Management of acute bleeding in a patient with congenital afibrinogenaemia

Congenital afibrinogenaemia is a rare bleeding disorder characterized by absence of fibrinogen and varying bleeding tendency. Treatment with fibrinogen concentrates is considered to be the best choice for afibrinogenaemic patients who experience bleeding. We report the case of a 22-year-old Greek patient who presented with large muscular haematomas and was treated with fibrinogen concentrates. The efficacy of this treatment and the problems that arose during his hospitalization are being discussed.     

Efficacy and tolerability of human fibrinogen concentrate administration to patients with acquired fibrinogen deficiency and active or in high-risk severe bleeding

Background and Objectives  Fibrinogen deficiency is a cause for massive haemorrhage whose management in emergency situations is the subject of debate. Plasma-derived fibrinogen concentrates are indicated for reversing the haemorrhagic diathesis found in congenital and acquired deficiencies.
Materials and Methods  We report on the results of an observational study that evaluated the effects of fibrinogen concentrates in patients suffering from various forms of acquired severe hypofibrinogenaemia with life-threatening consumptive thrombo-haemorrhagic disorders (surgery, trauma and digestive haemorrhage), or underlying disease states that limit fibrinogen synthesis (hepatic dysfunction, haematological malignancies).
Results  Sixty-nine patients were identified and included, in whom most of the processes (62%) corresponded to consumptive hypofibrinogenaemia. After a median dose of 4 g, a mean absolute increase of 1·09 g/l in plasma fibrinogen was measured and coagulation parameters were significantly improved ( P <  0·001). Mortality rates of 32·3% and 44·2% were reported after 24 h and 72 h, respectively.
Conclusion  We conclude that the administration of fibrinogen concentrates in unresponsive, life-threatening haemorrhage with acquired hypofibrinogenaemia improves laboratory measures of coagulation, and may also be life saving. Although observational in nature, our data indicate a direct relationship between plasma fibrinogen levels and survival in acquired fibrinogen deficiency. Further studies are warranted to ascertain a clear relationship between fibrinogen levels and survival.     

Fibrinogen giessen I: a congenital homozygously expressed dysfibrinogenemia with A alpha 16 Arg----His substitution

Clinical reports are published for only two patients with homozygously expressed congenital dysfibrinogenemia. The patients, both of whom have a bleeding diathesis, have amino acid substitutions in the fibrinogen molecule at A alpha 16 Arg----Cys and A alpha 19 Arg----Ser, respectively. We report that a third patient with dysfibrinogenemia (fibrinogen Giessen I) is homozygous for A alpha 16 Arg----His. Although this patient has had excessive postpartum bleeding, she has had normal hemostasis throughout several minor surgical procedures and hysterectomy. Elucidation of the amino acid alterations in patients with dysfibrinogenemia may expand our understanding of structural determinants of fibrinogen that are critical to its function in vivo.     

Effects of divalent cations on the conversion of fibrinogen to fibrin and fibrin polymerization

Effects of divalent cations on fibrinogen and its reaction with thrombin were re-examined and correlated to improve definition of mechanisms underlying the acceleration of clot formation by the ions. The rate of release of fibrinopeptides from fibrinogen was not affected by any of the specific ions studied, but increased rates of fibrin monomer polymerization were obtained with all but magnesium ions. Maximal acceleration of monomer polymerization was observed with the divalent ions at concentration of 2.5–5 mM, and no added specific ion effects were observed with much higher levels. The acceleratory ions were found to have a corresponding effect on the solubility of fibrinogen, as judged from acceleration of its precipitation at low temperature. Although magnesium ions had no effect on fibrin monomer polymerization, they did have a low ranking effect on cryoprecipitation. These data confirm that the principal effect of divalent cations in the fibrinogen-fibrin transformation is to accelerate fibrin monomer polymerization, and suggest that the acceleration is associated with effects on the solubility of fibrinogen.     

