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Chapter 137 Rare Coagulation Factor Deficiencies 2043

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associated with low factor VII include hematopoietic stem cell menorrhagia, which often required subsequent doses. Prophylaxis
transplantation, aplastic anemia, and sepsis. for invasive procedures may require treatment every 2 to 3 hours. In
The clinical spectrum of bleeding in factor VII deficiency is a study of 41 surgeries in 34 factor VII–deficient subjects receiving
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broad. Not surprisingly, significant bleeds tend to be most frequent rfVIIa, bleeding occurred in only three instances, and in those, the
with severe deficiency and patients with levels less than 1% of normal rfVIIa dose was considered low. The minimum treatment that ade-
may have a syndrome similar to severe hemophilia, with joint and quately prevented bleeding was 13 µg/kg/dose, and no less than three
soft tissue bleeding and hemarthrosis-related arthropathy. The best doses given on the day of surgery. However, patients may do quite
predictor of future bleeding risk seems to be the nature of bleeding (or well with much less. In one report, two doses on the day of surgery
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its absence) at the time of diagnosis. CNS hemorrhage is relatively followed by daily dosing successfully controlled bleeding. Continu-
common (4% to 17%). Patients with factor VII activity of ≥5% ous infusion rfVIIa has been used to cover surgical procedures and
of normal tend to have milder symptoms (epistaxis, menorrhagia, may reduce the total amount of drug administered by 70% to 90%
and bruising). Although little bleeding occurs in most patients with compared with bolus infusions.
factor VII levels ≥10% of normal, some have significant bleeding Patients with severe factor VII deficiency who have experienced
spontaneously or in response to hemostatic challenges. In one study, life-threatening bleeding may benefit from secondary prophylaxis,
36% of heterozygotes (factor VII activity 21% to 69%) reported particularly if bleeding involved the CNS (50% to 70% mortality).
bleeding problems, mostly involving skin and mucous membranes, FFP and plasma-derived factor VII concentrate have been used, but
whereas another study reported a greater risk for subcutaneous bleed- rfVIIa is the preferred agent. Interestingly, despite its short half-life,
ing in heterozygotes. Bleeding often complicates tooth extraction and rfVIIa is effective at doses of 20 to 30 µg/kg given 2 to 3 times per
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surgery on the oropharynx or urogenital tract in untreated patients. week. The large volume of distribution for both rfVIIa and plasma-
Abdominal surgery and hysterectomy are associated with fewer prob- derived FVII may explain this effect. In one registry, inhibitors were
lems. Postpartum bleeding is not common in factor VII–deficient reported in 4 of 225 patients with activity levels less than 4% who
women because factor VII levels rise in late pregnancy in all but received replacement. All were high titer responders (three developed
the most severely deficient patients. Risk of postpartum hemorrhage in infancy). Not all bleeding episodes in factor VII–deficient patients
correlates poorly with FVII level, leading some to suggest that recom- require factor replacement. Minor injuries may be controlled with
binant factor VIIa be available for excessive bleeding if it occurs. local measures. Fibrinolytic inhibitors, such as ε-amino caproic acid,
Thrombosis associated with factor VII deficiency is well docu- may be effective for minor bleeding, dental surgery, or other proce-
mented. A study of 33 reported cases (6 arterial, 27 venous) revealed dures involving mucous membranes. Fibrin glue may also be effec-
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15 with molecular studies. Nearly all patients had other thrombotic tive. Cryoprecipitate is not a source of factor VII. Plasma levels do
risk factors, usually acquired, and four had congenital thrombophilia. not respond to administration of DDAVP. An infant with severe
Of the 15 patients, 11 had either pArg304Gln (factor VII Padua) or deficiency was cured with liver transplantation. AAV-vector gene
pAla294Val. Those with factor VII Padua had no bleeding history, therapy has shown promising results in mice and macaques, raising
while mild bleeding was reported with pAla294Val. Treatment with FVII levels to therapeutic ranges.
vitamin K antagonists is problematic because the baseline PT is
abnormal as a result of the mutation. Therapy with low-molecular-
weight heparin or one of the newer direct oral anticoagulants may be FACTOR X DEFICIENCY (OMIM 227600)
a better option.
