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Chapter 137 Rare Coagulation Factor Deficiencies 2045

but do not prevent dimer formation (e.g., Gly400Val). In heterozy-
gotes, mutant and wild-type polypeptides form nonsecretable dimers, 3
trapping normal protein in the cell. This phenomenon likely accounts α−kal
for families in which severe to moderate factor XI deficiency appears XII
to be a dominant trait.
Factor XI levels decrease in liver disease and DIC but are not 2 1
affected by vitamin K deficiency or warfarin therapy. Mild to moder-
ate factor XI deficiency occurs in approximately 25% of patients with PK XIIIa XIa
Noonan syndrome and is common in carbohydrate-deficient glyco-
protein syndrome, a group of inherited disorders involving defects in HK 4
glycosylation of secretory glycoproteins. Antibody inhibitors to factor
XI are common after replacement therapy, particularly in patients XI
with no circulating factor XI. For example, one-third of individuals
homozygous for Glu117Stop develop inhibitors, often after a single HK
exposure to plasma.
Bleeding in severe factor XI deficiency is usually injury-related and
is most frequent in tissues with robust fibrinolytic activity, such as
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the oral and nasal cavities, and the urinary tract. Injury to these Fig. 137.5 CONTACT ACTIVATION. In the activated partial thrombo-
areas causes excessive bleeding in two-thirds of patients, regardless of plastin time assay, contact activation is initiated by conversion of factor XII
genotype. Bleeding with injury at other locations is less frequent and (XII) to α-factor XIIa (XIIa) (reaction 1) when plasma is exposed to a nega-
tends to occur in those with the lowest factor XI levels. Bleeding may tively charged surface (light green disk). Factor XIIa converts prekallikrein
start at the time of injury or be delayed by hours, and oozing from (PK) to the active protease α-kallikrein (reaction 2), and α-kallikrein recipro-
tooth extraction may persist for days. Excessive bleeding with skin cally activates additional factor XII (reaction 3). Factor XIIa initiates coagula-
laceration, circumcision, appendectomy, and orthopedic surgery is tion through conversion of factor XI (XI) to factor XIa (XIa) (reaction 4).
infrequent; spontaneous bleeding (except for menorrhagia) is uncom- PK and factor XI require high-molecular-weight kininogen (HK) to bind
mon. In a clinical trial testing reduction of plasma factor XI as pro- properly to the surface. Factor XIa ultimately promotes thrombin generation
phylaxis for venous thrombosis in knee replacement surgery, bleeding and fibrin clot formation through activation of factor IX (see Fig. 137.1).
was rare despite the fact that factor XI levels were less than 5% at the
time of surgery in some patients.
Bleeding correlates poorly with plasma factor XI activity (Table initial dose should not exceed 10 to 15 units/kg, and concentrates
137.2). 22,23 Patients with severe deficiency may not bleed excessively, should be used with caution (or avoided) in patients with a history
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even during surgery, and a patient may exhibit different bleeding of thrombosis, or risk factors for thrombosis. Antifibrinolytic therapy
tendencies over time. Opinions differ regarding the propensity to should probably not be used concomitantly with concentrate. Cryo-
bleed with mild deficiency (plasma level 20%–50%). Some studies precipitate does not contain factor XI.
describe minimal bleeding with tooth extraction, tonsillectomy, nasal Circumcision, orthopedic surgery, and appendectomy carry a low
surgery, and urologic surgery, while others report difficulty distin- bleeding risk, and replacement can often be withheld unless bleeding
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guishing severe and mild deficiency on clinical grounds. 22,23 In a study occurs. A similar “wait and see” approach has been proposed for
of 45 families, the odds ratios for excessive bleeding were 13.0 and factor XI–deficient women during labor and delivery, which is associ-
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2.6 for homozygotes and heterozygotes, respectively. Thus mild ated with a relatively low (~20%) rate of excessive bleeding.
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deficiency may confer a slightly increased risk for bleeding, but not However, others advocate replacement for childbirth. Dental proce-
as much as severe deficiency. A recent analysis indicated that ristocetin dures such as tooth extraction can be covered with antifibrinolytic
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cofactor activity is significantly lower in symptomatic patients with therapy. The effectiveness of DDAVP in mild factor XI deficiency
heterozygous factor XI deficiency, compared with nonbleeders, is not established, but there are reports that levels increase in response
raising the possibility that von Willebrand factor levels influence to this drug. Factor XI–deficient patients with inhibitors do not
bleeding propensity. Recent work suggests that thrombin generation usually have increased spontaneous bleeding. Recombinant factor
tests and analyses of fibrin clot structure can predict the propensity VIIa has been used successfully for surgery in factor XI–deficient
to bleed, but these findings require confirmation in prospective patients with and without inhibitors, and to cover epidural block in
studies. deficient women during labor and delivery.
In the aPTT assay, factor XI is bound to the contact surface
through high-molecular-weight kininogen (HK) and is activated by
factor XIIa (Figs. 137.1B and 137.5). Factor XIa, in turn, activates DEFICIENCIES OF FACTOR XII, PREKALLIKREIN OR
factor IX. Therefore, factor XI deficiency prolongs the aPTT, but not HIGH-MOLECULAR-WEIGHT KININOGEN
the PT. Diagnosis and severity are established by a modified aPTT
assay using factor XI–deficient plasma. The aPTT is often normal in Factor XII, prekallikrein, and HK are required for normal factor XI
heterozygotes. activation in the “contact phase” that initiates coagulation in the
Perioperative therapy should be individualized for factor XI–defi- aPTT assay (Figs. 137.1B and 137.5). Patients lacking one of these
cient patients (see box on Treating Factor XI–Deficient Patients). For proteins have prolonged aPTTs, but do not have abnormal hemosta-
those requiring replacement, FFP or factor XI concentrate (Hemo- sis, even with surgery or injury. Therefore, these proteins either do
leven or FXI concentrate) (Table 137.2), effectively prevent bleed- not participate in hemostasis, or redundant mechanisms compensate
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ing. The half-life of factor XI is 45 to 52 hours, facilitating daily or for their absence. No specific therapy is required to prepare deficient
every-other-day dosing. Hemoleven has orphan drug status in the patients for invasive procedures. Factor XII, prekallikrein or HK
United States. A 3-year postmarketing analysis of this concentrate deficiency must be distinguished from deficiencies of factors VIII, IX,
indicated that it was effective as prophylaxis for surgery, invasive or XI, which prolong the aPTT, but cause abnormal hemostasis.
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procedures, and pregnancy, and for treating bleeding. However, it
is recommended that concentrates be used sparingly due to potential
prothrombotic effects. In the past, factor XI concentrates were associ- Factor XII Deficiency (OMIM 234000)
ated with thrombosis and DIC, mostly in older patients with cardio-
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vascular disease receiving doses over 30 units/kg. However, more In 1955 Ratnoff and Colopy described asymptomatic individuals
recent analyses indicate that patients receiving 20 to 30 units/kg also with a novel abnormality of surface-induced coagulation. The missing
have thrombotic events. Based on this, it has been suggested that the plasma component was called Hageman factor, after the index case,