Physiological correction of hereditary mild hypofibrinogenemia during pregnancy

Introduction

Hereditary hypofibrinogenemia is a rare fibrinogen disorder characterised by decreased levels of fibrinogen. Pregnant women with hypofibrinogenemia are at risk of adverse obstetrical outcomes, depending on the fibrinogen level.

Aim

We investigated how the physiological changes of hemostasis throughout the pregnancy impact the hemostatic balance in a woman with hereditary mild hypofibrinogenemia.

Methods

Fibrin clot properties were analyzed by turbidimetry and scanning electron microscopy, clot weight and red blood cells retention were measured by whole clot contraction, and in vitro thrombin generation was assessed by calibrated automated thrombogram and ex vivo by TAT.

Results

Throughout the pregnancy, the fibrinogen levels increased reaching normal values in the third trimester (activity 3.1 g/L, antigen 3.2 g/L). In parallel, the fibrin polymerisation increased, the fibrinolysis decreased, the fibrin clot network became denser with thicker fibrin fibers, and the fibrin clot weight and red blood cells retention increased, reaching control's value at the third trimester. Similarly, in vitro and ex vitro thrombin generation increased, reaching maximum values at the delivery.

Conclusion

In this case of hereditary mild hypofibrinogenemia we observed a physiological increase of fibrinogen and thrombin generation. Future studies should focus on moderate and severe hypofibrinogenemia, to assess fibrinogen variation and the overall impact of increased TG on the hemostasis balance.     

Diagnostic utility of bleeding assessment tools in congenital fibrinogen deficiencies

Background

The assessment of clinical history is crucial before referring a patient for further laboratory testing. Bleeding assessment tools (BAT) are developed to standardize clinical evaluation. A small number of patients with congenital fibrinogen deficiencies (CFDs) have been evaluated with these tools without definitive results.

Aims

We compared the adequacy of the ISTH-BAT and the European network of rare bleeding disorders bleeding score system (EN-RBD-BSS) to identify patients with CFDs. The correlation between the two BATs and fibrinogen levels and patient clinical grade severity was further analyzed.

Methods

We included 100 Iranian patients with CFDs. Routine coagulation and fibrinogen-specific tests (fibrinogen antigen [Fg:Ag] and activity [Fg:C]) were performed. The ISTH-BAT and EN-RBD-BSS were used to assess the bleeding score (BS) of all patients.

Results

The ISTH-BAT and EN-RBD-BSS median (range) were 4 (0–16) and 2.21 (−1.49 to 6.71), with a statistically significant moderate correlation between the two systems (r = .597, P < .001). In patients with quantitative deficiencies (afibrinogenemia and hypofibrinogenemia), the correlation between Fg:C and the ISTH-BAT was moderately negative (r = −.4, P < .001), while the correlation between Fg:C and the EN-RBD-BSS was weakly negative (r = −.38, P < .001). Overall, 70% and 72% of patients with fibrinogen deficiencies were correctly identified by both the ISTH-BAT and EN-RBD-BSS, respectively.

Conclusion

These results suggest that in addition to the ISTH-BAT, the EN-RBD-BSS may also be useful in identifying CFD patients. We found a significant level of sensitivity for detecting fibrinogen deficiency in the two BATs, and bleeding severity classification correctly identified severity grades in almost two-thirds of patients.     

脑梗死患者纤维蛋白原β-148C／T基因多态性研究

目的：探讨脑梗死患者纤维蛋白原（Fg）β-148C／T基因多态性频率分布及其与血浆№水平的关系。方法：用聚合酶链反应限制性片段长度多态性（PCR-RFLP）分析方法，分析脑梗死组（88例）和对照组（80例）患者Fgβ-148C／T基因多态性频率分布，用凝血酶原时间法测定血浆F2水平。结果：脑梗死组T等位基因频率明显高于对照组（0．33比0．243，P〈0．05），血浆F2水平也明显增高（P〈0．01）。脑梗死患者CC和CT基因型亚组比水平均高于对照组（P〈0．05），而TT基因型亚组与对照组无明显差异（P〉0．05）。脑梗死组不同基因型患者血浆飑水平有显著差异，CT、TT和CT＋TT基因型组血浆Fg水平均明显高于CC基因型组（P〈0．05）；而在对照组中，TT基因型亚组均明显高于其他基因型亚组（P〈0．05）。结论：Fgβ-148C／T基因多态性与脑梗死有关，可能是通过T等位基因影响血浆比水平在脑梗死的发生机制中起作用。Fgβ-148T等位基因可能是脑梗死的易患因素。     

