# Presentation: 139887

## Potential impacts on availability of the draft plateletpheresis guidance on collection facilities Blood Products Advisory CommitteeGaithersburg, MDMarch 9-10, 2006

- Louis M. Katz MD
- Executive Vice President, Medical Affairs
- Mississippi Valley Regional Blood Center
- Davenport, IA

## (Some) issues with the draft guidance

- Longer deferral for ASA and formal deferral for NSAID use
- Physician on site within 15 minutes
- 500 consecutive bacterial cultures allowing a single positive to “validate” _***100%***_ QC testing of platelets
- Maximum of 24 components annually with specified intervals between single, double and triple collections

## ASA and bleeding time (minutes)The source of the AABB 36o standard 5.4.1A

|  | Fresh
platelets (n=6) | ASA 600 mg 1o+12o (n=8) | ASA 600 mg 36o (n=5) |
| --- | --- | --- | --- |
| 1o after transfusion | 9.1±.74 | 15.3±2.5
2 >20 minutes | 8.1±1.3 |
| 4o after transfusion | 7.0±.71 | 13.7±5.0
2 >20 minutes | 9.0±.05 |

- Thrombocytopenic (<20,000) children with leukemia or aplastic anemia transfused with fresh platelets or platelets from donors receiving ASA.  Template bleeding time.  p=NS for 36o v. fresh.
- Stuart, MJ et al.  NEJM.  1972

## Hemostatic effect of “aspirinated” platelets

- “We gave donors 0.6 g (10gr) of aspirin 18-24 hours before phlebotomy and transfused their pooled platelets into leukemic patients....  The transfusions resulted in...a striking decrease in the bleeding time.
- (W)e suggest that potential donors need not be rejected because of recent aspirin ingestion.”
- Benjamin, S and Hoffman, G.  NEJM. (Letter)  1972.

## ASA and bleeding time

- Template bleeding time after transfusion of stored or unstored platelets from 6 aspirin treated (1.2 g BID x 3 days _*and AM of collection*_) and untreated donors into  thrombocytopenic (<10,000) recipients.  Aspirinated platelets correct bleeding time like non-aspirinated but with 4-18o lag.
- “These data suggest that ASA-induced platelet dysfunction is reversible in vivo....  Since the impairment is transient, screening of donors for ASA ingestion is probably unnecessary.”
- Slichter and Harker.  B.J. Haem. 1976

## Considerations re:  non-ASA NSAIDs

- Effects are reversible
- T1/2 varies for individual agents so donor impact variable
- Regardless of T1/2, the relevance of  hemostasis data from NSAID treated patients to infusion of “_***treated platelets***_”  into _***untreated recipients ***_is not obvious
- Dose effects
- Relevance of in vitro studies in vivo function

## In vitro platelet function and NSAIDs

|  | Before | 3o | 6o | 24o |
| --- | --- | --- | --- | --- |
| ASA | 100 | 56 | 38 | 29 |
| Piroxicam | 100 | 46 | 27 | 44 |
| Naproxen | 100 | 59 | 54 | 59 |
| Indomethacin | 100 | 41 | 59 | 105 |
| Diclofenac | 100 | 67 | 45 | 107 |
| Ibuprofen | 100 | 45 | 59 | 109 |
| Diflunisal | 100 | 47 | 29 | 132 |
| Acetaminophen | 100 | 108 | 87 | ND |
| Epinephrine induced aggregation before and after ingestion of NSAIDs.  Percent of baseline in 5 volunteers.
Cronberg, S et al.  Scand. J. Hem.  1984. |  |  |  |  |

## Defect gone 24o after 7d. 600 Q8o ibuprofen [PFA (platelet function analyzer)-100]

- Defect gone 24o after 7d. 600 Q8o ibuprofen [PFA (platelet function analyzer)-100]

- Goldenberg et al.
- Ann. Int. Med.  2005

## NSAIDs except ASA

- 112 consecutive donors given written questionnaire re:  cessation of NSAIDs 3 days before plateletpheresis at MVRBC
- 2 would stop donating
- 21 use occasionally to regularly _***and would need a reminder***_
- 41 use at least occasionally but would remember to stop
- 48 do not use

## Type 3* reactions (apheresis v. whole blood)

- *Vagal signs and/or hyperventilation, neuromuscular, excitability, variable color (pale to cyanotic), incontinence, fainting, convulsive movements, true convulsions