In factor VII deficiency, the PT is prolonged and the aPTT is Factor X deficiency was first described in two patients more than 50
normal. The diagnosis is confirmed, and the severity determined, by years ago. The missing plasma factor was called Stuart-Prower factor
a modified PT assay using factor VII–deficient plasma. With very after the two index cases, and subsequently designated factor X.
sensitive thromboplastin reagents, the PT may be prolonged with Patient Stuart was thought to have factor VII deficiency, but mixing
factor VII levels at the lower end of the normal range. When assessing his plasma with factor VII–deficient plasma corrected the clotting
patients for factor VII deficiency, the source of the tissue factor must defect. Patient Prower had multiple coagulation assay abnormalities.
be considered. Factor VII Padua–type variants interact poorly with The prevalence of severe factor X deficiency is estimated at approxi-
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the rabbit tissue factor–based reagents widely used in North America; mately 1 in 1 million persons (Table 137.1). Factor X is a 58,000-Da
they function better with human tissue factor and best with ox tissue protein that is the precursor of the protease factor Xa. Factor X is
factor. We routinely retest patients with apparent factor VII deficiency activated by the factor VIIa/tissue factor complex and by the factor
in rabbit tissue factor-based assays with a human tissue factor throm- IXa/factor VIIIa complex (Fig. 137.1A). Factor Xa catalyzes conver-
boplastin reagent to detect Padua-type variants. sion of prothrombin to thrombin, and the conversion of factor V to
Major considerations when treating factor VII–deficient patients factor Va.
include the short plasma half-life of the protein (3 to 4 hours), rela- Congenital factor X deficiency is an autosomal recessive trait.
tively low recovery of infused material (possibly due to a large volume Factor X–deficient mice die in utero or shortly after birth from
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of distribution), and rapid clearance in children. A plasma factor bleeding, indicating the protein is necessary for life. Humans with
VII level of 15% of normal is probably the minimum required for the severest form of factor X deficiency (activity <1% of normal)
surgery, with 15% to 25% being adequate in most cases. Of 157 probably have a trace of factor X in their plasmas. More than 100
surgeries performed on 83 factor VII–deficient patients with a mean factor X gene mutations have been identified in factor X–deficient
baseline activity of 5% who did not receive prophylaxis, 15.3% had patients. Most are missense mutations and many are CRM+ vari-
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bleeding complications, suggesting that supplementing patients with ants. A three part classification system has been proposed. Type I
baseline levels below 10% should prevent bleeding. Factor replace- deficiencies involve CRM–mutations, and include patient Stuart
ment can be accomplished with several products (Table 137.3). FFP (homozygous for Val298Met). Type II deficiencies are CRM+ vari-
is widely used, but its effectiveness is limited because of the large ants lacking activity, and include patient Prower (compound hetero-
volumes required. PCC contains variable amounts of factor VII; zygote for Arg287Trp and Asp282Asn). Type III deficiency includes
however, these products contain other vitamin K–dependent factors variants that are activated normally by Russell viper venom but not
in higher concentrations than factor VII, which could increase the by factor VIIa/tissue factor or factor IXa/VIIIa, variants defective only
risk for thrombosis. Recombinant factor VIIa (rfVIIa) is the preferred in activation by factor VIIa/tissue factor, variants defective only in
therapy for treating or preventing bleeding in factor VII deficiency. activation by factor IXa/VIIIa, and variants with higher activity in
A prospective registry of FVII deficient patients recorded the replace- chromogenic assays than clotting assays. Factor X deficiency can be
ment therapy given for various bleeding events (hemarthrosis, soft- inherited with deficiencies of other vitamin K–dependent proteins
tissue hematomas, epistaxis, gum bleeding, menorrhagia and others) (see Combined Deficiency of Vitamin K–dependent Proteins) and in
and found that the majority responded adequately to a single rela- combination with factor VII deficiency when both genes are lost due
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tively large dose of rfVIIa (60 µg/kg). The exception was treating to a chromosome 13 q34 deletion.