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Cryoprecipitate and Fibrinogen Concentrates
CHAPTER 34
Cryoprecipitate and Fibrinogen Concentrates Beth H. Shaz, MD and Christopher D. Hillyer, MD
Product: Cryoprecipitated Antihemophilic Factor (thawed cryoprecipitated AHF; cryoprecipitated AHF, pooled; also called cryoprecipitate and cryo). Description: Cryoprecipitate is made from human plasma. When fresh frozen plasma (FFP) is thawed in the cold (1–6°C), a precipitate forms (the cryoprecipitate) which, after the supernatant (cryosupernatant, cryoprecipitate-poor or cryoprecipitate-reduced plasma) is removed, is refrozen. Its main constituents are fibrinogen, fibronectin, factor VIII, von Willebrand factor (vWF), and factor XIII. Human fibrinogen concentrates are derived from pooled plasma, purified fibrinogen products labeled with fibrinogen content, and virally inactivated. For these reasons, fibrinogen concentrates are being used instead of cryoprecipitate in some European countries.
Indications: Cryoprecipitate was historically used as a factor VIII replacement for hemophilia A patients, but now there are more purified and virally inactivated or recombinant products available, making it essentially contraindicated to use this product for this reason in the developed world. Similarly, this product should not be used to treat von Willebrand disease or factor XIII deficiency, as more purified and virally inactivated products containing vWF and factor XIII, respectively, are available. Cryoprecipitate is now used primarily for fibrinogen replacement, and in the manufacturing of fibrin sealants and glue (Table 34.1). Outside the US, TABLE 34.1 Primary and Secondary Indications, Common Misuses, and Underutilization of Cryoprecipitate Primary Indications Acquired/congenital hypofibrinogenemia Massive transfusion with bleeding As a component of fibrin glue/sealants Reversal of thrombolytic therapy with bleeding Secondary Indications Hemophilia A von Willebrand disease Factor XIII deficiency Uremic coagulopathy Common misuses Replacement therapy in patients with normal fibrinogen measurements Reversal of warfarin therapy Treatment of bleeding without evidence of hypofibrinogenemia Treatment of hepatic coagulopathy Common underutilization Massive transfusion with dilutional coagulopathy and bleeding Transfusion Medicine and Hemostasis. http://dx.doi.org/10.1016/B978-0-12-397164-7.00034-3 Copyright © 2013 Elsevier Inc. All rights reserved.
227
228
Beth H. Shaz, MD and Christopher D. Hillyer, MD
fibrinogen concentrates are used instead of cryoprecipitate for all fibrinogen replacement indications.
Fibrinogen Replacement: Hypofibrinogenemia occurs in patients with disseminated intravascular coagulopathy (DIC), liver failure, after cardiac surgery, during the anhepatic phase of liver transplantation surgery, and during massive transfusion. In an actively bleeding patient or prior to surgery, fibrinogen product should be given when fibrinogen levels fall below 100 mg/dl, and some suggest 150–200 mg/dl. When the fibrinogen does fall below 100 mg/dl, there is a prolongation of the prothrombin test (PT) and partial thromboplastin time (PTT) that cannot be corrected by the infusion of plasma products. Once the PT and PTT are critically abnormal and with significant bleeding in the patient, it can be more important to intervene with the transfusion of a fibrinogen product than to await laboratory results. Fibrinogen products are also used for fibrinogen replacement in patients with congenital or acquired abnormalities in fibrinogen, such as afibrinogenemia, hypofibrinogenemia, or dysfibrinogenemia. Massive Transfusion: Massive transfusion, defined as the replacement of one blood volume with red blood cell (RBC) products (i.e. 10 products in an adult), is often complicated by both a primary and secondary coagulopathy resulting in thrombocytopenia, hypofibrinogenemia and low coagulation factor levels. Fibrinogen decreases to 100 g/dl after approximately two blood volumes (i.e. 20 RBC products in an adult) are replaced. Therefore, fibrinogen product use should be incorporated into the treatment of massively transfused patients, either as part of a massive transfusion protocol or as replacement once fibrinogen levels reach a predefined threshold through measuring fibrinogen level or by thromboelastography (see Chapter 46).
