Lower Plasma Fibrinogen Levels Research Articles

The correlation between Plasma Fibrinogen Levels and Glycemic Status in type 2 Diabetes Mellitus

Abstract Introduction/Objective Background: Fibrinogen is considered a well-known contributor to the progression of atherosclerotic lesions and a predictor of cardiovascular events. Patients with diabetes mellitus (DM) have higher levels of fibrinogen, which may raise their thromboembolic risk for cardiovascular disease (CVD). Plasma fibrinogen is an indicator of inflammation, and endothelial dysfunction has been described as an independent risk factor for cardiovascular morbidity in type-2 diabetes mellitus (T2DM) patients. Poor glycemic control has been reported to be associated with hyperfibrinogenemia. Aim This study aims to estimate the levels of fibrinogen in patients with type-2 diabetes mellitus and determine its correlation with glycated hemoglobin levels. Methods/Case Report Subjects and methods: It is a cross-sectional analytic study conducted in the Benghazi Diabetic Clinic, Libya. Patients who were diagnosed with type 2 diabetes mellitus, either newly detected or already on diet or treatments, were included in the study during the period between May 2022 to December 2022. A total of 231 adult subjects were selected, with ages ranging from 20-80 years. Random blood sugar levels were assessed. Plasma fibrinogen levels (mg/dl) were estimated by the "Clauss method" and glycosylated hemoglobin (%) by the "immunoturbidimetric method." Patients were categorized into three groups depending upon the HbA1c values, i.e., into <5.7% (good control), 5.7-6.5% (fair control), and >6.5% (poor control). Results (if a Case Study enter NA) Result: Out of 231 subjects, (40.6%) were males and (59.4%) were females, with a mean±SD of age was (47.03±15.54) years. There was a significant positive correlation between fibrinogen and HbA1c in the fair control group (r=0.424, p=0.003) and the poor control group (r=0.369, P=0.000). Moreover, the difference between fibrinogen and age in the good control group was significant (p>0.05), whereas no significance was recognized in other groups. Conclusions Plasma fibrinogen levels are elevated in type 2 DM, and this elevation was associated with poor glycemic control; increased HbA1c levels. The other parameters which correlated with plasma fibrinogen levels were age. Lowering plasma fibrinogen levels could be an integral approach to cardiovascular complications reduction in type-2 DM.

Risk factors and clinical outcomes associated with acquired hypofibrinogenemia in patients administered hemocoagulase batroxobin for hemoptysis.

Hemocoagulase batroxobin is used to prevent hemostasis or bleeding in surgical and trauma patients; however, the role of batroxobin in patients with hemoptysis is not well understood. We evaluated the risk factors and prognosis of acquired hypofibrinogenemia in hemoptysis patients treated systemically with batroxobin. We retrospectively reviewed the medical charts of hospitalized patients who were administered batroxobin for hemoptysis. Acquired hypofibrinogenemia was defined as a plasma fibrinogen level >150 mg/dL at baseline, decreasing to <150 mg/dL after batroxobin administration. Overall, 183 patients were enrolled, of whom 75 had acquired hypofibrinogenemia after the administration of batroxobin. There was no statistical difference in the median age of the patients in the non-hypofibrinogenemia and hypofibrinogenemia groups (72.0 vs. 74.0 years, respectively). The patients in the hypofibrinogenemia group showed a higher rate of intensive care unit (ICU) admission (11.1% vs. 22.7%; P=0.041) and tended to have more massive hemoptysis than those in the non-hyperfibrinogenemia group (23.1% vs. 36.0%; P=0.068). The patients in the hypofibrinogenemia group further showed a higher requirement for transfusion (10.2% vs. 38.7%; P<0.000) than those in the non-hyperfibrinogenemia group. Low levels of baseline plasma fibrinogen and a prolonged and higher total dose of batroxobin were associated with the development of acquired hypofibrinogenemia. Acquired hypofibrinogenemia was associated with increased 30-day mortality [hazard ratio (HR), 4.164; 95% confidence interval (CI), 1.318-13.157]. The plasma fibrinogen levels in patients who were administered batroxobin for hemoptysis should be monitored, and batroxobin should be discontinued if hypofibrinogenemia occurs.

