Page 2300 - Hematology_ Basic Principles and Practice ( PDFDrive )

2042 Part XII Hemostasis and Thrombosis

plasma, factor V was taken up by megakaryocytes and was detectable 6 to 8 hours), oral contraceptives, levonorgestrel-releasing intrauterine
in platelets 2 weeks after it was no longer detectable in plasma. Many devices, replacement therapy, or surgical intervention (endometrial
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patients with factor V deficiency have reduced plasma TFPI levels, ablation or hysterectomy). Replacement should be adjusted to
13
which may offset the need for factor V in thrombin generation. maintain a factor V level of 10%–15% of normal. Factor V–deficient
Mucosal bleeding is the primary abnormality, with 60% of patients women may have significant bleeding with childbirth and should be
experiencing epistaxis, menorrhagia, or oral bleeding. Hematomas treated in a similar manner.
and hemarthroses occur in 25%, but debilitating arthropathy is Platelets are a source of factor V and may be particularly useful
infrequent. Postpartum hemorrhage is common. Severe bleeding in in patients with severe bleeding or factor V inhibitors. Platelet factor
the CNS or GI tract has been reported, but is relatively rare. 13,14 V may either be protected from inhibition or may be sufficiently
Trauma, surgery, and dental extraction are associated with a high different in structure from its plasma counterpart to not cross-react
bleeding risk in untreated patients. Bleeding with surgery involving with antibodies directed against factor V. However, platelet transfu-
the urogenital tract, the nose, or the mouth may be particularly sions are not recommended as routine first-line treatment for factor
problematic because of high local fibrinolytic activity. Mild factor V V deficiency because of the possibility of developing antiplatelet
deficiency (>10% of normal factor level) is usually not associated with alloantibodies. Cryoprecipitate is not a source of factor V, and plasma
excessive bleeding, 13,14 although 10%–15% of patients report some levels do not respond to administration of DDAVP.
symptoms.
Thrombosis has been reported in factor V–deficient patients. 13,14
In some cases, the deficiency may not have prevented thrombosis. FACTOR VII DEFICIENCY (OMIM 227500)
Indeed, with the exception of prothrombin or factor X deficiency,
thrombotic events have been reported in all severe coagulation factor Factor VII deficiency was first reported by Alexander and colleagues
deficiency states. However, the situation with factor V is more in 1951. Severe factor VII deficiency is the most common of the
complex. Deficiency can occur in patients with the common proco- nonhemophilic coagulation factor deficiencies (Table 137.1), with an
agulant polymorphism factor V Arg506Gln (factor V Leiden). If estimated prevalence of 1 in 500,000 persons.
Arg506Gln and a mutation causing deficiency occur on opposite Factor VII is the 50,000-Da precursor of the protease factor VIIa.
alleles (in-trans), most plasma factor V will have the Gln506 substitu- Factors VII and VIIa bind to tissue factor, and initiate coagulation
tion, increasing the thrombotic risk (pseudohomozygous activated through activation of factors X and IX (Fig. 137.1A). Factor VII levels
protein C resistance). Such patients usually do not bleed excessively, correlate weakly with clinical presentation (Table 137.2). Mice
despite reduced plasma factor V antigen. lacking factor VII develop normally in utero but succumb to bleeding
Factor V is required for normal prothrombin activation (Fig. at birth. An infant born lacking factor VII died from intracranial
137.1B), and factor V deficiency causes prolongation of the PT and hemorrhage 12 days after birth, while another survived with replace-
aPTT. The diagnosis and severity are established with a modified PT ment therapy. Thus low levels of factor VII appear to be necessary to
assay with factor V–deficient plasma. With severe deficiency the sustain life. Activity levels of <10%, 10%–20%, and >20% have been
template bleeding time may be prolonged. Patients with factor V proposed as criteria to classify deficiency as severe, moderate, or mild,
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deficiency should be tested for factor VIII deficiency so that combined respectively. However, many patients with levels <10% will not have
deficiency is not missed. Factor V inhibitors cause prolongations of significant bleeding, even with invasive procedures. A classification
the PT and aPTT that do not correct on mixing with normal plasma. system based on clinical presentation has also been suggested.
