Low Plasma Fibrinogen Concentration Research Articles

Fibrinogen Concentrate in Cardiovascular Surgery: A Meta-analysis of Randomized Controlled Trials.

Postoperative bleeding remains a frequent complication after cardiovascular surgery and may contribute to serious morbidity and mortality. Observational studies have suggested a relationship between low endogenous plasma fibrinogen concentration and increased risk of postoperative blood loss in cardiac surgery. Although the transfusion of fibrinogen concentrate has been increasing, potential benefits and risks associated with perioperative fibrinogen supplementation in cardiovascular surgery are not fully understood. PubMed, Cochrane Library, Ovid MEDLINE, Embase, Web of Science, and China National Knowledge Infrastructure were searched on January 15, 2017, with automated updates searched until February 15, 2018, to identify all randomized controlled trials (RCTs) of fibrinogen concentrate, whether for prophylaxis or treatment of bleeding, in adults undergoing cardiovascular surgery. All RCTs comparing fibrinogen infusion versus any other comparator (placebo/standard of care or another active comparator) in adult cardiovascular surgery and reporting at least 1 predefined clinical outcome were included. The random-effects model was used to calculate risk ratios and weighted mean differences (95% confidence interval [CI]) for dichotomous and continuous variables, respectively. Subgroup analyses by fibrinogen dose and by baseline risk for bleeding were preplanned. A total of 8 RCTs of fibrinogen concentrate in adults (n = 597) of mixed risk or high risk undergoing cardiovascular surgery were included. Compared to placebo or inactive control, perioperative fibrinogen concentrate did not significantly impact risk of all-cause mortality (risk ratio, 0.41; 95% CI, 0.12-1.38; I = 10%; P = .15). Fibrinogen significantly reduced incidence of allogeneic red blood cell transfusion (risk ratio, 0.64; 95% CI, 0.49-0.83; I = 0%; P = .001). No significant differences were found for other clinical outcomes. Subgroup analyses were unremarkable when analyzed according to fibrinogen dose, time of infusion initiation, mean cardiopulmonary bypass time, and rotational thromboelastometry/fibrinogen temogram use (all P values for subgroup interaction were nonsignificant). Current evidence remains insufficient to support or refute routine perioperative administration of fibrinogen concentrate in patients undergoing cardiovascular surgery. Fibrinogen concentrate may reduce the need for additional allogeneic blood product transfusion in cardiovascular surgery patients at high risk or with evidence of bleeding. However, no definitive advantage was found for reduction in risk of mortality or other clinically relevant outcomes. The small number of clinical events within existing randomized trials suggests that further well-designed studies of adequate power and duration to measure all-cause mortality, stroke, myocardial infarction, reoperation, and thromboembolic events should be conducted. Future studies should also address cost-effectiveness relative to standard of care.

Low Fibrinogen Is Associated with Increased Bleeding-Related Re-exploration after Cardiac Surgery.

Re-exploration after cardiac surgery remains a relatively frequent complication associated with adverse effects on outcome. We aimed to identify risk factors for re-exploration. We retrospectively reviewed 2,403 patients having undergone cardiac surgical procedure between January 2013 and December 2014. Re-exploration was required in 114 patients (4.7%). Patients with oral anticoagulation, infective endocarditis, or a clearly identified bleeding source were excluded. Therefore, 42 patients remained for analysis. A matched cohort was selected for age, sex, ejection fraction, creatinine, and procedure out of the non-re-explored patients. Demographic data were similar in both groups, except for a higher prevalence of diabetes (45 vs. 21%; p = 0.036) in the non-re-explored patients. Surgery was elective in two-thirds and preoperative plasma fibrinogen concentration was lower in patients requiring re-exploration (2.8 ± 0.9 vs. 3.6 ± 0.9 g/L; p = 0.002). During the initial operation, re-explored patients received more packed red blood cells (1.5 ± 3 vs. 0 ± 1 units; p < 0.001), Postoperatively, re-explored patients had higher lactate levels (1.7 ± 1.4 vs. 1.3 ± 0.6 mmol/L, p = 0.044), more chest tube drainage (1,245 ± 948 vs. 685 ± 413 mL; p < 0.001), higher hospital mortality (19 vs. 7%; p = 0.19), and longer intensive care unit (ICU) stays (8 ± 8 vs. 4 ± 7 days; p = 0.010). In addition, more fibrinogen was administrated during the initial surgery. Plasma fibrinogen concentration upon arrival at the ICU was lower in patients requiring re-exploration (2 ± 0.6 vs. 2.7 ± 0.7 g; p < 0.001). Multivariable linear regression analysis identified fibrinogen upon arrival at the ICU as an independent predictor of postoperative bleeding. Cardiac surgery patients with low perioperative plasma fibrinogen concentration appear to be more susceptible to bleeding and re-exploration. Re-exploration in this group of patients is associated with increased morbidity and mortality.

