Page 2184 - Williams Hematology ( PDFDrive )

2158 Part XII: Hemostasis and Thrombosis Chapter 125: Hereditary Fibrinogen Abnormalities 2159

LABORATORY FEATURES DIFFERENTIAL DIAGNOSIS
Phenotype Analysis Inherited dysfibrinogenemia has to be distinguished from acquired
Initial screening tests for fibrinogen dysfunction should include fibrin- dysfibrinogenemia. Liver diseases (e.g., cirrhosis, chronic active liver
ogen concentration, measured functionally and immunochemically, disease, hepatoma, liver failure) are the main causes of acquired dysfi-
TT, and reptilase time. Dysfibrinogenemia is diagnosed by a discrep- brinogenemia. l-Asparaginase treatment also may result in the produc-
ancy between clottable and immunoreactive fibrinogen. However, even tion of abnormal fibrinogen. In addition, there are a few case reports of
in specialized laboratories, this diagnosis can be difficult because the acquired dysfibrinogenemia secondary to pancreatitis, paraneoplastic
sensitivity of the tests depends on the specific mutation, reagents, and syndrome, and renal carcinoma. The acquired dysfibrinogenemias rep-
techniques. 93,94 resent a heterogeneous group of disorders with multiple pathogenetic
In classical dysfibrinogenemias, the functional assay of fibrinogen mechanisms, the most clearly defined fibrinogen abnormalities being
yields low levels compared with the immunologic assays, but levels are an increase in carbohydrate content in patients with liver disease. These
sometimes concordant and the functional level may even be normal abnormal fibrinogens are usually characterized by prolonged thrombin
(as well as TT). The determination of the precise nature of a fibrinogen and reptilase times, by abnormal fibrin monomer polymerization
defect has to be performed in highly specialized laboratories since it but with normal fibrinopeptide release. Fibrinogen concentration is
involves purification of fibrinogen, measurement of the rate of fibrino- variable.
peptide cleavage, analysis of fibrin monomer polymerization, and In some cases no underlying disease is found, and to determine
fibrinolysis. Thromboelastography, commonly used for decision mak- whether a fibrinogen abnormality is congenital or acquired may be diffi-
ing for fibrinolytic and anticoagulant therapy, may be particularly useful cult. The demonstration of the same fibrinogen abnormality in another
for investigation of dysfibrinogenemia. The thromboelastography signal family member is a strong argument for a congenital disorder. When
is fibrin dependant, its amplitude is enhanced by platelets and reflects measured in newborns, fibrinogen levels should be interpreted with
the stretch and recovery of the clot during its formation. 95 caution because neonatal fibrinogen has an altered content of carbo-
hydrate that can mimic dysfibrinogenemia in certain laboratory tests.
Rare cases of circulating autoantibodies to fibrinogen, for example
Genotype Analysis in systemic lupus erythematosus and in patients receiving surgical seal-
The gold standard for the diagnosis of dysfibrinogenemia is the char- ants containing bovine fibrinogen, have also been reported.
acterization of the molecular defect. However, although advances in
DNA analysis have made mutation detection easier, it is not always THERAPY
clear whether the identified mutation is the cause of the presenting
phenotype. Family studies showing segregation of the mutation with Any treatment considered in patients with dysfibrinogenemia should
the phenotype, exclusion that the DNA alteration is a common poly- be based on the personal and family history. Indeed, as already dis-
morphism in the general population, and structural correlations are cussed, subjects with hereditary dysfibrinogenemias may be asymp-
necessary for establishing the link between the DNA alteration and the tomatic throughout their whole life or may suffer from bleeding and/or
