# Presentation: 814403

## 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**

**Notes:**
References:
Aspirin: 
NSAIDs, Plavix, Ticlid: ASBPO

## 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- Reference not peer reviewed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)

## Agonist –induced platelet aggregation

**% aggregation**

- Untreated

- ASA or NSAID treated

- Strong agonist (thrombin, dual agonist (Epi+ADP)

- Weak agonist (ADP or Epi alone)

## 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, VolkerThe 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 |  |
| --- | --- | --- | --- | --- |
|  | + ASA
Group A | Control
Group B | + ASA
Group A | Control
Group 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 donation
- Group B = no meds

## Stuart et al. Platelet function in recipient of platelets from donors ingesting aspirin.  NEJM 287; 1105-1109, 1972

- 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

## Slide 18

| Medication | T 1⁄2 | 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 |

**Notes:**
Ibuprofen: Fenoprofen, Ketoprofen, Motrin, Orudis

## Slide 19

| Medication | T 1⁄2 | 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 |

**Notes:**
Ibuprofen: Fenoprofen, Ketoprofen, Motrin, Orudis

## Revised Proposed Deferrals

| 
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 |

**Drugs****	****	****	****         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

-     _***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.”