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Plasma Products

Three plasma products are generally available today: Fresh Frozen Plasma (FFP), Plasma frozen within 24 hours after Phlebotomy (FP24) and Thawed Plasma.  All of these products are usually prepared from a unit of whole blood, but may also be collected by apheresis. Each bag of plasma prepared from whole blood has a volume between 200 and 250 mL. Plasma prepared by apheresis contains a volume of 400 to 600 mL.

The major difference between FFP and FP24 is that FFP is separated from a unit of whole blood and frozen at -18^oC within 8 hours after collection, whereas a unit of FP24 is frozen within 8 to 24 hours after collection. Because of the delay in freezing, the Factor VIII content of FP24 is 20 to 40% lower than the pre-storage concentration. The decreased level of Factor VIII does not prevent FP24 from correcting a coagulopathy because the Factor VIII concentration of the unit remains above the minimal hemostatic level of 30% and many patients have elevated Factor VIII levels because it is an acute phase reactant.  Because of the logistical difficulties encountered with transporting and processing of blood from remote mobile collection sites, FFP has been replaced by FP24.

FFP and FP24 are thawed in a warm water bath (30 to 37^oC) and should be transfused within 24 hours after thawing. If a unit of FFP or FP24 is not transfused within 24 hours after thawing, it can be relabeled as Thawed Plasma and stored for an additional 4 days at 1 to 6^o C. The FDA has not issued guidance on conversion of FP24 to Thawed Plasma, but this appears to be common practice.  All coagulation factors are maintained at relatively normal levels, except for Factor VIII which declines to 40% of the prestorage level.  Conversion of FFP or FP24 decreases product wastage and improves turnaround time in emergency situations because it has already been thawed and can be issued immediately.

In the United States, most plasma for transfusion is collected from male donors or female donors who have never been pregnant to reduce the risk of transfusion related acute lung injury (TRALI). These donors are less likely to have developed human leukocyte (HLA) or human neutrophil (HNA) antibodies.  Alternatively, for products often in short supply, such as AB plasma, some blood centers have elected to screen female donors who have been pregnant for HLA and HNA to increase their plasma supply. These efforts have significantly decreased the incidence of TRALI.

Pre-transfusion crossmatching of plasma is not necessary.  Units of FFP should be ABO compatible whenever possible. Alternative ABO groups may be substituted as long as the recipients’ red blood cells are compatible with anti-A or B antibodies present in the donor plasma.  The following table provides guidelines for selection of compatible FFP units:       

ABO Compatible FFP

 

FFP Transfusion Guidelines

General guidelines for plasma transfusion include:

1. Treatment of  multiple coagulation factor deficiencies in patients who are bleeding or prior to an invasive procedure
2. Treatment of a single coagulation factor deficiency for which specific concentrates are unavailable.
3. Treatment of dilutional coagulopathy that accompanies massive transfusion
4. Plasma exchange for thrombotic thrombocytopenic purpura (TTP)
5. Prophylactic treatment for patients with hereditary angioedema

Often times, plasma is ordered prophylactically to rapidly correct an elevated INR in a patient receiving warfarin therapy prior to an invasive procedure. The INR results of 227 nonbleeding patients, who were transfused with plasma only, were analyzed between Oct 25, 2011 and May 16, 2012.

 

The longer the pre-transfusion INR, the greater the correction achieved with a single unit of plasma. An INR of 12 can usually be corrected to an INR of 2 with only 2 bags of plasma. Whereas, as many as 4 bags of plasma may be necessary to correct an INR of 1.8 to less than 1.5. When the INR is 1.8 or less, transfusion of plasma corrects INR an average of only 0.1 per unit transfused, largely because the INR of blood bank plasma itself ranges between 1.1 and 1.3. The difference in coagulation activity between donor plasma and patient plasma is so small that plasma transfusions produce minimal demonstrable effect on the patient’s INR.

Physicians performing invasive procedures want to avoid hemorrhagic complications and often regard a mild elevation of a coagulation test result as an indication to order plasma.  The decision to prophylactically transfuse plasma is based on two unproven assumptions:

1. Mild prolongation of PT/INR (defined as an INR <1.8) predicts  bleeding from an invasive  procedure
2. Prophylactic plasma transfusions result in fewer bleeding events

An analysis of the Vitamin K dependent coagulation factors at different INR values clearly contradicts the first assumption. As seen in the following table, vitamin K dependent coagulation factors still average 50% of normal at an INR of 1.8. Minimal hemostatic concentration (MHC) of each factor is not reached until the INR increases to 2.8.

 

These results explain why a mildly elevated INR is not usually associated with spontaneous hemorrhage and does not increase the risk of bleeding during routine invasive procedures. Studies during the last 20 years in patients undergoing liver biopsies, bronchoscopic biopsies, renal biopsies, central line vein cannulation, thoracentesis and angiography have repeatedly demonstrated that INR and PTT are not predictive of hemorrhage.  While a patient with an INR of 1.8 or less may bleed during an invasive procedure, the medical literature clearly demonstrates that the incidence of hemorrhage is not different from that of patients with a normal INR. However, it must be remembered that the risk of bleeding is greater if the platelet count is decreased, platelet function is abnormal, the patient has received antiplatelet medication, has experienced massive trauma or is undergoing extensive surgery.

