Donor deferral due to intake of anti-platelet medication
Sharyn Orton, Ph.D.Jaro Vostal, M.D., Ph.D.
OBRR/CBER/FDA
Blood Products Advisory Committee Meeting
March 9, 2006
Background
Draft “Guidance for Industry and FDA
Review Staff: Collection of Platelets by
Apheresis Methods”, published 9/30/2005.
Included new proposed deferrals for some
medications.
Changes in platelet transfusion practice that drive revision of donor deferrals due to NSAIDs or anti-
platelet medication
• Higher percentage of single donor apheresis platelets transfused – if platelets are inactive could lead to decreased hemostatic
performance when transfused
• Whole blood derived platelets are transfused as a pool– if one platelet unit out of the pool is inactive there will be less
effect on the over-all performance of the pool
– However pools are getting smaller (4-6 vs 6-10 units per pool) which could lead to a higher percentage of the pool being inactive if one donor has anti-platelet medication
• Lower transfusion triggers (5-10,000 vs 20,000)
Proposed Deferrals for Donors
Aspirin (ASA)
ASA-containing drugs
5
Non-steroidal Anti-inflammatory Drugs
(NSAIDS)
3
Plavix (Clopidogrel) 5
Ticlid (Ticlopidine) 14
Medicine Days from last dose
Comments to the Docket
Aspirin:
• Not based on current practice
• No observed adverse patient events from
apheresis platelets collected 36 – 48 hours after aspirin ingestion (refs provided)
• Will result in significant donor loss
• 10-30% of unaffected platelets necessary for normal platelet function
continued
NSAIDs:
• Reference not peer reviewed
• Platelet effect is reversible
• Some have no platelet effect
• Will result in donor loss
Plavix, Ticlid:
• Deferral should be 24 and 48 hours
continued
General:
• Too restrictive
• Donors willing to stop medications for a few days, but not likely more than 3
Reversibility of anti-platelet effect is based on whether the drug effect on target enzyme is reversible or
irreversible• In the donor (drug recipient)
– Reversible: time to reversal of anti-platelet effect depends on last drug ingestion and 4-5 plasma T1/2 of drug
– Irreversible: need to replace affected platelets (~10% per day)• In the patient (platelet transfusion recipient)
– Reversible: the effect on platelets depends on rate of elution of drug out of platelets
– Irreversible: platelets will remain inhibited for duration of their life span.
Aspirin Aspirin-containing drugs
• Short plasma T1/2 (30 minutes)
• Irreversible inactivation of COX-1 and COX-2
• Platelets have COX -1 and are inactivated for duration of their life span
Non aspirin containing non steroidal anti-inflammatory drugs
• Reversibly inhibit both COX-1 and COX-2 or are selective for COX-2
• COX-2 selective inhibitors do not inhibit platelets
• Inhibition of COX-1 is reversed when drug is not present in plasma– 4-5 plasma T1/2 s post last ingestion– If treated platelets are placed in medium that
contains no inhibitors (i.e. transfused)
Anti platelet drugs
• Clopidogrel (Plavix) and Ticlopidine (Ticlid)
• Irreversibly block platelet ADP receptors and inhibit activation
• Plavix: Platelet effect to normal by 5 days
• Ticlid: Platelet effect to normal by 10 days
Assessment of ASA effect on platelets
• Aggregation– Inhibited by ASA– Aggregation alone is not predictive of platelet efficacy in vivo
• Skin bleeding time– Standard size cut on skin– Measure time to cessation of bleeding– Prolonged by ASA– Not predictive of surgical bleeding risk– Not used to predict platelet efficacy in vivo
• Clinical trial– Thrombocytopenic patients transfused with ASA inactivated
platelets– Bleeding (WHO bleeding scale) as endpoint – S59 treated platelets (SPRINT Trial)
Time (minutes)
% a
ggre
gati
on
agon
ist
agon
ist
Untreated ASA or NSAID treated
Strong agonist (thrombin, dual agonist (Epi+ADP)
Weak agonist (ADP or Epi alone)
Agonist –induced platelet aggregation
Deferral of non-aspirin platelet inhibitors
• Ideally, deferral period should be based on time to reversal of platelet inhibition in the recipient.
