Thrombozytentransfusionen DGTI Seminar Bielefeld 2013

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1 Thrombozytentransfusionen DGTI Seminar Bielefeld 2013 Andreas Greinacher S. Felix Institut für Immunologie und Transfusionsmedizin Universitätsmedizin Greifswald Medizinische Klinik der königlichen Universität Greifswald

2 1850,,Die Transfusion ist einer der sichersten chirurgischen Eingriffe. Die Sterberate liegt bei einem von drei Patienten. Damit ist sie noch niedriger als nach der Behandlung von Eingeweidebrüchen und entspricht etwa der Sterberate von Amputationen 1850 Transfusion is one of the safest surgical interventions. Mortality is one in three patients. This is lower as after treatment of hernia and is approximately in the range of mortality after amputations. Quelle: Webseite Abteilung Transfusionsmedizin Universität Würzburg

3 transfused PCs Report according to 21 TFG % PEI-Webseite

4 Dogmas in der Transfusionsmedizin A newborn with severe neonatal immunethrombocytopenia and overt bleeding symptoms has to be treated with either: HPA-1a/5b negative platelets from a typed donor or with plasma depleted maternal platelets Transfusion of random PCs is unlikely to be effective (Guidelines for the use of platelet transfusions Br J Haematol 2003; 120:10)

5 Effect of random PC on platelet counts in acute NAIT Kiefel et al. Blood 2006

6 Leitlinien der Bundesärztekammer zur Therapie mit Blut und Blutprodukten

7 Evidenzgrade der Leitlinien - Grad 1: Nutzen für den Patienten gesichert - Grad 2: bestes Vorgehen unklar - Qualität A: große prospektive, randomisierte Studien - Qualität B: prospektive Studie mit widersprüchlichen Ergebnissen/ methodischen Schwächen - Qualität C: Fallbeobachtungen (nicht randomisierte Studien), Expertenmeinung - +: Schlussfolgerung eindeutig

8 Thrombozytopenie bei Intensivpatienten

9 % of patients Incidence of TP in ICU patients 12 studies 3162 patients 8 studies 2188 patients 5 studies 3104 patients medical and surgical ICU patients combined <150,000/µL <50,000/µL <150,000/µL during ICU stay during ICU stay at admission

10 Pseudothrombocytopenia Frequent in patients receiving GP IIbIIIa inhibitors! GP IIbIIIa inhibitor induced pseudo-tp also occurs in citrated blood. Review the blood smear!

11 Thrombocytopenia in the bleeding patient

12 Platelet transfusion trigger in acute bleeding massive and severe hemorrhage < /μl 2 C transfusion dependent bleeding < /μl 2 C German Guidelines We suggest maintenance of platelet count above 100,000/µL in patients with multiple trauma who are severely bleeding or have traumatic brain injury. Grade 2 C Management of bleeding following major trauma, Crit Care 2007

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14 Do not forget the hematocrit shear stress shear stress platelet red blood cell leukocyte Hct -15%, bleeding time prolongation by 60% Valeri et al. Transfusion 2001;41: In acute bleeding aim for Hct >30%

15 Admission due to symptomatic TP Blood smear + differential blood count Yes? No Thrombotic thrombocytopenic purpura (TTP) Leukemia Malaria Immune mediated ITP, drug dep.tp, Dengue fever Non-immune causes bone marrow failure sepsis Plasmatransfusion Plasmapheresis diagnostic platelet transfusion

16 Emergency: isolated symptomatic TP Transfusion of 2 platelet concentrates yes Platelet count increase 0.5-1h after transfusion no Platelet production defect, continue transfusion Increased platelet turnover

17 ICU patients with major bleeding TP patients Non-TP patients 39% 4.4% 27.1% 6.5% Vanderschueren et al. Crit Care Med 2000;28: Chakraverty et al. Brit J Haematol 1996;93: % 11% The only study with multivariate analysis: 33.3% 8.9% Ben Hamida et al. Int Care Med 2003;29: no significant difference Strauss et al. Crit Care Med 2002;30: Hui et al Chest

18 Admission due to severe disease associated with thrombocytopenia Admission due to symptomatic severe thrombocytopenia Thrombocytopenia developing after admission How to identify patients in whom TP indicates an underlying condition which requires a change in treatment?

