Page 2302 - Hematology_ Basic Principles and Practice ( PDFDrive )

2044 Part XII Hemostasis and Thrombosis

Acquired factor X deficiency occurs with warfarin therapy, poison- approved for clinical use in the United States and Europe and is
ing with rodenticides such as brodifacoum, vitamin K deficiency, liver considered the treatment of choice. As with prothrombin deficiency,
disease, and DIC, all of which reduce levels of other coagulation there are no reports of acquired alloantibody inhibitors to factor X
factors. Factor X deficiency has been reported with malignancies, after replacement therapy in congenitally deficient patients, consistent
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infections, burn injury, proteinuria, and medications. There are with the concept that these patients have trace amount of plasma
rare reports of acquired factor X inhibitors, most of which resolve factor X at baseline. Severe factor X deficiency was cured by liver
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after treatment of underlying conditions. Acquired factor X defi- transplantation in a child.
ciency may accompany systemic amyloidosis, occurring in 8.7% to Patients with acquired factor X deficiency and amyloidosis have
14% of patients with AL amyloidosis, but rarely in secondary (AA) variable responses to infusion of products containing factor X, making
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amyloidosis. Factor X binds to amyloid fibrils, which reduces the individual pharmacokinetic studies of factor X replacement therapy
plasma half-life of the protein. Distinguishing this disorder from important. Treatment may involve chemotherapy, splenectomy,
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inherited factor X deficiency is based on the clinical setting and plasma exchange, PCCs, activated factor VIIa and factor X concen-
evidence of poor clinical response to infusion of factor X–containing trate. The optimal hemostatic management for invasive procedures
products in amyloidosis patients. has not been determined. In one series, complications occurred in
A clinical classification system for factor X deficiency has been only 13% of procedures, and there was a poor correlation between
proposed based on factor X activity (severe, <10%; moderate, the risk for bleeding and factor X levels.
10%–40%; mild, >40% of normal activity) (Table. 137.2). Bleeding
in factor X deficiency is severe and occurs earlier in life in patients
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with the lowest plasma levels. There is an impression that factor FACTOR XI DEFICIENCY (OMIM 264900)
X–deficient patients bleed more severely than patients with other
congenital coagulopathies. In a series of 102 factor X–deficient In 1953 Rosenthal and colleagues described three members of a
patients, the most frequent symptom was easy bruising (55%) fol- family with abnormal hemostasis, prolonged time to clot formation
lowed by hematomas (43%). Epistaxis and hemarthrosis were in a glass tube, and a normal PT. In mixing studies, patient plasma
common. Intracranial hemorrhage was seen in patients homozygous shortened the clotting times of hemophilia A and B plasmas, indicat-
for the pGly380Arg mutation. Among homozygotes, hemarthrosis ing the missing factor was distinct from factors VIII and IX. Unlike
was very common, and all women suffered from menorrhagia. the X-linked hemophilias, the new disorder (sometimes called hemo-
Umbilical stump bleeding occurred in 28% of newborns. Moderate philia C) was transmitted as an autosomal trait. The missing factor
to mildly affected persons (activity >10%) may have increased bruis- was called plasma thromboplastin antecedent and subsequently factor
ing or bleeding with trauma. While heterozygotes tend to be asymp- XI. It is estimated that severe factor XI deficiency (<15% of normal
tomatic, up to one-third may have excessive bleeding from mucous plasma level) occurs in 1 per million persons (Table 137.1), although
membranes with invasive procedures, or with childbirth. perhaps this number should be higher, as patients with milder defi-
Because factor X is a component of the common pathway of ciencies are often symptomatic. Severe factor XI deficiency is common
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coagulation (Fig. 137.1B), its absence prolongs the PT and aPTT, in persons of Ashkenazi Jewish ancestry (incidence of 1 in 450).
and factor X deficiency must be distinguished from deficiencies of Factor XI is the precursor of the 160,000-Da protease factor XIa,
fibrinogen, prothrombin, or factor V. Definitive diagnosis and deter- which contributes to clotting by activating factor IX (Fig. 137.1A).
