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Chapter 137 Rare Coagulation Factor Deficiencies 2047

many PTT assays into the normal range. Prekallikrein is the 95,000- of severe factor XIII deficiency is estimated at 1 in 2 million (Table
Da precursor of the protease α-kallikrein. Prekallikrein deficiency is 137.1). 25,26 Factor XIII in blood is distributed between plasma and
an autosomal trait, presenting in the homozygous or compound platelets, with a small amount in monocytes. The plasma protein is
heterozygous forms with plasma levels usually less than 1% of normal. a 330,000-Da tetramer composed of two catalytic A subunits and
CRM+ variants account for about half of cases, and are common in two carrier B subunits. 25,26 Factor XIII in platelets, monocytes, and
white and Japanese patients, while most black patients are CRM −. placenta has only A subunits. The A subunit of the protein in plasma
Partial deficiency (10%–50 %) may be seen in patients with severe appears to be synthesized primarily in hematopoietic cells, while the
HK deficiency, likely due to increased clearance because prekallikrein B subunit comes from the liver. Factor XIII is converted to the
circulates in complex with HK. Severe prekallikrein deficiency pre- transglutaminase factor XIIIa by thrombin, and catalyzes formation
sents as a prolongation of the aPTT in a person without a history of of γ-glutamyl-ε-lysyl bonds between fibrin monomers (Fig. 137.1A),
excessive bleeding. While thrombotic events have been described in resulting in a fibrin mesh resistant to dissolution in mild acid or urea.
deficient patients, it is not clear that the deficiency contributed to Factor XIIIa also cross-links fibrin to plasma, extracellular matrix, and
thrombosis. Indeed, studies in mice indicate that reducing prekalli- cytoskeletal proteins, enhancing clot adherence to an injury site.
krein levels actually attenuates thrombus formation. A recent analysis Congenital factor XIII deficiency is an autosomal recessive condition.
raised the possibility that the incidence of hypertension may be The current classification scheme recognizes factor XIII-A and factor
higher in prekallikrein deficient individuals than the general popula- XIII-B defects. Factor XIII-A deficiency is divided into type I (quan-
tion, possibly related to reduced bradykinin formation. titative) and type II (qualitative) deficiencies. In patients with appar-
In the aPTT assay, prekallikrein is converted to α-kallikrein by ent combined FXIII-A and -B deficiency, low levels of the A subunit
factor XIIa, which then activates factor XII (Fig. 137.5). Severe are likely the result of rapid clearance because of the absence of the
prekallikrein deficiency causes a prolonged aPTT, and the diagnosis stabilizing B subunit.
is confirmed using a modified aPTT with prekallikrein deficient Most cases of congenital factor XIII deficiency are due to muta-
plasma. The prolonged aPTT in prekallikrein deficiency may be tions in the A subunit gene, with less than 5% in the B subunit gene.
shortened by increased incubation time with the contact reagent, More than 75 different mutations have been reported in the factor
which facilitates factor XII activation independently of prekallikrein. XIII-A gene, and more than 20 in the factor XIII-B gene (www.f13-
This distinguishes prekallikrein deficiency from deficiencies of factors database.de). The incidence of factor XIII mutations affecting plasma
VIII, IX, XI XII, and HK, in which the prolonged aPTT does not activity is probably higher than suspected, considering that screening
correct with prolonged incubation. Those aPTT reagents that use test abnormalities occur mostly in those with severely decreased
ellagic acid as the contact activator are relatively insensitive to prekal- plasma activity (<5% of normal). A few mutations show evidence of
likrein, and may fail to detect some deficient patients. a founder effect, with the IVS5–1 G>A splice-site defect and Arg-
661Stop nonsense mutation each identified in 10 apparently unrelated
High-Molecular-Weight Kininogen Deficiency individuals.
