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2142 Part XII: Hemostasis and Thrombosis Chapter 124: Inherited Deficiencies of Coagulation Factors II, V, V+VIII, VII, X, XI, and XIII 2143

The currently described 105 mutations that cause factor X that is greater than 40 percent of normal should be the goal. In patients
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deficiency include large deletions, small frameshift deletions, nonsense with particularly severe bleeding manifestations, prophylactic therapy
mutation, and missense mutations; the missense mutations group is the should be considered. FFP also can be used to treat patients with factor
largest (80 percent), while mutations in the 3′- and 5′-UTRs are com- X deficiency, however, the administration of FFP can be associated with
pletely absent (see http://www.isth.org/?MutationsRareBleedin and complications, particularly in children and elderly patients with cardiac
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Ref. 13). Activation through the TF pathway may be affected when the disease, because of fluid overload. The arrival on the market of a new
mutations are located, for example, in the Gla domain, as in Glu7Gly freeze-dried human factor X concentrate has facilitated prophylaxis in
(St. Louis II) or Glu19Ala. 19,199,200 Activation through factor IXa is patients with factor X deficiency (Factor X P Behring) ; however, fac-
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affected by, for example, Thr318Met (Roma). Activation of factor X tor X P Behring also contains factor IX, although in a known amount.
201
through Russell viper venom is almost intact in the Pro343Ser (Fri- A clinical trial investigating the pharmacokinetics of a new high-purity
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uli) mutation. Two interesting clusters of unrelated families were factor X concentrate has been completed (ClinicalTrials.gov identifier:
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described in Algeria, with Phe31Ser mutation, and in the border 00930176).
region between Turkey and Iran, with the Gly222Asp mutation. 204
FACTOR XI DEFICIENCY
CLINICAL MANIFESTATIONS DEFINITION AND HISTORY
The clinical manifestations of factor X deficiency are related to the
functional levels of the protein. According to the recent results of the Factor XI deficiency initially was described as a “new hemophilia” in
EN-RBD study, strong associations between clinical bleeding sever- two sisters and their maternal uncle by Rosenthal and colleagues in
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ity and coagulation factor activity level were shown in factor X defi- 1953. Because it manifested in both sexes—two sisters and their
ciency; consequently, patients with factor X activity levels less than 10 maternal uncle—the clinical features were not consistent with hemo-
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percent of normal have a higher occurrence of spontaneous major philia A or B and was called hemophilia C. The deficiency was erro-
bleeding. Bleeding occurs primarily into joints and soft tissues, from neously thought to be transmitted as an autosomal dominant disorder
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the umbilical cord and mucous membranes. The bleeding tendency with variable expressivity. Later studies clearly established that, in most
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may appear at any age, although patients with factor X activity less than cases, the mode of transmission of factor XI deficiency is autosomal
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2 percent present early in life with, for instance, umbilical-stump or recessive. Affected subjects have been described in most populations,
CNS hemorrhage. 13,205,206 but the disorder is common in Jews, particularly those of Ashkenazi
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In an analysis of 102 patients from Europe and Latin America, three origin.
mutations were associated with intracerebral hemorrhage (Gly380Arg, Factor XI deficiency as a result of a dysfunctional protein is rare, as
IVS7–1G>A, and Tyr163delAT) and Gly Arg mutation was associ- only a few patients with deficiency of factor XI activity and seemingly
−20
217–220
ated with severe hemarthrosis. The most common bleeding symp- normal antigen levels have been described thus far.
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tom reported at all levels of severity of the deficiency is epistaxis.
Patients with severe deficiencies commonly experience hemarthrosis PROTEIN
and hematomas, but gastrointestinal and umbilical cord bleeding, Factor XI is a glycoprotein that consists of two identical 80-kDa poly-
hematuria, and CNS bleeding also occur. In a small group of patients peptide chains linked by a disulfide bond. Each subunit contains 607
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with factor X deficiency, one-third of heterozygous patients who had amino acids with a serine protease domain at the C-terminus and four
dental extraction, surgery, or delivery without prophylactic replace- tandem repeats of 90 or 91 amino acids, designated “apple domains,” at
ment therapy showed postoperative bleeding which required treat- the N-terminus. The described crystal structure of factor XI dimer
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ment. Menorrhagia is a common symptom affecting women with all defined the interface of the monomers in apple 4 domains in which
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degrees of severity and PPH was also reported in 4 of 14 pregnancies. three residues—Leu284, Ile290, and Tyr329—are essential for nonco-
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Two successful pregnancies out of four pregnancies were reported in a valent binding between the monomers. This binding enables the for-
woman only when receiving regular prophylaxis; the other two preg- mation of a disulfide bond between Cys321 residues in the fourth apple
nancies, without regular prophylaxis, resulted in preterm labor (both domain of each monomer. 223,224
babies died in the neonatal period). Other case reports, however, Although factor XI is synthesized by the liver, very low levels of
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have described successful term pregnancies in women with severe fac- factor XI transcript can also be detected in megakaryocytes and plate-
tor X deficiency without antenatal prophylaxis. 207,209 Knockout mice lets, renal tubules, and pancreatic islet cells. Factor XI circulates in
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show partial embryonic lethality (E11.5–E12.5); complete absence of blood as an equimolar complex with high-molecular-weight kininogen
factor X is incompatible with murine survival to adulthood, but min- (HK) at a concentration of 3 to 7 mcg/mL. The importance of the
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imal factor X activity (range: 1 to 3 percent) is sufficient to rescue the factor XI–HK interaction is not fully understood. Activation of factor
lethal phenotype. 210–212 XI involves cleavage of an Arg369-Ile370 bond, yielding a heavy chain
containing the four apple domains linked by a disulfide bond to a light
chain that contains the catalytic domain. The physiologic activator of
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THERAPY factor XI during hemostasis has long been debated. The original scheme
Therapy for inherited factor X deficiency usually is administration of of the coagulation cascade—according to which factor XI is activated
heated and solvent-detergent–treated PCCs containing factor X, in by factor XIIa through the intrinsic pathway (the “contact phase”)—was
addition to factors II, VII, and IX. Use of these concentrates carries challenged by the observation that deficiencies of factor XII as well as of
a low risk of transmission of bloodborne viruses. However, a risk of the other contact factors (HK and prekallikrein) are not associated with
thrombosis, including venous thromboembolism, diffuse intravascular a bleeding diathesis. 14
coagulation, and myocardial infarction has been reported. The major activator of factor XI in vivo is thrombin. 227,228 Factor XI
For soft-tissue, mucous membrane, and joint hemorrhage, the aim binds through its apple 3 domain to lipid rafts on platelets containing
of treatment should be maintaining a factor X level that is at least 10 to glycoprotein Ib–IX–V complex. This glycoprotein complex also binds
20 percent of normal. For more serious hemorrhage, a factor X level thrombin; thus, both substrate and enzyme are colocalized at the same

Kaushansky_chapter 124_p2133-2150.indd 2142 17/09/15 3:42 pm