19 The platelet count is very dynamic, reflecting the bone marrow production of about 150 billion platelets daily

20 Constant production of thrombopoietin in the liver (free thrombopoietin) free thrombopoietin Bone marrow megakaryocytopoiesis

21 Platelet count (x10 9 /L) 500 orthopedic surgery platelet count nadir cardiac surgery rebound of the platelet count after day Postoperative day (day 0 = day of surgery) Greinacher A & Selleng K; Hematology 2010

22 Platelet count (x10 9 /L) Nijsten et al. Crit Care Med. 2000;28: Akca et al. Crit Care Med. 2002;30: trauma 400 orthopedic surgery vascular surgery 300 platelet count nadir abdominal surgery cardiac surgery rebound of the platelet count after day Postoperative day (day 0 = day of surgery) Greinacher A & Selleng K; Hematology 2010

23 Platelet count (x10 9 /L) Early platelet count nadir: information about magnitude of platelet consumption/severity of trauma Recovery of plt. count: information about intact physiologic response Postoperative day (day 0 = day of surgery) Greinacher A & Selleng K; Hematology 2010

24 Blunted platelet count recovery as prognostic marker Surgical ICU patients mortality: TP until day 4: 33% persistent TP until day 14: 66%. Akca S, et al. Crit Care Med. 2002;30: Cardiac surgery ICU patients 30-day mortality: TP < day 5: 1.3% persistent TP <100 x 10 9 /L: 12.0% Selleng S, et al. JTH 2010;8:30-36 Median increase of platelet counts: ~ 30,000/µL x day in ICU survivors ~ 6,000/µL x day in non-survivors (p<0.001). Nijsten MW, et al. Crit Care Med. 2000;28:

25 Platelets and liver transplantation Survival depends on the number of platelets provided by Prof F de Groot, Utrecht

26 TP and Mortality (ICU and in-hospital) Mortality (OR; 95% CI) (multivariate analysis) 2.7 ( ) Study Stephan et al. Crit Care 1999; 3: ( ) NS 4.4 ( ) Plt < 50 G/L NS 2.12 ( ) 26.2 ( ) 3.10 ( ) Vanderschueren et al. Crit Care Med 2000;28: Strauss et al. Crit Care Med 2002;30: Brogly et al. J of Infektion 2007;55: Cherif et al. Support Care Cancer 2007;15: Martin et al. Rit Care Med 2009;37:81-8 Caruso et al.eur J Canc Care 2010;19:260-6 Vandijck et al. Heart and Lung 2010;39:21-6 Hui et al Chest

27 TP and Mortality Low platelet counts seem to be a marker for adverse outcome. Successful treatment of underlying disease results in normalization of platelet counts. Does normalization of platelet counts improves outcome? This is unkown!

28 Platelets, Friend or Foe? Platelet transfusion is an important risk factor for mortality after liver transplantation Pereboom et al. Anesth Analg.2009;108:

29 ICU Patients/ Sepsis Platelet transfusion in sepsis/dic only in case of relevant bleeding, no prophylactic platelet transfusion 2 C Do not treat numbers German Guidelines

30 Chirurgische Patienten

31 Prä-OP Thrombozytentransfusion Grenzwerte (elektive Eingriffe) kleinere operative Eingriffe (Blutung sichtbar und ggf komprimierbar) - bei Thrombozytenzahlen < /µl. Grad 2C größere operative Eingriffe, Eingriffe mit hohem Blutungsrisiko - bei Thrombozytenzahlen < /µl. Grad 2C operative Eingriffe mit einem sehr hohen Blutungsrisiko (Neurochirurgie, Netzhaut) - bei Thrombozytenzahlen < /µl. Grad 1C Herz-Lungen-Maschine - bei Thrombozytenzahlen < /µl. Grad 2C

32 Problempatienten in der perioperativen Situation

33 Patienten mit koronaren Stents Shuchman et al, NEJM 2006

34 Drug eluting Stent oder bare metal Stent? Implantation vor > 3 Monate, > 6 Monate, > 1 Jahr? Bei BMS < 3 Monate und bei DES < 6, besser 12 Monate (ESC-Empfehlung, 2009) sollten elektive Eingriffe wirklich vermieden werden.

