January, 1999 - Plasma Alternatives Update

Introduction

Human plasma continues to be the major source of coagulation factor replacement therapy for patients with clotting factor deficiency. Originally plasma was provided as part of a unit of whole blood and more recently as a specific component, fresh frozen plasma (FFP). The emergence of several new alternatives to FFP requires the review of the relative merits of each product.

Fresh frozen plasma (FFP)

Each unit of FFP is derived from a single unit of whole blood. The volume is 220-300ml and it is frozen within 8 hours of collection to maintain normal levels of all coagulation factors. FFP can be stored frozen for up to one year at Ł -18° C. When ordered for transfusion it is thawed in a 37° C water bath (takes approximately 25-30 minutes) and can be kept up to 24 hours in a refrigerator (1-6° C). Only ABO identical or compatible FFP can be transfused.

Indications

FFP therapy is indicated for patients who are bleeding or undergoing an invasive procedure and have a documented coagulopathy. (i.e. prolonged prothrombin [PT] time or activated partial thromboplastin time [APTT]). Multiple studies have shown that patients with mild prologations of the PT (i.e. <3-4 seconds) are NOT at increased risk for bleeding.^1-8 The most common inappropriate use of FFP is to correct minor prolongations of the PT or APTT.

Dosage

For patients with significant coagulation factor deficiency the dose of FFP should be 10-20 ml/kg. Thus in a 70 kg patient at least 3-4 units of FFP are required to provide sufficient factors to improve hemostasis.⁹

Liquid plasma (LP)

Each unit of liquid plasma is derived from a single unit of whole blood. The plasma is removed from the whole blood and is stored refrigerated, not frozen like FFP. The volume is 220-300ml and it can be stored refrigerated for up to 26 days. LP differs from FFP in that it contains normal levels of all coagulation factors except factor VIII and factor V. Factor VIII declines to <10% of normal levels, however factor VIII levels in most patients with coagulopathy (i.e. liver disease) are typically normal or elevated since it is an acute phase reactant. Factor V levels decline to 35% of normal which is above the hemostatic level of factor V which is 20-25%. When ordered for transfusion it can be issued rapidly since thawing is not required. Only ABO identical or compatible LP can be transfused.

Indications

The indications for LP are nearly identical to FFP except for patients with consumptive coagulopathy, such as DIC, in which factor VIII levels may be low. In such cases FFP is preferred.

Dosage

Same as FFP.

Solvent Detergent plasma (SD plasma)

SD plasma is a new plasma product which was approved by the FDA in August, 1998. SD plasma has undergone treatment with the solvent tri-N-butyl phosphate (TNBP) and the detergent Triton X-100 to destroy any lipid bound viruses including: HIV1,2, HCV, HBV and HTLVI,II. The process does not destroy non-enveloped viruses such as parvovirus, hepatitis A virus, and prion particles. The SD process includes pooling up to 2500 units of thawed FFP, treating it with the solvent and detergent, and then refreezing the treated plasma into 200 ml aliquots. SD plasma can be stored for up to one year frozen at Ł -18° C. When ordered for transfusion it is thawed in a 37° C water bath (takes approximately 25-30 minutes) and can be kept up to 24 hours in a refrigerator (1-6° C). Only ABO identical or compatible SD plasma can be transfused.

Indications For SD Plasma

Same as FFP

Dosage SD Plasma

Same as FFP

DONOR RETESTED PLASMA

Donor retested plasma (DRP) is an alternative to SD plasma which also has reduced infectivity for the lipid bound viruses HIV1,2, HCV, HBV, and HTLVI,II. DRP reduces the risk of transmitting these viruses by holding a unit of donated FFP until the donor comes back to donate a second time at least 112 days later. If testing on the second donation is negative then the first unit can be released since the two negative tests span the "window period" for each virus. Each unit of DRP represents a single donor exposure.

The dosage and indications for DRP are identical to FFP.

