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Chapter 137 Rare Coagulation Factor Deficiencies 2039

and FGA-Arg16Cys occur in asymptomatic individuals as well as
Adjuncts to Factor Replacement Therapy in Congenital Factor
Deficiencies patients with bleeding or thrombosis.
Bleeding symptoms tend to be relatively mild, with epistaxis, easy
The antifibrinolytic agents ε-amino caproic acid and tranexamic acid can bruising, and menorrhagia being common. 9,10 More serious bleeding
be effective adjuncts to factor replacement when treating congenital or events including soft tissue hematomas, hemarthroses, postoperative
acquired bleeding disorders, and are useful alternatives to replacement hemorrhage, and bleeding during and after pregnancy do occur, but
therapy for mild bleeding or minor procedures. These drugs inhibit are rarer. Major bleeding seems to occur primarily between the ages
clot dissolution by interfering with plasminogen activation and plasmin of 20 and 40 years, partly due to hemostatic challenges related to
activity, and are particularly effective when bleeding involves tissues childbirth. Abnormal wound healing and spontaneous abortions have
with high fibrinolytic activity such as the oral and nasal cavity. They are been reported.
also useful for treating menorrhagia, limiting blood loss with surgery, Thrombotic events primarily involve the venous circulation,
controlling epistaxis and reducing some types of GI bleeding. A typical 9,10
loading dose of ε-amino caproic acid is 50 to 100 mg/kg followed by although arterial events occur. The mean age for venous and arte-
50 mg/kg every 6 hours (for adults dose 2 to 4 g every 6 hours). If rial events in one study (34 and 49 years) was significantly lower than
10
bleeding subsequently occurs, the dose can be increased, but should for the general population. There was a high prevalence of venous
not exceed 24 grams in 24 hours. ε-Amino caproic acid is available in thromboembolism (VTE) at the time of diagnosis, with an incidence
oral and intravenous formulations. Identical dosing for either prepara- during follow-up similar to that for carriers of the factor V Leiden
tion may be used due to excellent bioavailability. For dental extraction (G1691A) polymorphism. A strong relationship exists between
in factor VIII or IX deficiency, many centers utilize a single 50% to certain fibrinogen variants and venous thrombosis. Thrombosis-
100% dose of factor concentrate followed by seven days of ε-amino associated mutations tend to cluster at the C-terminus of the Aα-chain
caproic acid, and it is reasonable to use this approach for patients and near the thrombin cleavage site on the Bβ chain. Abnormalities
with some rare bleeding disorders. Patients with factor XI deficiency do
well with antifibrinolytic agents alone for tooth extraction (see Treating in fibrin polymerization and cross-linking, clot structure, and suscep-
Factor XI Deficient Patients). Prolonged therapy with antifibrinolytics tibility to fibrinolysis have been described. The “Dusart Syndrome”
must be undertaken with caution in patients who are not mobile, caused by FGA-Arg554Cys (fibrinogen Paris V) was associated with
who have a history of thrombosis, or who have significant urogenital venous thrombosis and sudden death in adolescents and young adults
bleeding. These drugs interfere with urokinase-mediated fibrinolysis in several families. Dysfibrinogenemia was reported in 5 of 33 patients
in the genitourinary tract that can lead to thrombotic occlusion of with chronic thromboembolic pulmonary hypertension, with the
the ureter. Concomitant use of antifibrinolytic agents with activated FGB-Pro235Leu substitution identified in three unrelated patients.
prothrombin complex concentrates or recombinant factor VIIa may Altered fibrin structure and susceptibility to fibrinolysis may result in
result in a particularly high risk of thrombus formation. Patients may poor clot dissolution in these patients. Despite these associations, a
develop nausea or vertigo with high doses of ε-amino caproic doses,
and rarely, rhabdomyolysis. review of 2376 patients with venous thrombosis found dysfibrino-
Recombinant factor VIIa may stop or prevent hemorrhage in rare genemia in less than 1%, so testing for abnormal fibrinogen in
bleeding disorders. The mechanism by which this agent works is patients with venous thrombosis is not widely recommended.
