An e-network member wrote that his donor center has been experiencing an increased number of FFP units being returned from hospitals because the thawed plasma products contain "clots". The donor center has attempted to solve this problem by drawing their whole blood units "ports down" to increase mixing with anticoagulant, by more frequent mixing of units during collection, and by minimizing the buffy coat content during processing of the units. In spite of all their efforts, 'clotted' FFP units continue to be returned from the hospitals. Most of the returned units have only a very small piece of what looks like "tissue" floating in the thawed plasma. However, a few thawed FFP units have significant clumps that appear to be fibrin, but these clumps are so large that they would not have been able to fit through the port during separation of red cells from plasma (the donor center does not make platelet concentrates). The inquiring member believes that his donor center staff are complying with proper technique. Furthermore, the clots occur regardless if the whole blood has been drawn at fixed or mobile sites, and there is no pattern as to a specific phlebotomist or member of the production staff. The donor center believes that they have ruled out a technique problem by one individual. The inquiring member wonders if the clots might represent residual platelets that have become activated with concurrent fibrin formation, or if the clots might represent a precipitant of some sort.

The following ideas were submitted in response to the plight of the above e-network member's donor center:

1. One member commented that several months ago her hospital donor center had a similar problem, and units of FFP were returned from patient care areas because they contained 'clots'. The responding member wanted the readership to appreciate that the units actually looked like they contained "egg drop soup".
(EDITOR's NOTE: It is interesting that the responding member wanted the forum to know that the 'clots' looked like "egg drop soup" since her institution is just a short drive from some great Asian restaurants).

They looked at the following variables for all of the units:

a. COLLECTION VARIABLES:

• Collection date, time
• Phlebotomist
• Duration of collection
• Blood collection scale number
• Volume collected
• Collection bag lot number

b. COMPONENT PROCESSING VARIABLES:

• Elapsed time from collection to separation of plasma
• Did the RBC unit have clots?
• Date and time thawed
• Date and time issued
• Method used to thaw (they use both the Thermogenesis and a water bath)
• Technologist who performed the FFP thawing
• Record of inspection as products were issued

In spite of a comprehensive evaluation, there appeared to be NO connection between the "clots" and any collection parameter. None of the RBCs from which FFP was produced contained clots. (The responding member reasoned that if the clots were caused by failure to adequately mix a whole blood unit at collection, there would be clots in the RBC also.) A big clue was that four of five returned units had been THAWED in a water bath by the SAME individual at the SAME time. Following thawing, all were placed into a storage refrigerator at 1-6 C, and the products stayed there for at least one hour before issuing. No clots were seen as the products were visually inspected at issuing. The returned units were investigated upon being returned, and it was found that when the units were fully re-warmed in the water bath, the "clots" went away. An interview with the who did the 'batch' thawing disclosed that there was a large quantity of product being thawed at the same time. Most probably, the water bath was no longer at 37 C. The staff member indicated that she "crunched up" the plasma to hasten thawing, and the product was liquid but not warm to the touch as she removed it from the bath and placed it in the refrigerator. The conclusion was that by not assuring that the water bath was at the correct temperature for thawing plasma, and by not assuring that the product was fully thawed prior to placement in the refrigerator, they ended up creating cryoprecipitate in their plasma. When they issued the product, the precipitate was not visible to the blood bank staff, but the precipitate became evident to the nursing staff. As corrective action, the plasma thawing step is now more carefully documented, and the staff are retrained regarding the need to fully thaw the product at the appropriate temperature. The responding member would be interested to know how far other facilities are going in documenting the thawing process. This member's hospital documents time thawed, but does not capture water bath temperature at the time of thaw or the length of time the product is in the water bath. They have had the FDA come very close to asking for time in / time out and the method used.

