1. 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

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

3. 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.

4. Thrombocytopenia
Platelet count N=
>50.000
<5.000
*Gaydos et al, N Engl J MEd 1962
Frequency of bleeding episodes asymptomatic rare, easy bruisability % of days 50% of days 65-92% of days.

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

6. Thrombocytopenia

7. 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

8. 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)

9. 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).

10. 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.

11. 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.

12. 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

13. 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.

14. Platelets products
1 unit of platelets is expected to increase the platelet count by an average of 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.

15. 2014/2015 Total PLT: 91,937
Total PLT: 94,145

16. 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 Jun;56(6):
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 per 1,000,000, p < ) and
more severe and life-threatening reactions (respectively, 241 vs 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 per 1,000,000, p < 0.001).

17. Platelet utilization in Canada

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

21. 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

22. Age of patient population receiving blood products

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

24. 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

25. Platelet challenges

26. 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

29. 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.

30. 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.

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

32. 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

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

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

35. 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

36. 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 = vs identical).
Minor incompatibility not associated with increased retransfusion rates at 120 hours (p = 0.57 vs. identical).

37. 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

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

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

40. 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!!!

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

42. Platelet refractoriness

43. Assessment of platelet transfusion response
1 unit of platelets is expected to increase the platelet count by an average of 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> good response
CCI= satisfactory response
CCI < 7.5 or on 2 consecutive transfusions indicate platelet refractoriness

44. Platelet refractoriness

45. 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

46. Assessment of platelet transfusion response
1hr post-ABO matched platelet transfusion platelet count distinguish.
Immune platelet destruction has greatest effect 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.

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

48. 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

49. 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

50. 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…

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

52. Increase platelet demand and platelet refractoriness

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

54. An on going challenge