Page 2168 - Williams Hematology ( PDFDrive )

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

site. Factor XI activation also can occur on the fibrin surface after a a subsequent study of 33 women who had approximately 70 uneventful
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clot forms. Factor XIa, once generated, activates factor IX by limited pregnancies out of 105 pregnancies. In the subsequent study, only three
proteolysis of two peptide bonds in the presence of calcium ions. women had factor XI activity less than 15 IU/dL, and none of them had
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The presence of factor XI contributes to the activation of thrombin- PPH. 42
activatable fibrinolysis inhibitor (TAFI), that once activated, removes Whether heterozygotes exhibit a bleeding tendency (except for
terminal lysine residues from fibrin, which impairs binding of cer- those bearing mutations causing a dominant negative effect) is contro-
tain forms of plasminogen to fibrin and disrupts tissue plasminogen versial because there are reports on both heterozygotes with no bleeding
activator-induced plasmin generation in the blood clot. Large complications following a variety of surgical procedures, and reports
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amounts of thrombin are necessary for TAFI activation, but the reaction that 20 to 48 percent of heterozygotes do bleed. 215,238,243,246,247
is substantially augmented when thrombin is bound to thrombomod- In regard to venous thrombosis, it was reported that in five patients,
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ulin. It follows that impaired generation of thrombin, for example, in two developed pulmonary embolism following infusion of factor XI
inherited deficiency of factor VIII, IX, or XI, not only delays clot forma- concentrate 248–250 and a third patient developed thrombus in the inferior
tion but also enhances premature lysis of clots. These data fit well with vena cava following cryptococcal infection. In contrast, severe factor XI
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clinical observations in factor XI–deficient patients who are particularly deficiency was shown to confer protection against ischemic stroke. 251
susceptible to bleeding following injury at sites exhibiting local fibrino- Mice homozygous for a knockout factor XI allele show a tendency for
lytic activity. 18 slightly prolonged tail transection bleeding times and are protected from
vessel-occluding fibrin formation after transient ischemic brain injury. 252,253

GENETICS
The 23-kb gene encoding for factor XI consists of 15 exons and THERAPY
14 introns and is located on chromosome 4q34–35. 235,236 Available treatments for patients with the severe form of factor XI defi-
Three mutations, designated types I, II, and III, were first described ciency are FFP and factor XI concentrate. Factor XI concentrates cur-
in six Ashkenazi-Jewish patients with severe factor XI deficiency. rently available (Bio Products Laboratory, United Kingdom, and LFB
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The types II and III, a change in exon 5 at Glu117 leading to a stop Biomedicaments, France) are associated with thrombosis even after
codon and a change in exon 9 that results in a substitution of Phe283 by adding heparin to the antithrombin in the Bio Products Laboratory
Leu, respectively, account for 95 percent of cases in Ashkenazi Jewish product, and antithrombin and heparin to the C1 esterase in the LFB Bio-
patients. Most patients with factor XI deficiency are Jewish. 18,216,238 A medicaments product. 14,254 Therefore, it is advisable to monitor patients
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recent study indicated that both type II and type III mutations are also for clinical and laboratory signs of coagulation activation, in particu-
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prevalent in the Italian population, although at a much lower rate. In lar in elderly patients, in those with cardiovasclar disease and in those
patients belonging to different ethnic groups, a significantly higher level undergoing surgery with thrombotic potential, especially when factor
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of allelic heterogeneity has been reported. Remarkable exceptions are XI concentrate or rFVIIa is considered. 256,257 In addition, the presence
represented by some “closed populations” harboring mutations compat- of an inhibitor, particularly in patients with less than 1 percent of factor
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ible with a founder effect: Cys38Arg in French Basques, Gln88Stop XI activity and previously exposed to plasma, factor XI concentrates,
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in French families from Nantes, Cys128Stop in Britons, Ile436Lys in or immunoglobulins, should be evaluated. Low doses of rFVIIa along
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Northeastern Italy, and Q263X in Korean patients. 242 with tranexamic acid seem promising in the treatment of patients with
As of this writing, 220 mutations have been reported in non-Jew- inhibitors. When procedures are planned at tissues exhibiting fibrino-
ish and Jewish patients of various origins, including 154 missense, 23 lytic activity, which is associated with higher risk of bleeding in com-
nonsense, and 23 del/ins mutations, with the remaining being splice site parison to sites without fibrinolytic activity, the use of antifibrinolytic
(18 mutations) and 5′- and 3′-UTR (2 mutations). Inheritance of factor agents alone or in combination with other treatments is recommended.
XI deficiency is usually autosomal recessive, as other RBDs, although Patients undergoing dental extractions do not require replacement ther-
some missense mutations exert a dominant negative effect through het- apy. No plasma replacement therapy is necessary during or after labor
erodimer formation between the mutant and wild-type polypeptides, unless excessive bleeding occurs. Patients with factor XI deficiency and
resulting in a pattern of dominant transmission. 243 inhibitor do not bleed spontaneously. Acquired inhibitors that neutral-
ize the activity of factor XI have been described in patients with severe
factor XI deficiency and baseline activity of less than 1 IU/dL after being
CLINICAL FEATURES exposed to plasma, after injections of Rh immunoglobulin and with-
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Factor XI deficiency is the only RBD in which the EN-RBD study showed out previous exposure to blood products, or after exposure to factor
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no association between clinical bleeding severity and coagulation factor XI concentrates. Use of PCCs 262,263 and rFVIIa have been successful for
activity level. This disorder manifests as a mild to moderate bleeding major surgical procedures, and an in vitro study revealed that abnormal
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manifestations and most bleeding episodes of patients with severe FXI thrombin generation in the plasma of patients with an inhibitor was cor-
deficiency are injury-related. Most bleeding manifestations of patients rected by adding moderate amounts of rFVIIa. 262
with severe FXI deficiency are injury-related. Some patients with severe
factor XI deficiency may not bleed at all following trauma. The phe-
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notype of bleeding is not correlated with the genotype but frequently FACTOR XIII DEFICIENCY
with site of injury. 18,238,244 Surgical procedures involving tissues with high
fibrinolytic activity (urinary tract, tonsils, nose, tooth sockets) frequently DEFINITION AND HISTORY
are associated with excessive bleeding in patients with severe factor XI The first clinical report of factor XIII deficiency was in 1960 ; since
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deficiency, irrespective of the genotype. 245 then, more than 500 cases of factor XIII deficiency have been identified
Most women with severe factor XI deficiency are asymptomatic worldwide, with an incidence of one individual in 1 to 3 million popu-
or minimally so. During 93 deliveries (85 vaginal, eight cesarean), 43 lation. 22,264 Congenital factor XIII deficiency is characterized by severe
of 62 women did not experience PPH despite no prophylactic treat- delayed spontaneous bleeding and recurrent abortion with normal
ment, which was confirmed not to be mandatory for these women, by coagulation screening tests.
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