DEVELOPMENT OF THE PLATELET ANNEX FOR THE

NATIONAL BLOOD SUPPLY CONTINGENCY PLAN (NBSCP)

Executive Summary

The following document details the purpose, methodology and clinical consensus statements that have been developed by the Blood Service on behalf of the NBA regarding the clinical indications for platelets and their respective priority in a time of supply shortage.

Table of Contents

Introduction Page 2

Background Page 2

Part A: Clinical indications for platelet transfusion Page 3

Consensus Statement 1 – Clinical indications for platelet transfusion for patients with

clinically significant bleeding

Page 3

Consensus Statement 2 – Clinical indications for prophylactic platelet transfusion for

prevention of bleeding

Page 3

Consensus Statement 3 – Clinical contraindications for platelet transfusion Page 4

Part B: Clinical guidance to assist in prioritisation of platelet supply during periods of

supply constraints

Page 5

Consensus Statement 4 - Platelet Priority 1 Page 5

Consensus Statement 5 - Platelet Priority 2 Page 6

Consensus Statement 6 - Platelet Priority 3 Page 6

Part C: Consensus Methodology Page 7

Part D: Supporting evidence Page 8

Disclaimer:

This document has been prepared by the Australian Red Cross Blood Service on behalf of the National Blood Authority and is being released for consultation for the purpose of gaining consensus for the clinical indications of platelets. Appropriate processes were followed to ensure the accuracy of the information included in the document as at the date of publication. The Blood Service and the National Blood Authority take no responsibility for reliance on the information contained in the document by any third party.

IntroductionWhilst it is acknowledged that Patient Blood Management (PBM) is influencing transfusion practice by moving the focus from appropriate use of blood components to appropriate patient management, by necessity, this document focuses on platelet components and provides guidance to the clinical approach that may be required during periods of reduced availability of platelets. As context, the document also contains guidance as to the appropriate indications for platelet therapy during periods where supply is not constrained. The indications for platelet transfusion included in this document are based, where possible on the recommendations and practice points included in the National Blood Authority (NBA) PBM Guidelines, their supporting literature review and expert consensus.

BackgroundThe National Blood Supply Contingency Plan (NBSCP) was developed by the NBA to facilitate and coordinate a rapid national response in the event of a domestic threat or disaster that affects the provision of a safe and adequate blood supply in Australia. It outlines the crisis planning, preparation and mitigation of a crisis, response framework and recovery arrangements for a crisis affecting the supply of blood and blood products. It also provides guidance on the escalation of contingency management from NBSCP arrangements to the Australian Health Protection Principal Committee (AHPPC). As part of this framework the NBA has prepared NBSCP Annex C – Platelets to support the response to a range of risks identified for platelet supply including the prioritisation of requests for platelets during periods when platelet supply is constrained.

Platelets have a short shelf-life and for this reason an interruption to production or a sudden, large unexpected increase in demand will have a rapid impact on supply. Similarly, the short shelf-life of platelets makes redistribution between centres and between jurisdictions within a useful time-frame more challenging compared with other blood components.

As agreed by consensus, the NBSCP Annex C – Platelets does not require further categorisation into specific platelet types because during periods of supply constraints the available mix of apheresis derived and whole blood derived platelets is likely to be significantly different to the planned supply mix because strategies to increase demand will be influenced by the immediately available surge capacity of both panels.

The platelet count is the primary criteria used for prioritising patients who require platelet therapy, with clinical risk factors for bleeding and the extent of bleeding also influencing the decision to transfuse.

The document is presented in three sections as follows:

Part A: Clinical indications for platelet transfusion

Part B: Clinical guidance to assist in prioritisation of platelet supply during periods of supply constraints

Part C: Consensus methodology

Part D: Supporting evidence

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Part A: Clinical indications for platelet transfusion Platelet transfusion can be given for prevention or treatment of bleeding due to thrombocytopenia or defects of platelet function. As with all transfusion decisions, the benefit achieved with the prescription and transfusion of platelets should be balanced against the associated risk.

Consensus Statement 1 – Clinical indications for platelet transfusion for patients with clinically significant bleedingThe clinical indications for platelet transfusion for patients with clinically significant bleedinga are as follows:

1. Platelet transfusion is indicated for all patients with clinically significant bleeding in whom thrombocytopenia is thought to be a major contributory factor, even if the platelet count is >10x109/L.

2. In patients with critical bleeding requiring massive blood transfusion. In these patients, the use of a Massive Transfusion Protocol (MTP) which includes platelet transfusions may reduce the risk of mortality.

3. Platelet transfusion is indicated for patients with congenital or acquired functional platelet defects (including complex cardiac surgery and/or patients on dual antiplatelet therapy requiring surgical intervention) who are actively bleeding, although platelet counts are not a reliable indicator in this case.

4. Whilst there is no consensus on a target platelet threshold for the management of bleeding patients with thrombocytopenia secondary to Disseminated Intravascular Coagulopathy (DIC), aiming to maintain platelet counts >50x109/L would seem to be reasonable, as well as correction of the underlying aetiology and replacement of coagulation factors. Platelet transfusion is not indicated for patients with chronic DIC or for whom there is no bleeding.

5. In general, platelet transfusion is not indicated in immune thrombocytopenia unless there is clinically significant bleeding

Consensus Statement 2 – Clinical indications for prophylactic platelet transfusion for prevention of bleeding

The clinical indications for prophylactic platelet transfusion for prevention of bleeding are as follows:

1. Patients with severe thrombocytopenia undergoing chemotherapy and haematopoietic stem cell transplantation should receive prophylactic platelet transfusion at a platelet count of <10x109/L in the absence of risk factors and at <20x109/L in the presence of risk factors (e.g. fever).

2. In critically ill patients, in the absence of acute bleeding, the administration of platelet transfusion may be considered appropriate at a platelet count of <20x109/L. The administration of platelet transfusion may be considered appropriate at a higher platelet count for neonates, such as <25x109/L for term neonates and <30-50x109/L for preterm neonates or any neonate with Neonatal Alloimmune Thrombocytopenia (NAIT). Although in NAIT it is preferable to give platelets without the relevant HPA antigen, random donor platelets may be effective

3. For patients with other causes of bone marrow failure with chronic failure of platelet production (e.g. myelodysplasia and aplastic anaemia), a specific threshold for transfusion may not be appropriate and such patients should be managed on an individual basis. Long term prophylactic platelet transfusion may be best avoided because of the risk of complications.

a Webert Bleeding Severity Measurement Scale defines clinically significant bleeding (Grade 2). Webert KE, Arnold DM, Lui Y, Carruthers J, Arnold E, Heddle NM. A new tool to assess bleeding severity in patients with chemotherapy-induced thrombocytopenia (CME). Transfusion. 2012 Nov; 52 (11): 2466-2474

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4. In patients undergoing invasive procedures, there is insufficient evidence to define a threshold platelet count that is associated with increasing risk of bleeding, however:

In general, for patients undergoing procedures such as insertion of central venous catheters, endoscopy and biopsy, lumbar puncture and laparotomy, a platelet count ≥50 x109/L is considered safe.

