (select all that apply) a.Surgical bleeding b.Factor deficiency c.Residual platelet inhibitor effect d.Anticoagulant effect e.Diminished platelet adhesion What additional information would help with your decision? Answer Next

27. Exercise 4 Select all the possible causes of bleeding that could be indicated by the above TEG tracing and indicate an how you could differentiate between the different causes. a.Surgical bleeding b.Factor deficiency c.Platelet dysfunction d.Anticoagulant effect e.Hypothermina cup temperature @ 37.1°C Answer Next

28. Exercise 5 Post-protamine, Cup temperature: 37.1°C The above TEG was performed post-protamine. The patient is dry and the surgeon is ready to close the patient. The surgeon has asked for the results of the TEG. How would you explain the above tracing? a.Poor sampling technique or preparation b.Hemodilution c.Hypothermina effect d.Residual heparin e.In vitro protamine effect Answer Next

29. Exercise 1: Trauma patient in ER Black: cup temperature @ 37.1°C Green: cup temperature @ patient temperature (34.6°C) Using the TEG Decision Tree, what is (are) the possible cause(s) of bleeding in this patient? [Select all that apply] a. Factor deficiency – could be result of bleeding plus crystalloid or colloid volume replacement. b. Platelet deficiency or dysfunction – could be result of bleeding plus crystalloid or colloid volume replacement. c. Hypothermia – not a primary cause of bleeding since both cups demonstrate similar coagulapathy. Transfusion of warmed fluids is recommended to diminish further drop in core temperature d. Hemodilution – result of bleeding plus crystalloid or colloid volume replacement leading to factor and platelet deficiency. e. Anticoagulant effect Back Next

30. Exercise 2: Trauma patient in the ER The above patient came into the ER with a core temperature of 35.8°C. The patient has received 2.5 L of crystalloid volume. The patient is now hemodynamically stable, but his core temperature is 34.3°C and he has started to bleed. What would be the best treatment option for this patient at this time to stop the bleeding? a. Lasix – although the patient may be hemodiluted, it is not the main cause of bleeding. b. Cryoprecipitate c. Platelets d. Warm patient to > 35.5°C – best and least costly treatment option at this time. e. DDAVP – there could be a possible platelet adhesion defect in this patient What additional information would help you with your decision? Run a TEG at 34.3°C to determine if coagulapathy is temperature-related. Back Next

31. Exercise 3 Post-protamine The above 47 yr patient (male, aortic valve replacement) is bleeding after administration of protamine. All suture sites appear to be intact. What is (are) the most likely cause(s) of bleeding in this patient? (select all that apply) a.Surgical bleeding b.Factor deficiency c.Residual platelet inhibitor effect d.Anticoagulant effect e.Diminished platelet adhesion – this is the most likely cause of bleeding, unless the patient was taking platelet inhibitors for vascular disease. Consider treatment with DDAVP. What additional information would help with your decision? Current medications such as platelet inhibitors, or a family history of vWD. Back Next

32. Exercise 4 Select all the possible causes of bleeding that could be indicated by the above TEG tracing and indicate a common treatment for each cause. Surgical bleeding Factor deficiency – elongated R suggests factor deficiency. A likely cause is hemodilution. Common treatment: FFP Platelet dysfunction – low MA suggests platelet dysfunction. This could be due to a variety of factors, including hemodilution or a decrease in platelet number due to sequestration or loss of platelets. Common treatment: platelet transfusion Anticoagulant effect – the elongated R also suggests residual heparin, especially since it is a KH sample. Common treatment: protamine Hypothermina – cannot be completely ruled out, but not likely. cup temperature @ 37.1°C Back Next

33. Exercise 5 The above TEG was performed post-protamine. The patient is dry and the surgeon is ready to close the patient. The surgeon has asked for the results of the TEG. How would you explain the above tracing? a.Poor sampling technique or preparation – possible, but uncommon cause. b.Hemodilution c.Hypothermina effect d.Residual heparin e.In vitro protamine effect – check with anesthesia for protamine ratio used to reverse the heparin Back Next Post-protamine, Cup temperature: 37.1°C

34. End of module 4