Inherited factor coagulation deficiencies and vascular bleeding disorders, associated with bleeding of various severity, are often classified as rare bleeding disorders (RBDs). These include inherited fibrinogen disorders, inherited platelet function disorders (IPFD) and hereditary haemorrhagic telangiectasia (HHT). In the last decades, there have been large increases in knowledge on the epidemiology, genetics, physiopathology, clinical features, and diagnosis of RBDs, but improvements in management have been more limited and remain challenging. The treatment mainstay of RBDs is based only on replacement of a few available coagulation factor concentrates or cryoprecipitates. There is growing interest in therapeutic agents that enhance coagulation or inhibiting anticoagulant pathways in RBDs. In severe IPFD, the optimal platelet transfusion strategy is not yet established. Moreover, data is scarce on the effectiveness and safety of desmopressin and/or antifibrinolytic drugs often used for milder IPFD treatment. The best fibrinogen replacement strategy (prophylaxis vs. on demand) in afibrinogenemia is still debated. Similarly, the optimal trough fibrinogen target level for treatment of acute bleeding, and the role of fibrinogen replacement during pregnancy in mild hypofibrinogenemia and dysfibrinogenemia, have not been properly evaluated. The therapeutic arsenal in HHT includes antifibrinolytics and a series of antiangiogenic agents whose potential efficacy has been tested in small studies or are under investigation for treatment of bleeding. However, there is need to address several issues, including the optimal dosing strategies, the potential emergent toxicity of longer-term use, and the impact of systemic antiangiogenic treatment on visceral arteriovenous malformations.

Congenital fibrinogen disorders (CFDs) are a heterogeneous group of rare congenital quantitative and/or qualitative fibrinogen deficiencies. The spectrum of molecular anomalies is broad, leading to several subtypes of fibrinogen disorders (ie, afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia). Pregnancy in women with CFDs is a high-risk clinical situation, with an increased tendency for miscarriages, bleeding, and thrombosis. Even though it is well established that management of such pregnancies requires a multidisciplinary approach involving specialists (hematologists and maternal/fetal medicine experts with expertise in the management of inherited bleeding disorders), specific guidelines are lacking. In this International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee communication, we aim to propose an expert consensus opinion with literature evidence where available on the strategy for management of pregnancy, delivery, and puerperium in CFDs.