A lower threshold may be tolerated for minor procedures such as dental extractions, skin biopsy and insertion of peripherally inserted central catheters (PICC) where adequate surface pressure can be applied.

For patients undergoing intracranial, intraocular and neuraxial surgery, it is generally suggested that the platelet threshold be raised to ≥100x109/L.

5. In patients with head injury, it is suggested to keep the platelet count >100x109/L.

6. Functional platelet disorders include inherited or acquired platelet function disorders. In these groups of patients, prophylactic platelets may be considered before invasive procedures.

Consensus Statement 3 – Clinical contraindications for platelet transfusionThe clinical contraindications for platelet transfusions are as follows:

1. Platelet transfusion is contraindicated in patients where bleeding is unrelated to a decreased platelet count or to functional platelet defects.

2. For patients with Heparin Induced Thrombocytopenia (HIT) and Thrombotic Thrombocytopenic Purpura (TTP), platelet transfusion is contraindicated unless there is life-threatening haemorrhage as it can exacerbate the underlying conditions. There are limited case reports regarding the successful use of platelets in patients with Haemolytic Uraemic Syndrome (HUS) and TTP to cover invasive procedures that cannot be postponed until the underlying disease has been resolved (e.g. central line placement for plasma exchange therapy).

3. The routine prophylactic use of platelets after cardiac surgery is not supported.

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Part B: Clinical guidance to assist in prioritisation of platelet supply during periods of supply constraintsDuring periods of platelet supply constraints, it may be necessary to prioritise the supply of platelet transfusions to patients with the greatest clinical need and to delay the supply of platelets to other patients pending stock availability (such as when infectious disease screening is completed). In this scenario, all clinically appropriate requests for platelet supply are able to be met, albeit the supply for some patients may be briefly delayed. Prioritisation of platelet supply in this scenario is undertaken by medical staff at the Australian Red Cross Blood Service.

However, where the supply constraint is more severe, it may be necessary to restrict the supply of platelets to particular patient categories. In these situations, the NBSCP will be activated and there will be communication between stakeholders, including the NBA, Jurisdictional Blood Committee (JBC), AHPPC and the Blood Service. Prescribing clinicians will be informed about the necessity to reduce the demands for platelets.

This document provides guidance for the prioritisation of requests for platelets during periods when platelet supply is constrained. In descending order of urgency, patients can be classified in Platelet Priority 1-3, with patients in Platelet Priority 1 having the highest priority for transfusion.

Consensus Statement 4 - Platelet Priority 1During periods when platelet supply is constrained, the following patients have the highest priority for platelet transfusion and are classified as “Platelet Priority 1”.

Patients with clinically significant bleedingb

Patients with clinically significant bleeding in whom thrombocytopenia or platelet dysfunction is thought to be a major contributory factor.

Patients with critical bleeding requiring massive blood transfusion.

Patients with clinically significant bleeding in the presence of acute Disseminated Intravascular Coagulopathy (DIC) and a platelet count <50x109/L.

Patients requiring platelet support for immediate or urgent surgeryc

Patients who require immediate or urgent surgery with a platelet count <50 x109/L or with functional platelet defects.

Patients who require immediate or urgent neurosurgery, intraocular or neuroaxial surgery with a platelet count <100x109/L or with functional platelet defects.

Consensus Statement 5 - Platelet Priority 2b Webert Bleeding Severity Measurement Scale defines clinically significant bleeding (Grade 2). Webert KE, Arnold DM, Lui Y, Carruthers J, Arnold E, Heddle NM. A new tool to assess bleeding severity in patients with chemotherapy-induced thrombocytopenia (CME). Transfusion. 2012 Nov; 52 (11): 2466-2474c I m m e d i a t e : Immediate life, limb or organ-saving operation. Resuscitation simultaneous with surgical treatment. Operation within minutes of decision to operate (e.g. laparotomy / thoracotomy for control of haemorrhage). Ur g e n t: Acute onset or deterioration of conditions that threaten life, limb or organ survival or for relief of distressing symptoms. Operation within hours of decision to operate and normally once resuscitation completed (e.g. laparotomy for perforation). Australia & New Zealand Gastric & Oesophageal Surgery Association Audit Data Dictionary. Version 3. Morbidity Audits Department Research, Audit and Academic Surgery Division; Jan 2013. Urgency of Surgery; p. 43.

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During periods when platelet supply is constrained, the following patients have moderate priority for platelet transfusion and are classified as “Platelet Priority 2”.

Patients at high risk of critical bleeding

Patients with head injury and a platelet count <100x109/L.

Neonates with Neonatal Alloimmune Thrombocytopenia (NAIT) (platelet count <30x109/L).

Neonates with severe thrombocytopenia (<25x109/L for term neonates and <30-50x109/L for preterm neonates).

Patients requiring prophylactic platelet transfusion for prevention of bleeding

Patients with severe thrombocytopenia undergoing chemotherapy and haematopoietic stem cell transplantation with a platelet count of <10x109/L in the absence of risk factors and at <20x109/L in the presence of risk factors (e.g. fever).

Critically ill patients with a platelet count of <20x109/L.

Consensus Statement 6 - Platelet Priority 3During periods when platelet supply is constrained, the following patients have the lowest priority for platelet transfusion and are classified as “Platelet Priority 3”.

Patients requiring platelet support for expedited surgeryd or invasive procedures

Patients who require expedited surgery with a platelet count <50x109/L or with functional platelet defects.

Patients who require expedited neurosurgery, intraocular or neuroaxial surgery with a platelet count <100x109/L or with functional platelet defects.

Patients requiring expedited invasive procedure or biopsy with a platelet count <50x109/L or with functional platelet defects.

Patients requiring platelet support for elective surgerye

Elective surgery in patients who may require platelet support for thrombocytopenia or functional platelet defects.

d E x p e d it e d : Stable patient requiring early intervention for a condition that is not an immediate threat to life, limb or organ survival. Operation within days of decision to operate). Australia & New Zealand Gastric & Oesophageal Surgery Association Audit Data Dictionary. Version 3. Morbidity Audits Department Research, Audit and Academic Surgery Division; Jan 2013. Urgency of Surgery; p. 43.e E l ec ti v e : Surgical procedure planned or booked in advance of routine admission to hospital. Operation at a time to suit both patient and surgeon. ). Australia & New Zealand Gastric & Oesophageal Surgery Association Audit Data Dictionary. Version 3. Morbidity Audits Department Research, Audit and Academic Surgery Division; Jan 2013. Urgency of Surgery; p.43.