Congenital afibrinogenemia

Congenital afibrinogenemia is a rare disorder with unusual clinical manifestations. The disease is inherited as an autosomal recessive trait and consanguinity is common among affected families. Clinical manifestations range from minimal bleeding to catastrophic hemorrhage. Congenitally afibrinogenemic patients seem to be peculiarly susceptible to spontaneous rupture of the spleen. Coagulation tests which depend on clot formation as an end point may be infinitely prolonged and abnormalities of platelet function are usually present. The diagnosis is established by demonstrating trace or no immunoreactive fibrinogen. The disease is caused by markedly reduced or absent synthesis of fibrinogen by liver cells, but the genetic defect remains unknown. Bleeding episodes can be effectively treated with cryoprecipitate. Purified virally inactivated fibrinogen concentrates have been used in Europe and may soon be widely available. © 1994 Wiley-Liss, Inc.     

Effect of epinephrine on fibrinogen receptor exposure by aspirin-treated platelets and platelets from concentrates in response to ADP and thrombin

Synergistic effects between agonists on platelet aggregation have long been appreciated. Recently epinephrine was reported to induce maximal aggregation of aspirin-treated platelets when combined with ADP or thrombin, and to increase fibrinogen binding of non-aspirin treated platelets stimulated with low doses of ADP. The present study extends these observations to correlate fibrinogen binding in response to various combinations of ADP, epinephrine, and thrombin with platelet aggregation and 14C-serotonin release using aspirin-treated platelets as well as platelets from stored concentrates. When fresh platelets were stimulated with epinephrine (5 microM) together with either ADP (10 microM) or thrombin (150 mU/ml), fibrinogen binding increased by 180% compared to binding observed in response to ADP or thrombin alone. This was accompanied by enhanced platelet aggregation, but no increase in 14C-serotonin release. While both ADP and epinephrine potentiated the aggregation and fibrinogen binding of stored platelets in response to high doses of thrombin (150 mU/ml), maximal aggregation was achieved only with thrombin (150 mU/ml) and epinephrine (5 microM) in combination. The data thus suggest that 1) epinephrine induces maximal aggregation of aspirin-treated platelets stimulated with thrombin or ADP by significantly enhancing fibrinogen receptor exposure independently of the cyclooxygenase-mediated release reaction; 2) epinephrine stimulates platelets by a mechanism different from that of thrombin or ADP; and 3) as demonstrated by others, the ability of platelets from stored concentrates to aggregate and to bind fibrinogen in response to ADP can be enhanced by epinephrine, and, in addition, these platelets can aggregate and bind fibrinogen maximally when stimulated with combinations of epinephrine and thrombin.     

蕲蛇毒检验肝硬化凝血功能的评价

中国蕲蛇毒有类凝血酶功能,可用于检查异常纤维蛋白原。本文报告了68例肝硬化的蕲蛇毒时间,其异常率为91.2％,远较凝血酶时间的异常率为高。提示蕲蛇毒时间为一种较好的检查肝硬化的新方法。     

Hepatic Fibrinogen Storage Disease Due to the Fibrinogen γ375 Arg → Trp Mutation “Fibrinogen Aguadilla” is present in Arabs

The mutation γ375Arg → Trp (fibrinogen Aguadilla) is one of four mutations (Brescia, Aguadilla, Angers, and AI duPont) capable of causing hepatic storage of fibrinogen. It has been observed in four children from the Caribbean, Europe, and Japan, suffering from cryptogenic liver disease. We report the first case of hepatic fibrinogen storage disease in Arabs due to a mutation in the fibrinogen γ-chain gene in a 3-year-old Syrian girl presenting with elevated liver enzymes. The finding of an impressive accumulation of fibrinogen in liver cells raised the suspicion of endoplasmic reticulum storage disease. Sequencing of the fibrinogen genes revealed a γ375Arg → Trp mutation (fibrinogen Aguadilla) in the child and in her father. In conclusion, when confronted with chronic hepatitis of unknown origin, one should check the plasma fibrinogen level and look carefully for the presence of hepatocellular intracytoplasmic globular inclusions to exclude hepatic fibrinogen storage disease.     

