Page 2183 - Williams Hematology ( PDFDrive )

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

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As of this writing, more than 100 distinct mutations have been interactions are the driving force of fibrin polymerization. The inter-
identified in patients with dysfibrinogenemia and hypodysfibrinogene- face for the end-to-end D:D site in the γ chain lies between R301 (R275)
mia. The described mutants are very often named after the city of origin and S326 (S300), with T306 (T280) contacting R301 (R275) at the D:D
of the family or the city of the laboratory characterizing the mutation. interface. Mutations at the R301 (R275) residue to C (CGT→TGT) or
Many cases are asymptomatic and are only identified as a result of rou- H (CGT→CAT) are the second most common cause of dysfibrinogene-
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tine coagulation screening. Indeed, a compilation of approximately 250 mia, accounting for around 10 percent of fibrinogen variants. Impaired
cases revealed that 55 percent of patients were asymptomatic, 25 percent polymerization has been observed for all substitutions at this position.
had a history of bleeding, and 20 percent, a tendency toward throm- Most of these cases are asymptomatic, but some patients heterozygous
bosis. However, our retrospective multicentric study of the long-term for R301C (R275C) have thrombophilia, sometimes in association with
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outcomes of 101 genotyped patients suggests that bleeding and throm- an additional thrombotic risk factor such as factor V Leiden. 84
botic events are more frequent. 76
Mutations Accounting for Hypodysfibrinogenemia
ETIOLOGY AND PATHOGENESIS Hypodysfibrinogenemia which is defined by low levels of a dysfunc-
tional protein can be caused by different molecular mechanisms. One
Dysfibrinogenemic abnormalities usually are reflected in one or more mechanism is heterozygosity for a single mutation that leads to syn-
phases of the fibrinogen-fibrin conversion and fibrin assembly process, thesis of an abnormal fibrinogen chain which is secreted less efficiently
notably impaired release of fibrinopeptides and defective fibrin poly- than normal fibrinogen, for example, fibrinogen Kyoto IV. Another
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merization or factor XIIIa–mediated crosslinking. 77,78 Other abnormal- mechanism is the presence of two different mutations with one muta-
ities involve abnormal tissue deposition such as in renal amyloidosis, tion responsible for the fibrinogen deficiency (the “hypo phenotype”)
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defective fibrinolysis, abnormal interactions with platelets, 77,80 and and one mutation responsible for the abnormal function of the mole-
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defective calcium binding. 81 cule (the “dys phenotype”). For example, in fibrinogen Keokuk, there
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is compound heterozygosity for the common afibrinogenemia splice-
Mutations Resulting in Abnormal “A” Knobs or Deficient site mutation c.510G→T and a premature truncating nonsense mutation
Fibrinopeptide Release in FGA Q347X (Q328X). Another example is fibrinogen Leipzig II in
Fibrinogen Detroit was the first abnormal fibrinogen in which the which the common hypofibrinogenemia mutation FGG A108G (A82G)
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specific mutation was identified at the protein level. This FGA R38S and FGG G377S (G351S) are located on the same allele. Homozygosity
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(R19S) mutation is located in the “A” knob (i.e., GPRV) resulting in for a single mutation, which allows reduced secretion of a functionally
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impaired fibrin polymerization and a bleeding tendency. Other substi- impaired molecule, has been described in fibrinogens Otago and Mar-
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tutions involving residue R38 (R19) have been found to be associated burg. Finally, maternal uniparental disomy for a nonsense mutation in
with bleeding in some cases, for example, Munich I, R38N (R19N), FGB, W323X (W293X), was found to be the cause of severe hypodysfi-
and Mannheim I, R38G (R19G), and with thrombosis in other cases, brinogenemia in a Chinese patient. 90
for example, Aarhus and Kumamoto, which are also a result of R38G
(R19G). The mechanism for thrombophilia remains unclear, but coex-
isting risk factors may contribute to the clinical manifestations. Further- CLINICAL FEATURES
more, the inability of a mutant fibrin to effectively bind and sequester Patients with inherited dysfibrinogenemia are frequently asymptom-
thrombin may play a role in such a clinical presentation. Bleeding that atic and can be discovered incidentally because of abnormal coagula-
occurs under conditions involving defective fibrinopeptide release or tion tests. A compilation of more than 260 cases of dysfibrinogenemia
production of a defective “A” knob is most likely related to the reduced revealed that 55 percent of the patients had no clinical complications
polymerization potential of the mutant fibrins that are produced, with while 25 percent exhibited bleeding, and 20 percent had a tendency to
resulting defective clot formation. 82 thrombosis, mainly venous. However, when 2376 patients with deep
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Missense mutations at residue FGA R35 (R16) which is part of the vein thrombosis were screened for thrombophilia, the prevalence of
thrombin cleavage site in the fibrinogen α chain appear to be the most dysfibrinogenemia was very low (0.8 percent) and hence testing for
common causative mutations accounting for dysfibrinogenemia, based dysfibrinogenemia in patients with deep vein thrombosis is not recom-
on information compiled in the GEHT registry for hereditary fibrin- mended. Patients with dysfibrinogenemia associated with hemorrhage
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ogen abnormalities. The R35 (R16) residue can be mutated to either bleed most often after trauma, surgery, or during the puerperium.
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H (CGT→CAT) or C (CGT→TGT) leading to delayed or absent FpA Thrombosis may also occur during pregnancy and in the postpartum
release, respectively, and subsequent delayed polymerization. A pro- period. Women with dysfibrinogenemia can also suffer from spontane-
longed reptilase time is observed for both variants. Most patients do ous abortions. The problems during and after pregnancy are not neces-
not have a bleeding tendency. Some patients have been found to be sarily correlated to the fibrinogen concentration.
homozygous for these mutations or phenotypically homozygous, as a Some mutations in the Aα chain of fibrinogen are associated with
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result of compound heterozygosity for an R35 (R16) missense mutation a particular form of hereditary amyloidosis. 79,92 The E545V (E526V)
and the large 11-kb FGA deletion first characterized in afibrinogenemia. amino acid substitution is the most common of these mutations. The
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In these cases, a mild bleeding tendency is observed. abnormal fibrinogen fragments form amyloid fibrils and the extracel-
Missense mutations in FGB affecting FpB release have been iden- lular deposition of these fibrils leads to renal failure. Chronic renal
tified, but are much less common than those affecting FpA release. dialysis is performed for managing renal failure. Renal transplanta-
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tion can be envisaged as an alternative to chronic dialysis. However,
Mutations Leading to Polymerization Defects in the D Region continuous fibrinogen-related amyloid deposition ultimately results
Sites in the D region important for fibrin polymerization are affected in in allograft destruction. Combined liver and kidney transplantation
many dysfibrinogenemias. Mutations affecting hole “a” in the γ chain prevents further amyloid deposition in the renal allograft and else-
are numerous, while no naturally occurring mutation involving hole “b” where but is associated with additional perioperative and subsequent
in the Bβ chain has been described, compatible with the view that A:a risks.

Kaushansky_chapter 125_p2151-2162.indd 2158 9/18/15 5:48 PM