Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH

Casini, Alessandro; Undas, Anetta; Palla, Roberta; Thachil, Jecko; Moerloose, Philippe de

doi:10.1111/jth.14216

Cited by 115 publications

(155 citation statements)

References 25 publications

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“…1 According to the levels of fibrinogen activity and antigen, HFD are classified into quantitative (afibrinogenemia and hypofibrinogenemia) or qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. 2 The spectrum of symptoms is broad and heterogeneous among patients with HFD, even if bleeding is the most common complication of all HFD sub-types. 3 The bleeding phenotype is mostly correlated to the fibrinogen level, 4 ranging from life-threatening haemorrhage to postsurgical bleeding.…”

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confidence: 99%

Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future

Casini

Moerloose²

2019

Haemophilia

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Hereditary fibrinogen disorders (HFD) are rare coagulation disorders resulting from mono-or bi-allelic mutations in fibrinogen genes. 1According to the levels of fibrinogen activity and antigen, HFD are classified into quantitative (afibrinogenemia and hypofibrinogenemia) or qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. 2 The spectrum of symptoms is broad and heterogeneous among patients with HFD, even if bleeding is the most common complication of all HFD sub-types. 3 The bleeding phenotype is mostly correlated to the fibrinogen level, 4 ranging from life-threatening haemorrhage to postsurgical bleeding. In afibrinogenemia, the majority of patients suffer from severe bleeding such as umbilical cord bleeds, muscle haematomas, haemarthroses and bleeding in the central nervous system. 5 Paradoxically, thrombotic events can occur in patients with afibrinogenemia, even in the absence of fibrinogen administration. 6 In hypofibrinogenemia, spontaneous bleeding is less frequent and complications are mainly associated with trauma or surgery. 7 In dysfibrinogenemia, the cumulative incidence of major bleeding has been estimated to be about 19% at 50 years of age. 8 However, some dysfibrinogen variants are strongly associated with an increased risk of thrombosis. 9 In all types of HFD, surgery and pregnancy are high-risk bleeding situations.As for most coagulation factor deficiencies, in HFD, the bleeding prevention and management is based on replacement of the lacking protein. Three sources of fibrinogen are currently available: fresh frozen plasma, cryoprecipitate and lyophilized fibrinogen concentrate. 10 The latter is the best option, although still not widely available. It confers several advantages compared to fresh frozen plasma and cryoprecipitate: (a) it represents a safer therapeutic option due AbstractHereditary fibrinogen disorders (HFD) are rare coagulation disorders. Even if the spectrum of symptoms is broad depending on the sub-type, bleeding is the most common complication. Of the available sources of fibrinogen replacement, fibrinogen concentrate provides a safer and more effective option to treat and prevent bleeding.Recent clinical trials on established and new fibrinogen concentrates have increased our knowledge on the clinical pharmacology of these products, pointing out possible age and weight differences for dose adjustment. The efficacy of fibrinogen infusions has been demonstrated, especially for the management of acute bleeding with an excellent response based on investigator rating. The target fibrinogen levels in the setting of both minor and major surgeries have been better specified. The safety has been confirmed with a low number of adverse events but there still remains concern over possible thrombotic risks. Pharmacological, clinical aspects and future perspectives on the utilization of fibrinogen concentrates in the treatment and prevention of bleeding in patients with HFD are reviewed.

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confidence: 99%

Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future

Casini

Moerloose²

2019

Haemophilia

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“…CFDs are classified according to functional and antigenic fibrinogen levels as afibrinogenemia (complete absence of fibrinogen) and hypofibrinogenemia (proportional reduction of functional and antigenic levels) of quantitative disorders and dysfibrinogenemia (reduction of functional level and normal antigenic level) and hypodysfibrinogenemia (disproportional reduction of functional and antigenic levels) of qualitative disorders. 10 We reported previously a heterozygous variant fibrinogen (γA289V; Kanazawa III) as hypodysfibrinogenemia 11 ; however, Dear et al described the same heterozygous variant (Dorfen) as hypofibrinogenemia. 12 γA289 is located at the "D:D" interface, which plays a central role in the initial alignment of fibrin monomers into protofibrils.…”

Section: Introductionmentioning

confidence: 90%

“…Up to 400 congenital fibrinogen disorders (CFDs) have been listed on the GFHT homepage; however, these include heterogeneous groups with broad molecular abnormalities and clinical features. CFDs are classified according to functional and antigenic fibrinogen levels as afibrinogenemia (complete absence of fibrinogen) and hypofibrinogenemia (proportional reduction of functional and antigenic levels) of quantitative disorders and dysfibrinogenemia (reduction of functional level and normal antigenic level) and hypodysfibrinogenemia (disproportional reduction of functional and antigenic levels) of qualitative disorders . We reported previously a heterozygous variant fibrinogen (γA289V; Kanazawa III) as hypodysfibrinogenemia; however, Dear et al described the same heterozygous variant (Dorfen) as hypofibrinogenemia .…”

