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Cryoprecipitate

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 and then centrifuged to remove the supernatant. The remaining insoluble precipitate is suspended in 10 to 15 mL of residual plasma and refrozen at -18 oC within one hour. Cryoprecipitate outdates 6 hours after being thawed or 4 hours after being pooled.

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. Because cryoprecipitate is suspended in a small volume, it contains a higher concentration of these coagulation factors than is found in the original unit of plasma. The actual concentration can vary because of donor variability and inter-institutional processing differences.

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. Pools of 5 units of cryoprecipitate are supplied for blood groups A, B and O.

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.

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. If fibrinogen is decreased, bleeding may ensue.

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

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.

Cryoprecipitate should be given when the fibrinogen level falls below 100 mg/dL, which is the minimal level needed for hemostasis. Some trauma guidelines recommend transfusion of cryoprecipitate if significant bleeding is accompanied by a fibrinogen level below 150 to 200 mg/dL.

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 mg/dL. 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. 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. Besides fibrinogen replacement, cryoprecipitate can be used to correct bleeding associated with Factor XIII deficiency, acquired von Willebrand syndrome and uremia.

Cryoprecipitate can also be used to treat patients with documented factor XIII deficiency whom are actively bleeding or undergoing an invasive or surgical procedure. Factor XIII deficiency can usually be treated with 1 bag of cryoprecipitate for every 10 kg of body weight. Factor XIII assays should be used to evaluate the need for repeat administration in Factor XIII deficiency. A commercial concentrate of factor XIII is now available in the United States. 

Bleeding due to defects in vWF structure or function that are not inherited, but are consequences of other medical disorders, 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.

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.

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