Platelet transfusions A continuing challenge Irene Sadek Head, Division of Hematopathology Department of Pathology and Laboratory Medicine QEII Health Sciences Centre Professor of Pathology Dalhousie University

Objectives Indication for transfusion Platelet products Increased utilization Platelet inventory challenges Platelet refractoriness.

Platelet role and function Main function of platelets is to mediate primary hemostasis. They circulate in blood close to vessel walls until exposed to subendothelial matrix following injury to a blood vessel. Initially platelet binding occurs via the integrin α2β1 (the GP Ia/IIa receptor) and GP VI to the exposed subendothelial collagen. This stimulates transmembrane and intracellular signaling. vWF immobilized in the subendothelial collagen binds GP Ib/IX/V under high shear rates, causing platelet adhesion. Platelets undergo shape change increasing the area of surface contact. Alpha and dense storage granules are release producing a high concentration of procoagulant molecules at the site of injury. Coag cascade is initiated. Thrombin (most potent plt aggregating agent) is produced on the surface of the procoagulant surface of platelets. Plts aggregate together via integrin α2bβ3 (GP IIb/IIIa), binding fibrinogen= plt plug, and eventual fibrin clot. http://physrev.physiology.org/content/93/1/327

Thrombocytopenia Platelet count N=150.000-350.000 >50.000 20-50.000 10-20.000 5-10.000 <5.000 *Gaydos et al, N Engl J MEd 1962 Frequency of bleeding episodes asymptomatic rare, easy bruisability.... 38% of days 50% of days 65-92% of days.

Relation of bleeding risk to blood platelet count: computed per 1000 days at risk *Gmur et al , Lancet 1991

Thrombocytopenia

Causes of thrombocytopenia Decrease production Inc. destruction Sequestration BM aplasia Immune auto, allo Splenomegaly Infiltration Infection MDS Drugs Storage disease Toxic / Meds Non immune Malignancy Nutritional deficiency Sepsis RBC disorders infection MAHA Congestions Malignant hypertension

Indications for Plt transfusion Canadian Blood Services Clinical Guide There is limited high quality evidence to guide the use of platelet transfusions to treat bleeding. There is general agreement that the following patients should receive platelet transfusions. Patients with thrombocytopenia or platelet dysfunction to; Stop bleeding (therapeutic transfusion) Prevent bleeding (prophylactic transfusion)

Indications for Plt transfusion Patients with thrombocytopenia or platelet dysfunction to; Stop bleeding (therapeutic transfusion); consider cause! Pts with non-immune thrombocytopenia and clinically significant bleeding with platelet count < 50 x109/L. Immune mediated thrombocytopenia with severely reduced platelet count (<20 x 109/L) and significant bleeding. Head trauma or life threatening hemorrhage with a platelet count <100 x 109/L. Plt dysfunction from congenital or acquired causes (GABG, PHV, MDS, SLE, HCL) and clinically significant bleeding. As part of a massive transfusion protocol in bleeding patients. It’s important to consider the cause; in TTP and HIT, plt transfusion may increase thrombotic risk Acquired plt storage pool disorder due to antibody or contact initiated platelet activation and secretion of granule contents; Autoimmune, CABG, prosthetic heart valve, HCL, MDS).

Indications for Plt transfusion Patients with thrombocytopenia or platelet dysfunction to; Prevent bleeding (prophylactic transfusion) Hospitalized patients with therapy-induced hypoproliferative thrombocytopenia with a platelet count of ≤10x109/L. Elective central line with platelet count <20x109/L. Elective LP with platelet count <50x109/L. Major elective non-neuroaxial surgery with a platelet count <50x109/L. Neuroaxial surgery with a platelet count <100x109/L. Consider transfusion for patients undergoing CABG who exhibit peri-op bleeding with thrombocytopenia and/or evidence of platelet dysfunction.