Reference values for rotational thromboelastometry (ROTEM) in clinically healthy cats.

To establish reference intervals for rotational thromboelastometry (ROTEM) using feline blood. Prospective study. University teaching hospital. Twenty-three clinically healthy cats between 1 and 15 years. For each cat, whole blood was collected via jugular or medial saphenous venipuncture, and blood was placed into a serum tube, a tube containing potassium-EDTA, and tubes containing 3.2% sodium citrate. The tubes were maintained at 37°C for a maximum of 30 minutes before coagulation testing. ROTEM tests included the EXTEM, INTEM, FIBTEM, and APTEM assays. In addition, prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen concentration (Clauss method) were analyzed for each cat. Reference intervals for ROTEM were calculated using the 2.5-97.5th percentile for each parameter, and correlation with the standard coagulation profile was performed. Compared to people, clinically healthy cats had similar values for the EXTEM and INTEM assays, but had lower plasma fibrinogen concentrations (0.9-2.2 g/L), resulting in weaker maximum clot firmness (MCF, 3-10 mm) in the FIBTEM test. In 18 cats, maximum lysis (ML) values in the APTEM test were higher than in the EXTEM test, which seems unlikely to have occurred in the presence of aprotinin. It is possible that the observed high maximum lysis values were due to clot retraction rather than true clot lysis. Further studies will be required to test this hypothesis. Cats have a weaker clot in the FIBTEM test, but have a similar clot strength to human blood in the other ROTEM assays, which may be due to a stronger contribution of platelets compared to that found in people. In cats, careful interpretation of the results to diagnose hyperfibrinolysis is advised, especially with the APTEM test, until further data are available.

Preoperative plasma fibrinogen concentration, factor XIII activity, perioperative bleeding, and transfusions in elective orthopaedic surgery: A prospective observational study

BackgroundMajor orthopaedic surgery involves a calculated risk of bleeding. In other groups of surgical patients, low preoperative plasma fibrinogen concentration and factor XIII (FXIII) activity have been associated with an elevated risk of bleeding. In the present study we investigated the association between preoperative fibrinogen plasma concentration and FXIII activity on bleeding and transfusion requirements in patients undergoing a spinal fusion procedure or hip or knee arthroplasty. MethodsTwo hundred and forty-five adult patients undergoing spine fusion surgery (n=52), total unilateral primary hip arthroplasty (n=114), or total knee arthroplasty (n=79) were included in a prospective observational study. Blood samples were collected <24h before surgery and analysed for fibrinogen concentration and FXIII activity. Intraoperative and postoperative bleeding volume and transfusion requirements were recorded. ResultsSpinal fusion surgery patients with a low preoperative fibrinogen concentration (≤2.5g/L) had a greater total perioperative median bleeding volume than patients with fibrinogen>2.5g/L (2430 (400–6560) mL vs. 1390 (400–7420) mL, p=0.029). No significant association between low fibrinogen levels and perioperative bleeding volume was observed for arthroplasty patients. There was no association between low fibrinogen levels and transfusion requirements in any of the groups. Low FXIII activity was not significantly associated with bleeding volume and transfusion requirements in any group. ConclusionMeasurement of preoperative fibrinogen plasma concentration can identify spinal fusion patients with an increased risk of excessive perioperative bleeding. Measurement of FXIII activity cannot identify orthopaedic patients with elevated risk of bleeding.

