Picking Platelets Properly: focus on hematologic oncology patients

1. Picking Platelets Properly:focus on hematologic oncology patients Lunch debate Israel Society of Hematology May 31, 2006 Martin H. Ellis MD Meir Hospital

2. Platelets transfusions should be therapeutic, and not prophylactic “Slaughtering a sacred cow”

3. Outline • Prophylactic thresholds • Trials of prophylactic versus therapeutic transfusion • Retrospective review of platelet transfusions • Possibilities for a clinical approach • Future directions

4. Thresholds for prophylactic platelettransfusion Stanworth SJ, Hyde C, Heddle N, Rebulla P, Brunskill S and Murphy MF. The Cochrane Database of Systematic Reviews 2004 Issue 4

6. Trials of prophylactic versus therapeutic transfusion Stanworth SJ, Hyde C, Heddle N, Rebulla P, Brunskill S and Murphy MF. The Cochrane Database of Systematic Reviews 2004 Issue 4

10. The RCT data is weak • Aspirin use prevalent • Chilled platelets transfused • Non-uniform follow up • Non-uniform reporting • Unblinded studies • Small study sizes

11. Retrospective review of platelet transfusions Friedmann AM et al Trans Med Rev 2002:16;34 Do basic laboratory tests or clinical observations predict bleeding in thrombocytopenic oncology patients? A reevaluation of prophylactic platelet transfusions

