Rare inherited disorders of fibrinogen

Abstract

Summary. Fibrinogen, a hexameric glycoprotein encoded by three genes –FGA, FGB, FGG– clustered on chromosome 4q is involved in the final steps of coagulation as a precursor of fibrin monomers required for the formation of the haemostatic plug. Inherited disorders of fibrinogen abnormalities are rare and not as well clinically characterized as some other inherited bleeding disorders. To characterize the clinical manifestations, molecular defects and treatment modalities of these rare disorders, a Medline search from January 1966 to September 2007 for these disorders reported in large studies and registries was undertaken. Inherited fibrinogen disorders can manifest as quantitative defects (afibrinogenemia and hypofibrinogenemia) or qualitative defects (dysfibrinogenemia). Quantitative fibrinogen deficiencies may result from mutations affecting fibrinogen synthesis, or processing while qualitative defects are caused by mutations causing abnormal polymerization, defective cross‐linking or defective assembly of the fibrinolytic system. Clinical manifestations vary from being asymptomatic to developing catastrophic life‐threatening bleeds or thromboembolic events. Management of bleeds includes use of purified plasma‐derived concentrates, cryoprecipitate or fresh frozen plasma. Use of some of these products carries risks of viral transmission, antibody development and thromboembolic events. Establishment of registries in Iran, Italy and North America has fostered a better understanding of these disorders with an attempt to explore molecular defects. Rare Bleeding Disorder Registries developed through the United States and international efforts hopefully will encourage development and licensure of safer, effective products.

Venous ulcerations due to inherited fibrinogen disorder in two male siblings

“…Fibrinojenin trombin aracılığıyla çözünebilir fibrine dönüşümü pıhtı oluşumunda rol oynarken, fibrin aynı zamanda trombin aktivitesini negatif yönde düzenleyerek anti-trombin etkinliğe de sahiptir 2,3 . Kalıtsal fibrinojen bozuklukları nadir görülen durumlar olup, otozomal dominant ve otozomal resesif kalıtımlar bildirilmiştir 2 .…”

“…Kalıtsal fibrinojen bozuklukları nadir görülen durumlar olup, otozomal dominant ve otozomal resesif kalıtımlar bildirilmiştir 2 . Kalıtsal fibrinojen bozukluğunda fibrinojenin düzeyi (hipofibrinojenemi, afibrinojenemi) ve/veya niteliği (disfibrinojenemi) etkilenebilmektedir 2,4 . Kalıtsal fibrinojen bozuklukları asemptomatik olabileceği gibi klinikte umblikal kord kanaması, spontan ve/veya travma ile ilişkili kas hematomları, hemartroz, menoraji, birinci trimester düşükleri, üçüncü trimester fetal kayıpları, postpartum hemoraji, gecikmiş yara iyileşmesi, pulmoner emboli, arteriyel ve venöz tromboz gibi birbirinden çok farklı klinik durumlarla kendilerini gösterebilmektedirler 2,5-10 .…”

“…Bu klinik prezentasyonlar kanama eğilimi olabileceği gibi hiperkoagülabilite durumları şeklinde de kendini gösterebilmektedirler. Buna göre tedavide kriyopresipitat, taze donmuş plazma, fibrinojen konsantresi, antikoagülanlarla kombine fibrinojen konsantresi ve antifibrinolitik ajanlar kullanılabilmektedir 2,3 . Bizim olgularımıza da fibrinojen konsantresi ile birlikte antikoagülan tedavi verilmiş olup tedavi altındayken yeni ülserasyon gelişme sıklığı ve gelişen ülserasyonların iyileşme süresi belirgin ölçüde azalmıştır.…”

Molecular analysis of afibrinogenemic mutations caused by a homozygous FGA1238 bp deletion, and a compound heterozygous FGA1238 bp deletion and novel FGA c.54+3A>C substitution

“…The severity of the bleeding tendency varies in afibrinogenemic patients. The most typical symptom is umbilical cord bleeding and other relatively frequent symptoms are hemorrhage from the mucosal tracts, hemarthroses, and hematomas, although life-threatening bleeding such as splenic rupture, gastrointestinal hemorrhage and central nervous system bleeding may be rare [4,5].…”

siRNA down-regulation of FGA mRNA in HepG2 cells demonstrated that heterozygous abnormality of the Aα-chain gene does not affect the plasma fibrinogen level

“…Genetic abnormalities and the molecular bases in patients with afibrinogenemia have been found in all three genes and identified as missense, nonsense, or frameshift mutations; splice-site abnormalities; or large deletions [4][5][6][7][8][9]. In particular, reports causing large deletions between 1.2 and 15 kb were restricted in FGA [6].…”