Fibrin Glue/Sealant: Fibrin glue/sealant results from the mixture of a fibrinogen source (from plasma or heterologous/autologous cryoprecipitate) with a thrombin source (bovine, human, or recombinant). Fibrin glue is a non-FDA-approved thrombin/ preparation, and it has been widely used in Europe for many years. Fibrin sealants are FDA-approved alternatives to fibrin glue and have some advantages, such as standardization of production, over locally made fibrin glues, but are more expensive. Fibrin glues/ sealants can be used for multiple surgical purposes, including as topical hemostat, sealant, or adhesive. Multiple fibrin or thrombin containing products are FDA approved for use. The safety profile of each product differs depending on the product components and source. Bovine thrombin has been reported to cause anaphylaxis (due to bovine allergies), coagulopathy through formation of antibodies to factor V or II, and, rarely, death due to severe systemic hypotensive reactions. Consequently, bovine products have a FDA mandated black-box warning on their package inserts. Pooled human plasma sources have the potential risk of viral or prion disease transmission. Reports indicate that hepatitis A and parvovirus B19 are particularly difficult to remove from these products despite current cleansing and filtration methods, and it is recommended that patients be counseled about this risk. Some human plasma products also contain synthetic aprotinin, which is a potential source of allergic reactions. Recombinant products, while eliminating the risk of infectious transmission or antibody formation, may also cause allergic reactions due to the hamster or snake proteins used to manufacture
Cryoprecipitate and Fibrinogen Concentrates
229
the product. Lastly, autologous fibrin glue preparations have been used; the infectious risks associated with the use of heterologous fibrin glue are eliminated by replacement with the autologous source.
Factor XIII Deficiency: Factor XIII deficiency is a rare autosomal recessive congenital deficiency. Factor XIII plays an important role in the cross-linking of polymerized fibrin. Patients present with bleeding and delayed wound healing usually first noted at the umbilical stump or following circumcision. They have normal PT and PTT tests, but increased clot solubility. The half-life of factor XIII is 9–15 days. Factor XIII concentrate is the preferred therapy, and if unavailable, cryoprecipitate can be used.
Bleeding Complications after Thrombolytic Therapy: Approximately 1% and 6% of patients, who receive thrombolytic therapy for either myocardial infarction or stroke, respectively, have intracranial hemorrhage. Cryoprecipitate, as well as antifibrinolytics and plasma, have been used in the algorithm to treat these life-threatening bleeds; cryoprecipitate is especially indicated if the fibrinogen is <100 mg/dl.
Uremic Bleeding: Cryoprecipitate has been reported to shorten the bleeding time in some uremic patients, and it has a variable hemostatic effect. Therefore, in addition to DDAVP (1-deamino-8-D-arginine-vasopressin), platelet transfusion and dialysis, it may have an adjunctive role.
Processing and Storage: One unit of cryoprecipitate is manufactured from one unit of FFP, which was frozen to ≤−18°C within 8 hours of collection if collected in CPD, CP2D, or CPDA-1 anticoagulants, or within 6 hours if collected in ACD anticoagulant. Cryoprecipitate can be made from FFP within 12 months of the FFP collection. To make cryoprecipitate, FFP is slowly thawed to 1–6°C, the resulting cold insoluble proteins are centrifuged to the bottom of the bag, and the supernatant is expressed. The remaining proteins are refrozen within 1 hour at ≤−18°C in a small amount of remaining plasma/anticoagulant solution. The supernatant plasma, also known as plasma cryoprecipitate-reduced or cryoprecipitate-poor supernatant, is also refrozen for storage at ≤−18°C and later may be used in the treatment of thrombotic thrombocytopenic purpura (TTP). The volume of a single unit of cryoprecipitate is 10–15 ml, and for dosing purposes is usually pooled post-thaw, into a single bag of 10 pooled units for transfusion. Some blood centers supply cryoprecipitate in prepooled units from 5 donors. Cryoprecipitate must be used within 12 months of collection. Fibrinogen and factor XIII concentrates are manufactured from pooled human plasma, virally inactivated and lyophilized, and stored at room temperature.
Preparation and Administration: Cryoprecipitate: ABO/D Compatibility: Since cryoprecipitate contains negligible amounts of RBCs and minimal isohemagglutinins, anti-A and/or anti-B, choosing units with ABO or D compatibility is not necessary for most adult and pediatric patients; neonatal transfusion guidelines often recommend the use of ABO compatible cryoprecipitate.
230
Beth H. Shaz, MD and Christopher D. Hillyer, MD
Thawing and Pooling: Cryoprecipitate takes 10–15 minutes to thaw in a 30–37°C water bath and is usually pooled for easier administration which takes an additional 10–15 minutes. Cryoprecipitate can be prepooled which eases the process of thawing and administration, especially in times of emergency, such as trauma and liver transplantation. After thawing, the cryoprecipitate is maintained between 20–24°C. Expiration: Once thawed, a single unit of cryoprecipitate expires in 6 hours; pooled units in open system expire in 4 hours.
