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Blood Nov 2021Congenital dysfibrinogenemia (CD) is caused by structural changes in fibrinogen that modify its function. Diagnosis is based on discrepancy between decreased fibrinogen...
Congenital dysfibrinogenemia (CD) is caused by structural changes in fibrinogen that modify its function. Diagnosis is based on discrepancy between decreased fibrinogen activity and normal fibrinogen antigen levels and is confirmed by genetic testing. CD is caused by monoallelic mutations in fibrinogen genes that lead to clinically heterogenous disorders. Most patients with CD are asymptomatic at the time of diagnosis, but the clinical course may be complicated by a tendency toward bleeding and/or thrombosis. Patients with a thrombosis-related fibrinogen variant are particularly at risk, and, in such patients, long-term anticoagulation should be considered. Management of surgery and pregnancy raise important and difficult issues. The mainstay of CD treatment remains fibrinogen supplementation. Antifibrinolytic agents are part of the treatment in some specific clinical settings. In this article, we discuss 5 clinical scenarios to highlight common clinical challenges. We detail our approach to establishing a diagnosis of CD and discuss strategies for the management of bleeding, thrombosis, surgery, and pregnancy.
Topics: Afibrinogenemia; Disease Management; Female; Hemorrhage; Humans; Pregnancy; Pregnancy Complications, Hematologic; Thrombosis
PubMed: 33895794
DOI: 10.1182/blood.2020010116 -
Annales de Biologie Clinique Aug 2016Congenital fibrinogen disorders comprise quantitative disorders defined by a complete absence (afibrinogenemia) or by a decreased level (hypofibrinogenemia) of... (Review)
Review
Congenital fibrinogen disorders comprise quantitative disorders defined by a complete absence (afibrinogenemia) or by a decreased level (hypofibrinogenemia) of circulating fibrinogen and qualitative disorders characterized by a discrepancy between the activity and the antigenic levels of fibrinogen (dysfibrinogenemia and hypodysfibrinogenemia). The biological diagnosis is based on a standard haemostasis assessment. All the coagulation tests that depend on the formation of fibrin as the end point are affected; although in dysfibrinogenemia the specificity and sensitivity of routine test depend on reagent and techniques. A genetic exploration permits to confirm the diagnosis and may enhance the prediction of the patient's phenotype. Homozygous or composite heterozygous null mutations are most often responsible for afibrinogenemia while hypofibrinogenemic patients are mainly heterozygous carrier of an afibrinogenemic allele. Heterozygous missense mutations are prevalent in dysfibrinogenemia, with two hot spot localized in exon 2 of the FGA and in the exon 8 of the FGG. The correlation between phenotype and genotype has been identified in some fibrinogen variants, including six mutations clustered in exons 8 and 9 of the FGG leading to hypofibrinogenemia with hepatic inclusions of abnormal fibrinogen aggregates as well as a few mutations associated with an increase risk of thrombotic events. A familial screening and additional functional assays should be carried out when possible.
Topics: Afibrinogenemia; Blood Coagulation; Blood Coagulation Disorders, Inherited; Clinical Laboratory Techniques; Diagnosis, Differential; Fibrinogen; Fibrinogens, Abnormal; Humans; Molecular Diagnostic Techniques
PubMed: 27492693
DOI: 10.1684/abc.2016.1167 -
Seminars in Thrombosis and Hemostasis Jun 2016As our knowledge of the structure and functions of fibrinogen and fibrin has increased tremendously, several key findings have given some people a superficial impression... (Review)
Review
As our knowledge of the structure and functions of fibrinogen and fibrin has increased tremendously, several key findings have given some people a superficial impression that the biological and clinical significance of these clotting proteins may be less than earlier thought. Most strikingly, studies of fibrinogen knockout mice demonstrated that many of these mice survive to weaning and beyond, suggesting that fibrin(ogen) may not be entirely necessary. Humans with afibrinogenemia also survive. Furthermore, in recent years, the major emphasis in the treatment of arterial thrombosis has been on inhibition of platelets, rather than fibrin. In contrast to the initially apparent conclusions from these results, it has become increasingly clear that fibrin is essential for hemostasis; is a key factor in thrombosis; and plays an important biological role in infection, inflammation, immunology, and wound healing. In addition, fibrinogen replacement therapy has become a preferred, major treatment for severe bleeding in trauma and surgery. Finally, fibrin is a unique biomaterial and is used as a sealant or glue, a matrix for cells, a scaffold for tissue engineering, and a carrier and/or a vector for targeted drug delivery.