35 Blutungsrisiko Thromboserisiko Unser Vorschlag 2 TK weitere TK nach Klinik ASS Clopidogrel + ASS ASS letztmalig am Tag vor OP morgens präoperativ OP ~ 6h postop. ~ 12 h (1. Tag) postop. Thiele et al. JTH 2012

36 Patients requiring urgent surgery under ASA/Clopidogrel intake ID Indication for surgery Type of surgery Indication for ASA+ clopidogrel Restart of ASA [hours] Restart of clopidogrel [hours] RBCtransfusions [Units] Bleeding complications Coronary events 1 renal carcinoma renal excision DES mechanical ileus, diverticulitis fast track hemicolectomy prolonged postoperative bleeding DES no no NSTEMI 4 days after surgery 3 fracture of the femural neck total hip endoprothesis DES 6 6 hours 0 no no 4 subarachnoidal hemorrhage craniotomy BMS (renal artery stent) no no 5 fracture of the femural neck total hip endoprothesis transcathedral aortic valve no no 6 cervical epidural hematoma, myelocompression vertebral decompression BMS 6 not continued 4 no no 7 orbita bottom fracture eye socket reposition DES no no Thiele et al. JTH 2012

37 Hämato-onkologische Patienten

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39 Wir empfehlen die Thrombozytentransfusion bei Patienten mit akuter Thrombozytenbildungsstörung bei Erwachsene mit akuter Leukämie, prophylaktisch erst ab einem Thrombozytenwert von <10.000/µl oder bei manifesten Blutungen Kindern mit akuter Leukämie, bei denen kein erhöhtes Verletzungsrisiko vorliegt, prophylaktisch erst ab einem Thrombozytenwert von < /µl oder bei manifesten Blutungen Evidenzlevel und Grad der Empfehlung 1A 1C Patienten nach Knochenmark- oder Stammzelltransplantation ohne Komplikationen, wie schwere Graft versus Host Reaktion oder Mukositis, Cystitis, erst ab einem Thrombozytenwert von < /µl oder bei manifesten Blutungen 1C Patienten mit soliden Malignomen ohne zusätzliches Blutungsrisiko erst bei einem Thrombozytenwert < /µl oder bei manifesten Blutungen 1C

40 Hemato-Oncology Patients Slichter SJ et al. New Engl J Med 2010; 362:

41 2.1.4 Wir empfehlen die Thrombozytentransfusion bei hämatologisch-onkologischen und onkologischen Patienten mit akuter Thrombozytenbildungsstörung und zusätzlichen Blutungsrisiken bei Patienten mit zusätzlichen Risikofaktoren (Tabelle) bei einem Thrombozytenwert von < /µl Evidenzlevel und Grad der Empfehlung manifesten Blutungen 1C 2C Risikofaktoren für das Auftreten von Blutungskomplikationen bei Thrombozytopenie Infektionen Komplikationen (GVHD) Klinische Zeichen der Hämorrhagie (z.b. petechiale Blutungen), Fieber über 38 C, Leukozytose, plasmatische (pro-hämorrhagische) Gerinnungsstörung. Steiler Thrombozytenzahlabfall Vorbestehende Nekrosebereiche

42 Platelet Dose 2 recent trials (design & results) SToP (Strategies for Transfusion of Platelets) PLADO (Platelet Dose Study) Outcome - WHO Bleeding Grade 2

43 BEST SToP Study Design Eligible Patients Target: x 10 9 Informed Consent Strata Centre Diagnosis (2) Low Dose Standard Dose Daily Assessment for Bleeding Primary Outcome % Patients bleeds ( Grade 2) Secondary Outcomes Bleeding Recurrent event analysis Product utilization/donor exposures Duration of thrombocytopenia Target: x 10 9 Heddle N, et al. BLOOD 2009

44 SToP Stopped Early Sample size planned: approximately 600 patients DSMB requested the study be stopped after 129 patients were enrolled Grade 4 Bleeding Low Dose 5.2% 1 cerebral hemorrhage 2 cases of vision impairment (temporary) Grade 4 Bleeding Standard Dose 0% Heddle N, et al. BLOOD 2009

45 Percentage % of Patients with Bleeding (Grade 2, 3 & 4) (n=119) Standard Dose Low Dose Grade 1 Grade 2 Grade 3 Grade 4 >/= Grade2 Secondary Outcome Percentage of days with bleeding (proportion) Grade 2 Standard Dose Platelet (n=61) Low Dose Platelets (N = 58) 8.5 (73/854) 12.1 (111/918) Heddle N, et al. BLOOD 2009

46 SToP More Results Measure SToP Study Dose Low Standard # of PLT Tx Episodes Interval between PLT Tx 1.8* (1.1) 2.8* (1.8) # of PLT donor exposures Heddle N, et al. BLOOD 2009

47 Lessons learned from SToP Low dose platelet strategy: Will require more platelet transfusion episodes Will result in a shorter interval between prophylactic platelet transfusions May cause more donor exposures Severe bleeding - SToP Heddle N, et al. BLOOD 2009