Blood component requirements in liver transplantation: effect of 2 thromboelastometry-guided strategies for bolus fibrinogen infusion—the TROMBOFIB randomized trial

BackgroundA low plasma fibrinogen level influences blood component transfusion. Thromboelastometry provides clinical guidance for fibrinogen replacement in liver transplantation (LT). ObjectivesWe hypothesized that infusions of fibrinogen concentrate to reach an A10FibTem value of 11 mm during LT could reduce red blood cell (RBC) and other component and fluid requirements in comparison to standard care. MethodsThis randomized, blinded, multicenter trial in 3 hospitals enrolled 189 LT-scheduled patients allocated to an intervention target (A10FibTem, 11 mm) or a standard target (A10FibTem, 8 mm); 176 patients underwent LT with fibrinogen replacement. Data were analyzed by intention-to-treat (intervention group, 91; control group, 85). Blood was extracted, and fibrinogen kits were prepared to bring each patient’s fibrinogen level to the assigned target at the start of LT, after portal vein clamping, and after graft reperfusion. The main outcome was the proportion of patients requiring RBC transfusion during LT or within 24 hours. ResultsThe proportion of patients requiring RBCs did not differ between the groups: intervention, 74.7% (95% CI, 65.5%-83.3%); control, 72.9% (95% CI, 62.2%-82.0%); absolute difference, 1.8% (95% CI, −11.1% to 14.78%) (P = .922). Thrombotic events occurred in 4% of the patients in both groups; reoperation and retransplantation rates and mortality did not differ. Nearly 70% of the patients in both groups required fibrinogen concentrate to reach the target. Using an 11-mm A10FibTem target increased the maximum clot firmness without affecting safety. However, this change provided no clinical benefits. ConclusionThe similar low plasma fibrinogen concentrations could explain the lack of significant between-group outcomes.

494 Low plasma fibrinogen levels are associated with poor prognosis in cutaneous angiosarcoma of the head and neck

Angiosarcomas are malignant vascular tumors that account for 2% of all soft-tissue sarcomas. Due to the rarity of angiosarcomas, the prognostic factors are seldom reported. Here, we investigated plasma fibrinogen levels as a prognostic factor for angiosarcoma of the head and neck (ASHN). This retrospective study reviewed a cohort of patients histologically diagnosed with ASHN at Nagoya University Hospital between April 2006 and July 2019. The 22 patients with ASHN included in the present study. The cutoff value of plasma fibrinogen levels was determined to be 257 mg/dL. The Kaplan–Meier curve showed the OS rate to be significantly higher in the high plasma fibrinogen group than in the low plasma fibrinogen group (p=0.0027). The univariable model showed that patients with low plasma fibrinogen levels had a significantly poor OS [hazard ratio 6.78, 95% confidence interval 1.63 to 28.2, p-value of 0.008503]. Recently, high plasma fibrinogen levels were reported to predict poor prognosis in several malignancies. Unexpectedly, the present study suggests that low plasma fibrinogen levels predict poor prognosis. ASHN is an extremely hemorrhagic tumor. From repeated microbleeds and blood coagulation in ASHN lesions, plasma fibrinogen is considered to be consumed and to decrease in patients with ASHN. Therefore, we speculate that the reduced plasma fibrinogen levels might reflect tumor burden indirectly. In conclusion, the present study suggests that pre-treatment plasma fibrinogen levels are a useful prognostic factor for ASHN that may reflect tumor burden.

THE EFFECT OF FIBRINOGEN INFUSION APPLIED AFTER CARDIOPULMONARY BYPASS ON BLEEDING IN CORONARY ARTERY BYPASS GRAFT SURGERY: RETROSPECTIVE COMPARATIVE STUDY