Topics: Animals; Fibrin; Fibrinogen; Hemorrhage; Hemostasis; Humans; Infections; Inflammation; Mice; Mice, Knockout; Wound Healing; Wounds and Injuries
PubMed: 27056152
DOI: 10.1055/s-0036-1571342 -
Seminars in Thrombosis and Hemostasis Jun 2016Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenemia and hypofibrinogenemia) or the quality (dysfibrinogenemia) or both... (Review)
Review
Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenemia and hypofibrinogenemia) or the quality (dysfibrinogenemia) or both (hypodysfibrinogenemia) of plasmatic fibrinogen. Afibrinogenemia is often diagnosed at birth following prolonged umbilical cord bleeding and is characterized by spontaneous bleeding in all tissues, while hypofibrinogenemic patients are more often asymptomatic. Spontaneous spleen ruptures, painful bone cysts, cardiovascular events, and intrahepatic inclusions can complicate the clinical course of patients with quantitative fibrinogen disorders. Clinical manifestations of dysfibrinogenemia are very heterogeneous, from absence of symptoms to major bleeding or thrombosis, chronic thromboembolic pulmonary hypertension, and renal amyloidosis. Hypodysfibrinogenemic patients can suffer from both major bleeding and recurrent thrombosis. Pregnancy of women with congenital fibrinogen disorders is a high-risk situation. Owing to the absence of controlled randomized studies, clinical management is mainly based on expert consensus. For the treatment and/or the prevention of bleeding, plasma-derived fibrinogen concentrates are the optimal choice. Treatment of thrombosis may be challenging. More specifically, management strategies should be tailored to each patient, taking the personal and familial history of bleeding and thrombosis, the genotype, and the specific clinical situation into account.
Topics: Afibrinogenemia; Animals; Female; Hemorrhage; Humans; Pregnancy; Thrombosis
PubMed: 27019462
DOI: 10.1055/s-0036-1571339 -
Seminars in Thrombosis and Hemostasis Jun 2016Surgical bleeding has been decreasing steadily for the last 20 years, but there are still some hemorrhagic procedures occurring in scheduled surgical settings and... (Review)
Review
Surgical bleeding has been decreasing steadily for the last 20 years, but there are still some hemorrhagic procedures occurring in scheduled surgical settings and emergency procedures. The interest in potent hemostatic agents has recently focused on fibrinogen concentrates. A weak historical rationale based on the rapid decrease in fibrinogen concentration in the bleeding patient and several uncontrolled studies have prompted the use of fibrinogen concentrates in emergency units and in operating theaters. Very few positive randomized studies are available to confirm the usefulness of fibrinogen concentrates. The largest most recent double-blind studies are even negative. As recent guidelines recommend early and liberal use of fibrinogen concentrates in massive bleeding patients, this review reports the most important facts and studies on efficacy and raises some questions about safety.
Topics: Afibrinogenemia; Animals; Blood Loss, Surgical; Fibrinogen; Humans
PubMed: 27056153
DOI: 10.1055/s-0036-1572325 -
Clinical Advances in Hematology &... Sep 2018
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Diagnostics (Basel, Switzerland) Nov 2021Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia... (Review)
Review
Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management.
Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. The clinical phenotype is highly heterogeneous, being associated with bleeding, thrombosis, or absence of symptoms. Afibrinogenemia and hypofibrinogenemia are the consequence of mutations in the homozygous, heterozygous, or compound heterozygous state in one of three genes encoding the fibrinogen chains, which can affect the synthesis, assembly, intracellular processing, stability, or secretion of fibrinogen. In addition to standard coagulation tests depending on the formation of fibrin, diagnostics also includes global coagulation assays, which are effective in monitoring the management of replacement therapy. Genetic testing is a key point for confirming the clinical diagnosis. The identification of the precise genetic mutations of congenital fibrinogen disorders is of value to permit early testing of other at risk persons and better understand the correlation between clinical phenotype and genotype. Management of patients with afibrinogenemia is particularly challenging since there are no data from evidence-based medicine studies. Fibrinogen concentrate is used to treat bleeding, whereas for the treatment of thrombotic complications, administered low-molecular-weight heparin is most often. This review deals with updated information about afibrinogenemia and hypofibrinogenemia, contributing to the early diagnosis and effective treatment of these disorders.
PubMed: 34829490
DOI: 10.3390/diagnostics11112140 -
Expert Review of Hematology Jul 2016Congenital afibrinogenemia belongs to the group of autosomal recessive bleeding disorders and represents the absolute deficiency of fibrinogen detected by an antigenic... (Review)
Review
INTRODUCTION
Congenital afibrinogenemia belongs to the group of autosomal recessive bleeding disorders and represents the absolute deficiency of fibrinogen detected by an antigenic test. This can lead to severe clinical manifestations of the disorder. Therefore, it is very important to take afibrinogenemia into account in the process of the differential diagnostics of the patients.
AREAS COVERED
The authors provide a summary of currently available literature about afibrinogenemia. They collected the information from the scientific journals dedicated to thrombosis and hemostasis and searched world-wide databases. Expert commentary: The most frequent clinical manifestation of this disorder is mucosal bleeding, but musculoskeletal bleeding pattern, gynecologic and obstetric issues, spontaneous bleeding, episodes provoked by minor injury or any other intervention, and even paradoxical thromboembolic events have been published. Afibrinogenemia is the consequence of mutations of the homozygous or compound heterozygous type in gene FGA, FGB or FGG encoding fibrinogen. Pregnant women with a family history, or with a history of consanguinity ought to be properly counselled. However, primary prophylaxis of bleeding events is not suggested. The article deals with actual information about afibrinogenemia contributing to its early diagnosis and effective treatment, which in many cases requires multidisciplinary approach.