48 PLADO Study Design Eligible Patients Informed Consent Strata Centre Diagnosis (4) Low Dose Plts Target 1.1 x /m 2 Medium Dose Plts Target 2.2 x /m 2 High Dose Plts Target 4.4 x /m 2 Daily Assessment for Bleeding Primary Outcome % Patients bleed ( Grade 2) Slichter et al., NEJM 2010

49 PLADO Results Outcome % of patients LOW MEDIUM HIGH n = 417 n = 423 n = 432 Bleeding Grade No Bleeding or Grade Grade Grade Grade Death from Hemorrhage (# Pts) All P values were not significant Designed as a superiority study 85% power to detect an absolute difference of 12.5% 3 comparisons with adjustment of P value. Slichter et al., NEJM 2010

50 RESULTS Measure Interval between PLT Tx days 1.1** ( ) PLADO Study Dose Low Medium High 1.9** ( ) 2.9** ( ) Median # Plt Tx/Patient (IQR) 5 (3 9) 3 (2 6) 3 (2 6) Total # of PLTs Tx (x10 11 ) Slichter et al., NEJM 2010

51 Lessons learned from PLADO Low Dose Platelet Strategy: No increased risk of bleeding ( Grade 2) An increased number of transfusions A decreased number of platelets transfused High Dose Platelet Strategy: No decrease in the risk of bleeding Longer interval between transfusion Transfusion episodes similar to standard dose An increased number of platelets transfused Slichter et al., NEJM 2010

52 If bleeding is similar by dosing strategy what is the benefit? SToP Suggests no benefit More transfusion episodes? Trend to more donor exposures PLADO More Tx episodes with low dose Overall fewer platelet cells transfused

53 Are Prophylactic Plt Tx Necessary? Details Wandt (Germany) Stanworth (UK) Design Patients AML Autologous PBSCT Tx Arms Prophylactic at trigger of 10 Therapeutic only when bleeding or clinically unstable Parallel RCT, Non Inferiority Acute Leukemia Allo & auto SCT Prophylactic Therapeutic when Bleeding (WHO Grades 2) Primary Outcome % of patients with clinically significant bleeding (WHO Grades 2 ) % of pts with WHO Grades 2 up to 30 days following randomization

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55 Therapeutic vs. Prophylactic Platelet Tx Wandt H. et al Lancet 2012, epub

56 Wandt H. et al Lancet 2012

57 Why do we give Prophylactic Platelet Transfusions? ANSWER: To stop or prevent bleeding. To prevent: Death Why? Permanent Morbidity Temporary Morbidity Quality of Life mild to severe Avoid utilization of additional resources Which of these are the most important?

58 Depends on the Perspective Patient s Physician s Funder Society s Slide: Nancy Heddle, McMaster University Hamilton, Canada

59 Pool-PCs vs Apheresis PCs Donor Exposure Pool PCs are prepared by the PRP or buffy coat method using 4 6 donor products. Apheresis PCs are prepared from a single donor Result pool PCs in a 4-6 times higher donor eposure rate?

60 Pool-PCs vs Apheresis PCs Donor Exposure Patients requiring PCs usually require also other blood products. Donor exposure rate results from all blood products What is the total donor exposure rate in two centres using primarily pool PCs and apheresis PCs only for special indications?

61 Pool-PCs vs Apheresis PCs Donor Exposure Hamilton Health Sciences, McMaster University, Hamilton, Canada supplied by the CBS Universitätsmedizin Greifswald, Germany in-house transfusion service Observation period /

62 Hamilton Greifswald Data by Center Number of blood products transfused >100 Total Patients per group (%) 413 (15.4) 595 (22.1) 412 (15.3) 281 (10.4) 194 (7.2) 155 (5.8) 130 (4.8) 90 (3.3) 58 (2.2) 51 (1.9) 310 (11.5) 2689 (100) Actual donor exposures by preferential use of Pooled-PCs 2,897 9,197 10,381 9,967 8,731 8,607 8,507 6,832 4,932 4,884 57, ,012 Estimated donor exposures if only Apheresis-PCs are used Relative increase in donor exposure by use of Pooled-PCs over 100%Apheresis-PCs 1,541 6,359 7,822 7,582 6,673 6,552 6,611 5,116 3,585 3,597 37,073 92, Patients per group (%) 4,282 (44.6) 2,264 (23.6) 1,128 (11.7) 621 (6.5) 363 (3.8) 246 (2.6) 194 (2) 126 (1.3) 100 (1) 53 (0.6) 231 (2.4) 9608 (100) Actual donor exposures by preferential use of Pooled-PCs 35,992 46,818 38,828 30,645 23,192 19,754 18,122 14,503 12,959 7,382 51, ,923 Estimated donor exposures if only Apheresis-PCs are used Relative increase in donor exposure by use of Pooled-PCs over 100%Apheresis-PCs Combined relative increase Greifswald/Hamilton 22,480 33,446 28,246 21,734 16,387 13,570 12,568 9,490 8,555 5,060 35, ,

