Natural history of patients with congenital dysfibrinogenemia

Abstract

Key Points• Major bleeding, thrombosis, and postpartum hemorrhage are frequent in propositi and relatives with congenital dysfibrinogenemia.• Hotspot mutations were not predictive of either phenotype or outcome.We conducted a multicenter study of 101 patients with congenital dysfibrinogenemia (CD) to characterize the incidence of hemorrhagic and thrombotic events as well as complications of pregnancy and surgery. At the time of diagnosis, 10.9% and 13.9% had experienced major bleeding and thrombotic events, respectively. During a mean followup of 8.8 years after CD diagnosis, the incidence of major bleeding and thrombotic events was 2.5 and 18.7 per 1000 patient-years, respectively, with estimated cumulative incidences at age 50 years of 19.2% and 30.1%. We identified 111 pregnancies with an overall incidence of spontaneous abortions and postpartum hemorrhage of 19.8% and 21.4%, respectively. The risk of postpartum hemorrhage was associated with a previously identified bleeding phenotype (odds ratio, 5.8; 95% CI, 1.2 to 28.0). Among 137 surgical procedures analyzed, 9 (6.5%) were complicated by abnormal bleeding. Propositi vs relatives, sex, mutation hotspots, fibrinogen levels, and activity:antigen ratios were not associated with the risk of thrombotic or bleeding outcomes. In conclusion, the results of our study, the largest in genotyped CD and the first including long-term history, indicate that propositi with CD and their relatives carry not only a high risk of major bleeding, including postpartum hemorrhage, but also of thrombotic event. (Blood. 2015;125(3):553-561) Medscape Continuing Medical Education online This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint providership of Medscape, LLC and the American Society of Hematology. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 581. Disclosures The authors, Associate Editor José A. López, and CME questions author Laurie Barclay, freelance writer and reviewer, Medscape, LLC, declare no competing financial interests. Learning objectives1. Describe complications of major bleeding and thrombosis in persons with congenital dysfibrinogenemia (CD) and their affected relatives.2. Identify complications of pregnancy and surgery in persons with CD and their affected rela...

Identification and characterization of novel mutations implicated in congenital fibrinogen disorders

“…CD mutations are often inherited in an autosomal dominant manner and are commonly found in exon 2 of FGA , which encodes the thrombin cleavage site for EA exposure enabling EA‐D interactions, or in exon 8 of FGG , which is involved in D:D end‐to‐end assembly of fibrin 12. Clinical presentation is highly variable13 and approximately 50% of CD patients are diagnosed incidentally 14, 15. Hypodysfibrinogenemia is defined by disproportionately decreased fibrinogen antigen and decreased function 5.…”

Fibrin clot structure in patients with congenital dysfibrinogenaemia

“…The clinical phenotype of dysfibrinogenaemic patients is highly heterogeneous, from absence of symptoms to major bleeding or thrombotic events, including pulmonary hypertension and renal amyloidosis [3]. During the natural course of the disease, even asymptomatic patients at the time of the diagnosis are at risk of developing adverse outcomes [5]. However, neither standard haemostasis assays nor specific genotypes, with exception of some thrombotic-related mutations [6], are able to predict the clinical phenotype.…”

“…Levels of total fibrinogen antigen were measured by a latex immunoassay (Liaphen Fibrinogen, Hyphen BioMed, France) on a BCS® XP coagulometer (Siemens, Germany). The patient genotype was determined as previously reported [5]. Causative fibrinogen mutations are described with amino acid residues and substitutions numbered from the initiator methionine.…”

Rare coagulation disorders: fibrinogen, factor VII and factor XIII

“…Clinical manifestations of dysfibrinogenaemia are highly heterogeneous, ranging from asymptomatic (the majority) to major bleeding and/or thrombosis [4]. Bleeding is frequent, but usually mild.…”

“…Dysfibrinogenaemic child-bearing women are also particularly affected and diagnosis of dysfibrinogenaemia during pregnancy is not rare. In a series of 111 pregnancies [4], 19 (21.4%) were complicated by a postpartum haemorrhage. In parity and age-adjusted logistic regression analysis, women with a bleeding phenotype in the preconception period had an increased risk of postpartum haemorrhage (OR 5.8; 95% CI 0.2-3.0; P = 0.03).…”