Objective: To analyze the phenotype and genotype of two pedigrees with inherited fibrinogen (Fg) deficiency caused by two heterozygous mutations. We also preliminarily probed the molecular pathogenesis. Methods: The prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and plasma fibrinogen activity (Fg∶C) of all family members (nine people across three generations and three people across two generations) were measured by the clotting method. Fibrinogen antigen (Fg:Ag) was measured by immunoturbidimetry. Direct DNA sequencing was performed to analyze all exons, flanking sequences, and mutated sites of FGA, FGB, and FGG for all members. Thrombin-catalyzed fibrinogen polymerization was performed. ClustalX 2.1 software was used to analyze the conservatism of the mutated sites. MutationTaster, PolyPhen-2, PROVEAN, SIFT, and LRT online bioinformatics software were applied to predict pathogenicity. Swiss PDB Viewer 4.0.1 was used to analyze the changes in protein spatial structure and molecular forces before and after mutation. Results: The Fg∶C of two probands decreased (1.28 g/L and 0.98 g/L, respectively). The Fg∶Ag of proband 1 was in the normal range of 2.20 g/L, while it was decreased to 1.01 g/L in proband 2. Through genetic analysis, we identified a heterozygous missense mutation (c.293C>A; p.BβAla98Asp) in exon 2 of proband 1 and a heterozygous nonsense mutation (c.1418C>G; p.BβSer473*) in exon 8 of proband 2. The conservatism analysis revealed that Ala98 and Ser473 presented different conservative states among homologous species. Online bioinformatics software predicted that p.BβAla98Asp and p.BβSer473* were pathogenic. Protein models demonstrated that the p.BβAla98Asp mutation influenced hydrogen bonds between amino acids, and the p.BβSer473* mutation resulted in protein truncation. Conclusion: The dysfibrinogenemia of proband 1 and the hypofibrinogenemia of proband 2 appeared to be related to the p.BβAla98Asp heterozygous missense mutation and the p.BβSer473* heterozygous nonsense mutation, respectively. This is the first ever report of these mutations.
目的： 对两个杂合突变导致遗传性纤维蛋白原缺陷症家系进行表型和基因突变分析，并初步探讨其分子致病机制。 方法： 采用凝固法检测两个先证者及其各自家系成员（3代9人和2代3人）凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）、凝血酶时间（TT）和纤维蛋白原活性（Fg∶C），免疫比浊法检测纤维蛋白原抗原（Fg∶Ag）。DNA直接测序法分析先证者FGA、FGB和FGG基因所有外显子和侧翼序列及家系成员相应的突变位点区域。通过凝血酶诱导进行纤维蛋白原聚集试验；用ClustalX-2、1-win软件分析突变位点的保守性；用Mutation Taster、PolyPhen-2、PROVEAN、SIFT和LRT在线生物信息学软件预测突变位点的致病性；用Swiss-pdb Viewer4.0.1分析突变前后蛋白质空间结构及分子作用力的变化。 结果： 家系1先证者和家系2先证者Fg∶C明显下降（分别为1.28 g/L、0.98 g/L）；家系1先证者Fg∶Ag正常（2.20 g/L），家系2先证者Fg∶Ag降低（1.01 g/L）。基因分析发现，家系1先证者的FGB基因第2号外显子存在c.293C>A（p.BβAla98Asp）杂合错义突变；家系2先证者的FGB基因第8号外显子存在c.1418C>G（p.BβSer473*）杂合无义突变。同源性分析表明Ala98和Ser473残基在同源物种间呈不同保守状态；在线生物信息学软件预测显示p.BβAla98Asp和p.BβSer473*突变为致病突变；蛋白模型分析显示，p.BβAla98Asp突变使氨基酸之间的氢键发生改变，p.BβSer473*突变产生了截短蛋白。 结论： 家系1先证者的异常纤维蛋白原血症和家系2先证者的低纤维蛋白原血症可能分别与p.BβAla98Asp杂合错义突变及p.BβSer473*杂合无义突变有关。.

Fibrinogen deficiencies are very rare. Qualitative fibrinogen deficiencies (dysfibrinogenaemia and hypodysfibrinogenemia) are functional disorders that can present with both haemorrhagic symptoms and with thrombotic phenomena as unique and paradoxical manifestation. We present the case of a 77-year-old man being investigated for a partially thrombosed abdominal aortic aneurysm as well as an ischaemic stroke 20 years previously. Basic coagulation tests were normal but extended tests revealed a lengthened thrombin time (TT) combined with a significant drop in fibrinogen concentration measured with the Clauss assay and by nephelometry. After secondary fibrinogen deficiencies were ruled out, a heterozygous variant in the FGG gene was detected by next-generation sequencing, and congenital hypodysfibrinogenemia was diagnosed. Acenocumarol was initiated and no new thrombotic or haemorrhagic events had occurred after a year of follow-up. In almost 25% of cases, thrombotic events may be the only clinical manifestation of functional fibrinogen deficiencies. They are a rare cause of thrombophilia, and are probably underdiagnosed due to normal standard coagulation test results as well as a possible absence of haemorrhagic events. Consequently, a TT test (an initial \'rule out\' test) should be requested in order to promptly identify these patients. Moreover, discrepancies in derived and Clauss fibrinogen test results should suggest a functional disorder. Finally, new coagulation techniques based on the functional characterization of clot formation, such as ROTEM or thrombin generation assay, could help characterize these entities and suggest new therapeutic approaches.
CONCLUSIONS: Functional fibrinogen deficiencies can present with thrombotic manifestations only, and are a rare and probably underdiagnosed cause of thrombophilia.Thrombin time is a highly sensitive test to rule out other conditions as aPTT and PT results may be within normal ranges, especially in functional deficiencies.Discrepancies between derived and Clauss fibrinogen findings, fibrinogen protein measurements and the use of new techniques (ROTEM or thrombin generation) are important for correct approach.