As for factor VIII inhibitors, factor V inhibitor titers are established Although factor VII deficiency is considered an autosomal recessive
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using the Bethesda method. However, unlike inhibitors to factor trait, the observation that bleeding symptoms are reported in up to
VIII, which typically take 1 to 2 hours to fully inactivate their target, one-third of patients with heterozygous deficiency raises questions
factor V inhibitors inhibit factor V almost immediately. The throm- about this concept.
bin time should be normal, except in cases of inhibition induced by More than 200 factor VII gene mutations associated with factor
bovine topical thrombin, where antithrombin antibodies are also VII deficiency have been described, well over half of which are mis-
present. In patients with the East Texas bleeding disorder or factor V sense mutations. Most have been identified in single families, but
Amsterdam the prolonged PT and aPTT are due to the inhibitory some are widespread. In surveys of patients from Europe and Latin
effects of TFPI. In these patients the PT and aPTT will not com- America, pAla244Val accounted for 84% of abnormal factor VII
pletely correct on mixing with normal plasma, and the factor V alleles in 88 unrelated Jewish patients, and in 14% and 7% of
activity level will be normal. abnormal factor VII alleles in Germany and France, respectively.
No factor V concentrate is commercially available (Table 137.3). CRM+ variants are common. Some factor VII variants demonstrate
Administration of FFP is recommended for serious bleeding or prior variable activity in PT assays, depending on the species of origin of
to surgery. The minimum factor V level for hemostasis is 10%–15% the tissue factor used. The name “factor VII Padua” has been applied
1,2
of normal. In a patient with less than 1% plasma factor V, this can to these variants, many of which have an Arg304Gln substitution
be achieved by administering 15 to 20 mL/kg FFP, followed by that causes a defect in the interaction with tissue factor from rabbits,
5 mL/kg every 12 hours. A plasma level of at least 25% is recom- but not humans or oxen.
mended for major surgery. Estimates of the factor V plasma half-life Factor VII deficiency may occur in combination with deficiencies
vary widely, but 12 to 14 hours should be assumed for replacement of other vitamin K–dependent proteins (see Combined Deficiency of
purposes. Infusion of 20 mL/kg FFP (over 3 to 4 hours) before Vitamin K–Dependent Proteins) and in combination with factor X
surgery, followed by 5 to 10 mL/kg every 12 hours is usually adequate. deficiency as a result of loss of both genes due to a chromosome 13
Infusions should be continued for 7 to 10 days to permit wound q34 deletion. Factor VII deficiency has also been reported in cases of
healing. Care must be taken to avoid fluid overload from large trisomy 8 and in conjunction with abnormalities of bilirubin metabo-
volumes of FFP. Plasma exchange has been successful in a few factor lism, mental retardation, microcephaly, epicanthus, cleft palate, and
V–deficient patients requiring surgery. Mucosal bleeding from the patent ductus arteriosus.
nose and mouth may respond to ε-amino caproic acid, and superficial Reduced levels of factor VII occur with warfarin therapy, poi-
lacerations usually respond to local pressure. Although the defect soning with rodenticides such as brodifacoum, liver disease, DIC,
caused by factor V deficiency would hypothetically render therapy biliary tract disease, vitamin K deficiency, and cephalosporin therapy.
with recombinant factor VIIa ineffective, this agent has been used In these situations other vitamin K–dependent factors are usually
successfully in a patient with severe factor V deficiency requiring decreased, although the effect on factor VII is often greater because
surgery. of its short half-life. Alloantibody inhibitors to factor VII have been
Menorrhagia is common in factor V–deficient women. Symptoms reported in deficient patients after replacement therapy. Acquired
may be managed with antifibrinolytic therapy (ε-amino caproic acid factor VII deficiency has been reported as a paraneoplastic syndrome
50 to 60 mg/kg every 4 to 6 hours or tranexamic acid 15 mg/kg every with atrial myxoma and Wilms tumor. Other scenarios rarely