Plasma factor XIII levels decrease in DIC and liver disease. Sig-
(OMIM 228960) nificant deficiency is rare in liver disease and may indicate a poor
prognosis. Acquired deficiency has been reported in leukemia, Crohn
In 1974 Schiffman and Lee reported that a plasma factor distinct disease, ulcerative colitis, and Henoch-Schönlein purpura, but levels
from prekallikrein was required for factor XI activation by factor XIIa. are usually greater than 30% of normal and replacement is not
In 1975 asymptomatic individuals from three distinct families were required. Alloantibodies to factor XIII induced by replacement
described with in vitro abnormalities of coagulation, fibrinolysis, and therapy are relatively uncommon in factor XIII–deficient patients.
kinin generation who appeared to lack the unknown factor. The Neutralizing autoantibodies that block the activation, activity, or
condition, originally named for the affected families (Fitzgerald trait, fibrin binding capacity of the factor XIII-A subunit, or that enhance
Williams trait, and Flaujeac trait), was subsequently determined to factor XIII clearance from plasma, have been reported in older adults,
be due to HK deficiency. The disorder appears to be very rare. HK in patients with systemic lupus erythematosus and lymphoprolifera-
is a 110,000-Da protein containing the vasoactive peptide bradyki- tive disorders, and with medications such as isoniazid, penicillin,
nin. Prekallikrein and factor XI circulate in complex with HK. procainamide, phenytoin, and practolol. An autoantibody to the B
Low-molecular-weight kininogen and HK are products of a single subunit that developed in a patient with systemic lupus erythematosus
kininogen gene; however, low-molecular-weight kininogen does not enhanced clearance of the protein from plasma and was associated
play a role in coagulation in vitro. HK deficiency is an autosomal with life-threatening bleeding.
recessive trait. Depending on the genetic abnormality, patients may In patients with factor XIII levels ≤5% of normal, delayed bleed-
have isolated HK deficiency or combined HK and low-molecular- ing from the umbilical stump occurs in 80% to 90% of newborns
weight kininogen deficiency. HK deficient patients are usually identi- with severe factor XIII deficiency and is considered a diagnostic
fied by the incidental finding of a prolonged aPTT, and they do not feature of the disorder. 25,26 Ecchymoses, soft tissue hematomas,
bleed excessively. and prolonged bleeding with trauma are common, and recurrent
In the aPTT assay, HK facilitates binding of prekallikrein and soft tissue bleeding may lead to formation of hemorrhagic cysts
factor XI to the contact surface, enhancing their activation by factor (pseudotumors). 25,26 Hemarthroses is less frequent than in factor VIII
XIIa (Fig. 137.5). Severe deficiency is characterized by a very pro- or IX deficiency. Bleeding that is delayed 12 to 36 hours postinjury
longed aPTT, and definitive diagnosis is established using a modified is characteristic of factor XIII deficiency, although hemorrhage is
aPTT with HK deficient plasma. Partial prekallikrein deficiency is immediate in some cases. Bleeding at the time of invasive procedures
common in severe HK deficiency, likely due to increased catabolism may be minimal, but delayed hemorrhage often occurs. Intracranial
of prekallikrein when it is not in complex with HK. bleeding is more frequent in factor XIII deficiency than in other
inherited coagulation disorder, with an incidence as high as 30%, 25,26
FACTOR XIII DEFICIENCY (OMIM 134570 [A SUBUNIT] justifying prophylactic replacement. Delayed wound healing has
been observed, possibly related to a defect in angiogenesis. Spon-
AND 134580 [B SUBUNIT]) taneous abortions occur with most pregnancies in untreated factor
XIII–deficient women, 25,26 possibly due to abnormal formation of
In 1944 Robbins demonstrated that fibrin formed from purified the cytotrophoblastic shell and poor attachment of the placenta to
fibrinogen was soluble in weak acid, while fibrin formed in the the uterus. The issue of excessive bleeding in patients with milder
presence of serum or plasma was not. He proposed that a fibrin- (>5% of normal) factor XIII deficiency is more controversial. In at
stabilizing factor was present in plasma. In 1960 Duckert and col- least two studies, patients heterozygous for factor XIII deficiency
leagues described the first patient with deficiency of fibrin-stabilizing reported excessive bleeding, but these studies lacked control
factor, which was subsequently designated factor XIII. The incidence groups. Experience with pregnant women with severe factor XIII