BACKGROUND: Venom-induced consumption coagulopathy (VICC) is characterized by coagulation dysfunction accompanied by decreased coagulation factor activity and fibrinogen (FBG) concentrations. We report a patient with VICC caused by snake bite who manifested persistent FBG deficiency without abnormal coagulation factor activity. This information may be helpful in diagnosing and treating VICC.
METHODS: A 49-year-old man who had been bitten by a snake 13 h previously was admitted to the Emergency Department of our hospital with visible swelling of a finger and a bleeding puncture site. The provisional diagnosis was VICC, this being made based on persistent bleeding from the puncture site and subcutaneous hemorrhage. Laboratory evidence of coagulation abnormalities, including fibrinolysis, and findings on thromboelastography confirmed VICC. He had persistent afibrinogenemia requiring intravenous infusions of cryoprecipitate and fresh frozen plasma, together with continuous large doses of human FBG. After this treatment, the patient\'s right upper limb swelling improved significantly and his subcutaneous hemorrhage resolved. All of his abnormal laboratory findings returned to normal by day 25. During 6 months\' of follow-up, the patient had no further hemorrhagic events.
CONCLUSIONS: Hemorrhagic snake venom can result in coagulation dysfunction characterized by persistent FBG deficiency without abnormal coagulation factor activity.

Blood coagulation is a process involving several chemical reactions governed by coagulation factors, during which the shear elastic coefficient, μ, varies as the medium transitions from liquid to gel phase. This work used ultrasound to measure μ during the clotting of human plasma samples by tracking the motion of a glass sphere located inside a cuvette filled with the plasma. A 2.03 MHz ultrasonic system generated an impulsive acoustic radiation force acting on the sphere, and a 4.89 MHz pulse-echo ultrasonic system tracked the sphere displacement induced by that force. Measurements of μ were determined by fitting a μ-dependent theoretical model to the motion waveform of the sphere immersed in clotting normal plasma and plasma samples with fibrinogen (FI) concentrations of 1.2 (FI-deficiency) and 3.6 (FI-normal) g/L. For normal plasma, μ started at 14.22 Pa and increased rapidly until 2 min, then slowly until it reached 210.23 Pa at 35 min after the clotting process started. A similar trend was exhibited in plasma samples with FI concentrations of 1.2 and 3.6 g/L, with μ reaching 120.55 and 679.42 Pa, respectively. A theoretical model, related to the kinetics of clot-structure formation, describes the time changes of μ for the clotting plasma samples. The sphere-motion-based acoustic-radiation-force approach allowed us to measure the shear elastic coefficient during the coagulation process of plasma samples with normal and deficient FI concentrations. Our results suggest that the method used in this study is capable of being used to detect bleeding disorders.

Hypodysfibrinogenemia (HD) is a heterogeneous disorder in which plasma fibrinogen antigen and function are both reduced but discordant. This report addresses the key clinical question of whether genetic analysis enables clinically useful subclassification of patients with HD. We report a new case and identify a further eight previously documented cases that have the laboratory features of HD but biallelic inheritance of quantitative and qualitative fibrinogen gene variants. The cases displayed both bleeding and thrombosis and sometimes had undetectable fibrinogen activity. In all cases, the predicted effect of the coinherited variants is reduced levels of circulating fibrinogen that is all dysfunctional. We propose the term pseudohomozygous dysfibrinogenemia for this subtype of recessively inherited HD that is distinct from the more commonly recognized monoallelic HD caused by a single fibrinogen gene variant.