63 Pool-PCs vs Apheresis PCs Donor Exposure Total donor exposure rates are not increased by 4 6 times if a primarily pool PC transfusion policy is applied. The biggest increase is seen in patients requiring <10 blood transfusions with a 1.9 fold increase in donor exposure. In all other patient groups the increase is fold

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65 Der Transfusions-refraktäre Patient Verbrauch, Medikamente (Amphotericin), HLA Antikörper, Thrombozytenantikörper 2 ABO gematchte, frische TKs transfundieren Wenn kein Anstieg: HLA AK bestimmen, wenn positiv und weiter kein Anstieg Thrombozyten Antikörper bestimmen Nur bei klinisch relevanter Blutung transfundieren Grad 2C

66 Screening vor Hochdosischemotherapie HLA und Thrombozyten Antikörper Testpanel und autologe Thrombozyten negativ positiv unausgewählte Thr.-Spender ausgewählte Thr.-Spender Überwachung des Inkrements kein Anstieg

67 Der Transfusion Erfolg Es gibt keine Studie, die die klinische Relevanz der Bestimmung der Thrombozytenwerte nach Transfusion für eine Vorhersage von Blutungen zeigt Patienten John Hopkins Oncology Center Baltimore : keine Korrelation zwischen Thrombozytenwerten nach Transfusion und Risiko für Blutungen Friedmann et al. Transfus Med Rev 2002;16:34-45 Trotzdem wird empfohlen: Thrombozytenwerte nach Transfusion zu bestimmen Ab bestimmten Grenzwerten Thrombozyten zu transfundieren

68 Metaanalysis of RCTs pathogenreduced PCs Vamvakas EC; Transfusion 2011;51:

69 Odds ratios of bleeding complications Metaanalysis of RCTs pathogenreduced PCs Vamvakas EC; Transfusion 2011;51:

70 X X vonhundelshausen & Weber Circ Res 2007;100:27-40

71 Lipid mediators 12-HETE, Thromboxane - substrates for leukocytes - inflammation Microbicidal proteins -host defence Chemokines -recruitment of immune cells -atherosclerosis

72 Febrile nicht-hämolytische TR Temperatur Anstieg 1-3 C nach der Transfusion ~1-5% aller Thrombozyten Transfusionen Enright et al. Transfusion 2003;43:1545 ~20-30% aller Patienten (nicht Leuko-depletiert) Heddle et al New Engl J Med 1994;331:625 HLA > HPA 5b > 1b > 5a >2b > 1a Kiefel et al. Transfusion 2001;41:766 Chemokine: Rantes, TARC, MIP1alpha CD40L Phipps et al. Lancet 2001; Kaufman et al. J Thromb Haemost 2007 Antigen kompatible Thrombozyten, Paracetamol? Wang et al. Am J Hematol 2002, Dolantin ½ Ampulle

73 Allergische Reaktionen Pruritus, Urtikaria >> Bronchokonstriktion >> Hypotension >>> Schock Temperaturanstieg selten (~3%) IgE AK, Spender IgG gegen Empfänger Proteine oder Empfänger IgG gegen Spender Proteine (IgA Mangel < 0,05 mg/dl) Cytokine, Chemokine, Histamine Leukozyten-Depletion, frische Thrombozyten Waschen

74 Hämolytische TR Isoagglutinine im Spender Plasma ABO gleiche Thrombozyten Transfusion ABO ungleiche Thrombozyten Transfusion nicht vermeidbar Spender BG A oder B oder auf Hämolysine testen Plasma-reduzierte TKs Pietersz et al. Vox Sang. 2005

75 Weitere immunologische TR TRALI: HNA AK, HLA I, HLA II Spender IgG gegen Empfänger Leukozyten Passive Alloimmunthrombozytopenie Spender IgG gegen Empfänger Thrombozyten Post transfusionelle Purpura Empfänger IgG gegen Spender HPA werden zu Autoantikörpern Transfusions-assoziierte Graft vs Host Reaktion Spender Lymphozyten gegen Empfänger Gewebe