mination of severity are established using a modified PT or aPTT The protein is a homodimer, a feature that has implications for
assay with factor X–deficient plasma. Some factor X variants prefer- inheritance of factor XI deficiency. Factor XI is activated by factor
entially prolong either the PT or the aPTT. Congenital factor X XIIa in the aPTT assay (Fig. 137.1B); however, it is probably activated
deficiency cannot be distinguished from acquired deficiency due to by other proteases in vivo because factor XII deficiency does not cause
amyloidosis in the laboratory, because factor X-dependent assays abnormal bleeding. For example, factor XI is also activated by throm-
correct after mixing with normal plasma in both conditions. The bin (Fig. 137.1A).
absence of a lifelong bleeding disorder, findings of a serum M-protein, Factor XI deficiency in the Jewish population and in many other
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signs of amyloidosis, and histologic confirmation of amyloid in patients is an autosomal recessive condition. Two point mutations
tissues point toward AL amyloidosis. A poor response to factor X account for over 90% of mutant factor XI alleles in Ashkenazi Jews.
infusion in the absence of an inhibitor also distinguishes the two Glu117Stop encodes a truncated protein, and homozygotes lack
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conditions. plasma factor XI. Glu117Stop is at least 2500 years old and is
Factor X–deficient patients are treated with FFP or PCC for found in Jews from different ethnic backgrounds, and non-Jewish
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bleeding episodes (Table 137.2). A trough level of 10% to 20% is patients. Phe283Leu, occurs primarily in Jews of European ancestry
usually sufficient for hemarthroses and soft tissue bleeding. The half- and is likely of recent origin. It causes a defect in dimer formation
life of factor X is 20 to 40 hours. FFP administered as a loading dose resulting in poor secretion; with homozygotes having about 10% of
of 10 to 20 mL/kg followed by 3 to 6 mL/kg every 12 to 24 hours normal plasma factor XI activity. Compound heterozygotes for
usually keeps trough levels above 10 to 20%. 2,18 Higher factor X levels Glu117Stop and Phe283Leu have about 3% normal activity, while
may be required for severe bleeding or surgery, and accumulation of heterozygotes for either mutation have activities of 50% to 60%. The
factor X in plasma can be achieved by increasing the transfusion allele frequencies of Glu117Stop and Phe283Leu in Ashkenazi Jews
frequency to every 12 hours. PCCs with a factor X to factor IX ratio (2.2% and 2.5%, respectively) indicate a carrier frequency for an
of approximately 1 : 1 will increase plasma factor X levels by 1.5% for abnormal factor XI allele of approximately 5%.
each factor IX unit/kg body weight. A dose of 15 to 20 factor IX More than 200 human factor XI gene mutations have been identi-
units/kg every 1 to 2 days has been suggested for major surgery. 2,18 fied, and several are relatively widespread with evidence of founder
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While no patient with congenital factor X deficiency has been effects. Cys38Arg has an allele frequency of 0.5% in French Basques,
reported to have thrombosis, there is a risk of thrombosis or DIC Cys128Stop accounts for 10% of abnormal alleles in Great Britain,
with PCC, and it is recommended that the plasma factor X level not and Gln88Stop is present in several families from France. In most
exceed 50% of normal when using these products, unless absolutely deficient patients, factor XI activity and antigen are comparably
necessary. Factor X levels will rise slightly in pregnancy, but severely reduced (CRM − deficiency). CRM+ factor XI mutations are rare. A
deficient patients will require prophylaxis with invasive procedures three-category scheme has been proposed for classifying CRM −
and at delivery to prevent hemorrhage. A factor X level of 20%–40% factor XI deficiency. Category one contains mutations that prevent
is recommended. For patients with severe deficiency and recurrent protein synthesis (e.g., Glu117Stop), while mutations in category two
hemorrhage, prophylactic PCC or factor X concentrate infusion is interfere with dimer formation (e.g., Phe283Leu). Inheritance in
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effective. Minor bleeding can be treated with local measures and/or both categories follows a recessive pattern, because mutant polypep-
ε-amino caproic acid. Cryoprecipitate lacks factor X, and DDAVP tides do not interfere with the product of the normal allele in het-
infusion does not affect factor X levels. A factor X concentrate is now erozygotes. Category three includes mutations that impair secretion