A Florida physician wonders what criteria colleagues currently use to choose between using FFP, Cryo-Poor Plasma, or Thawed Plasma when doing a Therapeutic Plasma Exchange (TPE) for a patient with Thrombotic Thrombocytopenic Purpura (TTP). They routinely use Cryo-Poor Plasma at his institution, when that product is available. Their reason for using Cryo-Poor Plasma is based on anecdotal experience. Clinicians at his institution do not have strong feelings one way or the other about using Cryo-Poor Plasma versus FFP, and they will use FFP (or thawed plasma for that matter), if Cryo-Poor Plasma is not available.

Editor's NOTE: Colleagues may find the discussions at the following links to be germane to the Floridian's question:

• Selection of Plasma After Marrow Transplantation
• High-dose plasma infusion versus plasma exchange as early treatment of thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome
• Stability of ADAMTS13 in thawed cryoprecipitate poor plasma (CPP) stored for more than 24 hours
• Experience in the use of Thawed Plasma

The following comments have been received.

ADDENDA Dec. 23, 2005

1. A transfusion medicine physician in Maryland reports that in his opinion, there are five potential benefits of therapeutic plasma exchange using "plasma, cryoprecipitate reduced" (AKA, Cryo-Poor Plasma), for patients with thrombotic thrombocytopenic purpura:

1. Removal of antibodies against the vWF-cleaving protease
2. Removal of large vWF multimers
3. Replacement of the vWF-cleaving protease
4. Replacement of normal vWF multimers
5. Reduction in fibrinogen concentration

Removal of antibodies and large multimers is mechanical and should not be effected by the choice of replacement solution. Younger solutions should have higher concentrations of the vWF-cleaving protease, but over the 5-day shelf life of thawed plasma or cryo-poor plasma the losses are modest and may not be very improtant. Replacement of normal vWF multimers might be a goal if the patient is suffering extensive purpuric bleeding. Reducing fibrinogen might be a goal if the patient is suffering from thrombotic complications in brain and kidneys. Because the later complications are the most feared, weighing them heavily is reasonable in the early phase of treatment when most mortality occurs.

He adds that as trauma surgeons are using more cryoprecipitate to treat the coagulopathy of trauma, efficient use of the remaining cryo-poor plasma in the treatment of TTP can potentially optimize resource use and reduce costs.

2. Editor's Note: Readers may be interested in this excerpt from: Brecher ME ed. Collected Questions and Answers. 7th edition, Bethesda, MD: American Association of Blood Banks, 2001, 86 pages.

See pages 43-44.

Question
With increasing frequency, the blood bank receives orders for cryosupernatant instead of fresh frozen plasma (FFP) for plasma exchange in patients with thrombotic thrombocytopenic purpura (TTP). This shift towards using cryosupernatant sometimes creates problems for our blood bank, because our inventory is not large, plasma exchange for TTP occurs at all hours of the day and night, and a delay in filling orders could be detrimental to the patient. Why is cryosupernatant now being used instead of FFP in plasma exchange for TTP?

Response
Untreated TTP has a mortality rate in excess of 95 percent. A major breakthrough occurred when plasma was used to treat patients with TTP. Later, studies showed that plasma exchange resulted in lower mortality than infusion of FFP. It was postulated then that plasma exchange was more effective than plasma infusion, because it not only supplied something present in the plasma but also removed some plasma constituent. Insight into the pathogenesis of TTP occurred in the early 1980s when unusually large multimers of von Willebrand factor (vWF) were found in patients with relapsing TTP and were thought to be responsible for the abnormal platelet aggregation that was observed. More recently, two groups identified an enzyme in normal plasma that is involved in breaking down the largest vWF multimers. This vWF-cleaving protease was found to have reduced or absent activity in patients with different types of TTP. In addition, in most patients with acute idiopathic TTP, an inhibitor of the vWF-cleaving protease was identified that consisted of an IgG autoantibody. This new understanding of pathophysiology now allows us to understand why plasma exchange is effective in TTP. The plasma serves as a source of vWF-cleaving protease. In addition, removing the patient’s plasma in an exchange procedure results in removal of the vWF-cleaving protease inhibitor and the removal of the unusually large vWF multimers. By comparison, plasma infusion supplies only vWF-cleaving protease and is limited by the volume that can be delivered.