- Data from Hoxworth
- provided by AABB

## 499/500 negative bacterial cultures

- >90% of apheresis platelets (9-10/2004) are tested with a culture based method in AABB survey (submitted for publication)
- Positives (successes) are discarded
- Collection facilities have strong economic incentive to minimize false positives
- False negatives are the more important remaining issue and this requirement has no impact on false negative rates

## 939 donors, 11,464 collections at NIH(1994-98)

- “Regular plateletpheresis donors develop sustained decreases in platelet count. However, clinically significant thrombocytopenia is unusual....”
- Lazarus et al.  Transfusion.  2001

## MVRBC

- 43 hospitals in IA, IL, WI
- 102,622 RBCs
- 11,232 apheresis platelets distributed
- 4 fixed-site plateletpheresis centers
- 3.5 hours from main center to furthest
- 1 doc
- Fenwal Amicus®
- Gambro Trima®
- 1.47 products/apheresis session _***2005***_
- 24 karat donors (24K)

## Frequency of plateletpheresis 2004:  MVRBC

- A restriction to 24 components/yr
- would have reduced collections
- by 12.5% (minimally) based on
- 1.47 products/procedure
*	**	**	**(1404 products)*

## MVRBC 24K* (n=60) donors:  2005Davenport, IA fixed site

| Total platelets | 2439 |
| --- | --- |
|  | (20% of total collections) |
| Platelets/donation | 1.7 |
| Platelets per donor in 2005 | 40.7 |
| Platelets lost per donor with 24 limit | 16.7 |
| Platelets lost with 24 limit | 41% or 1000 platelets |
| *24 apheresis donations in calendar 2005 |  |

## Approx. replacement donors needed at MVRBC with 24 product limitation(modeled from 2004 and 2005 data)

| Freq. in 2004 | N | Ave. don/yr | Prod/
donation | Total prod | Prod lost @ 24/year |
| --- | --- | --- | --- | --- | --- |
| <16 | 797 | 4.4 | 1.47 | 5153 | 0 |
| >16 | 142 | 22.4 | 1.7 | 5407 | 1999 |
| To replace 1999 products from >16 time donors with products from <16 time donors requires approximately 1999 products÷1.47 products/donation÷4.4 donations/year or 309 new donors.  Assumes no increase frequency among current donors.  This is ~33% of the current donor base |  |  |  |  |  |

## Frequency of plateletpheresis 2004American Red Cross

- 5.9% of components lost  (CY2004 data.)

## >24 component donors (n=3,896): ARC 2004 (6 regions)

| Total products | 129,290 |
| --- | --- |
| Products per donation | 1.8 |
| Products per donor | 33.2 |
| Products per donor lost with 24 component limit | 9.2 |
| Products lost with 24 product limit | 28% or 35,786 units |

**Data from ARC**

## Impact on supply and donor base

| Donors of >24 prod. | 102   (6.6% of all donors)  |
| --- | --- |
| Prod. donated | 3902       (36% of all prod.) |
| Prod. lost with 24 limit | 1454    (13.7% of all prod.) |
| Additional donors required based on distribution of donation frequencies in current donor base | 863  (56% of donor base) |

- Data from Dumont, L.  Gambro BCT

## 2005 precounts in 60 MVRBC 24K donors

- MVRBC 24K Donors
- Male	254 ± 48
- Female	289 ± 73
- Community (healthy*)
- Male	226 ± 49
- Female	260 ± 60
- J. Consamus MD,
- QC Metro Labs

- *Used to establish normal range of new instrument in commercial lab

## 2005 precounts in 60 MVRBC 24K donors

- None of these donors were deferred (even
- once) during 2005 for precount <150K.

## Precounts for 2005 and 1st 3 (ever) donations (1997-2003, n=31) in 60 MVRBC 24K donors

- Precounts for 2005 and 1st 3 (ever) donations (1997-2003, n=31) in 60 MVRBC 24K donors

- R2=.1%  p=.141

## Impact of frequent apheresis on precounts 2005 MVRBC 24K donors

- Mean=	+16.7 ± 37.0
- Median=	+10.00 (p>.05)

## Precounts in 20 frequent FBS donors from 2005 (donation “0” 4/97-1/05 baseline)

- Precounts in 20 frequent FBS donors from 2005 (donation “0” 4/97-1/05 baseline)

- Data provided by G. Leparc MD

## Platelet count:  yearly rate of change

- 91 donors (~5% sample from calendar 2002) followed forward with >14 average
- donations per year from 1/02-10/05 in 6 ARC regions.