Fibrinogen plasma concentration before delivery is not associated with postpartum haemorrhage: a prospective observational study

Low plasma fibrinogen concentration has been linked to postpartum haemorrhage. The primary aim of this study was to assess whether fibrinogen concentration at admission before labour is associated with severe postpartum haemorrhage. Secondary aims were to describe fibrinogen concentration before and after labour and to identify predictors for severe postpartum haemorrhage. 1951 healthy women were included in a prospective observational study. Fibrinogen concentration was determined at admission to the labour ward and in a subgroup of women (n=80) also after the placenta was delivered. Bleeding volume postpartum was estimated by weighing surgical sponges and pads and by measuring collected blood. Predictors for severe postpartum haemorrhage (>1000 ml) were identified with bivariate and multivariate regression analyses. Mean fibrinogen concentration was 5.3 (SD 0.8) g litre(-) (1). Median estimated blood loss was 450 (range 70-4400) ml and 250 (12.8%) women bled >1000 ml. Fibrinogen concentration was not correlated with postpartum haemorrhage in the entire cohort (r(s)=0.003, P=0.90) or in any subgroup. Fibrinogen concentration was not associated with bleeding >1000 ml (odds ratio 1.01 (CI 95% 0.85-1.19), P=0.93) and did not differ significantly before and after delivery. Oxytocin stimulation, instrumental delivery, Caesarean section and exploration of uterus were identified as independent predictors of haemorrhage >1000 ml. Fibrinogen plasma concentration at admission before labour does not predict severe postpartum haemorrhage in a general obstetric population. Fibrinogen concentration does not decrease significantly during normal labour. Excessive postpartum bleeding is mainly as a result of obstetric complications.

High plasma fibrinogen concentration and platelet count unfavorably impact survival in non-small cell lung cancer patients with brain metastases

High expression of fibrinogen and platelets are often observed in non–small cell lung cancer (NSCLC) patients with local regional or distant metastasis. However, the role of these factors remains unclear. The aims of this study were to evaluate the prognostic significance of plasma fibrinogen concentration and platelet count, as well as to determine the overall survival of NSCLC patients with brain metastases. A total of 275 NSCLC patients with brain metastasis were enrolled into this study. Univariate analysis showed that high plasma fibrinogen concentration was associated with age≥65 years (P = 0.011), smoking status (P = 0.009), intracranial symptoms (P = 0.022), clinical T category (P = 0.010), clinical N category (P = 0.003), increased partial thromboplastin time (P < 0.001), and platelet count (P < 0.001). Patients with low plasma fibrinogen concentration demonstrated longer overall survival compared with those with high plasma fibrinogen concentration (median, 17.3 months versus 11.1 months; P≤0.001). A similar result was observed for platelet counts (median, 16.3 months versus 11.4 months; P = 0.004). Multivariate analysis showed that both plasma fibrinogen concentration and platelet count were independent prognostic factors for NSCLC with brain metastases (R2 = 1.698, P < 0.001 and R2 = 1.699, P < 0.001, respectively). Our results suggest that high plasma fibrinogen concentration and platelet count indicate poor prognosis for NSCLC patients with brain metastases. Thus, these two biomarkers might be independent prognostic predictors for this subgroup of NSCLC patients.