not completely understood, particularly for deficiencies of common As discussed in the section on Fibrinogen Deficiency, maternal
pathway factors (prothrombin and factors V and X). For patients with fibrinogen is required to maintain pregnancies. Pregnancy loss, as well
rare bleeding disorders and an antibody inhibitor directed against the as peripartum bleeding and thrombosis, have been reported in dysfi-
missing factor, factor VIIa may be the treatment of choice. Doses range brinogenemic women. In contrast to older reports, the survey cited
from 15 to 120 µg/kg every 2 to 6 hours depending upon the severity of above did not identify an increased risk of spontaneous abortion, but
bleeding. Because of the risk of thromboembolism with factor VIIa, we there was a significant risk of postpartum bleeding, particularly in
recommend frequent reevaluation and reduction to the lowest effective
dose. Doses of 90 µg/kg every 2 to 3 hours have been used in patients patients with histories of prior bleeding.
with congenital factor V deficiency or combined deficiencies of factors V A group of mutations in the C-terminus of the fibrinogen Aα-
and VIII; with acquired factor X deficiency associated with amyloidosis, chain is associated with autosomal dominant hereditary amyloidosis.
and with antibody-mediated acquired prothrombin deficiency associ- The amyloid deposits contain fragments of the variant fibrinogen.
ated with lupus anticoagulants. With factor VIIa, as compared to FFP, The kidneys are initially affected, but wider visceral and nerve
the volume of infused material is smaller, and the risk is lower for involvement may occur. Renal grafts subsequently become involved
complications such as of fever, urticaria, transfusion-related acute lung with amyloid, and liver transplantation may be a better treatment
injury (TRALI) and anaphylaxis. Caution must be exercised when using option. The allele for one responsible mutation, FGA-Glu526Val, is
factor VIIa in older patients with cardiovascular disease, as arterial relatively common and may account for 5% of patients with apparent
thrombosis can result, particularly when therapy is combined with
antifibrinolytic therapy or prothrombin complex concentrate. sporadic amyloid. Acquired dysfibrinogenemia is most frequently
diagnosed in liver disease, with 80% to 90% of patients with cirrhosis
or liver failure showing fibrinogen dysfunction. Increased sialic acid
content similar to fetal fibrinogen seems to impair fibrin polymeriza-
tion in vitro, but the process probably does not contribute substan-
fibrinogen dysfunction. Variants easily detected in clinical laboratories tially to abnormal hemostasis. The monoclonal paraprotein in
typically have defects in fibrinopeptide release (e.g., FGA-Arg16His patients with multiple myeloma can interfere nonspecifically with
and FGA-Arg16Cys [fibrinogens Bicêtre and Metz]), or polymerize fibrin polymerization but usually does not cause abnormal hemosta-
slowly (e.g., FGG-Ser434Asn [fibrinogen Caracas II], FGG- sis. Acquired dysfibrinogenemia has been associated with other
Arg275Cys and FGG-Arg275His). Indeed, approximately 45% of malignancies and bone marrow transplantation.
the mutations in the dysfibrinogenemia database involve substitu- Dysfibrinogenemia often presents as an abnormality on routine
tions at FGA-Arg16 or FGG-Arg275, at least partly reflecting the coagulation testing (PT or aPTT). The thrombin time is frequently
ease with which these variants are detected by common functional used as a screening test for dysfibrinogenemia, although its sensitivity
assays. is not established. The test involves measuring time to clot formation
Most individuals with dysfibrinogenemia are asymptomatic. 9,10 In in plasma after addition of a standard amount of thrombin. The
a recent multicenter study of congenital dysfibrinogenemia 58% were specificity for dysfibrinogenemia is low, as heparin, direct thrombin
identified incidentally by an abnormal coagulation test. Over a mean inhibitors (argatroban, dabigatran, hirudin), elevated fibrin degrada-
follow-up of 8.8 years, the incidences of major bleeding and throm- tion products, paraproteins, and low levels of fibrinogen all prolong
10
bosis were 2.5 and 18.7 per 1000 patient years, respectively, with the thrombin time. The reptilase time has been used as an alternative
estimated cumulative incidences of 19.2% and 30.1% at age 50 years. screen and is useful in combination with the thrombin time.
There were no clear associations between symptoms and fibrinogen The assay involves inducing clot formation with an enzyme from
level, functional abnormalities, or gene mutations, consistent with a snake venom (Bothrops jararaca or Bothrops atrox) that releases
older observations that common substitutions such as FGA-Arg16His fibrinopeptide A (but not fibrinopeptide B) from fibrinogen, and is