2. A second member, also wonders if the "clots" are actually a cryoprecipitate that is forming. However, this second member proposes a slightly different mechanism, namely a freeze/thaw/re-freeze problem. If the 'clots' are really cryoprecipitate, there may be a problem with one of the freezers or the way that the units were frozen, or there may be a problem with partial thawing of product during storage. All of these possibilities should be investigated by the donor center with 'clotted' FFP problems.

3. A third member also suggested a freeze/thaw/re-freeze problem, and that the FFP units may have undergone an undetected rise in temperature to 0 degrees Centigrade or slightly warmer, and then been refrozen to the normal minus 18 degrees C or colder. This would have led to some cryoprecipitate being formed, a small portion of which could have been converted to fibrin. This temperature cycling could have happened in the original storage freezer, during the transit to the hospital or at the hospital.

4. A blood banker who works at a university medical center has also experienced an increased number of units being returned for clots (but in this case, their red cell units have shown clots in the segments, as well as in the FFP). She wonders whether this is due to the fact that the FDA has recently stepped up what is to be "reportable". That is, they are not sure whether there is truly an increase in the incidence of clots or simply that hospitals are reporting things that they didn't previously report. The responding member has not found any explanation for the clots, i.e., not related to new staff, no identifiable problems with the draws. They use Baxter bags, and there is no recent change in the bag as far as they are aware.

5. A blood banker from a very Northeastern part of the USA reported that his hospital experienced a similar problem about a year ago and finally traced it to units collected on the Haemonetics PCS that went into long, slender bags. The problem wasn't the bags themselves or their contents but that the configuration did not allow the entire bag to immersed in the 37C waterbath on thawing. When we worked with staff to ensure that the entire bag was immersed, the problem disappeared. What was the "stuff"? Most likely, it was primarily fibrinogen (based on analyses). Perhaps they were making a form of Cryoprecipitate by not warming the entire bag adequately. Interestingly, placing the thawed bag in the waterbath usually allowed the dissolution of the "stuff".

6. A blood banker in Northern California thinks that the "clots" or "egg-drop soup" material is simply cryoprecipitate. When it is seen, the institution should separate it out and measure the Factor VIII and fibrinogen content and compare these values to the residual plasma. The cryo will have much more fibrinogen and Factor VIII than the now, cryo-poor plasma. To keep the material in solution, one should keep the now thawed FFP as close to body temperature as possible.

7. A member from a large HMO asked if the donor center experiencing this problem has contacted the manufacturer of the blood bag? A number of years ago, the HMO experienced the same problem. Their blood bag manufacturer dispatched a technical specialist to their facility to observe their process and take samples. They analyzed the "clots" and determined that they were platelet material. They increased the centriguge RPM and spin time when preparing FFP and now have only an occasional product complaint about FFP.

EDITOR's query: Does any e-network forum member have an SOP for validation of FFP that addresses the product safety, potency and purity at every step from collection, separation from whole blood, freezing, storing, thawing, and dispensing, so that the final product is as standardized as possible, without clots or precipitate? If so, please share it with the network, as the above situations suggest that having such a validation procedure would be useful for many places.

ADDENDUM Dec. 5, 2001

8. A Texas blood banker wrote that her blood center has experienced a similar problem as that discussed in this particular forum. They pre-storage leukoreduce all of their units, and any clotting mechanism activation would be discovered during the filtering stage, in her opinion. She has attempted to grossly analyze the "clot", and does not believe it to be platelets. She believes it may be cryoprecipitate due to improper thawing, or, as mentioned, a problem during storage that causes a freeze-thaw-freeze cycle. She will be looking at her center's procedures to see if this may be the case. She looked at the same parameters as the other investigators reported above. She did notice yesterday (12/4/01) that some units being thawed in their old plasma thawer were not completely immersed. This could result in cryo formation. They also thaw 8-10 units at a time, and this could well cause the temperature to drop below 37C. She says that she is thankful that she was able to find this forum through a web search.

Please submit comments to the e-Network Forum.

Ira A. Shulman, MD
CBBS e-Network Forum Editor & Moderator