Fibrinogen Foxton: A novel BβA277V mutation causing low normal plasma fibrinogen concentration

Fibrinogen Foxton: A novel BβA277V mutation causing low normal plasma fibrinogen concentration -

Disseminated Intravascular Coagulation in Cats

The purpose of this study was to describe the clinical characteristics of cats with disseminated intravascular coagulation (DIC), including associated diseases and hemostatic abnormalities, and to identify risk factors for death and treatments that potentially altered outcome. Medical records for cats with DIC from 1990-2004 were evaluated retrospectively. Inclusion criteria were the presence of an underlying disorder associated with DIC and either postmortem examination findings of intravascular fibrin deposition or thrombosis, or both of 2 or more organs or coagulation profiles that meet 3 of 5 criteria: prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT), presence of fibrin degradation products (FDP), low plasma fibrinogen (FIB) concentration, and thrombocytopenia (<160,000 platelets/microL). Signalment, historical data, clinical findings, clinicopathologic data, underlying disorders, management, and outcome were recorded. Forty-six cats fulfilled the criteria for DIC. Cats ranged in age from 7 weeks to 17 years (median, 9 years). Hemorrhage was noted in 7 of 46 cats (15%). Three of 46 cats (7%) survived, whereas 43 of 46 (93%) died or were euthanized. The most common underlying disorders were lymphoma, other forms of neoplasia, pancreatitis, and sepsis. There was no association detected between outcome and signalment; underlying disease; hemorrhage; abnormalities in aPTT, FIB, FDPs, platelet count; transfusion of blood products; and heparin therapy. However, the median PT of nonsurvivors was more prolonged than in survivors (P < .005). DIC in cats can result from a variety of neoplastic, infectious, and inflammatory disorders, and is associated with a high case fatality rate.

Evaluation of the potential causes of epistaxis in dogs with natural visceral leishmaniasis

Haemostasis was evaluated in 19 dogs with natural Leishmania infection, six of them with a history of epistaxis, and the results were compared with the results from 24 healthy dogs....

Diagnosis of disseminated intravascular coagulation in dogs admitted to an intensive care unit

Objective To describe and evaluate hemostatic function in critically ill dogs with clinical signs of diseases that predispose to disseminated intravascular coagulation (DIC). Design Prospective case series. Animals 59 critically ill dogs (affected dogs) with clinical signs of diseases known to predispose to DIC and 52 clinically normal dogs (control dogs). Procedure Activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin clotting time (TCT), plasma fibrinogen concentration, serum concentration of fibrin and fibrinogen-related antigens (FRA), and plasma antithrombin III (AT III) activity were determined for all dogs. Results from affected dogs were compared with those of control dogs. In some affected dogs, postmortem tissue specimens were examined for evidence of microvascular thrombosis. A diagnosis of DIC was made by fulfilling at least 3 of the following criteria: 1) abnormal aPTT, PT, or TCT value, 2) low plasma fibrinogen concentration, 3) low plasma AT III activity, 4) high serum FRA concentration, or 5) low platelet count. To evaluate the severity of hemostatic dysfunction, 3 arbitrary categories (mild, moderate, and severe) were proposed. Results A diagnostic strategy based on moderate hemostatic dysfunction identified DIC in 16 of 59 (27.1%) affected dogs. The AT III activity was &lt; 70% in 15 of 16 dogs with DIC. Microvascular thrombosis was observed in tissue specimens from 7 of 8 affected dogs. Serum FRA and plasma fibrinogen concena did not contribute in establishing a diagnosis of DIC. Conclusions and Clinical Relevance A diagnosis of DIC can be made when hemostatic dysfunction is moderate in dogs with clinical signs of diseases associated with DIC. (J Am Vet Med Assoc 1999;215:798–804).

A Frame Shift Mutation in the Fibrinogen Aα Chain Gene in a Kindred With Renal Amyloidosis

A new American kindred with amyloidosis was found by single-strand conformation polymorphism analysis to have a mutation in the fibrinogen A alpha chain gene. Affected members in this kindred have autosomal dominant amyloid nephropathy. DNA sequencing showed a single nucleotide deletion at the third base of codon 524 of the fibrinogen A alpha chain genes (4904delG) that resulted in a frame shift and premature termination of the protein at codon 548. Antiserum was produced to a portion of the abnormal peptide predicted by the DNA sequence and amyloid deposits were immuno-histologically proven to contain this abnormal peptide. Two of the propositus' 4 children were positive for the mutant fibrinogen A alpha chain gene by restriction fragment length polymorphism analysis based on polymerase chain reaction. These two mutant gene carriers now in the second decade of life show no clinical symptoms of amyloidosis as yet but have lower plasma fibrinogen concentrations when compared with their normal siblings. This the first description of a kindred with renal amyloidosis and low plasma fibrinogen and also the first report of amyloidosis caused by a frame shift mutation.