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Part C: Consensus MethodologyCriteria for establishing the consensus group:As part of the NBA Platelets Project deliverables, the Blood Service was required to assemble a group of external expert clinicians to assist with the review of the NBSCP Annex C - Platelets and develop consensus statements incorporating:

Clinical indications and contraindications for platelet transfusion Clinical guidance to assist in prioritisation of platelet supply during periods of supply constraints

The Blood Service external Advisory Committee members were engaged as the consensus group members for this process. In addition, a Consultant Haematologist with paediatric and obstetric expertise was targeted to ensure broad clinical representation within the group. Final membership included representation from clinical and laboratory haematology, transfusion medicine, intensive care, microbiology, infectious diseases, molecular genetics, transplantation, research, anaesthetics, orthopaedics and oncology. A representative from the NBA was also included in the consensus group as an observer of the process. As part of the selection process, consensus group members had to be able to commit themselves to the consensus process and timelines for the project.

Drafting of the consensus statements:The PBM guidelines were used as the basis for the development of the clinical indications and contraindications for platelet transfusions. A targeted literature search was also conducted in order to develop the background paper and 6 associated consensus statements.

The consensus statements and supporting information were initially reviewed by the Blood Service National Blood Transfusion Committee. Membership of this committee includes internal and external haematology and transfusion medicine experts. A subsequent review and final approval was conducted by Blood Service personnel with laboratory and clinical haematology expertise prior to being disseminated to the consensus group members for consideration.

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Part D: Supporting evidenceD1: Sourced from the NBA PBM ModulesA multilevel management framework was established by the National Blood Authority (NBA) to coordinate the development of the new patient blood management guidelines. The management framework consisted of:

A Steering Committee, responsible for the overall development and governance of the entire project.

An Expert Working Group (EWG), responsible for clinical oversight and integration of the six modules.

Clinical/Consumer Reference Groups (CRGs – one for each of the six modules), with membership including representation from relevant colleges, societies and consumer groups, to provide expert knowledge and input.

Systematic reviewers and a technical writer, contracted by the NBA to review the literature and develop a draft of each module.

An independent systematic review expert, to provide advice and mentoring to the systematic reviewers, technical writer and CRGs; and to ensure that the development process and the guidelines produced comply with National Health and Medical Research Council (NHMRC) requirements.

Each patient blood management module has been endorsed by the NHMRC and this endorsement is valid for a period of 5 years. The date of endorsement for each of the modules is as follows:

Module 1: Critical Bleeding/ Massive Transfusion was approved by the NHMRC on 12 November 2010 and released on 1 March 2011.

Module 2: Perioperative was approved by the NHMRC on 15 November 2011 and released on 9 March 2012.

Module 3: Medical was approved by the NHMRC on 18 July 2012 and released on 19 September 2012.

Module 4: Critical Care was approved by the NHMRC on 14 December 2012 and released on 5 April 2013.

Each module includes:

Recommendations – based on evidence from the systematic review.

Practice points – based on consensus decision making, where the systematic review found insufficient high-quality data to produce evidence-based recommendations, but where it was considered that clinicians require guidance to ensure good clinical practice.

The indications for platelet transfusion included in this document are based, where possible, on the recommendations and practice points included in the NBA Patient Blood Management modules, their supporting literature review and expert consensus.

The following information, relevant to platelet transfusion, has been extracted from the NBA Patient Blood Management Guidelines.

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Patient Blood Management Guidelines: Module 1 Critical Bleeding / Massive TransfusionRecommendations:

It is recommended that institutions develop a Massive Transfusion Protocol (MTP) that includes the dose, timing and ratio of blood component therapy for use in trauma patients with, or at risk of, critical bleeding requiring massive transfusion (Ref 4, 5).

Practice Points:

Practice Point 1: In patients with critical bleeding requiring massive transfusion, the following parameters should be measured early and frequently: temperature, acid–base status, ionised calcium, haemoglobin, platelet count, PT/INR, APTT and fibrinogen level. With successful treatment, values should trend towards normal.

Practice Point 2: Values indicative of critical physiologic derangement include temperature < 35°C, pH <

7.2, base excess > –6, lactate > 4 mmol/L, ionised calcium < 1.1 mmol/L, platelet count < 50×109/L, PT > 1.5 × normal, INR > 1.5, APTT > 1.5 × normal and fibrinogen level < 1.0 g/L.

Practice Point 3: In critically bleeding patients requiring, or anticipated to require, massive transfusion, a

MTP should be used.

Practice Point 4: In patients with critical bleeding requiring massive transfusion, insufficient evidence was identified to support or refute the use of specific ratios of RBCs to blood components.

Practice Point 7: In patients with critical bleeding requiring massive transfusion, the use of an MTP to facilitate timely and appropriate use of RBC and other blood components may reduce the risk of mortality and ARDS.

Practice Point 10: In patients with critical bleeding requiring massive transfusion, suggested doses of

blood components are FFP: 15 mL/kg, platelets: 1 adult therapeutic dose and cryoprecipitate: 3–4 g. Or as directed by the haematologist/transfusion specialist in specific clinical situations, such as obstetrics.

Literature Review:

Five studies calculated the odds of predicting mortality (or survival) among patients with critical bleeding requiring massive transfusion (Ref 15, 61, 64, 65, 68). Although not strictly a study of massive transfusion (because patients included received ≥ 5 units RBCs within 24 hours of admission), Mitra (Ref 15) found that a number of factors were independent predictors of mortality:

• hypothermia (odds ratio [OR] = 0.72; 95%CI: 0.56, 0.92; p = 0.01)

• thrombocytopenia (OR = 0.99; 95%CI: 0.98, 1; p< 0.01)

increased international normalised ratio (INR) (OR = 1.62; 95%CI: 1.18, 2.24; p< 0.01)

prolonged partial thromboplastin time (OR = 1.01; 95%CI: 1.01, 1.02; p< 0.01)

• low fibrinogen level (OR = 0.52; 95%CI: 0.28, 0.99; p = 0.05)

• low pH (OR = 0.01; 95%CI: 0, 0.29; p = 0.01)

• low bicarbonate levels (OR = 0.86; 95%CI: 0.77, 0.96; p = 0.01).

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Insufficient studies were found to provide an evidence statement on the effects of hypothermia, metabolic acidosis, thrombocytopenia and coagulopathy on morbidity or transfusion rate.

A survival advantage is associated with decreasing the ratio of RBCs to fresh frozen plasma (FFP), platelets or cryoprecipitate/fibrinogen administered to patients undergoing massive transfusion (Ref 65, 76, 78, 89). The decrease in mortality associated with administering low versus high ratios of RBCs to blood components was associated with a significant decrease in deaths from exsanguination. This decrease was attributed to administration of lower ratios of RBCs to FFP, platelets, apheresis platelets and fibrinogen (Ref 61, 65, 76, 79).