OBJECTIVE: The effect of administered fibrinogen concentrates in reducing the risk of postoperative bleeding that remains a serious problem in open heart surgery is controversial. We aimed to present the effect of fibrinogen concentrates on postoperative bleeding applied after cardiopulmonary bypass (CPB) in coronary artery bypass grafting (CABG).MATERIAL AND METHODS: 67 patients who underwent CABG and measured below 2.5 g / L fibrinogen after CPB were included in the study. Data of 32 patients (Group F; n=32 patients) who were given fibrinogen concentrate were compared with 35 patients (Group NF; n=35 patients) who were not given fibrinogen concentrate.RESULTS: After CPB, fibrinogen concentrate was applied to patients in order to increase fibrinogen levels to 2.5 g/L and above. For both groups, fibrinogen levels decreased significantly after CPB compared to preoperative levels (p&amp;lt;0.01), however, there was no difference between the groups in terms of reduction rate (p = 0.321). 2.94±0.91 g fibrinogen was administered to the patients in Group F. Postoperative drainage between the groups was not significant in both the 0-12 hour period (p=0.142) and 12-24 hour period(p = 0.309).CONCLUSIONS: Fibrinogen concentrate may reduce the amount of postoperative drainage with secondary effects which increased low plasma fibrinogen levels and contributes to recovery of coagulation physiology. However, because this decrease was not statistically significant, we think that fibrinogen concentrates should be used only in patients with a high risk of bleeding and in patients with fibrinogen levels below &amp;lt;1.5 g/L after CPB.

Low plasma fibrinogen levels are associated with poor prognosis in cutaneous angiosarcoma of the head and neck

Angiosarcoma of the head and neck (ASHN) is one of the most aggressive malignancies of the skin, but the prognostic factors are not well known because of its rarity. Recently, high plasma fibrinogen levels were reported to predict poor prognosis in several malignancies. In the present retrospective study, we suggest that low plasma fibrinogen levels predict poor prognosis for ASHN.

A study of correlation of plasma fibrinogen levels with glycemic status in type 2 Diabetes Mellitus patients

Background: Plasma fibrinogen is an indicator of inflammation and endothelial dysfunction has been described as an independent risk factor for cardiovascular morbidity in type 2 Diabetes mellitus patients. Poor glycemic control has been reported to be associated with hyperfibrinogenemia and its complications. This study was aimed to find a correlation of mean fibrinogen level with glycemic control in complicated and uncomplicated cases of Type 2 Diabetes mellitus.&#x0D; Materials and methods: One hundred eight known cases of Type 2 Diabetes mellitus aged ≥ 30 were included in our study of which 39 cases were uncomplicated and 69 cases were complicated Diabetes mellitus. Hundred of non-diabetic age and sex-matched controls were analyzed. Blood samples were collected in Ethylenediaminetetraacetic acid and citrate bulb for estimation of HbA1c and plasma fibrinogen level respectively.&#x0D; Results: Mean fibrinogen level in complicated Type 2 Diabetes mellitus was high 450.43 ±108.51 mg/dl as compared to uncomplicated cases 372.30±123.78 mg/dl (p=0.0001). Mean HbA1c in total Diabetes mellitus cases was 8.02±1.88 mg/dl with a range of 5.50-14.50 mg/dl. A positive correlation was found between HbA1c and mean fibrinogen level (r=0.782, p= 0.001) in type 2 Diabetes mellitus. Duration of diabetes in years showed a significant correlation with mean fibrinogen levels (r=0.295, p=0.002).&#x0D; Conclusions: Plasma fibrinogen level was significantly associated with glycemic control (HbA1c) and duration of Diabetes mellitus in years. Thus, lowering plasma fibrinogen levels could be an important approach to the prevention of cardiovascular complications in diabetics.

Preoperative plasma fibrinogen level and transfusion in cardiac surgery: a biphasic correlation.

Coagulopathic bleeding is a serious complication of cardiac surgery. A very low preoperative plasma fibrinogen level (PFL) has been previously described as a risk factor for red blood cell (RBC) transfusion in the perioperative setting. Nevertheless, contradictory results have been published concerning preoperative fibrinogen infusion to decrease RBC transfusion. These results highlight the need for a better description of the relation between preoperative PFL and RBC transfusion. In this single-centre retrospective study, we showed that both high and low PFLs are associated with an increase in RBC transfusion. A pro-inflammatory preoperative status could be involved in the association between high PFL and the increase in RBC transfusion. This non-linear relation between PFL and RBC transfusion could explain the difficulty of decreasing postoperative bleeding using only an algorithm aimed at increasing preoperative PFL.