12. PROPHYLACTIC PLATELET TRANSFUSIONS Table 9. Multivariate Logistic Regression Model for the Prediction of Major Hemorrhage (Grade 3 or 4) in 368 Patients of 2994 Patients Studied 43 95% CI Predictor Variable OR Lower Limit Upper Limit Age (unit = 10 years) 1.03 0.97 1.08 .357 Diagnosis (hematologic malignancies) Brain tumors 0.09 0.00 12.79 .343 Nonmalignant disease 1.92 0.36 10.10 .442 AML, type M3 1.53 0.66 3.54 .321 Solid tumors 1.32 0.80 2.17 .282 Temperature (unit = 1 ~ C) 1.02 0.94 1.10 .632 Hypertension 1.16 1.00 1.34 .042 Platelet transfusion 7.55 5.25 10.85 <.001 First AM platelet count (40,000-49,000) For patients not transfused 30,000-39,000 0.80 0.57 1.13 .208 20,000-29,000 0.76 0.58 0.99 .039 10,000-19,000 1.20 0.94 1.52 .143 0-9,000 1.14 0,89 1.46 .298 For patients transfused 30,000-39,000 0.78 0.48 1.29 .335 20,000-29,000 0.80 0.55 1.18 .265 10,000-19,000 0.82 0.58 1.14 .241 0-9,000 0.98 0.69 1.39 .905 Lowest platelet count (unit = 10,000/mm 3) 1.00 0.94 1.06 >.90 Leukopenia 0.70 0.60 0.82 <.001 Hyperleukocytosis 2.76 0.87 8.83 .089 Bacteremia 1,01 0.81 1.26 >.90 Uremia 1,64 1.40 1.92 <.001 Albumin (unit = 1 gm/dL) 1.54 1.33 1.79 <.001 Direct bilirubin (unit = 1 mg/dL) 1.00 0.99 1.01 .698 SGPT (unit = 100 IU/L) 1.03 1.00 1.06 .066 Medications Steroids 1.13 0.97 1.32 .123 Amphotericin 0.97 0.84 1.13 >.717 Semisynthetic penicillins 0,94 0.80 1.09 .386 Aminocaproic acid 3.62 2.96 4.42 <:.001 Anticoagulants 0.94 0.09 10.12 >.605 NSAIDs 0.02 0.00 4.15 .156 BMT within previous 100 days 1.32 1.22 1.43 <.001 Bleed within previous 5 days 6.72 5.53 8.18 <.001 Abbreviations: SGPT, ; NSAIDs, nonsteroidal anti-inflammatory drugs. function have very short survival times, 33 patients were transfused more frequently and thus bled less often. As platelet transfusion was assessed as a dichotomous variable (given or not given on a particular day), we were unable to control for patient days on which multiple transfusions were given. These patient days were treated tile same as days on which only 1 transfusion was given. Two other findings that should be addressed are the positive associations between transfusion and bleeding and between amicar and bleeding. There was a significant interaction between platelet count and transfusion and a positive correlation between platelet count and bleeding when the interaction term was not included in the model, indicating that as patients bled, they were transfused and subsequentlyPROPHYLACTIC PLATELET TRANSFUSIONS Table 9. Multivariate Logistic Regression Model for the Prediction of Major Hemorrhage (Grade 3 or 4) in 368 Patients of 2994 Patients Studied 43 95% CI Predictor Variable OR Lower Limit Upper Limit Age (unit = 10 years) 1.03 0.97 1.08 .357 Diagnosis (hematologic malignancies) Brain tumors 0.09 0.00 12.79 .343 Nonmalignant disease 1.92 0.36 10.10 .442 AML, type M3 1.53 0.66 3.54 .321 Solid tumors 1.32 0.80 2.17 .282 Temperature (unit = 1 ~ C) 1.02 0.94 1.10 .632 Hypertension 1.16 1.00 1.34 .042 Platelet transfusion 7.55 5.25 10.85 <.001 First AM platelet count (40,000-49,000) For patients not transfused 30,000-39,000 0.80 0.57 1.13 .208 20,000-29,000 0.76 0.58 0.99 .039 10,000-19,000 1.20 0.94 1.52 .143 0-9,000 1.14 0,89 1.46 .298 For patients transfused 30,000-39,000 0.78 0.48 1.29 .335 20,000-29,000 0.80 0.55 1.18 .265 10,000-19,000 0.82 0.58 1.14 .241 0-9,000 0.98 0.69 1.39 .905 Lowest platelet count (unit = 10,000/mm 3) 1.00 0.94 1.06 >.90 Leukopenia 0.70 0.60 0.82 <.001 Hyperleukocytosis 2.76 0.87 8.83 .089 Bacteremia 1,01 0.81 1.26 >.90 Uremia 1,64 1.40 1.92 <.001 Albumin (unit = 1 gm/dL) 1.54 1.33 1.79 <.001 Direct bilirubin (unit = 1 mg/dL) 1.00 0.99 1.01 .698 SGPT (unit = 100 IU/L) 1.03 1.00 1.06 .066 Medications Steroids 1.13 0.97 1.32 .123 Amphotericin 0.97 0.84 1.13 >.717 Semisynthetic penicillins 0,94 0.80 1.09 .386 Aminocaproic acid 3.62 2.96 4.42 <:.001 Anticoagulants 0.94 0.09 10.12 >.605 NSAIDs 0.02 0.00 4.15 .156 BMT within previous 100 days 1.32 1.22 1.43 <.001 Bleed within previous 5 days 6.72 5.53 8.18 <.001 Abbreviations: SGPT, ; NSAIDs, nonsteroidal