More deaths were reported in patients receiving high ratios of RBCs to blood components compared with low-ratio recipients. However, these results should be interpreted carefully, because of the potential for survival bias (that is, patients who die early are more likely to have received a higher RBC: component ratio) (Ref 84).

The types and content of the studies varied in terms of blood components and the ratios given; therefore, the optimum target ratio is difficult to determine. In trauma patients, a ratio of RBC: FFP: platelets of ≤ 2:1:1 was associated with improved survival (Ref 5, 70, 71). A number of these studies used a ratio of, or near to, 1:1 (ref 4, 5, 70, 71, 76, 78, 79, 85, 89). Other studies used a ratio of < 2:1:1 (Ref 5, 70, 71). However, based on analysis of the available studies and the possibility of survival bias, it is not possible to recommend a target ratio of RBC: FFP: platelets.

In non-trauma patients, there were insufficient data to support or refute the use of a defined ratio of blood component replacement. Although these patients do not have the initial coagulopathy commonly seen in trauma, critical bleeding may still result in development of hypothermia, acidosis and coagulopathy. Coordination of the management of these patients through use of an MTP is recommended. Blood component replacement should be guided by clinical assessment and results of coagulation tests.

Four Level III studies examined the effect of FFP or platelet transfusion on mortality or morbidity (Ref 5, 61, 75, 95). An RBC: FFP ratio of ≤ 2:1 was reported to be associated with reduced mortality (Ref 61, 75). However, this outcome is potentially confounded by survivor bias. No studies investigated the use of fibrinogen or cryoprecipitate as an intervention.

References (from PBM Guidelines: Module 1 Critical Bleeding / Massive Transfusion):

Ref 4: Cotton BA, Au BK, Nunez TC, Gunter OL, Robertson AM and Young PP (2009). Predefined massive transfusion protocols are associated with a reduction in organ failure and postinjury complications. Journal of Trauma 66(1):41–48. http://www.ncbi.nlm.nih.gov/pubmed/19131804

Ref 5: Dente CJ, Shaz BH, Nicholas JM, Harris RS, Wyrzykowski AD, Patel S, Shah A, Vercruysse GA, Feliciano DV, Rozycki GS, Salomone JP and Ingram WL (2009). Improvements in early mortality and coagulopathy are sustained better in patients with blunt trauma after institution of a massive transfusion protocol in a civilian level I trauma center. Journal of Trauma 66(6):1616–1624. http://www.ncbi.nlm.nih.gov/pubmed/19509623

Ref 15: Mitra B, Mori A, Cameron PA, Fitzgerald M, Street A and Bailey M (2007). Massive blood transfusionand trauma resuscitation. Injury 38(9):1023-1029.http://www.ncbi.nlm.nih.gov/pubmed/17572415

Ref 61: Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, Sebesta J, Jenkins D,Wade CE and Holcomb JB (2007). The ratio of blood products transfused affects mortality in patientsreceiving massive transfusions at a combat support hospital. Journal of Trauma 63(4):805-813.http://www.ncbi.nlm.nih.gov/pubmed/18090009

Ref 64: Gonzalez EA, Moore FA, Holcomb JB, Miller CC, Kozar RA, Todd SR, Cocanour CS, Balldin BC and

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McKinley BA (2007). Fresh frozen plasma should be given earlier to patients requiring massivetransfusion. Journal of Trauma 62(1):112-119. http://www.ncbi.nlm.nih.gov/pubmed/17215741

Ref 65: Stinger HK, Spinella PC, Perkins JG, Grathwohl KW, Salinas J, Martini WZ, Hess JR, Dubick MA,Simon CD, Beekley AC, Wolf SE, Wade CE and Holcomb JB (2008). The ratio of fibrinogen to red cellstransfused affects survival in casualties receiving massive transfusions at an army combat supporthospital. Journal of Trauma 64(2 Suppl):S79-85.http://www.ncbi.nlm.nih.gov/pubmed/18376176

Ref 68: Moore FA, Nelson T, McKinley BA, Moore EE, Nathens AB, Rhee P, Puyana JC, Beilman GJ and CohnSM (2008). Massive transfusion in trauma patients: tissue hemoglobin oxygen saturation predictspoor outcome. Journal of Trauma 64(4):1010-1023.http://www.ncbi.nlm.nih.gov/pubmed/18404069

Ref 70: Cinat ME, Wallace WC, Nastanski F, West J, Sloan S, Ocariz J and Wilson SE (1999). Improved survival following massive transfusion in patients who have undergone trauma. Archives of Surgery 134(9):964–968.http://www.ncbi.nlm.nih.gov/pubmed/10487591

Ref 71: Gunter OL, Jr., Au BK, Isbell JM, Mowery NT, Young PP and Cotton BA (2008). Optimizing outcomes in damage control resuscitation: identifying blood product ratios associated with improved survival. Journal of Trauma 65(3):527–534.http://www.ncbi.nlm.nih.gov/pubmed/18784564

Ref 75: Duchesne JC, Hunt JP, Wahl G, Marr AB, Wang YZ, Weintraub SE, Wright MJ and McSwain NE, Jr.(2008). Review of current blood transfusions strategies in a mature level I trauma center: were wewrong for the last 60 years? Journal of Trauma 65(2):272-276.http://www.ncbi.nlm.nih.gov/pubmed/18695461

Ref 76: Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, Gonzalez EA, PomperGJ, Perkins JG, Spinella PC, Williams KL and Park MS (2008). Increased plasma and platelet to redblood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Annals ofSurgery 248(3):447-458.http://www.ncbi.nlm.nih.gov/pubmed/18791365

Ref 78: Maegele M, Lefering R, Paffrath T, Tjardes T, Simanski C and Bouillon B (2008). Red-blood-cell toplasma ratios transfused during massive transfusion are associated with mortality in severemultiple injury: a retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft furUnfallchirurgie. Vox Sanguinis 95(2):112-119.http://www.ncbi.nlm.nih.gov/pubmed/18557827

Ref 79: Perkins JG, Andrew CP, Spinella PC, Blackbourne LH, Grathwohl KW, Repine TB, Ketchum L,Waterman P, Lee RE, Beekley AC, Sebesta JA, Shorr AF, Wade CE and Holcomb JB (2009). Anevaluation of the impact of apheresis platelets used in the setting of massively transfused traumapatients. Journal of Trauma 66(4 Suppl):S77-84.http://www.ncbi.nlm.nih.gov/pubmed/19359974

Ref 84: Snyder CW, Weinberg JA, McGwin G, Jr., Melton SM, George RL, Reiff DA, Cross JM, Hubbard-Brown J,Rue LW, 3rd and Kerby JD (2009). The relationship of blood product ratio to mortality: survival benefitor survival bias? Journal of Trauma 66(2):358-362.http://www.ncbi.nlm.nih.gov/pubmed/19204508

Ref 85: Sperry JL, Ochoa JB, Gunn SR, Alarcon LH, Minei JP, Cuschieri J, Rosengart MR, Maier RV, Billiar TR, Peitzman AB and Moore EE (2008). An FFP:PRBC transfusion ratio >/=1:1.5 is associated with a lower risk of mortality after massive transfusion. Journal of Trauma 65(5):986–993. http://www.ncbi.nlm.nih.gov/pubmed/19001962

Ref 89: Zink KA, Sambasivan CN, Holcomb JB, Chisholm G and Schreiber MA (2009). A high ratio of plasma and platelets to packed red blood cells in the first 6 hours of massive transfusion improves outcomes in a large ulticentre study. American Journal of Surgery 197(5):565–570.