Impact of polymorphisms in the alpha- and beta-fibrinogen gene on plasma fibrinogen concentrations of coronary heart disease patients

Despite many investigations in a variety of experimental settings, uncertainty remains concerning the size of the genetic contribution to plasma fibrinogen levels. We used the polymerase chain reaction to amplify the polymorphic sites for the restriction enzymes TaqI in the α-fibrinogen gene and HaeIII, HindIII and BclI in the β-fibrinogen gene. Three hundred and eighty-four male coronary heart disease patients were investigated. Two alleles for each enzyme (+ or − designating, respectively, the presence or absence of the cutting site) were detected. The HaeIII and HindIII cutting sites were in complete linkage disequilibrium. A small but significant increase in fibrinogen level was associated with the rare cutting sites of HaeIII HindIII , BclI and TaqI. At all polymorphic sites homozygosity for the frequent alleles was associated with about 0.20 g/l lower plasma fibrinogen concentrations than heterozygosity at the respective sites (p < 0.05). The frequencies and natures of the rare alleles were as follows: TaqI (+) 0.28, HaeIII HindIII (−) 0.22 and BclI (+) 0.17. Mean fibrinogen levels in patients heterozygous for each of the four polymorphisms were 0.47 g/l greater than in subjects homozygous for the frequent allele at each cutting site ( HaeIII HindIII + −, TaqI + −, BclI + ÷ fibrinogen level 3.58 g/l (n = 32); HaeIII HindIII + +, TaqI − −, BclI − ÷ fibrinogen level 3.11 g/l (n = 99), p = 0.003). Each polymorphism accounted for between 0.5 and 1.4% of the overall variance in fibrinogen concentration. Together, the polymorphisms in HaeIII, HindIII and TaqI explained 5.8% of overall variance, a proportion equivalent to that explained by age, smoking and body mass index (5.5%). In conclusion, there is a hereditary component to plasma fibrinogen concentrations in men. Individuals predisposed to increased fibrinogen levels can be detected using restriction fragment length polymorphisms.

Reliability of the simple 20 minute whole blood clotting test (WBCT20) as an indicator of low plasma fibrinogen concentration in patients envenomed by Bothrops snakes

A simple whole blood clotting test (WBCT20) was assessed for its efficacy in determination of severe defibrinogenation in patients envenomed by Bothrops snakes in Brazil. There was a close relationship between the results of the WBCT20 and plasma fibrinogen levels in 69 moderately envenomed patients. The advantage of the WBCT20 over estimation of plasma fibrinogen concentrations in patients is that it is a simpler, faster and more reliable test. It is also of use in assessing the effectiveness of antivenom therapy in relation to the restoration of blood coagulability.

Bleeding complications of thrombolytic treatment

The mechanism and incidence of bleeding in patients undergoing fibrinolytic therapy are discussed, the role of laboratory findings in predicting the patient's clinical course is described, and guidelines concerning patient management are presented. Plasminogen activators have more similarities than differences in the mechanisms by which they dissolve thrombi and hemostatic plugs and, therefore, in their potential for vascular reperfusion or bleeding complications. The duration of an active lytic state in the blood varies according to the half-life of the activator; regardless of the agent chosen, however, plasma fibrinogen concentrations do not return to normal levels for one to two days following treatment. If plasminogen activator is still circulating, control of surgical bleeding after plasminogen activator treatment requires correction of the low plasma fibrinogen concentration with cryoprecipitate and administration of antifibrinolytic agents. Tests of coagulation and fibrinolysis can demonstrate a lytic state during therapy, but manipulation of drug therapy based on laboratory results is unlikely to control the patient's clinical course. Safe and effective therapy with plasminogen activators depends more on clinical judgment than on strict interpretation of laboratory test results.