Genetic Analysis of Afibrinogenemia and Hypofibrinogenemia: Novel Mutations in the FGB Gene in the Turkish Population

Introduction: Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. Hypofibrinogenemia is characterized by fibrinogen levels <1.5 g/L. Objective: In this study, we analyzed fibrinogen beta chain gene mutations in Turkish afibrinogenemia and hypofibrinogenemia patients. Methods: We evaluated 20 afibrinogenemia and hypofibrinogenemia patients and 80 healthy controls. We have sequenced all exons of the FGB gene using the DNA isolated from the peripheral blood samples of patients and controls. Results and Conclusion: We found a nonsense mutation in exon 4 at nucleotide 630 that encoded serine amino acid, and in the same exon a missense mutation of T to C at nucleotide 647, resulting in a transition from leucine to proline (p.L198P) in a child with hypofibrinogenemia. These mutations have been shown for the first time in the same patient of Turkish descent. Furthermore, there was a novel heterozygous guanine-to-adenine nucleotide change in exon 3. This caused the change of arginine amino acid to threonine amino acid at position 136 (p.A136T) in a protein, which has not been described in the literature before.

Intrahepatic fibrin(ogen) deposition drives liver regeneration after partial hepatectomy in mice and humans

AbstractPlatelets play a pivotal role in stimulating liver regeneration after partial hepatectomy in rodents and humans. Liver regeneration in rodents is delayed when platelets are inhibited. However, the exact mechanisms whereby platelets accumulate and promote liver regeneration remain uncertain. Thrombin-dependent intrahepatic fibrin(ogen) deposition was recently reported after partial hepatectomy (PHx) in mice, but the role of fibrin(ogen) deposits in liver regeneration has not been investigated. We tested the hypothesis that fibrin(ogen) contributes to liver regeneration by promoting intrahepatic platelet accumulation and identified the trigger of rapid intrahepatic coagulation after PHx. PHx in wild-type mice triggered rapid intrahepatic coagulation, evidenced by intrahepatic fibrin(ogen) deposition. Intrahepatic fibrin(ogen) deposition was abolished in mice with liver-specific tissue factor deficiency, pinpointing the trigger of coagulation after PHx. Direct thrombin activation of platelets through protease-activated receptor-4 did not contribute to hepatocyte proliferation after PHx, indicating that thrombin contributes to liver regeneration primarily by driving intrahepatic fibrin(ogen) deposition. Fibrinogen depletion with ancrod reduced both intrahepatic platelet accumulation and hepatocyte proliferation after PHx, indicating that fibrin(ogen) contributes to liver regeneration after PHx by promoting intrahepatic platelet accumulation. Consistent with the protective function of fibrin(ogen) in mice, low postoperative plasma fibrinogen levels were associated with liver dysfunction and mortality in patients undergoing liver resection. Moreover, increased intrahepatic fibrin(ogen) deposition was evident in livers of patients after liver resection but was remarkably absent in patients displaying hepatic dysfunction postresection. The results suggest a novel mechanism whereby coagulation-dependent intrahepatic fibrin(ogen) deposition drives platelet accumulation and liver regeneration after PHx.

Fibrinogen Gamma Chain Mutations Provoke Fibrinogen and Apolipoprotein B Plasma Deficiency and Liver Storage.

p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen γ. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, Turkey, and China. All reported children presented with a variable degree of histologically proven chronic liver disease and low plasma fibrinogen levels. In addition, one Japanese and one Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown origin. We report here on an additional child from Turkey with hypofibrinogenemia due to the Aguadilla mutation, massive hepatic storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The liver biopsy of the patient was studied by light microscopy, electron microscopy (EM), and immunohistochemistry. The investigation included the DNA sequencing of the three fibrinogen and APOB–lipoprotein regulatory genes and the analysis of the encoded protein structures. Six additional Fibrinogen Storage Disease (FSD) patients with either the Aguadilla, Ankara, or Brescia mutations were investigated with the same methodology. A molecular analysis revealed the fibrinogen gamma p.R375W mutation (Aguadilla) but no changes in the APOB and MTTP genes. APOB and MTTP genes showed no abnormalities in the other study cases. Light microscopy and EM studies of liver tissue samples from the child led to the demonstration of the simultaneous accumulation of both fibrinogen and APOB in the same inclusions. Interestingly enough, APOB-containing lipid droplets were entrapped within the fibrinogen inclusions in the hepatocytic Endoplasmic Reticulum (ER). Similar histological, immunohistochemical, EM, and molecular genetics findings were found in the other six FSD cases associated with the Aguadilla, as well as with the Ankara and Brescia mutations. The simultaneous retention of fibrinogen and APOB-lipoproteins in FSD can be detected in routinely stained histological sections. The analysis of protein structures unraveled the pathomorphogenesis of this unexpected phenomenon. Fibrinogen gamma chain mutations provoke conformational changes in the region of the globular domain involved in the “end-to-end” interaction, thus impairing the D-dimer formation. Each monomeric fibrinogen gamma chain is left with an abnormal exposure of hydrophobic patches that become available for interactions with APOB and lipids, causing their intracellular retention and impairment of export as a secondary unavoidable phenomenon.