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http://www.ncbi.nlm.nih.gov/pubmed/19393349

Ref 95: Bochicchio GV, Napolitano L, Joshi M, Bochicchio K, Meyer W and Scalea TM (2008). Outcome analysis of blood product transfusion in trauma patients: a prospective, risk-adjusted study. World Journal of Surgery 32(10):2185-2189.http://www.ncbi.nlm.nih.gov/pubmed/18575931

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References

Patient Blood Management Guidelines: Module 2 Perioperative Practice points:

Practice Point 17 - In general, patients with a platelet count ≥50 × 109/L or an INR ≤2 can undergo invasive procedures without any serious bleeding; however, lower platelet counts and higher INRs may be tolerated.

Practice Point 18 - Specialist guidelines or haematology advice should be sought for at-risk patients undergoing intracranial, intraocular and neuraxial procedures, and for patients with severe thrombocytopenia or coagulopathy.

Practice Point 19 - The prophylactic use of platelets after cardiac surgery is not supported.

Literature Review

The systematic review identified 16 relevant studies (6 Level II and 10 Level III, of fair to good quality) examining the effect of abnormal coagulation parameters on outcomes in patients undergoing surgery or invasive procedures (Ref 241- 255). These studies included a diverse range of invasive procedures, including biopsies (visceral, endoscopic and laparoscopic), central venous cannulation, lumbar puncture, nephrostomy and femoral arteriography. There was insufficient evidence to define a threshold platelet count, fibrinogen level or INR that is associated with significant adverse events (Ref 241-255). Worsening thrombocytopenia may be associated with an increase in minor bleeding complications (Ref 242, 243, 248, 252, 256). Appendix E

Three fair-quality Level III studies that investigated the effect of platelet transfusion on patient outcomes in a perioperative population were identified (Ref 259 -261). All studies were in cardiac surgery patients. The largest and smallest of these studies demonstrated an association between the administration of platelets, and hospital mortality and morbidity (Ref 260, 261). The remaining study did not demonstrate this association (Ref 259).

References (from PBM Guidelines: Module 2 Perioperative):

Ref 241: Dillon JF, Simpson KJ and Hayes PC (1994). Liver biopsy bleeding time: an unpredictable event. Journal of gastroenterology and hepatology 9(3):269-271.http://www.ncbi.nlm.nih.gov/pubmed/8054526

Ref 242: Doerfler ME, Kaufman B and Goldenberg aS (1996). Central venous catheter placement in patients with disorders of hemostasis. Chest 110(1):185-188.http://www.chestjournal.org/cgi/doi/10.1378/chest.110.1.185

Ref 243: Fisher NC and Mutimer DJ (1999). Central venous cannulation in patients with liver disease and coagulopathy--a prospective audit. Intensive care medicine 25(5):481-485.http://www.ncbi.nlm.nih.gov/pubmed/10401942

Ref 244: Foster PF, Moore LR, Sankary HN, Hart ME, Ashmann MK and Williams JW (1992). Central venous catheterization in patients with coagulopathy. Archives of Surgery 127(3):273-275.http://www.ncbi.nlm.nih.gov/pubmed/1550472

Ref 245: Howard SC (2000). Safety of lumbar puncture for children with acute lymphoblastic leukemia and thrombocytopenia. Journal of the American Medical Association 284(17):2222-2224.http://jama.ama-assn.org/cgi/doi/10.1001/jama.284.17.2222

Ref 246: Mainwaring CJ, Natarajan A, Peckham C, Readett D, Singhal R, Vazzalwar R, et al. (Untreated thrombocytopenia and lumbar puncture-related bleeding risk at diagnosis of childhood acute lymphoblastic leukemia (ALL) [abstract]. In: Poster Presentations, Conference of the British Society for Haematology; April 27–30 1998; Glasgow, Scotland.

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Ref 247: Martin JH, Rosser CJ, Linebach RF, McCullough DL and Assimos DG (2000). Are coagulation studies necessary before percutaneous nephrostomy? Techniques in urology 6(3):205-207.http://www.ncbi.nlm.nih.gov/pubmed/10963488

Ref 248: McVay PA and Toy PT (1990). Lack of increased bleeding after liver biopsy in patients with mild hemostatic abnormalities. American journal of clinical pathology 94(6):747-753.http://www.ncbi.nlm.nih.gov/pubmed/2123077

Ref 249: Misra S, Gyamlani G, Swaminathan S, Buehrig CK, Bjarnason H, McKusick MA, et al. (2008). Safety and diagnostic yield of transjugular renal biopsy. Journal of Vascular and Interventional Radiology 19(4):546-551.http://www.ncbi.nlm.nih.gov/pubmed/18375299

Ref 250: Ray CE and Shenoy SS (1997). Patients with thrombocytopenia: outcome of radiologic placement of central venous access devices. Radiology 204(1):97-99.http://www.ncbi.nlm.nih.gov/pubmed/9205228

Ref 251: Ruell J, Karuvattil R, Wynn R and Will A (2007). Platelet count has no influence on traumatic and bloody lumbar puncture in children undergoing intrathecal chemotherapy. British journal of haematology 136(2):347-348.http://www.ncbi.nlm.nih.gov/pubmed/17156399

Ref 252: Vavricka SR, Walter RB, Irani S, Halter J and Schanz U (2003). Safety of lumbar puncture for adults with acute leukemia and restrictive prophylactic platelet transfusion. Annals of hematology 82(9):570-573.http://www.ncbi.nlm.nih.gov/pubmed/12904898

Ref 253: Weigand K, Encke J, Meyer FJ, Hinkel UP, Munder M, Stremmel W, et al. (2009). Low levels of prothrombin time (INR) and platelets do not increase the risk of significant bleeding when placing central venous catheters. Medizinische Klinik 104(5):331-335.http://www.ncbi.nlm.nih.gov/pubmed/19444412

Ref 254: Weiss SM, Hert RC, Gianola FJ, Clark JG and Crawford SW (1993). Complications of fiberoptic bronchoscopy in thrombocytopenic patients. Chest 104(4):1025-1028.http://www.ncbi.nlm.nih.gov/pubmed/8404159

