- Last Update On : 2016-10-03
Cryoprecipitate refers to the proteins that precipitate out of solution when a unit of fresh frozen plasma is slowly thawed in the cold. Each unit of cryoprecipitate is prepared from one unit of fresh frozen plasma that is thawed at 1 to 6o C. The unit is centrifuged at 5000 x g for 6 minutes and the supernatant is removed. The remaining insoluble precipitate is suspended in 10 to 15 mL of residual plasma and refrozen at -18 oC within one hour. Cryoprecipitate can be stored at -18 C for up to 12 months
Since several bags of cryoprecipitate are transfused at a time, the transfusion service or blood center pools them into a sterile plastic transfer pack and stores them at 20-24oC until administration. Blood centers supply pools of 5 units of cryoprecipitate for blood groups A, B and O. Cryoprecipitate outdates 6 hours after being thawed or 4 hours after being pooled.
ABO compatible cryoprecipitate is desirable if large volumes will be transfused, but Rh compatibility is not important because no red blood cells are present. Cryoprecipitate should be infused through a standard blood filter at a rate of 4 to 10 mL/minute. At this rate, a pool of 10 bags can be infused in approximately 30 minutes. The risk of viral transmission from cryoprecipitate is the same as other plasma products.
Each bag of cryoprecipitate contains Factor VIII, fibrinogen, von Willebrand factor, and Factor XIII. It also contains platelet membrane microparticles which may retain some haemostatic function.
The transfusion service often receives orders for fresh frozen plasma (FFP) to treat the prolonged protime (PT) and activated partial thromboplastin time (aPTT) associated with hypofibrinogenemia. Although FFP contains fibrinogen, it is not the optimal blood component because of the very large volumes of plasma that are required to increase fibrinogen to hemostatic levels. Cryoprecipitate is preferred because it contains the same concentration of fibrinogen as FFP in less than one-twentieth of the volume. For example, the concentration of fibrinogen is approximately 1500 mg/dL in cryoprecipitate and 100-300 mg/dL in plasma. The actual concentration can vary because of donor variability and inter-institutional processing differences.
Conversion of fibrinogen into fibrin is the last stage of the coagulation sequence. Fibrinogen plays an important role in fibrin clot formation and platelet aggregation. Low fibrinogen is a risk factor for perioperative bleeding in a number of clinical settings including cardiovascular surgery, trauma and obstetrics.
Hypofibrinogenemia is the term used to describe a fibrinogen concentration below the reference range of 200 – 450 mg/dL. Historically, a fibrinogen concentration of 100 mg/dL was considered sufficient to prevent bleeding in patients with congenital fibrinogen deficiency. Patients with acquired hypofibrinogenemia may require a higher threshold because they may have additional coagulation factor deficiencies or hemostatic defects. Some trauma guidelines recommend transfusion of cryoprecipitate if significant bleeding is accompanied by a fibrinogen level below 150 to 200 mg/dL.
Acquired hypofibrinogenemia is most commonly associated with:
- Severe liver disease
- Head trauma
- Postpartum hemorrhage
- Acute DIC
- Tissue plasminogen activator (TPA) therapy
- Streptokinase & urokinase therapy
- Chemotherapy with asparaginase
- Plasma exchange with albumin
Each bag of cryoprecipitate contains 200 to 250 mg of fibrinogen and will increase the plasma fibrinogen level of a 70-kg adult by 6 to 8 mg/dL. FDA advises giving 0.2 units of cryoprecipitate per kilogram of body weight (e.g. 14 units to a 70 kg adult). Generally, 10 bags of cryoprecipitate are given if the fibrinogen level is between 50 and100 mg/dL and 20 bags are given if it is less than 50 mg/dL. A fibrinogen level should be measured at 30 to 60 minutes after completion of the transfusion to determine if additional doses are needed. The therapeutic goal is to keep the plasma fibrinogen level above 100 t0 200 mg/dL, depending on the clinical situation. The circulating half life of fibrinogen is 3 to 5 days.
Cryoprecipitate may be given prophylactically for head trauma because of the associated disseminated intravascular coagulation that can result in intracranial hemorrhage. In patients with either blunt or penetrating head trauma, 10 units of cryoprecipitate may be given empirically or when serial fibrinogen levels indicate a precipitous drop in fibrinogen level.
Pregnancy is associated with physiologically elevated fibrinogen concentration of approximately 500 mg/dL. Severity of postpartum hemorrhage is correlated with fibrinogen concentration. Better outcomes are associated with maintenance of fibrinogen levels above 300 mg/dL. Cryoprecipitate is recommended when fibrinogen levels fall below 200 mg/dL..
Cryoprecipitate should be transfused to patients with congenital fibrinogen deficiency only when they are bleeding or prior to an invasive or surgical procedure. Fibrinogen concentrate is commercially available as a pasteurized lyophilized powder that is reconstituted with sterile water for injection to a final concentration of 2000 mg/dL. Fibrinogen concentrate is considered to be safer than cryoprecipitate because it is virally inactivated, depleted of antigens and antibodies, and available in a standard dose. Fibrinogen concentrate is licensed in the United States only for treatment of congenital afibrinogenemia or hypofibrinogenemia.