Adenosine, lidocaine and Mg2+ (ALM) fluid therapy attenuates systemic inflammation, platelet dysfunction and coagulopathy after non-compressible truncal hemorrhage.

BackgroundSystemic inflammation and coagulopathy are major drivers of injury progression following hemorrhagic trauma. Our aim was to examine the effect of small-volume 3% NaCl adenosine, lidocaine and Mg2+ (ALM) bolus and 0.9% NaCl/ALM ‘drip’ on inflammation and coagulation in a rat model of hemorrhagic shock.MethodsSprague-Dawley rats (429±4 g) were randomly assigned to: 1) shams, 2) no-treatment, 3) saline-controls, 4) ALM-therapy, and 5) Hextend®. Hemorrhage was induced in anesthetized-ventilated animals by liver resection (60% left lateral lobe and 50% medial lobe). After 15 min, a bolus of 3% NaCl ± ALM (0.7 ml/kg) was administered intravenously (Phase 1) followed 60 min later by 4 hour infusion of 0.9% NaCl ± ALM (0.5 ml/kg/hour) with 1-hour monitoring (Phase 2). Plasma cytokines were measured on Magpix® and coagulation using Stago/Rotational Thromboelastometry.ResultsAfter Phase 1, saline-controls, no-treatment and Hextend® groups showed significant falls in white and red cells, hemoglobin and hematocrit (up to 30%), whereas ALM animals had similar values to shams (9–15% losses). After Phase 2, these deficits in non-ALM groups were accompanied by profound systemic inflammation. In contrast, after Phase 1 ALM-treated animals had undetectable plasma levels of IL-1α and IL-1β, and IL-2, IL-6 and TNF-α were below baseline, and after Phase 2 they were less or similar to shams. Non-ALM groups (except shams) also lost their ability to aggregate platelets, had lower plasma fibrinogen levels, and were hypocoagulable. ALM-treated animals had 50-fold higher ADP-induced platelet aggregation, and 9.3-times higher collagen-induced aggregation compared to saline-controls, and had little or no coagulopathy with significantly higher fibrinogen shifting towards baseline. Hextend® had poor outcomes.ConclusionsSmall-volume ALM bolus/drip mounted a frontline defense against non-compressible traumatic hemorrhage by defending immune cell numbers, suppressing systemic inflammation, improving platelet aggregation and correcting coagulopathy. Saline-controls were equivalent to no-treatment. Possible mechanisms of ALM's immune-bolstering effect are discussed.

Novel heterozygous dysfibrinogenemia, Sumida (AαC472S), showed markedly impaired lateral aggregation of protofibrils and mildly lower functional fibrinogen levels

