What is Cryoprecipitate?
Cryoprecipitated Antihemophilic Factor (Cryo AHF), known typically as its shorthand cryoprecipitate or even shorter, "Cryo", is product made from plasma used for patients with bleeding or bleeding tendency presenting with low levels of fibrinogen (hypofibrinogenemia) or dysfunctional fibrinogen (dysfibrinogenemia).
Cryo contains concentrated amounts of multiple coagulation factors, such as Fibrinogen (Factor I), Factor VIII (Antihemophilic Factor), Factor XIII, von Willebrand factor, and fibronectin in some amounts.
Fibrinogen gets activated and converted into fibrin during tissue or vascular injury that helps to form a strong clot by creating polymerized strands that will eventually be used to bind and hold together a clot, stopping bleeding from occurring or continuing.
Factor VIII is a coagulation factors essential for blood clotting. Hemophilia A presents as a defect in the Factor VIII gene, thus patients with Hemophilia A will present with impaired/deficient factor VIII activity. (Cryo cannot be used to assist with Hemophilia B patients)
Factor XIII is another coagulation factor essential for blood clotting. It cross-links the fibrin polymers created from fibrinogen and helps stabilize the clot.
Von Willebrand factor is an essential factor involved in helping platelets adhere to the endothelium of the blood vessel
Fibronectin also plays a part in forming a clot and protects underlying area and as a result promotes proper wound healing.
Cryoprecipitate Manufacturing -- How is it made?
Units of cryoprecipitate are processed from units of Fresh Frozen Plasma (FFP). FFP is a specific product in which donated blood plasma is frozen within 8 hours of collection. FFP is used for cryo manufacturing to ensure the clotting factors remain stable and do not degrade. There are studies and new technologies coming forth testing the idea of using FP24 for cryoprecipitate manufacturing. FP24 is plasma frozen within 24 hours of collection. This study specifically showed that there was an acceptable range of cryo constituents in the units made from FP24. The FDA and AABB would need to approve this method before use. The FDA would also require it to be labeled as a separate product from regular cryoprecipitate, suggesting a name such as Cryo24.
For regular FFP/Plasma transfusions, plasma is generally thawed at 30-37degC. For cryoprecipitate manufacturing, units of FFP are thawed at refrigeration temperatures (1-6degC). Thawing at these low temperatures causes the "cold insoluble" proteins to precipitate out of solution and become visually apparent. These proteins that precipitate out include all of the ones listed above (fibrinogen, factor VIII, etc.). Blood Centers will then centrifuge the units to separate the precipitated proteins from the rest of the plasma. They can then remove this precipitate to create a single unit of cryoprecipitate. 10-15mL of plasma is typically re-added to the newly created cryo unit. The cryo unit is then refrozen and can be given to transfusion centers for use. When the transfusion center needs to transfuse the cryo, they will thaw it out at 30-37degC (just like normal plasma/FFP). The "cold insoluble" proteins will be soluble or "dissolvable" at these temperatures and mix into the plasma in the bag. After thawing, the unit will be homogenous and ready for transfusion!
One thawed, cryoprecipitate is held at Room Temperature (20-24degC). It has an outdate of only six hours post thaw and should NOT be refrozen if not used. Single units pooled together post-thaw at a transfusion center has an outdate of only four hours. This does not apply to Pre-pooled cryo that is frozen as pool of five units. This short outdate is both to preserve the coagulation factors as well as ensuring that the units are free from bacterial growth.
Something interesting to note: If a transfusion center thaws FFP/Plasma for transfusion (at 30-37degC) but fails to thaw the unit fully then puts the unit in the fridge (which is where FULLY thawed plasma is placed) it is possible to see this very same action of cold insoluble proteins precipitating out of the plasma. The solution is to put the unit back into a 30-37degC thaw bath for a few minutes to fully dissolve the proteins.
Often times, a blood center will pool multiple units of cryoprecipitate together to create a unit of Pre-Pooled Cryoprecipitate. Typically, five single units of cryoprecipitate are pooled together into one bag before freezing. This is useful because the typical adult "dose" of cryoprecipitate is 10 units. Thus, a transfusion center would only need to thaw two units of pre-pooled Cryo rather than ten single units. This also saves the transfusion center time, as they would not have to manually pool the units at time of thaw. This is certainly possible, and can be done when pre-pools are not available or to prevent single units from outdating. Individual units of cryo are often used in the neonatal and pediatric populations.
Cryoprecipitate used to historically to create something called a Fibrin Glue that would be applied topically during certain surgeries, especially certain Cardiothoracic surgeries. Most transfusion centers don't offer this product anymore, as there are commercially available, virally inactivated manufactured versions of the product. Baxter, for example makes a fibrin sealant known as Tisseel
that performs the same duties as a fibrin glue made from cryoprecipitate.
Cryoprecipitate Specifics / Transfusion
Per the Association for the Advancement of Blood and Biotherapies' (AABB) Circular of Information a single of unit of cryo must contain greater than or equal to 80 International Units (IU) of Factor VIII and greater than or equal to 150 mg of fibrinogen. Most units are well above this minimum, but a minimum must be set to ensure quality. A pre-pool (five units pooled together) can be assumed to have, at minimum, five times this amount.
In an average adult, 10 units of cryoprecipitate, which is the standard "dose" (or two Pre-pools) would be expected to raise their fibrinogen levels by roughly 100mg/dL. A lab result of less than 150mg/dL is considered to be a deficiency. During a massive bleed, attempts to keep fibrinogen above 100mg/dL is essential.
Pediatric dosages vary from organization to organization. The Circular of Information suggests 1-2 single units per 10kg of weight or 2-3mL of cryo per Kg of body weight.