Section: Introductionmentioning

confidence: 91%

Heterozygous variant fibrinogen γA289V (Kanazawa III) was confirmed as hypodysfibrinogenemia by plasma and recombinant fibrinogens

Kaido

Yoda

Kamijo

et al. 2020

Int J Lab Hematology

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Introduction Congenital fibrinogen disorders are classified as afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia. However, difficulties are associated with discriminating between dysfibrinogenemia, hypofibrinogenemia, and hypodysfibrinogenemia using routine analyses. We previously reported a heterozygous variant fibrinogen (γA289V; Kanazawa III) as hypodysfibrinogenemia; however, the same variant had previously been described as hypofibrinogenemia. To clarify the production of γA289V fibrinogen, we expressed recombinant γA289V (r‐γA289V) fibrinogen and compared it with wild‐type (WT) and adjacent recombinant variant fibrinogens. Methods Target mutations were introduced into a fibrinogen γ‐chain expression vector by site‐directed mutagenesis, and the vector was then transfected into Chinese hamster ovary cells to produce recombinant fibrinogen. Fibrinogen was purified from the plasma of the proposita, and culture media and fibrinogen functions were analyzed using fibrin polymerization, plasmin protection, and FXIIIa‐catalyzed fibrinogen cross‐linking. Results The fibrinogen concentration ratio of the culture media to cell lysates was markedly lower for r‐γA289V fibrinogen than for WT. Because the secretion of recombinant γF290L (r‐γF290L) fibrinogen was similar to WT, we compared r‐γF290L fibrinogen functions with WT. The fibrin polymerization of Kanazawa III plasma (K‐III) fibrinogen was significantly weaker than normal plasma fibrinogen. Moreover, K‐III fibrinogen showed a markedly reduced “D:D” interaction. However, all functions of r‐γF290L fibrinogen were similar to WT. An in silico analysis confirmed the above results. Conclusion The present results demonstrated that γA289 is crucial for the γ‐module structure, and the γA289V substitution markedly reduced fibrinogen secretion. Moreover, K‐III fibrinogen showed markedly reduced fibrin polymerization and “D:D” interactions. γA289V fibrinogen was confirmed as hypodysfibrinogenemia.

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“…Congenital fibrinogen defects can be quantitative (afibrinogenemia or hypofibrinogenemia), qualitative (dysfibrinogenemia), or a combination of both (hypodysfibrinogenemia). Congenital afibrinogenemia (the complete absence of circulating fibrinogen) is an autosomal recessive disorder with a prevalence of 1:1.000.000 . The disorder typically presents at birth with umbilical cord bleeding.…”

Section: Introductionmentioning

confidence: 99%

“…Other types of frequently occurring bleeding are easy bruising, soft tissue bleeding (spontaneous), muscle and joint bleeding, gastrointestinal bleeding, genitourinary bleeding, and intracranial hemorrhage . Interestingly, patients with afibrinogenemia may also have an increased risk of thrombosis because they form loosely packed and unstable thrombi with a tendency to embolize . Obstetric complications, such as first‐trimester pregnancy loss or antepartum and postpartum hemorrhage (often caused by placental abruption), are also common .…”

Section: Introductionmentioning

confidence: 99%

Pregnancy outcome in afibrinogenemia: Are we giving enough fibrinogen concentrate? A case series

Saes

Gorkom

Coppens

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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Congenital afibrinogenemia is a rare autosomal recessive disorder associated with an increased risk of hemorrhage, thrombosis, and obstetric complications. This case series of 4 pregnancies in 2 related patients seeks to address the key clinical question of the necessary doses of fibrinogen concentrate during pregnancy and puerperium. One pregnancy without the prophylactic use of fibrinogen concentrate resulted in spontaneous abortion. The second pregnancy was complicated by a subchorionic hematoma despite the prophylactic administration of fibrinogen concentrate to maintain the plasma trough levels at ≥0.6 g/L. Labor was complicated by postpartum hemorrhage with a blood loss volume of 1480 cc. Two weeks later, the patient presented with postpartum thrombosis. The other 2 pregnancies were uncomplicated with fibrinogen trough levels ≥1.0 g/L during pregnancy and ≥1.5 g/L during labor. These cases illustrate that during pregnancy, patients may benefit from fibrinogen trough levels ≥1.0 g/L. In addition, the increased risk of postpartum thrombosis with prolonged fibrinogen supplementation warrants personalized postpartum advice that is guided by postpartum blood loss.

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Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH

Cited by 115 publications

References 25 publications

Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future

Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future

Heterozygous variant fibrinogen γA289V (Kanazawa III) was confirmed as hypodysfibrinogenemia by plasma and recombinant fibrinogens

Pregnancy outcome in afibrinogenemia: Are we giving enough fibrinogen concentrate? A case series

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