Criteria for selection of plasma products when performing TPE for TTP patients

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.
   
   
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.

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.

ADDENDA Dec. 27, 2005

3. A transfusion medicine physician in North Carolina reports that albumin might be considered an alternative replacement supplement for therapeutic pheresis treatments of patients with TTP. He comments that use of albumin for the first half of the replacement followed by plasma has also been shown to be effective in the treatment of TTP. The use of a combination of albumin and plasma (FFP or CPP) may be of particular advantage in the case of limited supplies of ABO compatible plasma such as with a group AB patient or in those patients who have repeated and difficult to treat allergic reactions (a common occurrence in this patient population). Colleagues may find the following references germane to the comments by the North Carolina physician.

• Bandarenko N, Brecher ME. Unites States thrombotic thrombocytopenic purpura apheresis study group (US TTP ASG): Multicenter survey and retrospective analysis of current efficacy of therapeutic plasma exchange. J Clin Apheresis 1998; 13:133-141
• Reutter JC, Sanders KF, Brecher ME, Jones HG, Bandarenko N. Incidence of allergic reactions with fresh frozen plasma or cryo-supernatant plasma in the treatment of thrombotic thrombocytopenic purpura. J Clin Apher. 2001;16(3):134-8.

ADDENDA Dec. 28, 2005

4. The North Carolina physician (posting #3 above) adds to his previous comments that the article "The pathogenicity of von Willebrand factor in thrombotic thrombocytopenic purpura: reconsideration of treatment with cryopoor plasma" by Thomas J. Raife, Kenneth D. Friedman, Denis M. Dwyre published in Transfusion, Volume 46 Page 74 - January 2006 is germane to the present discussion.
   
   
5. A transfusion physician at an academic medical center in New Hampshire acknowledges that although CryoPoor Plasma offers a theoretically attractive alternative as a replacement solution in treatment of TTP, he does not think that there are enough data to support its use in every case of TTP. In his institution they routinely initiate therapeutic plasma exchange with FFP and only if there is no or only minimal clinical response within 7 to 10 days do they consider switching to CryoPoor Plasma. As the significant majority of patients with TTP do respond within this time frame (likely because they have a low level of anti-ADAMTS13 antibody) only very few patients would be considered for CryoPoor Plasma. The advantages mentioned by prior participants in this discussion are interesting but rather theoretical and not clearly supported by clinical outcomes. The potential drawback of using CryoPoor Plasma is inventory management and what to do with the units which are not being used by the TTP patient. It would take a very large number of patients to answer the question which replacement solution (i.e. FFP vs. CryoPoor Plasma) is more efficient in treatment of TTP, as the use of FFP offers more than 90% survival rate.

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