Page 1976 - Hematology_ Basic Principles and Practice ( PDFDrive )

1750 Part XI Transfusion Medicine

Transfusion Medicine Advisory Group of British Columbia, Canada a sealant in breast cancer surgery, and to reduce air leaks in lung
Guidelines for cryoprecipitate transfusion). volume reduction procedures. Side effects of this compound can
be significant, however, and include nerve and muscle necrosis,
sinoatrial node damage, calcium metabolism abnormalities, mucosal
Fibrinogen Deficiency and skin irritation, adhesive emboli, limitation of aortic growth, and
pseudoaneurysms.
Fibrinogen deficiency is the primary indication for cryoprecipitate
transfusion. The deficiency may be caused by congenital afibrinogen-
emia or dysfibrinogenemia, severe liver disease, DIC, or massive Uremic Bleeding
transfusion. Patients with the later indications often have concomi-
tant decreases in clotting factor levels and require the coadministra- Abnormal bleeding is a common complication of uremia and is
tion of plasma products. It is important to obtain fibrinogen primarily caused by platelet dysfunction and defective interaction
measurements because levels less than 100 mg/dL cause prolongation with endothelium. Use of cryoprecipitate as a source of vWF has been
of the PT and PTT, despite adequate clotting factor replacement. speculated to correct the platelet dysfunction. However, cryoprecipi-
Very low levels of fibrinogen occur during liver transplantation tate has been shown not to affect platelet aggregation in vitro, but
(<100 mg/dL), where transfusion support with cryoprecipitate is does shorten the bleeding time. In 1980, a single study published in
vital. the New England Journal of Medicine led to the widespread, but
A specific purified human fibrinogen concentrate is now available, temporary, use of cryoprecipitate for the treatment of uremic bleed-
and may represent a safer alternative for direct fibrinogen replacement ing. Since that time, variable response reports have been published.
in isolated fibrinogen deficiencies, such as inherited hypofibrinogen- Numerous alternative strategies are currently available for the preven-
emia. Fibrinogen concentrates undergo viral inactivation and have a tion and treatment of uremic type bleeding including dialysis,
standardized fibrinogen content; these are used preferentially over erythropoietin, RBC transfusion, desmopressin, and conjugated
cryoprecipitate in some countries, but studies have not demonstrated estrogens, and, as such, cryoprecipitate is now rarely used in the
a clinical benefit over cryoprecipitate. In the United States, fibrinogen prevention or treatment or uremic bleeding.
concentrate is FDA approved for treatment of bleeding in patients
with congenital fibrinogen deficiency.
Massive Transfusion
Fibrin Glue/Sealant While most studies regarding massive transfusion evaluate the use of
platelets and plasma, some studies suggest that regular doses of
Fibrin glue/sealant results from the mixture of a fibrinogen source cryoprecipitate may also help improve survival. In general, the current
(from plasma, platelet-rich plasma, or allogeneic/autologous cryopre- use of cryoprecipitate in massive support is not standardized and the
cipitate) with a thrombin source (bovine, human, or recombinant). use is based on theoretic efficacy. According to the recently published
The enhanced local hemostasis achieved by the sealant product is PROMMTT study, there are wide differences (7–82%) in the use of
through the action of thrombin on fibrinogen. “Fibrin glue” is a cryoprecipitate at U.S. level 1 trauma centers, and inclusion of
non–FDA-approved thrombin/preparation, and it has been widely cryoprecipitate in massive transfusion protocols vary significantly.
used in Europe many years. Fibrin and thrombin sealants are FDA- Specifically, some PROMMTT sites used cryoprecipitate after a
approved alternatives to fibrin glue and are advantageous over locally certain number of RBC units infused, while others used fibrinogen
made fibrin glues, because of standard dosing. Fibrin and thrombin triggers, such as 100 mg/dL. While the PROMMTT study found no
containing glues/sealants can be used for multiple surgical purposes, significant differences in mortality between those that did and did
including as a topical hemostat (creating a blood clot to halt bleed- not receive cryoprecipitate, other studies have shown benefit. One
ing), as a sealant (agents to prevent leakage of potentially nonclotting study found that a high transfusion ratio involving cryoprecipitate in
fluids, i.e., cerebrospinal fluid), or as an adhesive (bonds different 214 massive transfusion patients resulted in improved 30-day survival
tissues together). Multiple fibrin or thrombin containing products are (66% versus 41%). Another key study found that maintaining a
now FDA approved for use. ≥0.2 g fibrinogen/RBC (10 units of cryoprecipitate used for every 10
The safety profile of each product differs depending on the units of RBCs) unit ratio resulted in significantly higher survival rates
product components and source. Bovine thrombin has been reported (76% versus 48%). Lastly, military trauma patients in the MATTERs
to cause anaphylaxis (because of bovine allergies), coagulopathy II study who received a combination of cryoprecipitate and
through formation of antibodies to factor V or II, and rarely death Tranexamic acid had the lowest observed mortality despite high
caused by severe systemic hypotensive reactions. Consequently, injury severity scores (odds ratio, 0.34). While a small randomized
bovine products have an FDA mandated black-box warning on their feasibility study has been performed (CRYOSTAT trial), and dem-
package inserts. Pooled human plasma sources have the potential risk onstrated that cryoprecipitate can be prepared early during trauma
of viral or prion disease transmission. Reports indicate that hepatitis resuscitation, larger randomized prospective clinical trials are still
A and parvovirus B19 are particularly difficult to remove from these needed. Consequently, while still under investigation, current data
products despite current cleansing and filtration methods, and it is tentatively support the use of cryoprecipitate in the context of massive
recommended that patients be counselled about this risk. Recombi- transfusion protocols, however cryoprecipitate remains indicated in
nant products, while eliminating the risk of infectious transmission the treatment of hypofibrinogenemia. See box “Severe Maternal
or antibody formation, may also cause allergic reactions because of Hemorrhage.”
the hamster or snake proteins used to manufacture the product.
Lastly, autologous fibrin clot preparations have been used, although
the infectious risks (e.g., HIV and hepatitis) associated with the use Dosage
of heterologous fibrin glue are eliminated by replacement with the
autologous source, but are resource intensive. Given the current safety The dosage of cryoprecipitate is calculated on the basis of the amount
of the blood supply, the infectious risks are extremely low, particularly of fibrinogen present in 1 unit of cryoprecipitate, the plasma volume,
for pathogen inactivated products. and the desired increment. The difficulty in determining the correct
Alternatively, albumin mixed with glutaraldehyde has been amount to administer is primarily caused by variability in the fibrino-
used to form both an effective sealant and adhesive. The FDA has gen content of cryoprecipitate, secondary by variability in donors and
currently approved an albumin-based product to seal large blood component processing and preparation. The goal of therapy should
vessel anastomoses and to reattach layers of the aorta in the context be to maintain the measured fibrinogen at greater than 100 mL/dL,
of an aortic dissection. Other successful reported uses include as although increasing studies and some consensus recommendations