- Change In Platelet Count Per Year (Thousand)

- Mean:	-3900
- Decrease:	     54
- Increase:	     37
- Source:  ARC

## Yearly platelet count change @ 3 levels of average annual product production91 frequent donors 1-02 to 10-05

- Data from ARC

- Change in donor platelet count (x109/L)

- Number of donors

## Precount v. products made 60 24K MVRBC donors in 2005

## Single blood center reported to Gambro12/5/2004 – 12/5/2005

| Donors |   1,535 |
| --- | --- |
| Donation sessions |   6,371 |
| 	Triple sessions |      992 (15.6%) |
| 	Double sessions |   2,743 (43.1%) |
| 	Single sessions |   2,199 (33.9%) |
| 	< single |      477   (7.5%) |
| Therapeutic doses
(3 – 5.9 x1011 plt) | 10,621 |
| Donors  8 donation sessions |      285 (18.6%) |

- Platelet counts by donation frequency and number of products
- entered in mixed linear model.  Dumont, L. Gambro BCT

**Notes:**
 In this 12 month period, 1535 donors sat for 6371 donation sessions resulting in 10,621 therapeutic doses of apheresis platelets; therapeutic dose being defined as Trima predicted final yield 3.0-5.9x1011 platelets. The number of donation sessions resulting in various quantities of therapeutic doses were: triple platelet products 992 (15.6%), double platelet products 2743 (43.1%), single platelet product 2199 (33.9%) and less than 3x1011 platelets in 477 sessions (7.5%). Maximum donation sessions per year was 24 for any given donor. We further examined donors with  8 donations sessions in the period (NB: 8 x 3 = 24).

## Higher frequency of donation and number of components do not decrease platelet counts

- Data from Dumont, L.  Gambro BCT

- Increasing number of platelets donated from more frequent donation and/or more doses per donation result in increasing platelet counts after a 12 mos.  In all donors in model there was no significant decrease (p=0.539).

**Notes:**
Model estimates (mean +/- SE) for 1 or 3 therapeutic doses per donation: 8, 12, or 24 donations in the period. Average beginning of period platelet count 246K. Increasing number of platelets donated in the period either from more frequent donation and/or more doses per donation result in increasing platelet counts after a 12 month period.

## Platelets before/after multiple productsAre postcounts useful??

- Platelets before/after multiple productsAre postcounts useful??

- 105 index don. 	11/29-12/08/05
- 87 F/U don.	12/13-12/28/05
- Source:  	G. McPherson.
- 		Hemacare Inc.

## Precount vs. interdonation intervalMVRBC 24K donors 2005

## There is no reason to specify interdonation intervals according to components produced60 MVRBC 24K donors 2005

## Plasma volume losses

- “...(V)olume (excluding anticoagulant) collected from a donor during a 12-month period should not exceed:
- 12 liters (12,000 mL) for donors weighing 110-175 lbs
- 14.4 liters (14,400 mL) for donors weighing more than 175 lbs”
- There is concern about the impact of high volume plasma removal on plasma protein concentrations
- Collection facilities will commit to provide FDA data on total protein and albumin levels in frequent donors if this is requested

## Guidance as published

- Increased deferrals for ASA and NSAIDs problematic and evidence base is not compelling
- Close 3/4 MVRBC plateletpheresis sites
- No Dr. available in 15 minutes
- >67% loss of components
- 499/500 negative cultures to validate _***100%***_ QC
- True bacteremic donors in that interval are success! False negatives remain of concern
**>**12.5% loss from restriction on products v. procedures
- All 60 24K donors had _***all***_ pre-counts >150,000
- Platelet counts stable with frequent donation

## Recommendations

- Amend changes for ASA and NSAIDs
- 36o for ASA is supported by limited data,
- none needed for short T1/2 NSAIDs, longer for piroxicam et al (prolonged T1/2) also not established
- Drop physician attendance requirement
- Drop “validation” requirements for bacterial culture.
- Centers with higher rates of positivity will investigate and remediate processes that contribute to false positives
- Drop limit on components collected
- Further data on both platelet counts (and platelet mass?) in frequent donors can be collected and provided to the agency to confirm those presented
- No need for post-platelet counts

## Acknowledgment

- Kim Palmer 		MVRBC
- Kay Gregory		AABB
- Anne Eder		ARC
- Ed Notari		ARC
- German LeParc	Florida Blood Services
- Susan Wilkinson    	Hoxworth Blood Center
- Celso Bianco		ABC
- Larry Dumont		Gambro BCT
- Susan Leitman	NIH

## Slide 37