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Keywords:

  • thrombotic thrombocytopenic purpura;
  • solvent/ detergent-treated plasma;
  • coagulation factors;
  • protein S;
  • deep venous thrombosis

The recent British Committee for Standards in Haematology (BCSH) guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias (Allford et al, 2003) serve to highlight the fact that the optimal replacement fluid for plasma exchange remains unclear. Cryosupernatant (CSP) and solvent/detergent-treated (S/D) plasma offer theoretical appeal over fresh-frozen plasma (FFP), as both lack the largest von Willebrand factor (VWF) multimers. Moreover, S/D plasma also reduces the risk of transfusion-related viral transmission associated with multiple FFP infusions, and may reduce allergic reactions (Klein et al, 1998). These issues have led to the introduction of S/D plasma as first-line replacement therapy in acute thrombotic thrombocytopenic purpura (TTP) (Horowitz & Pehta, 1998), particularly in countries such as Ireland where S/D plasma has entirely replaced standard FFP in clinical practice.

S/D plasma is drawn from pools of approximately 1500 volunteer donors, and undergoes treatment with a combination of Tris(n-butyl)phosphate (TNBP) solvent and Triton X-100 detergent. This combination effectively inactivates lipid-enveloped viruses by causing a direct irreversible disruption of the lipid envelope (Klein et al, 1998). As a result of simple plasma dilution, S/D processing of plasma inevitably causes a small reduction in the coagulation factor concentration. However, in vitro studies have shown that different coagulation factors (in particular, protein S, α2-antiplasmin and α1-antitrypsin levels) are affected to different degrees by S/D processing (Leebeek et al, 1999). We have recently shown that protein S activity is reduced by approximately 50% in Octaplas® (an S/D plasma) compared with either FFP or CSP (Doyle et al, 2003). Other reports have demonstrated a comparable reduction in functional protein S in other S/D plasmas (Leebeek et al, 1999; Flamholz et al, 2000). However, neither total nor free protein S antigen levels are affected by S/D processing, suggesting that the S/D treatment directly affects protein S function (Leebeek et al, 1999; Flamholz et al, 2000).

The clinical significance, if any, of the low protein S level in S/D plasma remains unclear. However, a recent report described three individuals with TTP who developed deep venous thrombosis during plasma exchange with an S/D plasma (Plas+SD®; V. I. Technologies, NY, USA) (Flamholz et al, 2000). All three patients had significantly reduced protein S levels (24–28%) at the time of their thrombotic events. Although low protein S levels have previously been reported in association with TTP, baseline protein S levels in two of the patients prior to commencement of S/D plasma exchange were 49% and 72% respectively. Furthermore, the daily use of S/D plasma was also shown to result in acquired protein S deficiency in other patients who failed to develop thrombosis, and the substitution of CSP for S/D plasma exchange resulted in correction of plasma protein S levels to within the normal range in all cases.

Timely plasma exchange represents the gold-standard management of acute TTP. Although S/D plasma has potential advantages over FFP and CSP, we believe it important to recognize that its use may be associated with the development of a secondary acquired protein S deficiency. This observation will apply equally to patients receiving SD plasma exchange for other medical indications. Prospective studies will be necessary to determine whether this protein S deficiency has a direct bearing on clinical outcome in TTP. Pending the outcome of such studies, it is important to appreciate the altered coagulation factor content of S/D plasma, and to maintain a high index of clinical suspicion regarding the potential for venous thrombosis development in such patients. Whether there is a role for monitoring functional protein S levels in TTP patients undergoing S/D plasma exchange will require further study, but other reports have suggested that S/D plasma exchange should be used on an alternate day basis with either CSP or FFP respectively (Flamholz et al, 2000).

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