anti-inflammatory drugs. function have very short survival times, 33 patients were transfused more frequently and thus bled less often. As platelet transfusion was assessed as a dichotomous variable (given or not given on a particular day), we were unable to control for patient days on which multiple transfusions were given. These patient days were treated tile same as days on which only 1 transfusion was given. Two other findings that should be addressed are the positive associations between transfusion and bleeding and between amicar and bleeding. There was a significant interaction between platelet count and transfusion and a positive correlation between platelet count and bleeding when the interaction term was not included in the model, indicating that as patients bled, they were transfused and subsequently PROPHYLACTIC PLATELET TRANSFUSIONS Table 9. Multivariate Logistic Regression Model for the Prediction of Major Hemorrhage (Grade 3 or 4) in 368 Patients of 2994 Patients Studied 43 95% CI Predictor Variable OR Lower Limit Upper Limit Age (unit = 10 years) 1.03 0.97 1.08 .357 Diagnosis (hematologic malignancies) Brain tumors 0.09 0.00 12.79 .343 Nonmalignant disease 1.92 0.36 10.10 .442 AML, type M3 1.53 0.66 3.54 .321 Solid tumors 1.32 0.80 2.17 .282 Temperature (unit = 1 ~ C) 1.02 0.94 1.10 .632 Hypertension 1.16 1.00 1.34 .042 Platelet transfusion 7.55 5.25 10.85 <.001 First AM platelet count (40,000-49,000) For patients not transfused 30,000-39,000 0.80 0.57 1.13 .208 20,000-29,000 0.76 0.58 0.99 .039 10,000-19,000 1.20 0.94 1.52 .143 0-9,000 1.14 0,89 1.46 .298 For patients transfused 30,000-39,000 0.78 0.48 1.29 .335 20,000-29,000 0.80 0.55 1.18 .265 10,000-19,000 0.82 0.58 1.14 .241 0-9,000 0.98 0.69 1.39 .905 Lowest platelet count (unit = 10,000/mm 3) 1.00 0.94 1.06 >.90 Leukopenia 0.70 0.60 0.82 <.001 Hyperleukocytosis 2.76 0.87 8.83 .089 Bacteremia 1,01 0.81 1.26 >.90 Uremia 1,64 1.40 1.92 <.001 Albumin (unit = 1 gm/dL) 1.54 1.33 1.79 <.001 Direct bilirubin (unit = 1 mg/dL) 1.00 0.99 1.01 .698 SGPT (unit = 100 IU/L) 1.03 1.00 1.06 .066 Medications Steroids 1.13 0.97 1.32 .123 Amphotericin 0.97 0.84 1.13 >.717 Semisynthetic penicillins 0,94 0.80 1.09 .386 Aminocaproic acid 3.62 2.96 4.42 <:.001 Anticoagulants 0.94 0.09 10.12 >.605 NSAIDs 0.02 0.00 4.15 .156 BMT within previous 100 days 1.32 1.22 1.43 <.001 Bleed within previous 5 days 6.72 5.53 8.18 <.001 Abbreviations: SGPT, ; NSAIDs, nonsteroidal anti-inflammatory drugs. function have very short survival times, 33 patients were transfused more frequently and thus bled less often. As platelet transfusion was assessed as a dichotomous variable (given or not given on a particular day), we were unable to control for patient days on which multiple transfusions were given. These patient days were treated tile same as days on which only 1 transfusion was given. Two other findings that should be addressed are the positive associations between transfusion and bleeding and between amicar and bleeding. There was a significant interaction between platelet count and transfusion and a positive correlation between platelet count and bleeding when the interaction term was not included in the model, indicating that as patients bled, they were transfused and subsequently PROPHYLACTIC PLATELET TRANSFUSIONS Table 9. Multivariate Logistic Regression Model for the Prediction of Major Hemorrhage (Grade 3 or 4) in 368 Patients of 2994 Patients Studied 43 95% CI Predictor Variable OR Lower Limit Upper Limit Age (unit = 10 years) 1.03 0.97 1.08 .357 Diagnosis (hematologic malignancies) Brain tumors 0.09 0.00 12.79 .343 Nonmalignant disease 1.92 0.36 10.10 .442 AML, type M3 1.53 0.66 3.54 .321 Solid tumors 1.32 0.80 2.17 .282 Temperature (unit = 1 ~ C) 1.02 0.94 1.10 .632 Hypertension 1.16 1.00 1.34 .042 Platelet transfusion 7.55 5.25 10.85 <.001 First AM platelet count (40,000-49,000) For patients not transfused 30,000-39,000 0.80 0.57 1.13 .208 20,000-29,000 0.76 0.58 0.99 .039 10,000-19,000 1.20 0.94 1.52 .143 0-9,000 1.14 0,89 1.46 .298 For patients transfused 30,000-39,000 0.78 