Topics: Afibrinogenemia; Blood Coagulation Tests; Diagnosis, Differential; Disease Management; Female; Fibrinogen; Fibrinolytic Agents; Genetic Counseling; Hemorrhage; Humans; Liver Transplantation; Male; Phenotype; Pregnancy; Prenatal Diagnosis; Prevalence
PubMed: 27291795
DOI: 10.1080/17474086.2016.1200967 -
Thrombosis Research Sep 2022Ranging from bleeding to thrombosis, the clinical features of congenital fibrinogen qualitative disorders, including dysfibrinogenemia and hypodysfibrinogenemia, are... (Review)
Review
Ranging from bleeding to thrombosis, the clinical features of congenital fibrinogen qualitative disorders, including dysfibrinogenemia and hypodysfibrinogenemia, are highly heterogeneous. Although the associations between some specific fibrinogen mutations and the thrombotic phenotypes have been well elucidated, the underlying mechanism between fibrinogen variants and bleeding events remains underestimated. After systematically reviewing the literature of (hypo-)dysfibrinogenemia patients with bleeding phenotypes, we identified several well-characterized bleeding-related fibrinogen variants in those patients. Several possible pathomechanisms are proposed to explain the genotype-phenotype associations: 1, mutations in the NH-terminal portion of the Aα chain hamper fibrinogen fitting into the active site cleft of thrombin and drastically slow the conversion of fibrinogen into monomeric fibrin; 2, mutations adding new N-linked glycosylation sites introduce bulky and negatively charged carbohydrate side chains and undermine the alignment of fibrin monomers during polymerization; 3, mutations generating unpaired cysteine form extra disulfide bonds between the abnormal fibrinogen chains and produce highly branched and fragile fibrin networks; 4, truncation mutations in the fibrinogen αC regions impair the lateral fibril aggregation, as well as factor XIII crosslinking, endothelial cell and platelet binding. These established relationships between specific variants and the bleeding tendency will help manage (hypo-)dysfibrinogenemia patients to avoid adverse bleeding outcomes.
Topics: Afibrinogenemia; Blood Coagulation Tests; Fibrin; Fibrinogen; Fibrinogens, Abnormal; Hemorrhage; Humans; Thrombosis
PubMed: 35853369
DOI: 10.1016/j.thromres.2022.07.005 -
Journal of Thrombosis and Haemostasis :... Aug 2023Women with hereditary fibrinogen disorders (HFDs) seem to be at an increased risk of adverse obstetrical outcomes, but epidemiologic data are limited.
BACKGROUND
Women with hereditary fibrinogen disorders (HFDs) seem to be at an increased risk of adverse obstetrical outcomes, but epidemiologic data are limited.
OBJECTIVES
We aimed to determine the prevalence of pregnancy complications; the modalities and management of delivery; and the postpartum events in women with hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia.
METHODS
We conducted a retrospective and prospective multicentric international study.
RESULTS
A total of 425 pregnancies were investigated from 159 women (49, 95, and 15 cases of hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia, respectively). Overall, only 55 (12.9%) pregnancies resulted in an early miscarriage, 3 (0.7%) resulted in a late miscarriage, and 4 (0.9%) resulted in an intrauterine fetal death. The prevalence of live birth was similar among the types of HFDs (P = .31). Obstetrical complications were observed in 54 (17.3%) live birth pregnancies, including vaginal bleeding (14, 4.4%), retroplacental hematoma (13, 4.1%), and thrombosis (4, 1.3%). Most deliveries were spontaneous (218, 74.1%) with a vaginal noninstrumental delivery (195, 63.3%). A neuraxial anesthesia was performed in 116 (40.4%) pregnancies, whereas general or no anesthesia was performed in 71 (16.6%) and 129 (44.9%) pregnancies, respectively. A fibrinogen infusion was administered in 28 (8.9%) deliveries. Postpartum hemorrhages were observed in 62 (19.9%) pregnancies. Postpartum venous thrombotic events occurred in 5 (1.6%) pregnancies. Women with hypofibrinogenemia were at an increased risk of bleeding during the pregnancy (P = .04).
CONCLUSION
Compared with European epidemiologic data, we did not observe a greater frequency of miscarriage, while retroplacental hematoma, postpartum hemorrhage, and thrombosis were more frequent. Delivery was often performed without locoregional anesthesia. Our findings highlight the urgent need for guidance on the management of pregnancy in HFDs.
Topics: Female; Humans; Pregnancy; Abortion, Spontaneous; Afibrinogenemia; Fibrinogen; Gastrointestinal Hemorrhage; Hematoma; Hemostatics; Postpartum Hemorrhage; Prospective Studies; Retrospective Studies; Thrombosis
PubMed: 37172732
DOI: 10.1016/j.jtha.2023.04.035