Cryoprecipitate can be transfused rather quickly, much like platelets and plasma. A Cryo Pool of 5 units should take 15-30 minutes, thus a full adult dose should take about an hour to transfuse.
Cryoprecipitate vs Concentrates/Synthetics?
The main use for cryoprecipitate today is mostly for fibrinogen in acquired hypofibrinogenemia and occasionally for Factor VIII deficiencies. There does exist, however, factor concentrates which are manufactured concentrates of these different factors. They are typically given as intravenous injections. RiaSTAP, for example, is a fibrinogen concentrate that is indicated for patients with congenital (genetic) fibrinogen deficiencies. It is not indicated in dysfibrinogenemia where fibrinogen exists as an abnormal form of the protein and doesn't function as it should.
Most Hemophilia A patients who lack functional Factor VIII will generally receive a recombinant factor VIII concentrate to replenish their deficiency of factor VIII. Only when there is difficulty in obtaining vials of factor concentrate, would cryoprecipitate be considered for transfusion to replenish these factors.
For those with low levels of von Willebrand factor, generally the first line of treatment is to give DDAVP (desmopressin). It is actually an antidiuretic that in turn causes storage cells in the endothelium to release more von Willebrand factor.
The upside to using factor concentrates as opposed to cryoprecipitate include knowing the exact dosage of fibrinogen or Factor VIII being given. Cryoprecipitate has a minimum yet variable amount. Additionally, there is very little time needed to prepare a vial of factor concentrate. RiaSTAP's package insert, for example, says that once the vial is rehydrated and swirled, it should be ready to use. This compares to cryoprecipitate, which does take time to thaw out. Additionally, factor concentrates do not need to worry about being ABO (Blood type) compatible which cryoprecipitate generally does.
On the other hand, cryoprecipitate is cheaper to use. Factor concentrates are generally very expensive, and used in situations like congenital factor deficiencies such as Hemophilia or a congenital afibrinogenemia / hypofibrinogenemia.
The Circular of Information specifically states that cryoprecipitate should not be used in situations where factor concentrates are available for patients with von Willebrand's disease, hemophilia A, or factor XIII deficiency.
Cryoprecipitate is used most often in acquired hypofibrinogenemia settings such as from trauma, surgery, bleeding, obstetrics emergency / traumatic child-birth, sepsis, DIC, etc., where fibrinogen is being used up during the bleeding. It is also used when first line factor concentrate / pharmaceutical treatment does not work or is not available.
Low Fibrinogen Causes
There are multiple reasons for acquired hypofibrinogenemia that may require transfusion of Cryoprecipitate. Some include:
Liver disease -- Since the liver creates most of the bodies proteins, protein synthesis and production is impaired in patients with a sub-optimally functioning liver.
Acute Leukemias -- a number percentage of patients with leukemia present with hypofibrinogenemia. This can be to a disruption in coagulation due to Disseminated Intravascular Coagulation or due to a treatment called L-asparaginase which is commonly used to treat Acute Lymphoblastic Leukemia (ALL). A large portion of patients on L-asparaginase will see falling fibrinogen levels as the drug may prevent the liver from synthesizing Fibrinogen.
Bleeding -- Bleeding from trauma, surgery, etc. will consume fibrinogen in the attempt to clot and cease the bleed.
DIC -- Disseminated Intravascular Coagulation -- where the body's coagulation factors get used up forming clots throughout the body, eventually causing bleeding in other areas of the body as factors get used up.
Malnutrition -- if someone is severely protein malnourished, they will potentially not be able to make fibrinogen in adequate amounts.
Surgery -- similar to bleeding. Cardiac and Liver Transplant surgery patients may be at an elevated risk of hypofibrinogenemia as a result of complications from the surgeries. Cardiac surgeries, especially those in which the patient is placed on Cardiopulmonary Bypass, tend to lower coagulation factors in patients both through dilution and consumption. Liver Transplant patients may see lowered Fibrinogen during the anhepatic phase, which is the period of time in which there is no liver (original or donor) connected to circulation.
Some patient's may experience Acquired Dysfibrinogenemia for a number of reasons as well
Liver Disease -- Depending on the presentation of liver disease and the staging of the disease, the liver may create Fibrinogen proteins but fail to be modified correctly due to production of other essential enzymes being attenuated by disease. This is known as a failure in post-translational modification. This is typically the most common cause of Acquired Dysfibrinogenemia.
Autoimmune (Antibody) Induced -- Patients with certain autoantibodies caused by Lupus (SLE), Multiple Myeloma or MGUS, and certain therapeutic drugs may develop an acquired dysfibrinogenemia. The autoantibody interferes with Fibrinogen's ability to polymerize and create a web of fibrin strands. An autoantibody may have an unknown, idiopathic, origin as well.
-- certain cancers such as Renal Cell Carcinoma
and Cervical Cancer may activate the immune system and create antibodies that cross-react with fibrinogen. This effect is known as Paraneoplastic Syndrome and has been documented. Additionally, Fibrinogen levels may be increased in patients with these specific cancers, but the Fibrinogen that it is created is abnormal and doesn't function as it should.
It is rare to need a cryoprecipitate under these situations, but may be clinically warranted in circumstances of expected or excessive bleeding.
Other diseases such as Congenital Hypofibrinogenemia/Afibrinogenemia and Congenital Dysfibrinogenemia present as a result of a genetic mutation. These errors of fibrinogen production are present from birth and will affect the individual for life. It is these circumstances where cryoprecipitate transfusion is not indicated, and if needed, Fibrinogen concentrates should be used. Under circumstances where this may not exist, cryoprecipitate could be used. Usage of either will be under discretion of a physician. In most cases, patients will not need to receive treatment unless surgery or other issues are present that make bleeding more likely.