0.48 1.29 .335 20,000-29,000 0.80 0.55 1.18 .265 10,000-19,000 0.82 0.58 1.14 .241 0-9,000 0.98 0.69 1.39 .905 Lowest platelet count (unit = 10,000/mm 3) 1.00 0.94 1.06 >.90 Leukopenia 0.70 0.60 0.82 <.001 Hyperleukocytosis 2.76 0.87 8.83 .089 Bacteremia 1,01 0.81 1.26 >.90 Uremia 1,64 1.40 1.92 <.001 Albumin (unit = 1 gm/dL) 1.54 1.33 1.79 <.001 Direct bilirubin (unit = 1 mg/dL) 1.00 0.99 1.01 .698 SGPT (unit = 100 IU/L) 1.03 1.00 1.06 .066 Medications Steroids 1.13 0.97 1.32 .123 Amphotericin 0.97 0.84 1.13 >.717 Semisynthetic penicillins 0,94 0.80 1.09 .386 Aminocaproic acid 3.62 2.96 4.42 <:.001 Anticoagulants 0.94 0.09 10.12 >.605 NSAIDs 0.02 0.00 4.15 .156 BMT within previous 100 days 1.32 1.22 1.43 <.001 Bleed within previous 5 days 6.72 5.53 8.18 <.001 Abbreviations: SGPT, ; NSAIDs, nonsteroidal anti-inflammatory drugs. function have very short survival times, 33 patients were transfused more frequently and thus bled less often. As platelet transfusion was assessed as a dichotomous variable (given or not given on a particular day), we were unable to control for patient days on which multiple transfusions were given. These patient days were treated tile same as days on which only 1 transfusion was given. Two other findings that should be addressed are the positive associations between transfusion and bleeding and between amicar and bleeding. There was a significant interaction between platelet count and transfusion and a positive correlation between platelet count and bleeding when the interaction term was not included in the model, indicating that as patients bled, they were transfused and subsequently PROPHYLACTIC PLATELET TRANSFUSIONS Table 9. Multivariate Logistic Regression Model for the Prediction of Major Hemorrhage (Grade 3 or 4) in 368 Patients of 2994 Patients Studied 43 95% CI Predictor Variable OR Lower Limit Upper Limit Age (unit = 10 years) 1.03 0.97 1.08 .357 Diagnosis (hematologic malignancies) Brain tumors 0.09 0.00 12.79 .343 Nonmalignant disease 1.92 0.36 10.10 .442 AML, type M3 1.53 0.66 3.54 .321 Solid tumors 1.32 0.80 2.17 .282 Temperature (unit = 1 ~ C) 1.02 0.94 1.10 .632 Hypertension 1.16 1.00 1.34 .042 Platelet transfusion 7.55 5.25 10.85 <.001 First AM platelet count (40,000-49,000) For patients not transfused 30,000-39,000 0.80 0.57 1.13 .208 20,000-29,000 0.76 0.58 0.99 .039 10,000-19,000 1.20 0.94 1.52 .143 0-9,000 1.14 0,89 1.46 .298 For patients transfused 30,000-39,000 0.78 0.48 1.29 .335 20,000-29,000 0.80 0.55 1.18 .265 10,000-19,000 0.82 0.58 1.14 .241 0-9,000 0.98 0.69 1.39 .905 Lowest platelet count (unit = 10,000/mm 3) 1.00 0.94 1.06 >.90 Leukopenia 0.70 0.60 0.82 <.001 Hyperleukocytosis 2.76 0.87 8.83 .089 Bacteremia 1,01 0.81 1.26 >.90 Uremia 1,64 1.40 1.92 <.001 Albumin (unit = 1 gm/dL) 1.54 1.33 1.79 <.001 Direct bilirubin (unit = 1 mg/dL) 1.00 0.99 1.01 .698 SGPT (unit = 100 IU/L) 1.03 1.00 1.06 .066 Medications Steroids 1.13 0.97 1.32 .123 Amphotericin 0.97 0.84 1.13 >.717 Semisynthetic penicillins 0,94 0.80 1.09 .386 Aminocaproic acid 3.62 2.96 4.42 <:.001 Anticoagulants 0.94 0.09 10.12 >.605 NSAIDs 0.02 0.00 4.15 .156 BMT within previous 100 days 1.32 1.22 1.43 <.001 Bleed within previous 5 days 6.72 5.53 8.18 <.001 Abbreviations: SGPT, ; NSAIDs, nonsteroidal anti-inflammatory drugs. function have very short survival times, 33 patients were transfused more frequently and thus bled less often. As platelet transfusion was assessed as a dichotomous variable (given or not given on a particular day), we were unable to control for patient days on which multiple transfusions were given. These patient days were treated tile same as days on which only 1 transfusion was given. Two other findings that should be addressed are the positive associations between transfusion and bleeding and between amicar and bleeding. There was a significant interaction between platelet count and transfusion and a positive correlation between platelet count and bleeding when the interaction term was not included in the model, indicating that as patients bled, they were transfused and subsequently