IntroductionWe encountered a 6-year-old girl with systemic lupus erythematosus. Although no bleeding or thrombotic tendency was detected, routine coagulation screening tests revealed slightly lower plasma fibrinogen levels, as determined by functional and antigenic measurements (functional/antigenic ratio=0.857), suggesting hypodysfibrinogenemia. Materials and methodsDNA sequence and functional analyses were performed on purified plasma fibrinogen, and recombinant variant fibrinogen was synthesized in Chinese hamster ovary cells based on the results obtained. ResultsDNA sequencing revealed a heterozygous AαC472S substitution (mature protein residue number) in the αC-domain. AαC472S fibrinogen indicated the presence of additional disulfide-bonded molecules, and markedly impaired lateral aggregation of protofibrils in spite of slightly lower functional plasma fibrinogen levels. Scanning electron microscopic observations showed a thin fiber fibrin clot, and t-PA and plasminogen-mediated clot lysis was similar to that of a normal control. Recombinant variant fibrinogen-producing cells demonstrated that destruction of the Aα442C-472C disulfide bond did not prevent the synthesis or secretion of fibrinogen, whereas the variant Aα chain of the secreted protein was degraded faster than that of the normal control. ConclusionOur results suggest that AαC472S fibrinogen may cause dysfibrinogenemia, but not hypofibrinogenemia. The destruction and steric hindrance of the αC-domain of variant fibrinogen led to the impaired lateral aggregation of protofibrils and t-PA and plasminogen-mediated fibrinolysis, as well as several previously reported variants located in the αC-domain, and demonstrated the presence of disulfide-bonded molecules.

Recombinant γT305A fibrinogen indicates severely impaired fibrin polymerization due to the aberrant function of hole ‘a’ and calcium binding sites

IntroductionWe examined a 6-month-old girl with inherited fibrinogen abnormality and no history of bleeding or thrombosis. Routine coagulation screening tests showed a markedly low level of plasma fibrinogen determined by functional measurement and also a low level by antigenic measurement (functional/antigenic ratio=0.295), suggesting hypodysfibrinogenemia. Materials and methodsDNA sequence analysis was performed, and γT305A fibrinogen was synthesized in Chinese hamster ovary cells based on the results. We then functionally analyzed and compared with that of nearby recombinant γN308K fibrinogen. ResultsDNA sequence analysis revealed a heterozygous γT305A substitution (mature protein residue number). The γT305A fibrinogen indicated markedly impaired thrombin-catalyzed fibrin polymerization both in the presence or absence of 1mM calcium ion compared with that of γN308K fibrinogen. Protection of plasmin degradation in the presence of calcium ion or Gly-Pro-Arg-Pro peptide (analogue for so-called knob ‘A’) and factor XIIIa-catalyzed fibrinogen crosslinking demonstrated that the calcium binding sites, hole ‘a’ and D:D interaction sites were all markedly impaired, whereas γN308Kwas impaired at the latter two sites. Molecular modeling demonstrated that γT305 is localized at a shorter distance than γN308 from the high affinity calcium binding site and hole ‘a’. ConclusionOur findings suggest that γT305 might be important for construction of the overall structure of the γ module of fibrinogen. Substitution of γT305A leads to both dysfibrinogenemic and hypofibrinogenemic characterization, namely hypodysfibrinogenemia. We have already reported that recombinant γT305A fibrinogen was synthesized normally and secreted slightly, but was significantly reduced.

Elevated Plasma Fibrinogen Levels Are Associated with a Poor Prognosis in Patients with Hepatocellular Carcinoma

Objectives: Elevated plasma fibrinogen levels are associated with tumor progression and poor outcomes in cancer patients. We investigated the prognostic value of pretreatment plasma fibrinogen levels in patients with hepatocellular carcinoma (HCC). Methods: One hundred and thirteen patients with newly diagnosed HCC were retrospectively evaluated. We investigated the correlation between pretreatment plasma fibrinogen levels, clinicopathological parameters and overall survival. Both univariate and multivariate analyses were performed to identify the clinicopathological parameters associated with overall survival. Results: The median value of the pretreatment plasma fibrinogen level was 279 mg/dl. Elevated plasma fibrinogen levels were associated with larger tumor size, the presence of vascular invasion and higher Cancer Liver Italian Program scores. Lower plasma fibrinogen levels were associated with higher Child-Pugh grades. The overall survival rates in patients with pretreatment plasma fibrinogen levels ≥315 mg/dl were significantly lower than those with a pretreatment plasma fibrinogen level <315 mg/dl (p = 0.016). On multivariate analysis, the plasma fibrinogen levels (per 100 mg/dl) were found to be independently associated with overall survival (hazard ratio 1.236; p = 0.046). Conclusions: This study demonstrates that elevated pretreatment plasma fibrinogen levels are associated with tumor progression and are independently associated with a poor prognosis in patients with HCC.