Fibrinogen and Factor XIII Concentrate: Lyophilized products are mixed with sterile liquid (water). Product is dissolved then aseptically intravenously administered.
Cryoprecipitate Quality Assurance: Per AABB Standards, each unit of cryoprecipitate must contain a minimum of 150 mg of fibrinogen, but usually it contains 250–350 mg, and a minimum of 80 IU of factor VIII, but usually it contains 80–120 IU. In addition, cryoprecipitate contains 30–60 mg of fibronectin, 40–60 IU of factor XIII, and ~80 IU of vWF. Dose: Fibrinogen: One unit of cryoprecipitate will increase the fibrinogen concentration by approximately 50 mg/dl per 10 kg of body weight. Most clinicians will order a single dose of a 10 unit pool of cryoprecipitate (an equivalent of 1 blood volume’s worth) or 70 mg/kg × body weight (kg) of fibrinogen concentrate, and re-measure the fibrinogen level (see Chapter 39).
Factor XIII: One unit of cryoprecipitate for every 10–20 kg given every 3–4 weeks prophylactically, and higher doses more frequently in the setting of active bleeding is a common strategy, with laboratory measurements obtained as indicated. For factor XIII concentrate see Chapter 39 for dosing.
Adverse Events: Adverse reactions include fever, chills, and allergic reactions. Large volumes of ABO incompatible cryoprecipitate may cause a positive direct antiglobulin test and have rarely been reported to cause mild hemolytic transfusion reactions.
International Standards: In the UK, cryoprecipitate is manufactured from a single unit of FFP by rapid freezing to <−30°C then thawing slowly to 4°C. Current guidelines require 75% of the units of cryoprecipitate must include at least 140 mg of fibrinogen and 70 IU/ml of factor VIII with a 24 month storage period.
Recommended Reading Bolliger D, Gorlinger K, Tanaka K. (2010). Pathophysiology and treatment of coagulopathy in massive hemorrhage and hemodilution. Anesthesiology 113, 1205–1219. Hedges SJ, Dehoney SB, Hooper JS, Amanzadeh J, Busti AJ. (2007). Evidence-based treatment recommendations for uremic bleeding. Nat Clin Pract Nephrol 3, 138–153. Levy JH, Sziam F, Tanaka KA, Sniecienski RM. (2012). Fibrinogen and hemostasis: a primary hemostatic target for the management of acquired bleeding. Anesth Analg 11, 261–274.
Cryoprecipitate and Fibrinogen Concentrates Beth H. Shaz, MD and Christopher D. Hillyer, MD
Product: Cryoprecipitated Antihemophilic Factor (thawed cryoprecipitated AHF; cryoprecipitated AHF, pooled; also called cryoprecipitate and cryo). Description: Cryoprecipitate is made from human plasma. When fresh frozen plasma (FFP) is thawed in the cold (1–6°C), a precipitate forms (the cryoprecipitate) which, after the supernatant (cryosupernatant, cryoprecipitate-poor or cryoprecipitate-reduced plasma) is removed, is refrozen. Its main constituents are fibrinogen, fibronectin, factor VIII, von Willebrand factor (vWF), and factor XIII. Human fibrinogen concentrates are derived from pooled plasma, purified fibrinogen products labeled with fibrinogen content, and virally inactivated. For these reasons, fibrinogen concentrates are being used instead of cryoprecipitate in some European countries.
Indications: Cryoprecipitate was historically used as a factor VIII replacement for hemophilia A patients, but now there are more purified and virally inactivated or recombinant products available, making it essentially contraindicated to use this product for this reason in the developed world. Similarly, this product should not be used to treat von Willebrand disease or factor XIII deficiency, as more purified and virally inactivated products containing vWF and factor XIII, respectively, are available. Cryoprecipitate is now used primarily for fibrinogen replacement, and in the manufacturing of fibrin sealants and glue (Table 34.1). Outside the US, TABLE 34.1 Primary and Secondary Indications, Common Misuses, and Underutilization of Cryoprecipitate Primary Indications Acquired/congenital hypofibrinogenemia Massive transfusion with bleeding As a component of fibrin glue/sealants Reversal of thrombolytic therapy with bleeding Secondary Indications Hemophilia A von Willebrand disease Factor XIII deficiency Uremic coagulopathy Common misuses Replacement therapy in patients with normal fibrinogen measurements Reversal of warfarin therapy Treatment of bleeding without evidence of hypofibrinogenemia Treatment of hepatic coagulopathy Common underutilization Massive transfusion with dilutional coagulopathy and bleeding Transfusion Medicine and Hemostasis. http://dx.doi.org/10.1016/B978-0-12-397164-7.00034-3 Copyright © 2013 Elsevier Inc. All rights reserved.
