Page 2306 - Hematology_ Basic Principles and Practice ( PDFDrive )

2048 Part XII Hemostasis and Thrombosis

deficiency shows that the factor XIII level needs to be higher than TABLE
10% to reliably prevent pregnancy loss, indicating that clinically 137.4 Combined Familial Deficiency States.
significant problems can occur in patients with levels higher than 5%
of normal. Type Deficient Factors OMIM Designation Underlying Cause
The PT and aPTT measure time to fibrin clot formation, but do 1 V and VIII 227300 Mutations in LMAN1
not assess clot stability. Thus results for these assays are normal in or MCFD2 genes
factor XIII–deficient patients. Clots formed in plasma lacking factor
XIII are soluble in 5 M urea or 1% monochloroacetic acid, while 2 VIII and IX 134510 Unknown
clots from normal plasma are stable. Solubility in 5 M urea (urea clot 3 II,VII, IX, X, 277450 (gamma- Mutations in
stability assay) is often used to screen for factor XIII deficiency or Protein C, glutamyl γ-glutamyl
inhibitors. Plasma clots lacking α 2 -antiplasmin are also soluble in the and Protein S carboxylase) carboxylase
urea clot stability assay, and can be identified with specific assays. 607473 (vitamin K (GGCX) or vitamin
Solubility tests have low sensitivity for factor XIII deficiency, even oxidoreductase) K oxidoreductase
failing to detect some samples with <2% of normal activity and (VKORC1) genes
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probably almost all samples with levels ≥5% of normal. Chromo- 4 VII and VIII 134430 Unknown
genic assays that quantitatively measure factor XIIIa activity are 5 VIII, IX and XI 134520 Unknown
available and are replacing the urea clot stability assays in many
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institutions. These assays can also be used to detect and quantify 6 IX and XI 134540 Unknown
neutralizing factor XIII inhibitors, using a mixing method with VII and X Gene deletion
normal plasma. 13q34
The plasma half-life of factor XIII is 10 to 14 days, 25,26 facilitating OMIM, Online Mendelian Inheritance in Man.
prophylactic replacement therapy. Although some consider a level of
5% adequate for hemostasis, others suggest levels greater than 10%
are required to reduce bleeding risk. FFP and cryoprecipitate contain
factor XIII; however, the factor XIII concentrate Fibrogammin P
(marketed as Corifact in the United States; Table 137.2) is preferred Combined Factor V and Factor VIII Deficiency
for replacement. 25,26 Fibrogammin P contains factor XIII purified (OMIM 227300)
from human plasma and is pasteurized. Recombinant factor XIII-A
subunit (Tretten) received FDA approval in December 2013 to Combined factor V and factor VIII deficiency was first reported in
prevent bleeding in patients with congenital factor XIII A-subunit 1954. The familial form is an autosomal recessive trait caused by
deficiency. Tretten is produced in yeast and contains no human blood mutations in either the LMAN1 (mannose-binding lectin) or
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component. In a prospective study, prophylactic replacement with MCFD2 (multiple combined factor deficiency protein) gene. These
recombinant factor XIII to maintain activity at >0.05–0.2 IU/mL proteins form a cargo receptor that transports factors V and VIII from
prevented spontaneous bleeding without adverse effects. 28 the ER to the ER-Golgi intermediate compartment. Although the
Dosing regimens are the same for plasma derived and recombinant incidence of this disorder is thought to be 1 in 1 million persons, the
factor XIII. A regimen of 40 units/kg every 4 weeks is recommended allele frequency is particularly high (~1%) in Tunisian Jews originat-
for prophylaxis. Although concentrated recombinant or plasma- ing from a community on the island of Djerba.
derived factor XIII are preferred for prophylaxis (or treatment of Deficiency of LMAN1 or MCFD2 activity causes a defect in
acute bleeding), if it is not available, FFP (10–20 mL/kg every 4 to factor V and factor VIII secretion, lowering plasma levels to 5%–30%
6 weeks) or cryoprecipitate (1 unit for every 10 to 20 kg body weight of normal. In Tunisian Jews, a T-to-C substitution at a donor splice
every 3 to 4 weeks) can be used. A dose of 20 to 30 units/kg/day site in intron 9 causes LMAN1 deficiency. A history of consanguinity,
should be used with major surgery to keep the plasma activity 20% co-segregation of factor deficiencies, and similar reductions in factor
to 50% of normal. For minor surgery, 10 to 20 units/kg/day for 2 to V and VIII favor the familial disorder. Affected individuals bleed
3 days is sufficient. Bleeding can be treated with 10 to 30 units/kg/ primarily after trauma, and epistaxis, gingival bleeding, easy bruising,
day depending on severity. In pregnancy, replacement should be and menorrhagia are common. Hemarthrosis unrelated to trauma
started early, preferably before gestational week 5, because decidual may occur in 20% of patients, but bleeding from the GI tract or
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bleeding from implantation will occur without replacement. The intracranial hemorrhage is less common. Postpartum hemorrhage
optimal plasma factor XIII concentration in pregnancy is not estab- occurs in most affected women, and invasive procedures, including
lished, but >10% of normal is recommended. This can be achieved tooth extraction, are usually accompanied by bleeding in the absence
by infusing 250 units of concentrate every 7 days through week 22 of factor replacement. The PT and aPTT are prolonged. As isolated
of gestation, then 500 units per week until delivery, with a 1000 unit factor V deficiency also prolongs these tests, patients with factor V
bolus during labor. deficiency should have factor VIII levels measured to avoid missing
combined deficiency. Patients with mucosal bleeding and menor-
CONGENITAL DEFICIENCIES INVOLVING MULTIPLE rhagia may respond to antifibrinolytic therapy. For more significant
bleeds, or in preparation for surgery or tooth extraction, a combina-
COAGULATION FACTORS tion of FFP and factor VIII concentrate should be used. DDAVP
may raise factor VIII, but not factor V levels. Trough levels of
Numerous cases of congenital deficiencies of more than one coagula- approximately 50% for factor VIII and 25% for factor V have been
tion factor have been described. While most represent chance coin- recommended for surgery. Plasma exchange may be used to increase
heritance of distinct deficiencies, several represent familial syndromes factor V in situations in which volume overload from large volumes
(Table 137.4). Such syndromes are likely caused by abnormalities in of FFP is a concern. Recombinant factor VIIa was used successfully
intracellular protein processing or alterations in posttranslational to stop bleeding in one surgery patient.
modification. Common nonspecific inhibitors such as lupus antico-
agulants interfere with coagulation assays and can lead to erroneous
interpretations when they suggest multiple factor deficiencies. Simi- Combined Deficiency of Vitamin K–Dependent Proteins
larly, potent inhibitors directed at a single coagulation factor (e.g., (OMIM 277450 and 607473)
factor VIII) occasionally interfere with assays for other factors. Two
familial states, combined factor V and VIII deficiency (type 1) and In 1966 McMillan and Roberts described a newborn girl with
deficiency of vitamin K dependent factors (type 3), are well prolonged PT and aPTT; low levels of prothrombin and factors
characterized. VII, IX, and X; and no evidence of liver disease or malabsorption.