Page 2307 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 137 Rare Coagulation Factor Deficiencies 2049

Laboratory Testing in Rare Coagulation Factor Deficiencies
When deficiency of a coagulation factor is under consideration, it is inhibitor suggests a nonneutralizing antibody is present. In our practice,
important to keep in mind that (1) acquired conditions causing multiple we have observed severe acquired deficiencies of prothrombin, factor V,
factor deficiencies are more common than congenital deficiency of a factor X, factor XI, and factor XIII caused by (or presumed to be caused
single factor, and (2) common inhibitors of coagulation, such as lupus by) nonneutralizing antibodies.
anticoagulants, heparins, and the direct oral anticoagulants (DOACs) If the level of a vitamin K–dependent protein (prothrombin or factors VII,
interfere with coagulation factor assays. Unexplained prolongation of IX or X) is low, levels of factor V and at least one other vitamin K-dependent
the PT or aPTT should be evaluated in a qualified laboratory. If at factor should be measured. If multiple vitamin K–dependent factors are
all possible, the plasma should be prepared from blood collected by low and factor V is normal, a process affecting vitamin K is likely. If
venipuncture. In our experience, the common practice of collecting blood factor V is also low, liver disease or DIC should be considered. Tests
from central venous catheters/ports or peripheral intravenous catheters for hepatic function (albumin) or injury (transaminases) can facilitate
frequently introduces fluids or drugs that adversely affect clotting assays interpretation of the coagulation factor studies. Distinguishing DIC from
and contribute to misdiagnosis. We frequently use the thrombin time liver disease can be difficult, because results of standard tests such as
assay and factor Xa-based assays to screen samples for the presence the PT, aPTT, platelet count, fibrinogen and D-dimer may be abnormal in
of heparins or DOACs. both conditions. Measuring factor V and factor VIII may be useful in this
The initial evaluation of a plasma sample with a prolonged PT or aPTT situation, because both are often low in DIC, while factor VIII is normal
should start by repeating the abnormal test on a mixture of patient and or elevated in liver disease.
normal plasma to determine if the prolonged clotting time is related to a It is likely that the apparent rarity of congenital factor XIII deficiency is
clotting factor deficiency (clotting time becomes normal after mixing) or partly due to the insensitivity of clot solubility assays still used in many
an inhibitor that neutralizes clotting factor activity (clotting time remains places to screen for this disorder. Quantitative measurements of factor
prolonged after mixing). The mixing study should be performed with and XIII activity are preferable, and are replacing solubility assays at many
without incubation (2 hours), as some antibody inhibitors demonstrate a institutions.
time-dependent pattern of inhibition. Slight (a few second) prolongations Patients with factor XI, factor XII, prekallikrein or high-molecular-weight
of the PT or aPTT can be difficult to evaluate with a mixing study. We kininogen deficiency may require anticoagulation for treatment or prophy-
evaluate such samples with assays for lupus anticoagulants prior to laxis for thromboembolism. Assays based on contact activation such as the
measuring specific levels of coagulation factors. aPTT or the activated clotting time (ACT) cannot be used for monitoring
The antibodies to clotting factors that most physicians are familiar with therapy with heparin or the direct thrombin inhibitor argatroban in these
neutralize factor activity, and generate abnormal results on a mixing patients, because the baseline PTT and ACT are prolonged. Chromogenic
study (i.e., mixing with normal plasma fails to correct the abnormal clot- heparin assays based on factor Xa inhibition are now widely available for
ting time). However, nonneutralizing antibodies can cause severe factor monitoring heparin, and should be used in place of the aPTT in patients
deficiency. These antibodies typically enhance clearance of the clotting with these deficiencies. Alternatively, low-molecular-weight heparin,
factor from the plasma in vivo, and are not detected in a mixing study. A fondaparinux or a DOAC, which do not generally require monitoring, can
failure to respond to replacement therapy in the absence of a measurable be used instead of unfractionated heparin or argatroban.

She responded partially to large doses of vitamin K. Subsequently, long after ingestion because of their long half-lives. Some patients
low protein C and protein S levels were reported in association with have adequate clinical response to vitamin K 1 (10 mg weekly), but
mutations in the γ-glutamyl carboxylase (GGCX) gene. Although others require unusually high doses. Nonresponders, or respond-
the condition is considered autosomal recessive, severe bleeding ers with significant bleeding episodes, can be treated with FFP
was reported in a neonate heterozygous for a GGCX mutation. or PCC.
Prothrombin; factors VII, IX, and X; proteins C and S; and the bone
proteins osteocalcin and matrix Gla protein require γ-carboxylation
of glutamic acid residues in their N-terminal Gla-domains. This REFERENCES
process is mediated by GGCX, which uses reduced vitamin K as a
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