Page 2005 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 117 Transfusion Therapy for Coagulation Factor Deficiencies 1779

therapy, and dosing takes into consideration the long half-life of for the treatment of bleeding episodes, as well as escalating the dose
60–80 hours; however, some patients may have difficulty tolerating throughout pregnancy. 126
the large fluid volume of FFP. Although the half-life of factor XI in A recent, international, multicenter, phase III study of recombi-
S/D plasma is comparable to that of FFP, decreased levels of factor nant FXIII-A2 in patients 1–77 years old demonstrated that 35 IU/
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XI in the product (≈30%–50%) have been reported. Especially in kg monthly can safely be used as prophylaxis in patients with con-
those patients with absent factor XI protein, inhibitors have developed genital factor XIII A–subunit deficiency, irrespective of age; this
after exposure to factor XI products. Two virally reduced or inacti- product cannot be used for patients with a B-subunit deficiency. 132
vated factor XI concentrates have been developed using affinity
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chromatography or cation-exchange chromatography. These two
concentrates, licensed in France (Hemoleven, LFB Biomedicaments OTHER PLASMA-DERIVED PROTEIN CONCENTRATES
France) and England (FXI concentrate Bio Products Laboratory), are
not available in the United States, although the factor XI concentrate As discussed in Chapter 116, plasma fractionation processes also
from France can be obtained through compassionate use in the allow for the isolation of plasma components other than the coagula-
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United States. Both concentrates have been demonstrated to be tion proteins. Immunoglobulins are isolated by a variety of techniques
effective, but there have been reports of thromboembolic complica- from the Cohn fraction II–III. α 1-Antitrypsin and antithrombin are
tions with their use, presumably because of contaminant activated produced from fraction IV. As with other VKD proteins, protein C
factor IX. Both products are now formulated with antithrombin and may be isolated from Cohn fraction II.
heparin, but caution is advised with their use in elderly patients and
in patients with preexisting cardiovascular disease. In addition,
because of thromboembolic risk, when using factor XI concentrates, Anticoagulant Proteins (Protein C and Antithrombin)
antifibrinolytics should not be used concurrently. Doses should not
exceed 30 U/kg and peak factor XI should not exceed 70 U/dL. 126 Brief mention should be made of plasma-derived concentrates
Because bleeding occurs in patients with factor XI deficiency more enriched in protein C and recombinant antithrombin III. These
often in settings in which fibrinolysis is more active (oral mucosa, products have been used for a variety of indications, but both are
urinary tract), antifibrinolytic agents can be useful adjuncts in the licensed for the treatment of congenital deficiencies that result in
treatment of such bleeding episodes or used as sole agents to prevent thrombosis. Protein C concentrate has also been used in the treat-
bleeding with dental procedures. Fibrin glue can provide a useful ment of purpura fulminans with meningococcemia. Antithrombin in
adjunct or be used solely in topical bleeding (dental extractions, combination with defibrotide has been used for the successful treat-
circumcisions). DDAVP has been reported as useful for the preven- ment of veno-occlusive disease in patients who develop this complica-
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tion of surgical bleeding in factor XI deficiency. The mode of effect tion after undergoing bone marrow transplantation, heparin
of DDAVP is unclear but is likely caused by the coexistence of mild resistance in patients undergoing cardiopulmonary bypass, extra-
vWF deficiency. corporeal membrane oxygenation (ECMO) and sepsis. In addition,
antithrombin has been used in patients with acute lymphoblastic
leukemia who are receiving asparaginase. Early studies showed some
Factor XIII Deficiency efficacy in using activated protein C to treat sepsis. However, a
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recent update of a Cochrane review reported that in five randomized
Factor XIII is a transglutaminase that catalyzes the cross-linking of controlled trials, including 5101 patients, activated protein C did not
γ-glutamyl and ε-lysyl groups of fibrin monomers, stabilizing the decrease the risk of death and was associated with an increased risk
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forming clot by decreasing its susceptibility to fibrinolysis. Inherited of bleeding. Its utility for other indications is not yet known.
deficiency of factor XIII is autosomal recessive and results from
defects in the genes for the two subunits of factor XIII located on
chromosome 1 (B subunit) and chromosome 6 (A subunit). The Immunoglobulins
majority of reported defects involve the A subunit. Umbilical bleed-
ing in homozygotes may be observed at birth. Soft tissue bleeds, The use of immunoglobulins (both IV and hyperimmune products)
hemarthroses, excessive intracranial bleeding (relative to other coagu- for a variety of diseases is discussed elsewhere in this book.
lation deficiencies), pseudotumors, and bleeding during surgery are
observed in affected patients. Surgery is also complicated by poor
wound healing. Affected male patients may have oligospermia, and α 1 -Protease Inhibitor (Antitrypsin)
female patients may have recurrent miscarriages. Coagulation screen-
ing test results (PT, aPTT, and TCT) are normal. Solubility of clots α1-Protease inhibitor (or antitrypsin) concentrates (Prolastin, Bayer
is increased with factor XIII deficiency; thus, the diagnosis can be Healthcare LLC; Aralast, Baxter Biosciences; Zemaira, ZLB-Behring)
made by incubating clots in the presence of solubilizing agents such are available for the prophylactic treatment of people with congenital
as 5 M urea or 1% to 2% chloroacetic acid. This qualitative test fails deficiency of α 1 -antitrypsin. α 1 -Antitrypsin inhibits neutrophil elas-
to detect mild and moderate deficiency; therefore, it is not recom- tase, which is thought to be responsible for the alveolar damage
mended to perform quantitative factor XIII testing when suspecting resulting in emphysema. These replacement products, administered
a deficiency. Factor XIII has a long half-life (9–15 days). Previously, IV, are presumed to act to delay the progression of congenital emphy-
FFP (2–3 mL/kg) or cryoprecipitate (1 bag/10–20 kg) were the only sema associated with this protease inhibitor deficiency.
options for treating patients with factor XIII deficiency. However, in
February 2011, the first plasma-derived factor XIII concentrate
(Corifact, CSL Behring) was approved by the FDA for prophylaxis; FUTURE DIRECTIONS
this concentrate is given intravenously to maintain a trough level of
5% to 20% with the initial recommended dose being 40 IU/kg every Virally safe plasma-derived concentrates have been developed that are
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28 days. Because of the long half-life of factor XIII, replacement enriched in a variety of coagulation and other proteins. Initially,
can be used on a prophylactic basis (dosing every 3–4 weeks) to refinements in techniques of plasma fractionation formed the basis
prevent intracranial hemorrhage and other bleeding episodes. The for the development of these concentrates as an improvement over
United Kingdom Haemophilia Centre Doctors’ Organisation’s the use of blood component therapy (whole blood, plasma, and
current guidelines recommend lifetime prophylaxis for those patients cryoprecipitate). Plasma-derived protein concentrates were first
with a severe factor XIII deficiency and a personal or family history developed for the treatment of the more common hemophilias A and
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of bleeding. Dosing with factor XIII concentrate is 10–75 IU/kg B. Subsequent refinements were made to reduce and then eliminate
every 4–6 weeks, with lower doses for prophylaxis and higher doses the transmission of viral and other pathogens present in the human