Page 1992 - Hematology_ Basic Principles and Practice ( PDFDrive )

1766 Part XI Transfusion Medicine

inhibitors, neutralizing antibodies directed against factor VIII or of transgenic goats and also purified by heparin affinity chromatog-
factor IX. There are two primary means of treating bleeding in raphy. The two available AT concentrates are listed in Table 116.4.
inhibitor patients, both based on administration of activated clotting Protein C is a serine protease with a structure similar to clotting
factors. factors II, VII, IX, and X, but it is an anticoagulant that cleaves
Factor IX complex was known to be somewhat effective in pre- activated factors V and VIII. Patients deficient in protein C are sus-
venting bleeding in inhibitor patients, possibly because it contains ceptible to thrombosis. One plasma-derived protein C concentrate,
small amounts of activated clotting factors. Based on that informa- Ceprotin, is available. Ceprotin is listed in Table 116.4.
tion, two activated factor IX complex products were developed, one
of which, FEIBA, is still available. FEIBA, which is named for factor
eight inhibitor bypassing activity, is generically named anti-inhibitor Fibrin Sealant and Thrombin
coagulant complex and is indicated for inhibitor treatment in both
hemophilia A and B. Fibrinogen and thrombin are also used as topical hemostatic agents,
The hypothesis that administration of activated clotting factors together as fibrin sealant, and as standalone thrombin concentrates.
can bypass inhibitors also led to the development of NovoSeven, a The fibrin sealant and thrombin products available in the United
recombinant activated factor VII concentrate. NovoSeven has been States are listed in Table 116.5.
extensively studied and is currently the most widely used option for Fibrin sealant uses the clot-forming reaction of thrombin and
inhibitor treatment, especially for patients who have never been fibrinogen to form a physiologic glue or sealant that has become
exposed to plasma-derived products. However, both FEIBA and widely used in surgical procedures. All three fibrin sealant products
NovoSeven do carry a risk of thromboembolic complications. FEIBA on the US market are made from human plasma-derived fibrinogen
and NovoSeven are listed in Table 116.4. and thrombin. Fibrinogen is purified directly from cryoprecipitate
von Willebrand disease (vWD), caused by missing or abnormal followed by further purification steps. ARTISS and TISSEEL
vWF, is actually the most common inherited coagulation disorder. contain a plasmin inhibitor, synthetic aprotinin, which is used to
vWF is a large protein that circulates in a complex with factor VIII. delay clot lysis. EVICEL contains a more highly purified fibrinogen
It stabilizes factor VIII in the bloodstream but also has coagulation component that has minimal plasmin activity and therefore does not
functions of its own. Several intermediate-purity viral-inactivated contain a clot lysis inhibitor. Both fibrinogen preparations contain
AHF concentrates that contain significant amounts of vWF are also residual factor XIII for clot stabilization, and additional factor XIII
indicated for replacement therapy for vWD. These vWF/AHF con- is recruited from the patient’s bloodstream during use. Fibrin sealant
centrates are listed in Table 116.3. is also the basis of two patches or bandages that are used to promote
Fibrinogen is the final protein in the coagulation cascade. It is clotting.
cleaved by thrombin to form fibrin, a protein that naturally self- Thrombin is produced from prothrombin (factor II) purified from
associates to form a clot. RiaSTAP is a plasma-derived concentrate the factor IX complex captured by ion exchange from cryosupernatant
for replacement therapy in fibrinogen-deficient patients that is made plasma. Prothrombin is autocatalytically activated to thrombin in the
from the concentrated fibrinogen in cryoprecipitate. Interestingly, presence of calcium. Both the fibrinogen and thrombin components
fibrinogen was also one of the first plasma products developed, but are also treated for viral inactivation and removal. Three standalone
it was soon taken off the market because it almost universally trans- thrombin products are also available for use in promoting topical
mitted viral infections. RiaSTAP is pasteurized (heat treated) in hemostasis. For years, bovine thrombin was the standard of care for
solution for 20 hours at 60°C, twice as long as the typical treatment such use; however, research has suggested that it may have been
for pasteurized plasma products. Significant viral removal has also responsible for postsurgical hemostatic problems in some patients.
been demonstrated for its purification process, and the resulting The cause was apparently contamination with bovine factor V, against
product is considered safe. RiaSTAP is listed in Table 116.4. which some patients developed antibodies that cross-reacted with
Factor XIII does not participate directly in the coagulation cascade their own human factor V. Most bovine thrombin products were
but instead stabilizes the final clot by cross-linking the fibrin mol- taken off the market, but Thrombin-JMI, the sole remaining bovine
ecules. Factor XIII deficiency is rare and is characterized by weak clots product, was instead further purified to reduce bovine factor V to
prone to rebleeding. Before the availability of factor XIII concentrates, undetectable levels. A plasma-derived human thrombin product,
patients were usually treated with plasma or cryoprecipitate, both of EVITHROM, was also developed, which is the same thrombin used
which carry a risk of viral infection. Plasma-derived Corifact is puri- in EVICEL fibrin sealant.
fied from cryoprecipitate and employs a unique process step using The recombinant human thrombin product, RECOTHROM, is
Vitacel, a wheat-based vegetable fiber, to remove fibrinogen, after another example of a bioengineered protein. The VKD clotting
which the factor XIII is further purified by ion-exchange chromatog- factors contain a domain called the Gla region that is rich in a unique
raphy. Tretten is a recombinant version of the A subunit of factor amino acid, γ-carboxyglutamic acid (Gla). The posttranslational
XIII, a deficiency of which is the usual cause of factor XIII deficiency. modifications required to produce the Gla residues are a rate-limiting
Tretten is produced in yeast and purified by chromatography. Tretten step in the production of all of the VKD proteins in cell culture.
and Corifact are listed in Table 116.4. Presence of the Gla region is absolutely necessary for the function of
most of the clotting factors but not for thrombin. Therefore, the
Gla-less molecule prethrombin-1 is produced in CHO cells, with a
Anticoagulant Concentrates significant increase in production rate. Prethrombin-1 is activated to
thrombin using a proprietary enzyme system. RECOTHROM
Antithrombin III, now generally just called AT, is an anticoagulant. behaves similarly to human and bovine thrombin in clinical use.
As its name suggests, it inhibits thrombin (activated factor II), but it
also inhibits the activated forms of factors IX, X, XI, and XII. It
belongs to the serpin family named for their activity as serine protease PLASMA PROTEINASE INHIBITORS
inhibitors. Heparin is a cofactor that increases the native activity of
AT significantly, from 500- to 1000-fold for factor Xa inhibition up The proteinase inhibitors that are present in human plasma play
to 1 million-fold for factor IXa inhibition. The affinity of AT for critical roles in the regulation of the coagulation, fibrinolytic, comple-
heparin is also used to purify the protein by affinity chromatography ment, and kinin cascade systems. Most of these inhibitors have
on an immobilized heparin column. Thrombate III, the only plasma- similar amino acid and structural properties and are members of the
derived product currently on the US market, is purified by heparin serpin superfamily of proteins. AT, an anticoagulant, was discussed
affinity chromatography from Cohn fraction IV-1. ATryn, a recom- earlier. Two other proteinase inhibitors, API and C1 esterase inhibi-
binant AT, was the first recombinant human plasma protein produced tor, are also available for treatment of deficient patients. These con-
in transgenic animals to be approved anywhere. It is made in the milk centrates are listed in Table 116.6.