Ref 255: Wolf AT, Wasan SK and Saltzman JR (2007). Impact of anticoagulation on rebleeding following endoscopic therapy for nonvariceal upper gastrointestinal hemorrhage. American Journal of Gastroenterology 102(2):290-296.http://www.ncbi.nlm.nih.gov/pubmed/17100959

Ref 256: Darcy MD, Kanterman RY, Kleinhoffer MA, Vesely TM, Picus D, Hicks ME, et al. (1996). Evaluation of coagulation tests as predictors of angiographic bleeding complications. Radiology 198(3):741-744.http://www.ncbi.nlm.nih.gov/pubmed/8628863

Ref 257: Casbard AC, Williamson LM, Murphy MF, Rege K and Johnson T (2004). The role of prophylactic fresh frozen plasma in decreasing blood loss and correcting coagulopathy in cardiac surgery. A systematic review. Anaesthesia 59(6):550-558.http://www.ncbi.nlm.nih.gov/pubmed/15144294

Ref 258: Sarani B, Dunkman WJ, Dean L, Sonnad S, Rohrbach JI and Gracias VH (2008). Transfusion of fresh frozen plasma in critically ill surgical patients is associated with an increased risk of infection. Critical care medicine 36(4):1114-1118.http://www.ncbi.nlm.nih.gov/pubmed/18379235

Ref 259: Karkouti K, Wijeysundera DN, Yau TM, Callum JL, Meineri M, Wasowicz M, et al. (2006). Platelet transfusions are not associated with increased morbidity or mortality in cardiac surgery. Canadian Journal of

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Anesthesia 53(3):279-287.http://www.ncbi.nlm.nih.gov/pubmed/16527794

Ref 260: McGrath T, Koch CG, Xu M, Li L, Mihaljevic T, Figueroa P, et al. (2008). Platelet transfusion in cardiac surgery does not confer increased risk for adverse morbid outcomes. Annals of Thoracic Surgery 86(2):543-553.http://www.ncbi.nlm.nih.gov/pubmed/18640332

Ref 261: Spiess BD, Royston D, Levy JH, Fitch J, Dietrich W, Body S, et al. (2004). Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes. Transfusion 44(8):1143-1148.http://www.ncbi.nlm.nih.gov/pubmed/15265117

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Patient Blood Management Guidelines: Module 3 MedicalRecommendations:

Recommendation 8 - In patients undergoing chemotherapy and haematopoietic stem cell transplantation, the recommended strategy for prophylactic use of platelets is transfusion at a platelet count of <10 × 109/L in the absence of risk factors, and at <20 × 109/L in the presence of risk factors (e.g. fever, minor bleeding).

Practice Points:

Practice Point 20 - Platelet transfusion may be indicated for the prevention and treatment of haemorrhage in patients with thrombocytopenia or platelet function defects. Platelet transfusions are not indicated in all causes of thrombocytopenia, and may be contraindicated in certain conditions (e.g. TTP and HIT). Thus, the cause of the thrombocytopenia should be established and expert opinion sought.

Practice Point 21 - In patients with chronic failure of platelet production (e.g. myelodysplasia or aplastic anaemia), a specific threshold for transfusion may not be appropriate. These patients are best managed on an individual basis, in consultation with a relevant expert. Long-term prophylactic platelet transfusions may be best avoided because of the risk of complications (e.g. alloimmunisation and platelet refractoriness). Therapeutic platelet transfusions could be considered for treatment of bleeding.

Practice Point 22 - In patients undergoing chemotherapy and haematopoietic stem cell transplantation, there is no evidence to support a lower trigger for prophylactic platelet transfusion for patients with risk factors (e.g. fever, minor bleeding) or a strategy of therapeutic-only platelet transfusions (i.e. for treatment of clinically significant bleeding). Further research to determine the safety and efficacy of a lower platelet transfusion trigger is underway.

Literature Review:

Platelet transfusion is a therapeutic intervention used for the prevention and treatment of bleeding in patients with thrombocytopenia or significant platelet dysfunction. The different methods for producing platelets result in differences in the final products (e.g. in dose and risk profile); this should be taken into account when comparing studies. The focus of this systematic review was to first compare prophylactic and therapeutic transfusion strategies, and then compare different platelet transfusion doses.

Prophylactic and therapeutic transfusion strategies

A small number of eligible studies were identified; all involved patients with cancer, including haematological malignancies. Thrombocytopenia was most commonly due to chemotherapy or stem cell transplantation. One additional study was a multivariate analysis of association between transfusions and venous thromboembolism,

arterial thromboembolism and mortality in a broad population of hospitalised patients with cancer (Ref 90). No studies were found that included populations of special interest, such as patients receiving treatment with antifibrinolytic or antiplatelet therapy.

In patients with haematological malignancies receiving chemotherapy, mortality was reported in two

studies: an RCT (Level II) (Ref 131) that was inadequately powered to detect any clinically or statistically

significant differences, and a cohort study (Level IV) (Ref 132) that did not report any comparative data, but reported a mortality rate of 4.3% in patients receiving platelet transfusions.

The cohort study (Level III-2) in a broad population of hospitalised cancer patients (Ref 90) found that platelet transfusion was independently associated with in-hospital mortality, and venous and arterial thromboembolism. This study controlled for a range of variables; however, as a cohort study, it could not establish causality.

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Clinical guidance3

Two studies reported the incidence of bleeding events. One RCT (Level II) (Ref 133) reported no significant

difference between study arms, and one cohort study (Level IV) (Ref 132) found an incidence rate of 58.0% for grade 2 bleeding and 5.1% for grade 3 – 4 bleeding.

Four cohort studies reported the incidence of transfusion-related adverse events in patients receiving platelet transfusions (Ref 132,134-136). The incidences of adverse events ranged widely between studies. However, these discrepancies can probably be accounted for by differences in the study populations and the type of platelet product transfused.

Platelet transfusion doses

Five RCTs (Level II) assessed platelet dose in patients with haematological malignancies receiving chemotherapy (Ref 137-141). The definitions of thrombocytopenia and the assessed dose ranges varied widely

between the studies. Mortality was reported in only one study (Ref 137); this study found no significant difference between any of the assessed platelet doses, but was underpowered.

Four studies reported the incidence of bleeding events. Slichter et al (Ref 137) and Heddle et al (ref 138)

found no significant difference between study arms in any of the dose comparisons presented. Tinmouth et al found a higher risk of experiencing a minor bleed in patients receiving three platelet units than five platelet units, but no significant difference between different platelet doses for the incidence of major bleeds (Ref 139). The study by Sensebé et al was underpowered to detect an effect of platelet dose on the incidence of haemorrhage (ref 141).

There was no significant difference between study arms in the two studies that reported the incidence of transfusion-related serious adverse events (ref 132, 137). However, the overall rate of serious adverse events was relatively high in both studies.