disorder. As previously mentioned, two mutations “hotspots” are of thrombotic complications. 1,75,76 In patients who bleed, functional levels
−1
prime interest in screening for dysfibrinogenemia mutations: residue of fibrinogen should be raised above 1.0 g L and maintained above this
−1
R35 (R16) situated in FGA exon 2, and residue R301 (R275) in FGG threshold until hemostasis is secured and above 0.5 g L until wound
exon 8. Other causative mutations are common in the surrounding healing is complete. Topical fibrin glue or antifibrinolytic agents may be
residues. Thus, it is recommended to initially screen FGA exon 2 and used for superficial bleeds. In pregnant women with a bleeding pheno-
FGG exon 8 in cases of dysfibrinogenemia. In our recent study of 101 type, the recommendations for afibrinogenemia and hypofibrinogene-
dysfibrinogenemia cases, 87 percent of the causative mutations were mia can be followed. With a personal or familial history of thrombosis,
76
located in these two exons. Here, mutations of FGG R301 (R275) were thromboprophylaxis and antithrombotic treatments may be proposed
more common than mutations of FGA R35 (R16), 52 percent and 23 after a careful analysis of each particular situation. Long-term manage-
percent, respectively. ment strategies for thrombophilic dysfibrinogenemia are the same as
the strategies for patients with recurrent thromboembolism and may
include long-term anticoagulant therapy.
Genotype–Phenotype Correlations
As previously discussed, the clinical manifestations of dysfibrinogen-
emia are highly variable and may relate in some cases to differences in REFERENCES
clot strength, structure and stability. In a few cases, mutations are 1. de Moerloose P, Casini A, Neerman-Arbez M: Congenital fibrinogen disorders: An
1,17
predictive of the clinical phenotype, such as the R573C (R554C) sub- update. Semin Thromb Hemost 39:585, 2013.
stitution in the Aα chain (e.g., fibrinogens Chapel Hill III, Paris V, and 2. Asselta R, Duga S, Tenchini ML: The molecular basis of quantitative fibrinogen disor-
ders. J Thromb Haemost 4:2115, 2006.
Dusart) that predisposes patients to thrombosis. Impaired fibrinoly- 3. Galanakis DK: Afibrinogenemias and dysfibrinogenemias, in Hemostasis and
sis exhibited by this dysfibrinogen appears to be responsible for the Thrombosis: Basic Principles and Clinical Practice, 6th ed, edited by JS Bennett, WC Aird,
thrombotic complications. Other examples associated with thrombosis VJ Marder, S Schulman, GC White. Lippincott Williams and Wilkins, Baltimore, 2012.
include dysfibrinogens Barcelona III, Haifa I, or Bergamo II as a result 4. Neerman-Arbez M, de Moerloose P: Hereditary fibrinogen abnormalities, in
Williams Hematology, 8th ed, edited by M Lichtman, E Beutler, TJ Kipps, U Seligsohn,
of the common γ R301H (R275H) mutation and Cedar Rapids I caused K Kaushansky, J Prchal, p 2051. McGraw-Hill, New York, 2010.
by γ R301C (R275C). However, in fibrinogen Cedar Rapids I, only 5. Hanss M, Biot F: A database for human fibrinogen variants. Ann N Y Acad Sci 936:89,
patients heterozygous for both factor V Leiden and the FGG R301C 2001.
(R275C) substitutions were symptomatic, suggesting that this mutation 6. Mosesson MW: Update on antithrombin I (fibrin). Thromb Haemost 98:105, 2007.
7. Tennent GA, Brennan SO, Stangou AJ, et al: Human plasma fibrinogen is synthesized in
causes thrombosis when associated with another defect. On the other the liver. Blood 109:1971, 2007.
hand, several mutations in the aminoterminal region of the Aα chain, 8. Medved L, Weisel JW: Recommendations for nomenclature on fibrinogen and fibrin.
J Thromb Haemost 7:355, 2009.
such as fibrinogen Detroit R38S (R19S) and Mannheim I R38G (R19G), 9. Kant J, Fornace AJ Jr, Saxe D, et al: Organization and evolution of the human fibrinogen
are associated with bleeding. locus on chromosome four. Proc Natl Acad Sci U S A 82:2344, 1985.

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