227
228
Beth H. Shaz, MD and Christopher D. Hillyer, MD
fibrinogen concentrates are used instead of cryoprecipitate for all fibrinogen replacement indications.
Fibrinogen Replacement: Hypofibrinogenemia occurs in patients with disseminated intravascular coagulopathy (DIC), liver failure, after cardiac surgery, during the anhepatic phase of liver transplantation surgery, and during massive transfusion. In an actively bleeding patient or prior to surgery, fibrinogen product should be given when fibrinogen levels fall below 100 mg/dl, and some suggest 150–200 mg/dl. When the fibrinogen does fall below 100 mg/dl, there is a prolongation of the prothrombin test (PT) and partial thromboplastin time (PTT) that cannot be corrected by the infusion of plasma products. Once the PT and PTT are critically abnormal and with significant bleeding in the patient, it can be more important to intervene with the transfusion of a fibrinogen product than to await laboratory results. Fibrinogen products are also used for fibrinogen replacement in patients with congenital or acquired abnormalities in fibrinogen, such as afibrinogenemia, hypofibrinogenemia, or dysfibrinogenemia. Massive Transfusion: Massive transfusion, defined as the replacement of one blood volume with red blood cell (RBC) products (i.e. 10 products in an adult), is often complicated by both a primary and secondary coagulopathy resulting in thrombocytopenia, hypofibrinogenemia and low coagulation factor levels. Fibrinogen decreases to 100 g/dl after approximately two blood volumes (i.e. 20 RBC products in an adult) are replaced. Therefore, fibrinogen product use should be incorporated into the treatment of massively transfused patients, either as part of a massive transfusion protocol or as replacement once fibrinogen levels reach a predefined threshold through measuring fibrinogen level or by thromboelastography (see Chapter 46).
Fibrin Glue/Sealant: Fibrin glue/sealant results from the mixture of a fibrinogen source (from plasma or heterologous/autologous cryoprecipitate) with a thrombin source (bovine, human, or recombinant). Fibrin glue is a non-FDA-approved thrombin/ preparation, and it has been widely used in Europe for many years. Fibrin sealants are FDA-approved alternatives to fibrin glue and have some advantages, such as standardization of production, over locally made fibrin glues, but are more expensive. Fibrin glues/ sealants can be used for multiple surgical purposes, including as topical hemostat, sealant, or adhesive. Multiple fibrin or thrombin containing products are FDA approved for use. The safety profile of each product differs depending on the product components and source. Bovine thrombin has been reported to cause anaphylaxis (due to bovine allergies), coagulopathy through formation of antibodies to factor V or II, and, rarely, death due to severe systemic hypotensive reactions. Consequently, bovine products have a FDA mandated black-box warning on their package inserts. Pooled human plasma sources have the potential risk of viral or prion disease transmission. Reports indicate that hepatitis A and parvovirus B19 are particularly difficult to remove from these products despite current cleansing and filtration methods, and it is recommended that patients be counseled about this risk. Some human plasma products also contain synthetic aprotinin, which is a potential source of allergic reactions. Recombinant products, while eliminating the risk of infectious transmission or antibody formation, may also cause allergic reactions due to the hamster or snake proteins used to manufacture
Cryoprecipitate and Fibrinogen Concentrates
229
the product. Lastly, autologous fibrin glue preparations have been used; the infectious risks associated with the use of heterologous fibrin glue are eliminated by replacement with the autologous source.
Factor XIII Deficiency: Factor XIII deficiency is a rare autosomal recessive congenital deficiency. Factor XIII plays an important role in the cross-linking of polymerized fibrin. Patients present with bleeding and delayed wound healing usually first noted at the umbilical stump or following circumcision. They have normal PT and PTT tests, but increased clot solubility. The half-life of factor XIII is 9–15 days. Factor XIII concentrate is the preferred therapy, and if unavailable, cryoprecipitate can be used.
Bleeding Complications after Thrombolytic Therapy: Approximately 1% and 6% of patients, who receive thrombolytic therapy for either myocardial infarction or stroke, respectively, have intracranial hemorrhage. Cryoprecipitate, as well as antifibrinolytics and plasma, have been used in the algorithm to treat these life-threatening bleeds; cryoprecipitate is especially indicated if the fibrinogen is <100 mg/dl.
Uremic Bleeding: Cryoprecipitate has been reported to shorten the bleeding time in some uremic patients, and it has a variable hemostatic effect. Therefore, in addition to DDAVP (1-deamino-8-D-arginine-vasopressin), platelet transfusion and dialysis, it may have an adjunctive role.