There is controversy over the benefit of using FFP, cryoprecipitate and platelet concentrates to improve haemostasis in both procedural and non-procedural settings. In the absence of high-quality evidence, clinicians have traditionally relied on laboratory indexes for making decisions about transfusion of these products. The systematic review considered purported ‘transfusion-trigger’ levels of these various indexes, excluding studies of patients with massive bleeding or requiring warfarin reversal.

The use of prophylactic platelet transfusions in patients receiving myelosuppressive chemotherapy or undergoing allogeneic haematopoietic stem cell transplantation (HSCT) is significant. It currently accounts for most of the platelet concentrate usage in Australia. In this clinical setting – in the absence of acute bleeding or the need for an invasive procedure – prophylactic platelet transfusion is usually guided by platelet counts. The review examined studies concerning platelet count and bleeding risk, together with the intervention of platelet transfusion, but excluded studies in perioperative or acute bleeding settings.

The review identified four RCTs (Level II) comparing different platelet transfusion triggers. Three studies (ref

147-149) compared a platelet transfusion trigger of 10 × 109/L with one of 20 × 109/L. Another study used 30

× 109/L as the higher trigger (Ref 150). Of these studies, three (ref 147, 14, 150) did not demonstrate a significant difference in mortality between the two study arms. These three studies reported bleeding events, but none observed a significant difference in bleeding rates between the two study arms, nor in bleeding rates in relation to a more restrictive platelet transfusion trigger. RBC transfusion rates were reported in all four studies. None of the studies demonstrated significant differences in number of RBC units transfused, or in the number of transfusions, between study arms.

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ReferencesF

Based on these results, in patients undergoing myelosuppressive chemotherapy or HSCT, the

recommended strategy for prophylactic platelet transfusion is at a platelet count of <10 × 109/L in the

absence of risk factors, and at <20 × 109/L in the presence of risk factors (see recommendation R8 above).

There is no evidence at this time to support a lower threshold for prophylaxis, or for the absence of prophylaxis. However, these questions are the current focus of two major international RCTs.

References (from PBM Guidelines: Module 3 Medical):

Ref 14: National Health and Medical Research Council (NHMRC) (2009). NHMRC levels of evidence and grades for recommendations for developers of guidelines, NHMRC, Canberra, Australia. http://www.nhmrc.gov.au/guidelines/consult/consultations/add_levels_grades_dev_ guidelines2.htm

Ref 90: Khorana AA, Francis CW, Blumberg N, Culakova E, Refaai MA and Lyman GH (2008). Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer. Archives of Internal Medicine 168(21):2377 – 2381.http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L352743994,http://archinte.ama-assn.org/cgi/reprint/168/21/2377

Ref 131: Solomon J, Bofenkamp T, Fahey JL, Chillar RK and Beutel E (1978). Platelet prophylaxis in acute non-lymphoblastic leukaemia. Lancet 1:267.

Ref 132: McCullough J, Vesole DH, Benjamin RJ, Slichter SJ, Pineda A, Snyder E, et al. (2004). Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: The SPRINT trial. Blood 104(5):1534 – 1541.http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L39166535

Ref 133: Higby DJ, Cohen E, Holland JF and Sinks L (1974). The prophylactic treatment of thrombocytopenic leukemic patients with platelets: A double blind study. Transfusion 14(5):440 – 446.http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L5164451

Ref 134: Heim D, Passweg J, Gregor M, Buser A, Theocharides A, Arber C, et al. (2008). Patient and product factors affecting platelet transfusion results. Transfusion 48(4):681 – 687.http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L351430354

Ref 135: Osselaer JC, Messe N, Hervig T, Bueno J, Castro E, Espinosa A, et al. (2008). A prospective observational cohort safety study of 5106 platelet transfusions with components prepared with photochemical pathogen inactivation treatment. Transfusion 48(6):1061 – 1071.http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L351793479

Ref 136: Slichter SJ (1997). Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. New England Journal of Medicine 337(26):1861 – 1869.http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L28053025

Ref 137: Slichter SJ, Kaufman RM, Assmann SF, McCullough J, Triulzi DJ, Strauss RG, et al. (2010). Dose of prophylactic platelet transfusions and prevention of hemorrhage. New England Journal of Medicine 362(7): 600 - 613. http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L358334244

Ref 138: Heddle NM, Cook RJ, Tinmouth A, Kouroukis CT, Hervig T, Klapper E, et al. (2009). A randomized controlled trial comparing standard- and low-dose strategies for transfusion of platelets (SToP) to patients with thrombocytopenia. Blood 113(7):1564 – 1573.http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L354286700

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Ref 139: Tinmouth A, Tannock IF, Crump M, Tomlinson G, Brandwein J, Minden M, et al. (2004). Low-dose prophylactic platelet transfusions in recipients of an autologous peripheral blood progenitor cell transplant and patients with acute leukemia: A randomized controlled trial with a sequential Bayesian design. Transfusion 44(12):1711 – 1719.http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L39644055

Ref 140: Goodnough LT, Kuter DJ, McCullough J, Slichter SJ, DiPersio J, Romo J, et al. (2001). Prophylactic platelet transfusions from healthy apheresis platelet donors undergoing treatment with thrombopoietin. Blood 98(5):1346 – 1351.http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L35119599

Ref 141: Sensebé L, Giraudeau B, Bardiaux L, Deconinck E, Schmidt A, Bidet ML, et al. (2005). The efficiency of transfusing high doses of platelets in hematologic patients with thrombocytopenia: Results of a prospective, randomized, open, blinded end point (PROBE) study. Blood 105(2):862 – 864.http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L40070776

Ref 147: Rebulla P, Finazzi G, Marangoni F, Avvisati G, Gugliotta L, Tognoni G, et al. (1997). The threshold for prophylactic platelet transfusion in adults with acute myeloid leukemia. New England Journal of Medicine 337:1870 – 1875.

Ref 148: Heckman KD, Weiner GJ, Davis CS, Strauss RG, Jones MP and Burns CP (1997). Randomized study of prophylactic platelet transfusion threshold during induction therapy for adult acute leukemia: 10 000/microL versus 20 000/microL. Journal of Clinical Oncology 15:1143 – 1149.

Ref 149: Zumberg MS, Del Rosario MLU, Nejame CF, Pollock BH, Garzarella L, Kao KJ, et al. (2002).A prospective randomized trial of prophylactic platelet transfusion and bleeding incidence in hematopoietic stem cell transplant recipients: 10 000/(mu)L versus 20 000/(mu)L trigger. Biology of Blood and Marrow Transplantation 8(10):569 – 576.

Ref 150: Diedrich B, Remberger M, Shanwell A, Svahn BM and Ringden O (2005). A prospective randomized trial of a prophylactic platelet transfusion trigger of 10 109 per L versus 30 109 per L in allogeneic hematopoietic progenitor cell transplant recipients. Transfusion 45:1064 – 1072.

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Patient Blood Management Guidelines: Module 4 Critical CarePractice Points:

Practice Point 10 - The effect of platelet transfusion on transfusion-related serious adverse events is uncertain. The decision to transfuse platelets to an individual patient should take into account the relative risks and benefits.