Platelet Products Buffy coat method providing pooled platelets from 4 donors. Whole blood is collected, spun and platelets are separated from plasma and RBC. 4 units of platelets from same group donors are pooled and suspended in plasma from 1 of the male donors. Platelet count: >240x109/unit in ≥75% of units tested. https://professionaleducation.blood.ca/en/transfusion/clinical-guide/platelet-transfusion-alloimmunization-and-management-platelet

Platelet products Apheresis method providing platelets from a single donor. Platelet unit collected from a single donor using apheresis. Blood is drawn and separated into components by centrifuge. Platelets are collected while RBC and plasma are returned to donor. Platelet count: ≥300x109/unit in ≥75% of units tested https://simonsylvester.wordpress.com/

Platelet products Both products are used interchangeably Both are leukoreduced (containing <5 x106 leukocytes in all units tested), Contain <2mL RBC, Tested for bacteria, and are equivalent in most patients. Only absolute indication for apheresis platelets is the provision of matched platelets for patients with; Documented anti-platelet antibodies (either anti-HLA or anti-HPA antibodies), AND Allo-immune platelet refractoriness or post-transfusion purpura.

Platelets products 1 unit of platelets is expected to increase the platelet count by an average of 15-30 x 109/L. *Depends on underlying cause of thrombocytopenia, comorbidities and patient size. Platelets express ABH antigens (often at very high levels), but not Rh antigens.

2014/2015 Total PLT: 91,937 2015-2016 Total PLT: 94,145

790,854 PLT transfusions during the study period APCs were associated Apheresis platelets are more frequently associated with adverse reactions than pooled platelets both in recipients and in donors: a study from French hemovigilance data. Daurat A et al Transfusion. 2016 Jun;56(6):1295-303 790,854 PLT transfusions during the study period (477,747 [60%] with APCs, 313,107 [40%] with PPCs). APCs were associated with more adverse reactions (6244 vs. 2469 per 1,000,000, p < 0.001) and more severe and life-threatening reactions (respectively, 241 vs. 131 per 1,000,000, p < 0.001; and 182 vs. 121 per 1,000,000, p = 0.04). Mortality rates due to an adverse transfusion reaction were similar (15 vs. 6 per 1,000,000, p = 0.5). Serious adverse reactions were more frequent for apheresis procedures than for WB donations (5445 vs. 803 per 1,000,000, p < 0.001).

Platelet utilization in Canada

Who receives platelets? The AABB Blood Survey Report 2013 Estcourt LJ. Transf Med 2014

Increase platelet demand Aging population Increased prevalence of certain diseases (particularly hematologic malignancies) Improved survival of patients diagnosed with hematologic Malignancies Increase in numbers of patients undergoing stem cell transplantation

Age of patient population receiving blood products

Increase platelet demand Canadian population: %>65 years, historical and projected.

Platelet demand Healthcare spending is increasing • Platelets for transfusion are expensive to produce – Estimated cost of platelets – Apheresis platelet unit: $502 – Pooled whole blood platelet dose: $197

Platelet challenges

Platelet transfusion challenges Short platelet shelf life 5 days Actually 3 days on hospital shelves Two inventory CMV negative and CMV unscreened ABO specific platelets Antibody titers testing Platelet outdate Platelet refractoriness

Current revision and proposed recommendation The National Advisory Committee recommends that CMV safe (leukoreduced) and CMV IgG seronegative products be considered equivalent except for Intrauterine transfusion.

Dual inventory challenge As of November 1, 2016. The central zone Blood transfusion service do not carry CMV neg blood products Only CMV safe / leukoreduced blood products Provincial guideline development is on going.

The Need for ABO Matched Platelet Transfusions: Why the Debate? - Dr. Nadine Shehata, Hematologist, Mount Sinai Hospital Blood Matters 2014

ABO mismatched platelets Arguments against Arguments for Decreased CCI Decreased platelet function No impact on actual clinical efficacy (seen in clinical trials) Increased risk of transfusion reactions (for example, hemolysis with minor incompatible transfusion) This risk might be decreased by the provision of group O platelets with “low” titres of anti-A and/or anti-B to non-group O recipients Decreased outdating

Provision of low titer platelets by CBS? Central zone practice ABO specific platelets in >90% transfusions. Provision of low titer platelets by CBS?

Longevity and Retransfusion Rates of Major ABO-Incompatible Platelets. Covello et al, AABB Oct 2016

Time to 1st retransfusion, quartiles Incompat. status N Q1 (h) Median (h) Q3 (h) p vs. Identical 1980 24.4 47.5 94.2 N/A Major 233 25.0 48.1 71.8 0.108 Minor 109 23.9 44.2 76.9 0.344 Both 29 25.5 47.1 72.5 0.865 2009-2015

Freedom from retransfusion at 120h 20.6% of patients receiving ABO-identical transfusions free from retransfusion at 120 hours Compare 13.3% of those receiving major incompatible transfusions (p = 0.008 vs identical). Minor incompatibility not associated with increased retransfusion rates at 120 hours (p = 0.57 vs. identical).

