Continuing Education Activity

Fresh frozen plasma is indicated for the deficiency of coagulation factors with abnormal coagulation tests in the presence of active bleeding. Fresh frozen plasma is also indicated for a planned surgery or invasive procedure in the presence of abnormal coagulation tests, the reversal of warfarin in the presence of active bleeding, or planned procedure when vitamin K is inadequate to reverse the warfarin effect, thrombotic thrombocytopenic purpura, and congenital or acquired factor deficiency with no alternative therapy. This activity reviews the indications for fresh frozen plasma and highlights the role of the interprofessional team in managing patients with coagulopathy that requires the use of fresh frozen plasma.

Objectives:

• Identify the mechanism of action of fresh frozen plasma.
• Describe the adverse effects of fresh frozen plasma.
• Review the appropriate monitoring of patients who are administered fresh frozen plasma.
• Explain some interprofessional team strategies to improve care coordination and advance managing conditions treated with fresh frozen plasma.

Indications

Fresh frozen plasma is indicated for the deficiency of coagulation factors with abnormal coagulation tests in the presence of active bleeding. Fresh frozen plasma is also indicated for a planned surgery or invasive procedure in the presence of abnormal coagulation tests, for the reversal of warfarin in the presence of active bleeding, or planned procedure when vitamin K is inadequate to reverse the warfarin effect, thrombotic thrombocytopenic purpura, and congenital or acquired factor deficiency with no alternative therapy. Based on a systematic review, other specific recommendations for fresh frozen plasma include trauma patients requiring massive transfusion and warfarin-related intracranial hemorrhage. 

Other situations where the administration of fresh frozen plasma cannot be recommended for or against based on systematic review include fresh frozen plasma transfusion at a plasma-to-RBC ratio of 1 to 3 or more in trauma patients with massive transfusion. Conditions that cause the deficiency of multiple coagulation factors and may require the administration of fresh frozen plasma include liver disease and disseminated intravascular coagulation. Fresh frozen plasma transfusion may not be tolerated in patients with liver disease as patients may not tolerate the infusion volumes necessary to achieve adequate hemostatic levels of coagulation factors.[1][2][3]

Mechanism of Action

Fresh frozen plasma is the fluid portion of a unit of whole blood frozen in a designated time frame, usually within 8 hours. Fresh frozen plasma contains all coagulation factors except platelets. Fresh frozen plasma contains fibrinogen (400 to 900 mg/unit), albumin, protein C, protein S, antithrombin, tissue factor pathway inhibitor. It is free of erythrocytes and leukocytes.  Fresh frozen plasma corrects coagulopathy by replacing or supplying plasma proteins in patients who are deficient in or have defective plasma proteins. A standard dose of 10 to 20 mL/kg (4 to 6 units in adults) will raise factor levels by approximately 20%. An increase of roughly 10% of several factors is enough to bring about hemostasis. Also, fresh frozen plasma provides some volume resuscitation, as each unit contains approximately 250 ml.[4][5][6][7]

Administration

Fresh frozen plasma can only be administered intravenously. Fresh frozen plasma must be ABO compatible with the recipient’s red cells. Upon visual inspection, the fresh frozen plasma container and fluid should have no leakage, clots, or abnormal color. Fresh frozen plasma is stored at -30 Celsius. Before administration, fresh frozen plasma is thawed in a water bath at 30 to 37 Celsius over 20 to 30 minutes or in an FDA-cleared device as quickly as 2 to 3 minutes. Fresh frozen plasma should be administered immediately after thawing. If fresh frozen plasma is not given immediately after thawing, it should be stored at 1 to 6 Celsius. 

If the thawed fresh frozen plasma is not used in 24 hours, it should be discarded. Once thawed, the activity of clotting factors, particularly factor V and factor VIII, decline gradually. After the initial dosage, re-administration may be needed every 6 to 8 hours if there is ongoing bleeding due to the short half-life of factor VII; factor VII has a half-life of 2 to 6 hours.