A novel fibrinogen mutation (γ Thr277Arg) causes hereditary hypofibrinogenemia in a Chinese family

Congenital hypofibrinogenemia is a rare disorder caused by heterozygous mutations in one of the three fibrinogen genes--fibrinogen α-chain (FGA), fibrinogen β-chain (FGB) and fibrinogen γ-chain (FGG)--which code for the Aα, Bβ and γ chains, respectively. In this study, we identified a genetic defect in the FGG underlying the hypofibrinogenemia. The proposita had a prolonged blood clotting time (thrombin time 24.5 s, prothrombin time 16.8 s) and a low level of plasma fibrinogen (0.71 g/l by Clauss method and 0.79 g/l by immunoturbidimetry). DNA screening of the whole fibrinogen gene revealed a heterozygous GC mutation at nucleotide 7482 in her FGG gene. Her father and her half-brother are also heterozygous for this mutation. This mutation contributes to Thr277 → Arg in the γ chain of fibrinogen. To the best of our knowledge, this is the first report of such a mutation that is associated with hypofibrinogenemia.

Postoperative fibrinogen level is associated with postoperative bleeding following cardiothoracic surgery and the effect of fibrinogen replacement therapy remains uncertain

Traditionally, a fibrinogen level > 1 g L(-1) has been viewed as the critical plasma concentration required for hemostasis. No definitive trial has investigated the plasma fibrinogen hemostatic threshold and fibrinogen replacement in complex surgical patients with acquired bleeding. To explore the plasma fibrinogen level required for hemostasis in cardiothoracic surgery patients and assess the association of fibrinogen replacement therapy (using cryoprecipitate or fibrinogen concentrate) with reducing postoperative bleeding rate. Data from a prospectively collated database were used to examine the relationship between postoperative plasma fibrinogen level and the postoperative rate of bleeding within the hour of plasma fibrinogen measurement (n = 430) and to explore the effect of cryoprecipitate infusion (n = 76) or fibrinogen concentrate administration (n = 8) on postoperative bleeding rate. A low plasma fibrinogen level was significantly associated with bleeding, with an odds ratio of 3.06 for every 1 g L(-1) decrease in fibrinogen (95% confidence interval 1.05-8.90) with adjustment for confounders. A fibrinogen threshold associated with excess bleeding was not identified, but this relationship was a continuum. There was no reduction in bleeding following administration of cryoprecipitate or fibrinogen concentrate to raise the post-infusion fibrinogen level to a median of 2.00 and 1.70 g L(-1) , respectively. There is a continuum of bleeding severity with reducing fibrinogen concentration. Fibrinogen concentrate or cryoprecipitate infusion did not significantly reduce bleeding rate; however, confirmation by a randomized controlled trial is required. It remains uncertain whether low postoperative fibrinogen levels are causally associated with postoperative bleeding.

Plasma fibrinogen levels are associated with epidermal growth factor receptor gene mutation in Chinese patients with non-small cell lung cancer

The plasma fibrinogen levels had not only been used as an independent prognostic parameter for the patients with non-small cell lung cancer (NSCLC), but also as a promising biomarker for evaluating the efficacy of chemotherapy. This study aimed to investigate the correlation between the plasma fibrinogen levels and epidermal growth factor receptor (EGFR) gene mutation and clinical-pathological characteristics of Chinese patients with NSCLC. In this retrospective study, NSCLC specimens collected from 352 patients between November 2009 and November 2011 were selected to detect EGFR gene mutation with real-time polymerase chain reaction (RT-PCR). In these specimens, 308 ones were also detected EGFR gene copy number with fluorescence in situ hybridization (FISH). Coagulation makers were examined prior to the operations. The association between the plasma fibrinogen levels and EGFR gene mutation and clinical-pathological characteristics were analyzed using SPSS 16.0 software. The median pre-operation plasma fibrinogen level was 3.55 g/L (109/352) patients with higher plasma fibrinogen level (> 4.0 g/L). The lower plasma fibrinogen levels correlated significantly with EGFR gene mutations (P < 0.001), the similar result was seen in platelet counts (P = 0.026). A linear correlation was found between the plasma fibrinogen levels and the platelet counts in NSCLC patients (R 2 = 0.209, P < 0.001). Pre-operation plasma fibrinogen levels correlated with gender (P < 0.001), smoking status (P < 0.001), and histology (P < 0.001). There were significant link between the above clinical-pathological characteristics and EGFR gene mutations. In addition, EGFR gene mutation was correlated with FISH-positive status (P < 0.001). Moreover, both plasma fibrinogen level (P = 0.024) and the EGFR gene copy number (P = 0.040) had significant relationships with the pathological TNM stage. This study showed that a significant relevance between plasma fibrinogen levels and EGFR gene mutations. The plasma fibrinogen level might be as a clinical decision parameter for evaluating the efficacy of anti-EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. The patients of NSCLC had higher indicate have poor benefits from anti-EFGR TKIs. In addition, pre-operation plasma fibrinogen level could be used as an indepedent prognostic biomarker for the patients with NSCLC.