纤维蛋白原基因G(-455)A多态性与缺血性脑卒中的关系

目的　探讨缺血性脑卒中与纤维蛋白原基因G( 45 5 )A多态性的关系。方法　利用PCR技术和分子杂交技术对北京地区 2 94例缺血性脑卒中患者进行纤维蛋白原基因G( 45 5 )A多态性位点的检测和分析 ,并与 2 79例北京地区的非脑卒中患者进行比较。结果　缺血性脑卒中患者纤维蛋白原基因G( 45 5 )A多态性的基因型频率和等位基因频率与对照组相比无明显差异。结论　纤维蛋白原基因G( 45 5 )A多态性可能不是缺血性脑卒中发病的遗传学危险因素。     

Heparin binding sites are located in a 40-kD γ-chain and a 36-kD β-chain fragment isolated from human fibrinogen

Objective: We have previously shown that¹²⁵I-fibrinogen binds to heparin sepharose CL-6B. To identify the localization of the heparin binding domain in human fibrinogen, reduced and alkylated fibrinogen was digested by limited-Staphylococcus aureus V8 protease.Methods/Results: Two fragments have now been isolated and purified to apparent homogeneity by heparin-affinity chromatography. These fragments, denoted the 40-kD and 36-kD fragments, contain NH₂-terminal sequences of Ala-Ser-Ile-Leu-Thr-His-Asp and Thr-Val-Asn-Ser-Asn-Ile-Pro, respectively. These fragments established the positions of these peptides within the chain of fibrinogen as beginning with the residue tentatively designated 124 and within the B chain as beginning with the residue designated 186. Binding of¹²⁵I-fibrinogen to heparinsepharose CL-6B was completely inhibited by a mixture of these fragments, with an IC₅₀ of 3.2 M. The synthetic peptide of the chain carboxy-terminal 15 residues (GQQHHLGGAKQAGDV;G15) partially inhibited fibrinogen binding. The mixture of these fragments partially inhibited the ADP-induced aggregation of platelets.Conclusions: These data indicate that the domains for heparin binding may be present on both the chain and the chain of fibrinogen, and that the domain on the chain may be close to the binding domain on the carboxy terminus of the fibrinogen chain to glycoprotein IIb-IIIa.     

A novel fibrinogen variant--Praha I: hypofibrinogenemia associated with gamma Gly351Ser substitution

OBJECTIVES: A 25-yr-old man from Prague had abnormal bleeding after several surgical operations with low fibrinogen level and hypofibrinogenemia was suspected. PATIENTS AND METHODS: The patient, 25 yr-old male had a low fibrinogen concentration as determined by the thrombin time and immunoturbidimetrical method. His 48-yr-old mother presented with normal coagulation tests, normal fibrinogen level and reported no history of bleeding. To identify the genetic mutation responsible for this hypofibrinogen, genomic DNA extracted from the blood was analyzed. Fibrin polymerization measurement, kinetics of fibrinopeptide release, fibrinogen clottability measurement, mass spectroscopy, and scanning electron microscopy were performed. RESULTS: DNA sequencing showed heterogeneous fibrinogen gammaG351S mutation in the propositus. The mutant chain was found not to be expressed to the circulation by matrix-assisted laser desorption/ionization time of flight mass spectrometry. Scanning electron micrographs of the patient's fibrin clot as well as kinetics of fibrinopeptide release and fibrin polymerization were found to be normal. CONCLUSION: A case of hypofibrinogenemia gammaG351S was found by routine coagulation testing and was genetically identified.