Adverse Effects

The adverse effects of fresh frozen plasma administration are similar to those that pertain to whole blood and all blood components. They can be categorized into non-immunologic complications, immediate immunologic complications, and delayed immunologic complications. The acellularity of fresh frozen plasma spares certain disease transmission and blood immunogenicity: CMV and graft-versus-host disease cannot be transmitted by fresh frozen plasma as there are no viable leukocytes. Non-immunologic complications include the transmission of infectious agents, transfusion-associated circulatory overload (TACO), and metabolic complications like citrate toxicity. Infectious agents that are transmittable via fresh frozen plasma include HIV and hepatitis B and C. Screening and pathogen inactivation has reduced transmission rates of HIV to 1 in 7.8 million, hepatitis B virus to 1 in 153,000, and hepatitis C virus to 1 in 2.3 million.

TACO results from cardiogenic pulmonary edema and can occur after transfusion of excessive volumes or volumes at excessive rates. Immediate immunologic complications include hemolytic transfusion reaction, febrile non-hemolytic reaction, allergic reactions, anaphylactoid/anaphylactic reactions, and transfusion-related acute lung injury (TRALI). Hemolytic transfusion reaction occurs from anti-A and anti-B antibodies due to the failure of ABO matching. TRALI is the most common cause of transfusion-related death. TRALI is the acute onset of hypoxemia and non-cardiogenic pulmonary edema in the absence of other causes of acute lung injury or circulatory overload. TRALI occurs secondary to stimuli in blood components (white blood cell antibodies from donors and/or pro-inflammatory molecules that have accumulated in stored blood components) that trigger an inflammatory response resulting in injury to the alveolar-capillary membrane causing permeability pulmonary edema. Delayed immunologic complications include alloimmunization to plasma proteins.[8]

Contraindications

Fresh frozen plasma is contraindicated when coagulopathy can be corrected more effectively with specific therapy and when blood volume can be adequately replaced with other volume expanders. More specific treatments that merit consideration before fresh frozen plasma administration include vitamin K, cryoprecipitated antihemophilic factor, prothrombin complex concentrates, or specific coagulation factor concentrates like factor VII. In the absence of coagulation deficiencies and active bleeding, fresh frozen plasma should not be used as a volume expander. Fresh frozen plasma is contraindicated for the reversal of anticoagulation induced by heparin, direct thrombin inhibitors, or direct factor Xa inhibitors because fresh frozen plasma does not effectively reverse anticoagulation induced by these medications. Antidotes to reverse direct oral anticoagulants are better options.

Monitoring

The therapy of fresh frozen plasma is monitored clinically with signs of bleeding and chemically with coagulation studies and fibrinogen levels. Each unit of fresh frozen plasma contains approximately 200 to 250 mL. Apheresis-derived units can contain as much as 400 to 600 mL. The administration of one 250 mL unit should raise the fibrinogen level by 5 to 10 mg/dl. The goal of therapy is a cessation of bleeding. The laboratory value goal is to correct the prothrombin time/activated partial thromboplastin time to less than 1.5 times normal.[9][10][11]

Toxicity

Citrate toxicity can occur with the administration of fresh frozen plasma. The majority of citrate in whole blood products is present in fresh frozen plasma and platelets, not packed red blood cells. Citrate chelates calcium, and citrate intoxication causes hypocalcemia. Hypocalcemia signs and symptoms include hypotension, decreased pulse pressure, arrhythmias, mental status changes, and tetany. Treatment includes calcium administration.

Enhancing Healthcare Team Outcomes

There is a general assumption among healthcare workers that fresh frozen plasma is free of adverse effects and complications; nothing can be further from the truth. All interprofessional healthcare team members, including clinicians (MDs, DOs, NPs, PAs), nursing staff, and pharmacists, should know the indications for fresh frozen plasma administration and the monitoring process. The adverse effects of fresh frozen plasma are monitored like any other blood product administration. The patient’s vital signs (temperature, pulse, respiration, and blood pressure) are monitored before, during, and after administration. If a reaction is noted based on signs and symptomology, treatment is guided by the type of transfusion reaction. Usually, the administration of the product should immediately cease. Life-threatening reactions like TRALI and TACO may require aggressive respiratory support and often mechanical ventilation.

Proper administration and management of fresh frozen plasma require the efforts of an entire interprofessional team. Through proper knowledge and training, open information sharing and communication, and empowerment of each team member to contribute from their individual specialties, patients can achieve the best possible outcomes where fresh frozen plasma is indicated while having minimal adverse events. [Level 5]