• When this is not known, deferral should be based upon reversibility rate (rate at which platelet function becomes normal in the donor after discontinuation of the drug, i.e. 4-5 T1/2 of drug in plasma)
• Platelet function assessed by single agonist induced aggregation
Zeiler, Thomas, Gritzka, Debora, Karger, Ralf & Kretschmer, VolkerThe effect of ASA on platelet activation during apheresis and on in-vitro
properties of stored platelet concentrates.Transfusion 44 (9), 1300-1305, 2004.
Agonist Before donation After donation
+ ASAGroup A
ControlGroup B
+ ASAGroup A
ControlGroup B
ADP (4 uM) 39+10 73+10 34+14 77+8
ADP (10 uM)
50+9 77+7 48+13 76+6
Collagen (4 ug/ml)
63+6 76+5 62+12 77+7
Arachidonic acid (500 ug/ml)
10+2 70+19 10+2 70+19
Donors
Apheresis Products
Group A = 500 mg ASA 12 hours prior to donationGroup B = no meds
Stuart et al. Platelet function in recipient of platelets from donors ingesting aspirin. NEJM 287; 1105-1109, 1972
Bleeding time in thrombocytopenic patients
0
5
10
15
20
25
No transfusion No meds ASA 600mg (12 + 1 hrs prior)
ASA 600mg (36 hrs prior)
Blee
ding
tim
e (m
inut
es)
Transfused platelets from donors with
ASA exposure
Bleeding time in normal humanm volunteers
0
1
2
3
4
5
6
7
8
No meds 1 hr 1 day 2 days 3 days
Ble
edin
g t
ime
(min
ute
s)
Post 600 mg ASA
Epinephrine-induced Aggregation (2nd wave)
Present 10 0 0 3 10Equivocal 0 0 2 4 0Absent 0 10 8 3 0
Donors Thrombocytopenic patients
one hour post transfusion
Croneberg, S et al. Effect on platelet aggregation of oral administration of 10 non-steroidal analgesics to humans.
Scand. J. Haematology 33: 155-159, 1984
Number of donors with full single agonist-induced aggregation
Time after medicine discontinuation
Before 1hr 3 hr 6 hr 1 d 2 d 3 d 5-8 d
Aspirin 5 0 0 0 0 5
Piroxicam 4 0 0 0 0 0 4
Naproxen 4 0 0 0 2
Indomethacin
5 0 0 0 5
Ibuprofen 5 2 1 2 4
Medication T ½ Reversibility rate
Nabumetone, Relafen NA No plt effect
Ibuprofen 2 hrs Almost immediately
Cataflam, Diclofenac, Volteran
2 hrs 24 hrs
Difunisal, Dolobid 8-12 hrs 24 hrs
Indocin, Indomethacin 4.5 hrs 50% at 24 hrs
Toradol, Ketorolac 5.3 hrs 24 – 48 hrs
Medication T ½ Reversibility rate
Anaprox, Naprosyn, Naproxen
12-17 hrs
2 days
Feldene, Piroxicam 50 hr 3 days
Clinoral, Sulindac 8 hrs Unknown
Meclofenamate, Meclomen, Mefanamic acid
2 hrs Unknown
Non steroidal anti-
inflammatory
COX-1
Aspirin (ASA)ASA-containing drugs
3 5
Proprionic acid derivatives
(Motrin group)
None
All others (except Feldene)
1
Piroxicam (Feldene) 3
COX-2 None
Anti-platelet Plavix (Clopidogrel) 5 5
Ticlid (Ticlopidine) 10 14
Revised Proposed DeferralsDrugs Days post last ingestion
Revised Proposed
3
NOTE: FDA does not believe it is appropriate for individuals to stop taking medications prescribed for clinical conditions, in order to donate
Question to the Committee
Does the BPAC agree with the revised proposed
donor deferral criteria: • Aspirin: 3 days• Motrin group: no
deferral• All other COX-1 reversible inhibitors: 1 day
except Feldene 3 days• COX-2 inhibitors: no deferral• Plavix: 5 days• Ticlid: 10 days
Stuart et al. Platelet function in recipient of platelets from donors ingesting aspirin. NEJM 287; 1105-1109, 1972
• “Only in situations in which all platelets administered are from donors who have taken aspirin within 36 hours of donation, and in which the patient will make an inconsequential contribution to the total circulating platelet pool, should aspirin ingestion prove a problem to the recipient.”