Platelet outdates and rates—National Background Platelet outdates and rates—National Last year, 22.6% of all donated platelets expired without being transfused Last year, 22.6% of all donated platelets expired without being transfused Check these numbers…why not the same as the previous graph

National: Outdate In-date CPU 2014/2015: 21,931 895 $3,175,524 (APLT) + 3,009,025 (PP) = $6,184,549 2015/2016: 21,888 894

Hospital customer letter: Platelet utilization and inventory management best practices CBS initiative • Includes information about: – Blood Groups – Redistribution – Standing orders/inventory review – Clinical practice

7 day platelets • This is in the proposal stage only CBS initiative 7 day platelets • This is in the proposal stage only • Requires submission to Health Canada • If approved, the project targets to go live by Spring or Summer 2017 • More to come on this!!!

Decrease platelet outdate Central zone will be working on a new platelet inventory tool similar to the red cell inventory tool.

Platelet refractoriness

Assessment of platelet transfusion response 1 unit of platelets is expected to increase the platelet count by an average of 15-30 x 109/L. Platelet increment: 2 hours after transfusions, 62% of platelet are in the circulation. Average patient expect plt increment of 7,000-10,000 Corrected count increment plt increment/ml X BSA # of plt transfused (10 11) CCI> 10.000 good response CCI= 7.5-10.000 satisfactory response CCI < 7.5 or 5.000 on 2 consecutive transfusions indicate platelet refractoriness

Platelet refractoriness

Alloimmunization to Platelets Class I HLA ag are the most antigenic. Antibodies 75% develop HLA ab. 20 % develop plt specific ab 5% develop both Require HLA matched platelets: More expensive preparation No available histocompatible donor 40-60 % are unsuccessful transfusions

Assessment of platelet transfusion response 1hr post-ABO matched platelet transfusion platelet count distinguish. Immune platelet destruction has greatest effect 10-120 min post-transfusion. Non-immune causes yield poor 16-24hr counts. A 1hr post-transfusion Corrected Count Increment <7.5 x 109/L on 2 separate occasions is evidence of Allo-Immune refractoriness.

Prevention of Alloimmunization to Platelets Advantage: Simplify transfusions Increase safety of intensive chemotherapy Decrease platelet utilization Decrease Cost.

Prevention of Alloimmunization to Platelets Can SDP overcome refractoriness? TRAP study in 1997 (NEJM) Blinded, randomized trial of 530 patients Patients receiving induction for AML Randomized to receive RDP Leukocyte reduced RDP Irradiated RDP SDP

Prevention of Alloimmunization to Platelets Can SDP overcome refractoriness? TRAP study in 1997 (NEJM) No significant difference between leukocyte reduced groups Leukocyte reduction as effective as the use of SDP for preventing refractoriness

Clinical and laboratory correlates of platelet alloimmunization and refractoriness in the PLADO trial. Vox Sanguinis 2016 The platelet dose (PLADO) trial; largest prospective, randomized trial of prophylactic platelet therapy. Analyzing platelet allo-immunization and refractoriness. 40 of 816 platelet-transfused patients became allo-immunized (5%). Higher rates associated with prior pregnancy, chemotherapy, and low platelet dose 102 of 734 patients who received at least 2 platelet transfusion, met criteria for refractoriness (14%), regardless of their allo-immunization status. Alloimmunization was present in only 8 of 102 (8%) of observed cases of refractoriness, suggesting non-immune causes are frequent Incidence of new platelet allo-immunization was low (F/U only 30 days), Patient records were examined for evidence of platelet allo-immunization, defined as an increase in HLA Class I panel-reactive antibodies (PRA) to ≥20%, and clinical refractoriness, defined as two consecutive ≤4 h post-transfusion corrected platelet count increments (CCI) of <5 x109. Non-immune causes; fever, infection, DIC/MAHA, hypersplenism, medications…

Algorithm for platelet refractoriness CBS clinical guide to transfusion includes published ICTMG guidelines. “International Collaboration for Transfusion Medicine Guidelines”

Increase platelet demand and platelet refractoriness

Objectives Indication for transfusion Platelet products Increased utilization Platelet inventory challenges Platelet refractoriness.

An on going challenge