Social drift of cardiovascular disease risk factors in Africans from the North West Province of South Africa : the PURE study : cardiovascular topics

This study examined whether the association between socio-economic status (SES) and cardiovascular disease (CVD) risk factors in black South Africans from the North West Province had shifted from the more affluent groups with higher SES to the less affluent, lower SES groups over a period of nine years. Cross-sectional baseline data of 2 010 urban and rural subjects (35 years and older) participating in the Prospective Urban and Rural (PURE) study and collected in 2005 were analysed to examine the relationship of level of education, employment and urban or rural residence with dietary intakes and other CVD risk factors. These relationships were compared to those found nine years earlier in the Transition and Health during the Urbanisation of South Africans (THUSA) study conducted in the same area. The results showed that urban women had higher body mass index (BMI), serum triglyceride and fasting glucose levels compared to rural women and that both urban men and women had higher blood pressures and followed a more Westernised diet. However, rural men and women had higher plasma fibrinogen levels. The more highly educated subjects (which included both urban and rural subjects) were younger than those with no or only primary school education. Few of the risk factors differed significantly between education groups, except that more highly educated men and women had lower BMIs, and women had lower blood pressure and triglyceride levels. These women also followed a more prudent diet than those with only primary school education. Employed men and women had higher BMIs, higher energy intakes but lower plasma fibrinogen levels, and employed women had lower triglyceride levels. No significant differences in total serum cholesterol values were observed. These results suggest a drift of CVD risk factors from groups with higher SES to groups with a lower SES from 1996 to 2005, indicating that interventions to prevent CVD should also be targeted at Africans living in rural areas, those with low educational levels, and the unemployed.

Demonstration of heterodimeric fibrinogen molecules partially conjugated with albumin in a novel dysfibrinogen: Fibrinogen Mannheim V

A 30-year-old female experienced three miscarriages in early pregnancy. Extensive laboratory screening showed a low plasma fibrinogen level of approximately l g/l detected by PT-derived fibrinogen assay. The fibrinogen level in the immunological assay was 3 g/l. The functional Clauss assay yielded an intermediate result of 1.78 g/l. During her fourth and fifth pregnancy, the patient received fibrinogen concentrates (Haemocomplettan, CLS Behring, Marburg, Germany), starting with 4 grams of human fibrinogen, followed by 2 grams every second day until the 15(th) week of pregnancy. The further course of these pregnancies was uneventful. SDS-PAGE and immunoblotting showed doublet bands in the positions of the high-molecular weight (HMW)- and low-molecular-weight (LMW)-fibrinogen, a single LMW' fibrinogen band, plus additional bands with higher molecular weight than HMW-fibrinogen, which were also reactive with anti-human serum albumin (HSA) antiserum. These bands correspond to variant fibrinogen conjugated with albumin. Reduced SDS-PAGE and immunoblotting using polyclonal anti-fibrinopeptide A antiserum disclosed one additional Aalpha-chain band with lower molecular weight. Amplification and sequencing of exon 5 of the alpha gene indicated heterozygosity for a novel single nucleotide deletion at codon Aalpha494 (C1537delA). His494 is replaced by Pro and this is followed by 23 (LMKLPSSTLPQLEKHSQ VSSHLC) new amino acids before premature truncation after Cys517, yielding a free C-terminal cysteine, which may link with albumin. This new fibrinogen mutation, leads to a balanced array of homo- and heterodimeric fibrinogen molecules, some of which are conjugated to albumin.