Cryosupernatant or cryodepleted plasma is the plasma that remains after cryoprecipitate is removed. Cryosupernatant is, therefore, depleted of vWF. Because it was suspected that vWF was implicated in the pathogenesis of TTP, it was thought that cryosupernatant would be a more effective therapy. Anecdotal cases of efficacy were described in otherwise treatment resistant cases. One study from Canada that used a historical control suggested improved results with CPP compared to FFP replacement. To date, there have been no large prospective randomized studies comparing CPP to FFP. Based on theoretical considerations and the one historically controlled study of CPP versus FFP, many centers have switched to the use of CPP as the primary replacement fluid for TTP

References
Rock G. Shumak KH. Sutton DM. Buskard NA. Nair RC. Cryosupernatant as replacement fluid for plasma exchange in thrombotic thrombocytopenic purpura. Members of the Canadian Apheresis Group. British Journal of Haematology. 1996;94(2):383-6.

Rock GA. Shumak KH. Buskard NA. Blanchette VS. Kelton JG. Nair RC. Spasoff RA. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. [see comments]. New England Journal of Medicine. 1991;325(6):393-7, 1991

Cines DB. Konkle BA. Furlan M. Thrombotic thrombocytopenic purpura: a paradigm shift Thrombosis & Haemostasis. 2000;84(4):528-35.

Blackall DP, Uhl L,Spitalnik SL. Cryoprecipitate-reduced plasma: rationale for use and efficacy in the treatment of thrombotic thrombocytopenic purpura. Transfusion 2001;41:840-844.

Since the above was published there has been at least two additional relevant studies (one small and the other of moderate size):

1. Cryoprecipitate poor plasma does not improve early response in primary adult thrombotic thrombocytopenic purpura (TTP). Zeigler ZR, Shadduck RK, Gryn JF, Rintels PB, George JN, Besa EC, Bodensteiner D, Silver B, Kramer RE; North American TTP Group. J Clin Apher. 2001;16(1):19-22.

Abstract:
Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal disease that is treated with plasma exchange and typically with replacement with fresh frozen plasma (FFP). This approach results in an approximate 50% response rate following 1 week of therapy and 80% survival. Cryoprecipitate poor plasma (CPP) is plasma from which the cryoprecipitate fraction is removed. CPP has been reported to be successful as salvage therapy in refractory TTP and has been suggested to be superior to FFP in retrospective studies. The present report compares initial therapy of TTP with exchange using replacement with either FFP or CPP in a multi-institutional prospective randomized study performed by the North American TTP Group (NATG Group) from 1993 to 1995. Initial therapy also included corticosteroids. Antiplatelet drugs or vinca alkaloids were not employed. A severity score index, response score, and individual clinical parameters (platelet count, LDH x upper limit of normal, hemoglobin level, and creatinine) were compared at their nadir or peak values, baseline, and days +6 and +13 of therapy. Thirteen patients were randomized to FFP exchange and 14 to CPP exchange. Results were equivalent for all parameters. Survival was equal with three deaths in each group. These data indicate that the efficacy of FFP and CPP are the same in the initial treatment of TTP in adults.

2. Does cryosupernatant plasma improve outcome in thrombotic thrombocytopenic purpura? No answer yet. Rock G, Anderson D, Clark W, Leblond P, Palmer D, Sternbach M, Sutton D, Wells G; Canadian Apheresis Group; Canadian Association of Apheresis Nurses. Br J Haematol. 2005 Apr;129(1):79-86.

Summary:
A randomized prospective trial compared cryosupernatant plasma (CSP) to fresh frozen plasma (FFP) for treatment of thrombotic thrombocytopenic purpura (TTP). A total of 236 patients were required: 28 patients were treated with CSP and 24 with FFP within 30 months. There were no differences in survival at 1 month. By day 9, 17 of 26 patients with CSP and 18 of 24 with FFP had a platelet count >100 x 10(9)/l. At entry, von Willebrand factor (VWF) multimers were normal in all patients (range 1.1-3.95 IU/ml). ADAMTS-13 levels showed large variations ranging from 10% to 100% activity. At entry, no individual had <5% VWF cleaving protease. By day 9 (end of cycle), 89% (FFP) and 67% (CSP) had levels >50% of the controls. At 6 months some patients showed inhibitors to the enzyme in spite of adequate or normal platelet counts. The data from this study do not show an apparent advantage to the use of CSP in TTP. A large number of patients will be required to determine appropriate replacement therapy. We were not able to find a statistically significant relationship between the low level of protease activity at presentation of TTP and response.

These two more recent studies were unable to establish a clinical advantage of CPP over FFP. Thus, while there may be a theoretical advantage to CPP, the clinical advantage has not been proven.

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