Risks

The introduction of these plasma alternatives comes at a time when the risks of transfusion have declined dramatically and, for the major viruses, have become very small. Thus the increments of increased safety associated with these alternatives is very small. It is anticipated that HCV and HIV PCR screening of the entire blood supply will begin in the summer of 1999. PCR screening will further reduce the risk of transmission of HCV and HIV from that shown below.

FFP/Liquid Plasma

The risk profile for FFP and liquid plasma is the same and is summarized in Table 1.

TABLE 1: RISK ESTIMATES FOR TRANSFUSION TRANSMITTED VIRUSES PITTSBURGH VS U.S. Risk per tested unit - 1998
VIRUS	U.S.	PITTSBURGH
HIV-1	1:675,000	1:1,680,000
HBV	1:63,000	1:252,000
HCV	1:103,000	1:103,000
HTLV-1	1:641,000	1:641,000

* U.S. risks from Schreiber GB et al. NEJM 1996;334:1685

** Risks based on Central Blood Bank donor prevalence statistics

Solvent Detergent Plasma

The risk of HIV1,2, HBV, HCV and HTLV I,II transmission are essentially eliminated by proper solvent detergent treatment. The pooled nature of SD plasma however may increase the risk of non enveloped viruses such as parvovirus and hepatitis A. The presence of neutralizing antibody to parvovirus and hepatitis A virus in the pooled SD plasma is felt to prevent their transmission however insufficient clinical data are available at this time to estimate the risk of transmission. Theoretically there is also the risk that a new virus entering the blood supply which is not inactivated by SD treatment would be spread more rapidly because of the pooled nature of SD plasma.

Donor Retested Plasma

The risk of HIV1,2, HBV, HCV and HTLV I,II is greatly decreased by holding the plasma until the donor can be retested beyond the window period for these viruses. The risk reduction would be on the order of one log less than the risks noted in Table 1. Donor retested plasma does not require pooling and thus is not associated with the concerns noted for SD plasma.

Costs

The decisions regarding use of plasma alternatives also includes cost considerations. Approximate comparative costs are noted in Table 2.

Table 2
	FFP	45$/unit
	Liquid plasma	26$/unit
	SD plasma	125$/unit
	Donor retested	80-90$/unit (not yet available)

Summary

As new technologies drive the introduction of new plasma components, transfusion medicine specialists must provide relevant data to health care professionals and the public to make appropriate decisions regarding their incorporation into clinical practice.

References

McVay PA, et al. Lack of increased bleeding after liver biopsy in patients with mild hemostatic abnormalities. Am J Clin Path 1990; 94:747-53.

Zins M, et al. U.S.-guided percutaneous liver biopsy with plugging of the needle track: a prospective study in 72 high- risk patients. Radiology 1992; 184:841-43.

McVay PA, et al. Lack of increased bleeding after paracentesis and thoracentesis in patients with mild coagulation abnormalities. Transfusion 1991; 31:164-71.

Wachtel S, et al. The relationship of prothrombin time (PT) to clotting factor levels and the "transfusion trigger" for fresh frozen plasma. (abstract) Blood 1994; 84:Suppl:682a.

Squillante CE, et al. Fine-needle liver biopsy in patients with severely impaired coagulation. Liver 1993; 13:270-3.

Ewe K: Bleeding after liver biopsy does not correlate with indices of peripheral coagulation. Digest Dis Sc 1981; 26:388-93.

Friedman EW, Sussman II. Safety of invasive procedures in patients with the coagulopathy of liver disease. Alcohol Clin Lab Hematol 1989; 11:199-204.

Delougherty TG, Liebler JM, Simonds V, et al. Invasive line placement in critically ill patients: do hemostatic defects matter? Transfusion 1996; 36:827-31.

Sholevar D, Kiss JE, Triulzi DJ. Underutilization of FFP therapy. (abstract) Transfusion 1997; 37: Suppl:S146.