1 donald m. arnold mdcm, frcpc assist professor, mcmaster university mcmaster platelet immunology...
TRANSCRIPT
1
Donald M. Arnold MDCM, FRCPCAssist professor, McMaster UniversityMcMaster Platelet immunology LaboratoryCBS Hamilton
1
2
“Difficulties with Platelet Transfusion, HLA Serology & Management of NAIT & PTT”
NomenclatureLimited evidenceVariability in practiceSerious illnessesCostly, potentially dangerous
treatments 2
3
Learning Objectives
1. Understand the mechanism of platelet antigen sensitization
2. Explore pathophysiology of: platelet refractoriness fetal or neonatal alloimmune
thrombocytopenia post-transfusion purpura
3. Discuss management of PLT refractoriness, FNAT and PTP
8
Chosen name, or name related to individual with antigen (PlA1, Zav, Gov).
Currently all antigens are designated as human platelet antigen (HPA).
Antigens numbered in order of discovery. Higher frequency allele is “a”.
e.g. PLA1 = HPA-1a, PLA2 = HPA-1b8
Nomenclature
9
To date, more than 22 platelet specific alloantigens identified, with 6 diallelic system (HPA-1, 2, 3, 4, 5, 15). Almost all are associated with a single amino acid substitution (SNP).
Antibodies against HPA-1a are most commonly implicated in NAT, PTP.
9
11
Definition 1h corrected count incr < 5 – 10 x109/L Percent PLT recovery <20% 1h CCI < 5 x109/L x2 using ABO-identical
fresh platelets A post-transfusion platelet count that is
less than expected
11
12
Immune Anti-HLA, anti-ABO, anti-HPA
Non-immune Fever Sepsis Splenomegaly DIC Bleeding VOD GVHD
12
13
Alloimmunization occurs after transfusion, pregnancy, transplantation.
Alloimmunization does not mean refractory
Strategies to reduce refractoriness:1. Leukoreduction2. Platelet dose?3. Apheresis vs. whole blood derived
platelets13
1717
Decline in PLT responsiveness
A: In all patients (n=6334 transfusions; 533 patients)
B: In HLA-antibody-negative patients (n= 5484 transfusions; 477 patients)
Slichter Blood 2005
24
Low platelets and bleeding in a fetus or neonate caused by maternal antibodies directed against fetal platelet antigens inherited from the father.
24
Definition:
2525
Incidence: 1 in 1,000 to 1 in 2,000 births
N Incidence
Burrows and Kelton, 1993 15,932 1 in 1,700
Uhrynowska, 2000 24,101 1 in 2,400
Turner, 2005 26,000 1 in 5,000
Kjeldsen-Kragh, 2007 100,448 1 in 1,700
FNAT
26
Most common cause of severe TCP in infant Most common cause of ICH in term newborns First pregnancies, without warning Otherwise healthy babies
26
27
Fetal platelet antigen: Inherited from father
Sensitization: Transplacental
Immunization: Mother forms IgG allo-antibodies
Maternal antibodies: React with fetal platelets
Fetal platelet destruction: Spleen and RES
27
29
<150,000 - 1 in 100< 50,000 - 1 in 400
Infection Immune mediated Chromosomal abnormalities
<20,000 - NAT
29
Burrows, Kelton 1993
30
NAT HDN
Affected cells Platelets Red blood cells
Most common antigen HPA-1a Rh-D
Affected pregnancy First Second +
Timing of sensitization 16 weeks onwards At birth, or during a procedure
Affected Infant TCP, bleeding Hemolysis, jaundice, kernicterus
Affected fetus ICH Hydrops fetalis
Main risk factor Previously affected infant Rh-negative mothers
Treatment Supportive Supportive
Prevention IVIG RhIg (anti-D)
Efficacy of prevention ? 99%
30Arnold et al, Trans Med Rev 2008
31
Present without warning Require prompt recognition and treatment IVIg (2g/kg)
Effective in 75% of affected neonatesMueller-Eckhardt C, Blut 1989
Platelet transfusions: Antigen-negative (maternal) platelets
Allen, Blood 2007
Random-donor plateletsKiefel et al Blood 2006
31
32
IVIg 1g/kg/wk (2g/kg/wk for refractory) IVIg + corticosteroids Intrauterine platelet transfusions Fetal blood sampling (FBS)
32
3333
High Risk (n= 40) Standard Risk (n= 39)
(previous ICH or PLT<20) (neither)
IVIg vs. IVIg + pred IVIg vs. pred
(1g/kg/wk) (1mg/kg) (1g/kg/wk) (0.5mg/kg)
PUBS (20 wks, repeat 3-8 wks)
Outcome: increase in fetal platelet count
Berkowitz, Bussel, 2006
34
HIGH RISK Mothers(platelet count)
Pre 2-8 wks Birth
IVIg alone* 7,000 17,00067,000
IVIg + pred 8,000 67,00099,000
* One ICH
34
Berkowitz, Bussel, 2006
35
STANDARD RISK Mothers*(platelet count)
Pre 3-8 wks
IVIg alone >20,000 31,000
Pred alone >20,000 26,000
* 2 fetal deaths, 2 ICH
35
Berkowitz, Bussel, 2006
37
IVIG Cochrane collaboration 2006
Corticosteroids Berkowitz, Bussel, 2006 Invasive vs. non-invasive approach?
37
• Fetal blood sampling• FBS + intrauterine PLT
transfusions• Cesarean section
• No FBS• Empiric treatment• Vaginal delivery
38
N= 100,448 pregnancies screened (for HPA-1a)
Offered early c/s with compatible platelets.
3 of 161 (6%) screen-positive infants died or had ICH; versus 10 of 51 (20%) unscreened infants.
Kjeldsen-Kragh J, Blood, 2007
38
40
Frequency: uncertain 1 per 2 million RBCs (2008, SHOT)
Adults (~50 years); females (5x)
PLT <15 x109/L, Bleeding ++
Onset: 9 days post blood transfusion
Recovery: 7 – 48 days after onset
Mortality ~10% (intracerebral hemorrhage)
41
Sensitization
Sensitization by previous transfusions, pregnancy
Usually HPA-1bb recipients
Other at risk HPA genotypes
43
Transfusion of incompatible PLTs Typically, anti-HPA-1a Abs Destroy transfused and autologous
PLTs Theories:
1. Immune complexes2. Adsorbed PLT antigens3. Concomitant auto-Abs
Further research needed
45
Summary
Platelet sensitization
HLA antibodies are ubiquitous, transient Example: PLT refractoriness
HPA antibodies are rare, persistent Examples: FNAT, PTP