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• Reference not peer reviewed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.”