Background: Neonatal hypofibrinogenemia is often asymptomatic but can manifest as hemorrhage. Objective: This study was conducted to characterize clinical characteristics of neonates with hypofibrinogenemia and identify factors associated with hemorrhage. Methods: This was a retrospective study of neonates with plasma fibrinogen level (FIB) ≤1.0 g/L who were hospitalized at the Neonatology Department, People\'s Hospital, Chongqing, China, from January 2012 to December 2017. Based on severity, patients were grouped into severe, moderate, and mild hypofibrinogenemia (FIB < 0.5 g/L, 0.5 g/L ≤ FIB < 0.7 g/L, and 0.7 g/L ≤ FIB ≤ 1.0 g/L, respectively). Clinical characteristics associated with hemorrhage were analyzed. Results: Among 330 neonates, 52.7% showed mild hypofibrinogenemia, 25.5% had moderate hypofibrinogenemia, and 21.8% had severe hypofibrinogenemia. Severe hypofibrinogenemia was not associated with gestational age, but the mild form was frequent in neonates with low/normal birthweight (P = 0.018). Approximately 80.6% of neonates presented hypofibrinogenemia as variable combinations of thrombocytopenia or coagulopathies. Hemorrhage occurred in 38.8% of the cases, 60.9% of which were mild. Hemorrhage manifested as puncture site bleeding (47.7%) or spontaneous skin/mucous membrane bleeding (34.2%). The degree of hypofibrinogenemia was not associated with the severity or occurrence of hemorrhage. Among patients with hypofibrinogenemia and bleeding, 53.4% of the cases with coagulopathies showed mild hemorrhage, 85.7% of the cases with thrombocytopenia had moderate bleeding, while 53.8% of the cases with coagulopathy and thrombocytopenia showed severe hemorrhage. Conclusion: Neonatal hypofibrinogenemia is often comorbid and occurs with thrombocytopenia and/or coagulopathies. Although hemorrhage is not associated with the degree of hypofibrinogenemia, it may be severe when hypofibrinogenemia co-occurs with coagulopathies and/or thrombocytopenia.

暂无摘要。

Inherited bleeding disorders increase the risk of bleeding in the obstetric patient. Randomized controlled trials to compare prophylactic or therapeutic interventions are rare, and guidance documents rely heavily on expert opinion. Here we report the results of a systematic review of the literature for the treatment and prevention of peripartum bleeding in women with an inherited bleeding disorder. The highest-quality evidence is for the use of tranexamic acid in postpartum hemorrhage, which has been shown to decrease bleeding-related mortality in women without bleeding disorders. There is limited evidence for prophylactic use of this agent in women with inherited bleeding disorders. Desmopressin has also been used in observational studies of patients with von Willebrand disease and carriers of hemophilia A with some success, although concerns about the risk of hyponatremia persist. In patients with deficiencies of specific factors, replacement is generally the preferred approach, and concentrates have been studied in deficiencies of VWF and factors VII, VIII, IX, XI, and XIII as well as in patients with fibrinogen deficiency. Because of the small size of these studies, neither safety nor efficacy is well established, although the literature suggests that bleeding history may be more predictive of outcomes than factor levels in many cases. Goal factor levels have not been studied or systematically established in any of these diseases, although observational data suggest that achieving normal levels may be inadequate, particularly for VWF and factor VIII, which are physiologically elevated in pregnancy. For factor deficiencies in which no specific concentrate is available, such as factors II (prothrombin) and V, prothrombin complex concentrate or fresh frozen plasma may be used, and for platelet defects or deficiencies, such as Glanzmann thrombasthenia or Bernard-Soulier syndrome, platelet transfusion is generally first line, although use of recombinant FVIIa has been reported in patients with Glanzmann thrombasthenia to avoid development of, or treat patients with, antibodies to platelet glycoprotein IIbIIIa. Ultimately, data are lacking to definitively support an evidence-based approach to management in any of these disorders, and prospective, controlled studies are desperately needed.