Factor XIII catalyzes the cross-linking of fibrin, stabilizing clots. Factor XIII deficiency is a rare autosomal recessive disorder that presents as umbilical cord bleeding after birth, intracranial hemorrhage, spontaneous miscarriage, mucosal bleeding or delayed bleeding and wound healing after trauma. Factor XIII has a circulating half life of approximately 10 days. Cryoprecipitate can be used for patients with documented factor XIII deficiency whom are actively bleeding or undergoing an invasive or surgical procedure. A dose of 1 bag of cryoprecipitate for every 10 kg of body weight is usually sufficient. A commercially available factor XIII concentrate (Corifact, CSL Behring) is available. This concentrate is preferred over cryoprecipitate because it is virally inactivated and has a standardized dose. The recommended dose for prophylaxis is 40U/kg every 4 weeks to maintain trough levels of Factor XIII above 5%. Preoperative doses of 25 to 40U/kg, which increase Factor XIII levels to 60 to 100% have been reported to control hemostasis.
Bleeding due to acquired defects in vWF structure or function that are not inherited has been classified as acquired von Willebrand syndrome (AVWS) to distinguish it from congenital von Willebrand disease (vWD). Excessive bleeding associated with other cardiovascular disorders such as ventricular septal defect, hypertrophic obstructive cardiomyopathy, and placement of left ventricular assist device (LVAD) has also been attributed to development of AVWS. Various transfusion therapies have been tried to treat excessive bleeding associated with these cardiovascular disorders including plasma, desmopressin (DDAVP), aprotinin, tranexamic acid, aminocaproic acid and recombinant FVIIa (Novoseven). However, none of these products specifically addresses the specific underlying problem. Replacement of loss of high molecular weight vWF can best be achieved by transfusion of cryoprecipitate or a factor concentrate that contains Factor VIII and vWF, such as Humate P.
Cryoprecipitate is beneficial in correcting the thrombopathy associated with uremia. Ten bags of cryoprecipitate are usually required to reverse a qualitative platelet defect. The maximum therapeutic effect takes at least 4 hours after infusion to develop and lasts approximately 24 hours. Repeat administration of cryoprecipitate provides limited improvement. The use of cryoprecipitate to correct a qualitative platelet defect should be reserved for life-threatening hemorrhage or prior to an invasive procedure. Alternatively, dialysis can be used to correct the uremic platelet defect.
Because of the increased risk of hemorrhage, the National Comprehensive Cancer Network (NCCN) and the European Leukemia Net (ELN) have recommended higher transfusion thresholds for patients with acute promyelocytic leukemia (APL) than for other types of acute myelogenous leukemia (AML). Cryoprecipitate is recommended when the fibrinogen falls below 150 mg/dL in APL compared to below 100 mg/dL in other types of AML.
Cryoprecipitate can also be used as a local hemostatic sealant and this application is commonly referred to as fibrin glue. It is best used when cautery and suture cannot control localized bleeding. Diffuse bleeding will not improve with fibrin glue. The three essential ingredients of fibrin sealant are the fibrinogen present in cryoprecipitate, bovine or human thrombin, and calcium chloride. A vial of lyophilized thrombin is reconstituted with calcium chloride and aspirated into one chamber of a double-barreled syringe. One or two units of cryoprecipitate are generally used as a fibrin sealant depending on the severity of the bleeding and the surface area to be covered. A single unit of cryoprecipitate is aspirated into the other barrel. Both solutions are delivered simultaneously through a blunt tipped cannula or spray atomizer on to the bleeding site. A clot forms in a matter of seconds to minutes, and lasts up to 2 weeks. Adverse effects include the formation of antibodies to bovine thrombin and factor V, which may cause bleeding. Another potential complication is anaphylaxis.
Cryoprecipitate should not be used to treat von Willebrand’s disease except in life and limb-threatening emergencies when multimeric vWF-containing Factor VIII concentrate (Humate P, Alphanate, or Koate DVI) is not immediately available. A reasonable dose of cryoprecipitate is 1 bag for every 10 Kg of body weight. This dose should be repeated every 8 to 12 hours. The amount of von Willebrand factor contained within a given unit of cryoprecipitate is highly variable and dependent upon the donor’s plasma level.
Cryoprecipitate should be used to treat Hemophilia A only when Factor VIII concentrate is not available. Cryoprecipitate should never be used for the treatment of hemophilia B since it lacks Factor IX.
Cryoprecipitate has been withdrawn from many European countries because it is a pooled product that has not undergone pathogen inactivation and has a higher risk of transfusion transmitted disease. It has been replaced by commercial fibrinogen concentrates that are purified and pasteurized. In the United States, fibrinogen concentrate is licensed only for treatment of congenital afibrinogenemia or hypofibrinogenemia.
Callum JL, et al. Cryoprecipitate: The current state of knowledge. Transfusion Med Rev 2009;23:177-188.
Nascimento B. et al. Cryoprecipitate therapy. Brit J Anaesthesia 2014; doi:10.1093/bja/aeu158
Levy JH et al. Fibrinogen as a therapeutic target for bleeding: a reviw of critical levels and replacement therapy. Transfusion 2014;54:1389-1405.