15. Possibilities for a clinical approach • No correlation between AM or lowest platelet count and hemorrhage • Hemorrhage associated with: - recent severe bleed - uremia - hypoalbuminemia - recent BMT (<100 days)

16. Arguments for a patient – centered approach • Intracranial hemorrhage NOT associated with platelet count • In a randomized prophylactic transfusion study severe bleeding (WHO grade 3-4) occurred only in the 20 000 arm (versus 10 000 arm) Wandt, Blood 1998;91:3601

17. Guidelines-Leukemia patients • Platelets should be transfused at 5 x 109/L to 10 x 109/L (sepsis, Abx, abnormal hemostasis) (BCSH) • Platelets should be transfused at 10 x 109/L (ASCO) BJH 2003 JCO 2001

18. Future directions • Patient-centered approach rather than a laboratory-centered approach • Scoring system could be developed and validated • Ultimately, appropriate RCTs are needed

19. Single donor (apheresis) platelets should be transfused, and not random donor platelets “Vox populi, vox dei”

20. Outline • Platelet storage lesion • In vitro differences: RDP VS SDP • In vivo platelet survival: RDP VS SDP • Advantages of SDP over RDP

21. Platelet storage lesion • “The sum of changes that occur in platelets following their collection, preparation and storage as platelet concentrate for use in clinical practice” • Proteolysis of membrane proteins • Membrane phospholipid changes • Activation • Surface receptor changes • Secretion reaction • Other eg microparticle production

22. In vitro differences:RDP vs SDP

23. Stored platelet function:Cone and platelet analyser ADHESIONs. P<0.05 D. Alon, Unpublished

24. D. Alon, Unpublished

25. Stored platelet function:Cone and platelet analyser AGGREGATIONdays. P=NS D. Alon, Unpublished

26. D. Alon, Unpublished

27. In vitro characterisitcs: Summary

28. In vivo platelet survival: RDP versus SDP

30. Annexin V binding Arnold DM Shapira

31. Advantages of SDP over RDP

32. Not so, TRAP study, NEJM, 1999 SDP=2.1% RDP=0.8% Heal and Blumberg, Blood Rev, 2004

33. Potential advantages: SDP versus RDP • Reduced donor exposure • Reduced viral risk • Reduced septic reactions • Reduced transfusion reactions • Reduced febrile non-hemolytic reactions • Reduced Transfusion associated lung injury (TRALI) • Reduced allergic reactions • Higher platelet dose possible • 5 x 1011 versus 3 x 1011

34. Potential advantages: SDP versus RDP • Reduced donor exposure • Reduced viral risk • Reduced septic reactions (20% mortality rate) Snyder, Curr Opin Hematol; Stramer, NEJM, 2004

35. Potential advantages: SDP versus RDP • Reduced transfusion reactions • Reduced febrile non-hemolytic reactions • Related to duration of storage • RDP: 4.5% VS SDP:1.7% • Reduced Transfusion associated lung injury (TRALI) • Reduced allergic reactions Sarkodee, Transfusion, 1998 Logical, but no data

36. Potential advantages: SDP versus RDP • Higher platelet dose possible • 5 x 1011 versus 3 x 1011 Randomized, double blind study of AML and BMT patients 5 x 1011 versus 3 x 1011 Fewer transfusions overall Greater interval between transfusion (QoL) Cheaper No increased bleeding Klumpp, Transfusion, 1999

37. College of American PathologistsSurvey: 2005 82.1%

38. Vox populi, vox dei Latin idiom OR The masses are asses Winston Churchill