Practice Point 11 - In critically ill patients, in the absence of acute bleeding, the administration of platelets may be considered appropriate at a platelet count of <20 × 109/L.

Practice Point 12 - Assessment of bleeding risk is complex and requires careful consideration of patients’ clinical status and laboratory parameters. Specialist haematology advice may also be required. However, patients with a platelet count ≥50 × 109/L can generally undergo invasive procedures within the ICU without any serious bleeding; lower platelet counts may be tolerated in certain clinical situations.

Literature Review:

The systematic review identified little evidence regarding the use of FFP, cryoprecipitate, fibrinogen concentrate and platelets in this population. The literature search identified evidence relating to the use of platelets in two critically ill populations, being trauma patients and critically ill elderly patients.

Three poor-quality prospective cohort studies were identified that assessed the use of platelets in trauma patients (Ref 12, 49, 50). Of the two studies that reported the association between platelet transfusion and

mortality, (Ref 12, 50) neither found a significant association, although one of these studies (Ref 12) was probably underpowered. Transfusion-related serious adverse events were reported in all three included

studies; however, only one study (Ref 49) reported that platelet transfusion was independently associated with a range of transfusion-related serious adverse events.

One retrospective cohort study (Level III) studied the effects of platelet transfusion in 122 medical ICU

patients (Ref 21). This study found that platelet transfusion was significantly and independently associated with ARDS or ALI.

References (from PBM Guidelines: Module 4 Critical Care):

Ref 12: Bochicchio GV, Napolitano L, Joshi M, Bochicchio K, Meyer W and Scalea TM (2008). Outcome analysis of blood product transfusion in trauma patients: A prospective, risk-adjusted study. World Journal of Surgery 32(10):2185–2189.http://www.ncbi.nlm.nih.gov/pubmed/18575931

Ref 21: Khan H, Belsher J, Yilmaz M, Afessa B, Winters JL, Moore SB, et al. (2007). Fresh-frozen plasma and platelet transfusions are associated with development of acute lung injury in critically ill medical patients. Chest 131(5):1308–1314.http://www.ncbi.nlm.nih.gov/pubmed/17400669

Ref 49: Bochicchio GV, Napolitano L, Joshi M, Bochicchio K, Shih D, Meyer W, et al. (2008). Blood product transfusion and ventilator-associated pneumonia in trauma patients. Surgical Infections 9(4):415–422.http://www.ncbi.nlm.nih.gov/pubmed/18759678

Ref 50: Watson GA, Sperry JL, Rosengart MR, Minei JP, Harbrecht BG, Moore EE, et al. (2009). Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute respiratory distress syndrome. Journal of Trauma - Injury, Infection and Critical Care 67(2):221–227.http://www.ncbi.nlm.nih.gov/pubmed/19667872

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Patient Blood Management Guidelines: Module 5 &6

Obstetrics and Paediatrics/ Neonates modules are yet to be developed.

D2: Other literature

1. Stanworth SJ et al. The Effect of a No-Prophylactic Versus Prophylactic Platelet Transfusion Strategy On Bleeding in Patients with Hematological Malignancies and Severe Thrombocytopenia (TOPPS trial). A Randomized Controlled, Non-Inferiority Trial. 54th ASH Annual Meeting Plenary Scientific Session 2012. Available at https://ash.confex.com/ash/2012/webprogram/Session4376.html

The results of the TOPPS trial were presented at the American Society of Haematology (ASH) Annual Meeting in December 2012. TOPPS aimed to test the hypotheseis that a policy of no prophylactic platelet transfusions is as effective and safe as a policy of prophylactic platelet transfusions in patients with haematological malignancies and severe thrombocytopenia. The trial was a randomised, parallel group, open-label, non-inferiority trial, with 600 patients recruited from 14 UK and Australian hospitals over a 5 year period between August 2006 and August 2011. The primary outcome was the proportion of patients with a clinically significant bleeding up to 30 days from randomisation. The study results did not prove that a policy of no prophylaxis platelet transfusions is non-inferior to a policy of prophylactic platelet transfusions. Clinically significant bleeding (WHO Grade 2-4) occurred in 50% of patients in the no prophylaxis group versus 43% of the patients in the prophylaxis group (p value for non-inferiority 0.06). Patients in the no prophylaxis group had a shorter time to their first bleed, and had more days with WHO Grade 2-4 bleeding (1.7 versus 1.2 days). Whilst patients in the no prophylaxis group had more WHO Grade 3-4 bleeds, this did not reach statistical significance.

2. Stanworth SJ. Thrombocytopenia, bleeding, and use of platelet transfusions in sick neonates. Hematology Am Soc Hematol Educ Program 2012; 2012: 512-6.

This presentation by Simon Stanworth from ASH 2012 notes that in the United Kingdom, a telephone survey of all tertiary level neonatal units has shown variations in platelet transfusion practice, and the most common thresholds for transfusion in healthy or stable term and preterm infants were 25 x 109/L and 30 x109/L, respectively.

3. BSCH Transfusion guidelines for neonates and older children. British Journal of Haematology 2004; 124: 433- 453.

Thrombocytopenia is common in sick preterm infants and is associated with an increased risk of severe periventricular bleeding (PVH) (Andrew et al , 1987 ). However, the administration of platelets to manage moderate thrombocytopenia (platelets 50–100 × 109/l) did not appear to reduce the severity of bleeding (Andrew et al , 1993 ). In the absence of randomized, controlled trials in this patient group, recommendations for platelet transfusion must be made on the basis of clinical experience. Term infants are unlikely to bleed if the platelet count is maintained above 20 × 109/l but in small, preterm babies a higher threshold is generally recommended, particularly during the first few days when the risk of PVH is highest or if there is a co-existent coagulopathy ( level IV evidence, grade C recommendation). In neonatal alloimmune thrombocytopenia, HPA-compatible platelets will be required, in addition to high dose intravenous immunoglobulin. In these patients, a minimum platelet count of 30 × 109/l is recommended because the HPA antibody can impair platelet function (level IV evidence, grade C recommendation) (see also British Committee for Standards in Haematology, 2003b; Table III). Recommendations from Table III for transfusion thresholds for administration of platelets include: Preterm or term neonate with bleeding (50 × 109/l); Sick preterm or term infant not bleeding (30 × 109/l); Stable preterm or term infant not bleeding (20× 109/l).

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4. Ruggenenti P, Noris M & Remuzzi G. Thrombotic microangiopathy, haemolytic uraemic syndrome, and thrombotic thrombocytopaenic purpura. Kidney International 2001; 60(3): 831-846.

There are some case reports regarding the use of platelets in patients with HUS and TTP to cover invasive procedures that cannot be postponed until the underlying disease has been resolved (e.g. central line placement for plasma exchange therapy).

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