In view of this information, the common practice of prescribing plasma to correct a mildly elevated INR prior to an invasive procedure needs to be reevaluated. It is usually not necessary or efficacious to correct an INR below 1.8 to achieve adequate hemostasis.

In summary, plasma transfusion has minimal effect on normalizing the INR in patients with mildly prolonged INRs for the following reasons:

• Plasma produced from healthy blood donors can have an INR as high as 1.3
• Plasma transfusion to a patient with an INR of less than 1.8 has minimal effect
• Plasma transfusion to patients with an INR of less than 1.8 does not decrease the INR more than usual medical care without plasma transfusion

For elective surgery, the best strategy for warfarin reversal is to discontinue warfarin 3 to 5 days prior to the procedure. Patients presenting with minor bleeding may be treated by withholding the next dose of warfarin and giving oral Vitamin K.  When vitamin K replacement therapy is used, its effect does not begin until 6-12 hours after administration and is not complete until 36 hours. Patients with greatly elevated INR’s are at high risk for intracranial hemorrhage and should be given plasma concomitantly with vitamin K therapy.

Acquired abnormalities of hemostasis may occur with a variety of other clinical disorders. These usually involve multiple plasma coagulation factor deficits and are more common than inherited plasma deficiencies that usually involve single coagulation factor deficiencies. Consequently, there is a concurrent derangement of several coagulation tests as shown in following table.

Acquired Plasma Coagulopathies

Condition	Coagulation Defect
Liver disease – mild	Abnormal PT
Liver disease –moderate to severe	Abnormal PT, PTT, D-Dimer, platelet function
Acute DIC	PT, PTT, low platelet count, low fibrinogen, elevated D-Dimer
Postoperative bleeding	Minimal PT & PTT elevation, low platelet count
Massive Transfusion	Minimal PT & PTT elevation, low platelet count
Vitamin K deficiency, mild	PT (factor VII)
Vitamin K deficiency, moderate to severe	PT & aPTT  (II, VII, IX, X)

 

The goal of plasma transfusion is to increase the plasma level of each coagulation factor above 30%. Each bag increases the level of any coagulation factor 2 to 3% and fibrinogen 8 mg/dL in an average adult. A dose of 10 to 15 mL of plasma per kg body weight will increase coagulation factors by 8 to 10%, while a dose of 30 to 35 mL per kg body weight will increase them by 30 to 35%. The lower dose corresponds to 3 to 6 bags of plasma in an average 70 kg adult, while the higher dose corresponds to 8 to 14 bags. The PT and PTT should be rechecked before subsequent units are transfused. If the PT and PTT remain prolonged, more plasma may be indicated.

FFP is the treatment of choice for congenital factor deficiencies when more specific concentrates are not available. Examples include factors V and XI.

Congenital Coagulation Factor Deficiencies

 

Dosing of plasma for congenital factor deficiencies is dependent upon the degree of factor deficiency and the half-life of the deficient factor(s).  All of the factors noted above, except V and VII, have a half-life greater than 12 hours and do not need to be replaced more often than every 12 hours.  A practical approach for an average adult would be to give:

• Initial loading dose of 4 units of plasma prior to surgery
• Maintenance dose of 2 units of plasma every 12 hours
• Measure factor level after 24 hours
• Readjust dose as needed

Plasma may be needed for massive transfusions of greater than one blood volume in patients who have a demonstrable coagulopathy and continued bleeding. Thrombocytopenia is responsible for continued bleeding during massive transfusion more often than coagulation factor depletion. Platelet transfusion should be tried first if the platelet count is <50,000/uL. Current massive transfusion guidelines recommend a 1 to 1 ratio of RBCs and plasma.

Plasma is indicated for the treatment of Thrombotic Thrombocytopenic Purpura (TTP) and hemolytic uremic syndrome (HUS). Plasma can be given as a continuous infusion or during plasma exchange. Continuous infusion is not recommended because of its increased risk of fluid overload. A single plasma exchange, which replaces approximately 60% of a patient's plasma volume, usually requires 10 to 12 units of plasma.

Plasma can be used for prophylaxis in patients with hereditary angioedema who are undergoing oral surgery. Prophylaxis will prevent attacks of angioedema which are commonly precipitated by dental procedures and head and neck surgery. Infusion of 2 units of FFP the day before and again just prior to the procedure is recommended. Although FFP is recommended for prophylaxis, its use for treatment of an angioedema attack has not been established. Plasma transfusions have been reported to arrest attacks of angioedema. However, FFP could be hazardous because it contains complement factors C2 and C4 that may exacerbate the attack.  FFP should be reserved for life threatening attacks. Future treatment options include C1 Inhibitor concentrates that have been used for years in Europe and are currently under clinical investigation in the United States.

FFP should not be used as a volume expander, as a nutritional supplement, for the treatment of bleeding in the absence of documented coagulopathy, or as a standing order following surgery or massive transfusion.

It is important to remember that transfusion of FFP is not free of risk. FFP is the blood component most frequently associated with allergic reactions, transfusion-related acute lung injury (TRALI) and transfusion associated circulatory overload (TACO). As with any other blood component, the decision to transfuse FFP should be based on predictable benefit and clinically necessity.