Donald L. Kelley, MD, MBA
Assistant Medical Director
Centralized Transfusion Service

INTRODUCTION

Plasma and cryoprecipitate are employed in treating patients with coagulopathies due to deficiency of one or more coagulation factors.  These conditions may occur due to accelerated consumption of coagulation factors, (e.g. bleeding, DIC), impaired factor production states (vitamin K deficiency, warfarin effect, liver disease, congenital factor deficiencies), or both. 

Confusion over indications for transfusion, selection of appropriate product(s), and dosing can lead to over or under-transfusion, either of which can have a detrimental effect on patient care.  This review is intended to serve as a guideline for improving transfusion practice.

PRODUCTS

FRESH FROZEN PLASMA (FFP)
FFP is derived from whole blood donations.  It is stored at -18º C or less to maintain hemostatic levels of all coagulation factors, including the labile factors V and VIII.  For transfusion, FFP must be thawed in a 37º C water bath for approximately 30 minutes.  Each unit contains between 200 and 250 ml of plasma and will raise plasma factor levels by 3-5%.  Cross-matching is not required for transfusion, but type-specific or ABO-compatible plasma must be selected.

THAWED PLASMA
Plasma can be transfused as FFP for 24 hours after thawing.  It can then be stored at refrigerator temperature (1-6º C) for an additional 4 days and transfused as “thawed plasma.”  All coagulation factors are maintained, except Factor VIII, which declines to approximately 40% of normal, still above the level required to maintain effective hemostasis (30-35%).¹ 

As an acute phase reactant, Factor VIII tends to be elevated in most disease states, including liver disease.  Factor VIII content is, therefore, not critical to the efficacy of plasma transfusion in correcting most coagulopathies.  For the great majority of clinical situations, thawed plasma can be used interchangeably with FFP.

Using thawed plasma can improve turnaround time by eliminating the time required for thawing and also reduces product wastage by extending the 24-hour shelf life of FFP by 4 more days.

CRYOPRECIPITATE (CRYO)
When FFP is thawed slowly at 4º C, a white precipitate forms at the bottom of the bag, which can then be separated from the supernatant plasma.  This “Cryoprecipitated Anti-Hemophilic Factor” is 15-20 ml in volume and contains: 150-250 ml of fibrinogen, 80-100 units of Factor VIII, von Willebrand’s Factor, Factor XIII, and fibronectin.  It is stored frozen and must be transfused within 6 hours of thawing or 4 hours of pooling.

CRYO-REDUCED PLASMA
The supernatant plasma fraction from the manufacture of CRYO can be refrozen and transfused as an alternative to FFP in the treatment of thrombotic thrombocytopenic purpura (TTP).

INDICATIONS 

FFP
Transfusion of FFP is indicated for treatment of a “significant coagulopathy” in:

1. A bleeding patient.

2. A patient undergoing an invasive procedure.

So, when is a coagulopathy significant?

Several studies have shown that mild prolongation of the PT (3 to 4 seconds greater than normal) does not significantly increase bleeding risk.^2-5 A study of factor levels relative to prolongation of PT demonstrated that levels below the 30% required for adequate hemostasis occur only when the PT is prolonged greater than 4 seconds (corresponding to an INR of 1.6).⁶  Therefore, PT prolongations up to 3 seconds beyond the normal range represent a laboratory abnormality only and are not indicative of a significant coagulopathy. 

In the presence of a significant coagulopathy

(PT > 3 sec, INR > 1.5), FFP is indicated for:

1. Active bleeding.

2. Anticipated invasive procedure.

3. Massive PRBC transfusion (dilutional

4. coagulopathy).

5. Congenital deficiency of Factor II, V, X, XI, XII, or XIII with bleeding/invasive procedure (virally inactivated factor concentrates not available).

6. Emergent reversal of warfarin effect.
   (Vitamin K reversal takes 6 to 8 hours.)

7. It is also used in plasmapheresis for TTP.

THAWED PLASMA (TP)
The reduced Factor VIII activity of TP is not of concern for most indications, as Factor VIII is an acute phase reactant and tends to be elevated in many hospitalized patients.  Thus, TP may be substituted for FFP, except in cases of severe DIC with rapid consumption of coagulation factors, where FFP would be preferred.

CRYOPRECIPITATE
The primary indication for transfusion of CRYO is hypofibrinogenemia (fibrinogen < 100 mg/dL).  It may also be used in treating a uremic bleeding diathesis that is unresponsive to DDAVP. ⁷  CRYO can also be used to treat von Willebrand’s disease, but only when DDAVP is ineffective and plasma-derived factor concentrates containing vWF (Humate-P®, Alphanate®)) are unavailable.  Topical use, in combination with thrombin, as a surgical hemostatic agent (“fibrin glue”), is being discontinued, due to the availability of the virally-inactivated commercial product Tisseel®.

CRYO- REDUCED PLASMA
Cryo-reduced plasma is used as an alternative to FFP as a replacement fluid in plasmapheresis for TTP, either for initial treatment or for cases not responding to plasma exchange with FFP.

CONTRAINDICATIONS
Plasma transfusion should not be used for volume expansion or as a nutritional supplement, as other products are available that are both effective and do not carry the viral transmission risk of blood product transfusion.  In addition, plasma should not be transfused prophylactically in cases of massive red cell transfusion or after cardiopulmonary bypass. 

For those coagulation factors that are commercially available as recombinant or virally inactivated concentrates (VII, VIII, IX, Anti-Thrombin III), plasma should be transfused only in emergencies when concentrates are unavailable.  Similarly, transfusion of CRYO for von Willebrand’s disease should be reserved for emergent situations when vWF-containing Factor VIII concentrates cannot be obtained in a timely manner. 

DOSAGE and ADMINISTRATION

PLASMA
Correction of a significant coagulopathy requires 10-20 ml/Kg of plasma (4-7 units for a 70 Kg adult).  Smaller volumes do not reliably provide correction and larger volumes are unnecessary.  Each unit may be transfused over as little as 20-30 minutes, provided the recipient’s cardio-respiratory system can tolerate that rate.

CRYOPRECIPITATE
CRYO is generally transfused in pools of 6 units each, which should increase an adult recipient’s fibrinogen level by 30-60 mg/dL.  For uremic bleeding, the dose of CRYO is 6-10 units.

REFERENCES

1. Downes KA, et al. Transfusion 2001; 41: 570.
2. McVay PA, et al. Am J Clin Path, 1990; 94: 747-753.
3. Zins M, et al. Radiology 1992; 184: 841-843.
4. McVay PA, et al. Transfusion 1991; 31: 164-171.
5. Squillante CE, et al. Liver 1993; 13: 270-272.
6. Wachtel S, et al. Blood 1994; 84: Suppl:682a.
7. Janson PA, et al. NEJM 1980; 303: 1318-22.

For questions regarding this TMU, please contact Donald L. Kelley, MD, MBA. at: (412) 209-7483.