Processing and Storage: One unit of cryoprecipitate is manufactured from one unit of FFP, which was frozen to ≤−18°C within 8 hours of collection if collected in CPD, CP2D, or CPDA-1 anticoagulants, or within 6 hours if collected in ACD anticoagulant. Cryoprecipitate can be made from FFP within 12 months of the FFP collection. To make cryoprecipitate, FFP is slowly thawed to 1–6°C, the resulting cold insoluble proteins are centrifuged to the bottom of the bag, and the supernatant is expressed. The remaining proteins are refrozen within 1 hour at ≤−18°C in a small amount of remaining plasma/anticoagulant solution. The supernatant plasma, also known as plasma cryoprecipitate-reduced or cryoprecipitate-poor supernatant, is also refrozen for storage at ≤−18°C and later may be used in the treatment of thrombotic thrombocytopenic purpura (TTP). The volume of a single unit of cryoprecipitate is 10–15 ml, and for dosing purposes is usually pooled post-thaw, into a single bag of 10 pooled units for transfusion. Some blood centers supply cryoprecipitate in prepooled units from 5 donors. Cryoprecipitate must be used within 12 months of collection. Fibrinogen and factor XIII concentrates are manufactured from pooled human plasma, virally inactivated and lyophilized, and stored at room temperature.
Preparation and Administration: Cryoprecipitate: ABO/D Compatibility: Since cryoprecipitate contains negligible amounts of RBCs and minimal isohemagglutinins, anti-A and/or anti-B, choosing units with ABO or D compatibility is not necessary for most adult and pediatric patients; neonatal transfusion guidelines often recommend the use of ABO compatible cryoprecipitate.
230
Beth H. Shaz, MD and Christopher D. Hillyer, MD
Thawing and Pooling: Cryoprecipitate takes 10–15 minutes to thaw in a 30–37°C water bath and is usually pooled for easier administration which takes an additional 10–15 minutes. Cryoprecipitate can be prepooled which eases the process of thawing and administration, especially in times of emergency, such as trauma and liver transplantation. After thawing, the cryoprecipitate is maintained between 20–24°C. Expiration: Once thawed, a single unit of cryoprecipitate expires in 6 hours; pooled units in open system expire in 4 hours.
Fibrinogen and Factor XIII Concentrate: Lyophilized products are mixed with sterile liquid (water). Product is dissolved then aseptically intravenously administered.
Cryoprecipitate Quality Assurance: Per AABB Standards, each unit of cryoprecipitate must contain a minimum of 150 mg of fibrinogen, but usually it contains 250–350 mg, and a minimum of 80 IU of factor VIII, but usually it contains 80–120 IU. In addition, cryoprecipitate contains 30–60 mg of fibronectin, 40–60 IU of factor XIII, and ~80 IU of vWF. Dose: Fibrinogen: One unit of cryoprecipitate will increase the fibrinogen concentration by approximately 50 mg/dl per 10 kg of body weight. Most clinicians will order a single dose of a 10 unit pool of cryoprecipitate (an equivalent of 1 blood volume’s worth) or 70 mg/kg × body weight (kg) of fibrinogen concentrate, and re-measure the fibrinogen level (see Chapter 39).
Factor XIII: One unit of cryoprecipitate for every 10–20 kg given every 3–4 weeks prophylactically, and higher doses more frequently in the setting of active bleeding is a common strategy, with laboratory measurements obtained as indicated. For factor XIII concentrate see Chapter 39 for dosing.
Adverse Events: Adverse reactions include fever, chills, and allergic reactions. Large volumes of ABO incompatible cryoprecipitate may cause a positive direct antiglobulin test and have rarely been reported to cause mild hemolytic transfusion reactions.
International Standards: In the UK, cryoprecipitate is manufactured from a single unit of FFP by rapid freezing to <−30°C then thawing slowly to 4°C. Current guidelines require 75% of the units of cryoprecipitate must include at least 140 mg of fibrinogen and 70 IU/ml of factor VIII with a 24 month storage period.
Recommended Reading Bolliger D, Gorlinger K, Tanaka K. (2010). Pathophysiology and treatment of coagulopathy in massive hemorrhage and hemodilution. Anesthesiology 113, 1205–1219. Hedges SJ, Dehoney SB, Hooper JS, Amanzadeh J, Busti AJ. (2007). Evidence-based treatment recommendations for uremic bleeding. Nat Clin Pract Nephrol 3, 138–153. Levy JH, Sziam F, Tanaka KA, Sniecienski RM. (2012). Fibrinogen and hemostasis: a primary hemostatic target for the management of acquired bleeding. Anesth Analg 11, 261–274.