A Direct Hepatotoxic Effect of Valproic Acid

Nine patients treated with valproic acid had low plasma fibrinogen concentration and other liver function abnormalities. Several patients also had a low platelet count and prolonged bleeding time. The abnormal values returned promptly to normal when the drug therapy was discontinued or the dosage reduced. The liver function abnormalities are consistent with a direct, dose-related hepatotoxicity.

Results of ankle ststolic pressure measurements in patients with intermittent claudication being treated with clofibrate.

Ankle systolic pressure measurements in 67 patients with intermittent claudication treated with Clofibrate for an average period of 11 months and 32 untreated patients suggest that 1) patients with a raised initial plasma fibrinogen concentration have more severe disease than those with low initial plasma fibrinogen concentration and 2) the response to treatment with Clofibrate is significantly better in those with a raised plasma fibrinogen concentration. On the basis of the patients own estimation of their claudication distance there was marked symptomatic inprovement in the treated patients. There was also a significant decrease in mean plasma fibrinogen levels in the treated patients and it is suggested that the hypofibrinogenemic effect of Clofibrate may be responsible for the benefit of this drug in patients with vascular disease.

Toxic effects of warfarin in rats fed different diets

Toxic doses of warfarin were administered (0.8 mg/kg, po) daily for 5 days to one group of rats (250–300 g) fed oat groats and to another fed Purina laboratory chow. Five rats from each dietary group were sacrificed at 5, 29, 53, 77 and 101 hr after the initial dose. The plasma warfarin concentration increased more rapidly in the oat-fed rats than in those fed chow; however, the liver warfarin: plasma warfarin ratio following the first dose of warfarin indicated that the chow-fed rats were removing the warfarin from the plasma more rapidly. Presumably, the rate of metabolism of warfarin was more rapid in the chow-fed than in the oat-fed rats because the prothrombin times in the former increased at a slower rate. Apparently, less liver damage occurred in the chow-fed rats because they had lower plasma fibrinogen concentrations than those fed oats. There was a 50% decline in the hematocrit values in both groups. The linear decline in the total plasma protein in each group was a function of linear declines in plasma albumin and α-globulin. In both groups, the β- and γ-globulins remained stable until 101 hr, at which time they increased. It was concluded that the response of rats to repeated toxic oral doses of warfarin was influenced by protein in the diet; rats fed higher protein diets were more tolerant to warfarin.

Fibrinogen Philadelphia. A hereditary hypodysfibrinogenemia characterized by fibrinogen hypercatabolism.

A new, autosomally inherited abnormal fibrinogen associated with hypofibrinogenemia has been described in several members of a family. Plasma fibrinogen measured either as thrombin-clottable protein or by immunodiffusion revealed a fibrinogen level ranging between 60 and 90 mg/100 ml. The thrombin time of plasma or purified fibrinogen was prolonged and only partially corrected by the addition of calcium. Purified fibrinogen prolonged the thrombin time of normal plasma. Fibrinopeptide release by thrombin was normal in rate and amount, but fibrin monomer aggregation was grossly disturbed, especially in a high ionic strength medium. We have designated this fibrinogen "fibrinogen Philadelphia." Acrylamide gel electrophoresis of mixtures of [121I]normal and [125I]abnormal fibrinogens revealed a slight increase in the anodal mobility of fibrinogen Philadelphia. Similarly, DEAE-cellulose chromatography showed slightly stronger binding of fibrinogen Philadelphia than normal. To elucidate the mechanism responsible for the low plasma fibrinogen concentration, simultaneous metabolic studies of autologous (patient) and homologous (normal) fibrinogen, labeled with 125I and 121I, respectively, were performed in two affected subjects. Autologous fibrinogen half-life was short and the fractional catabolic rate was markedly increased in both family members. In contrast, homologous fibrinogen half-life and fractional catabolic rate were normal. These metabolic studies demonstrate that rapid degradation of fibrinogen Philadelphia is largely responsible for the depressed levels of a plasma fibrinogen. This represents the first example of a mutant plasma protein in which the molecular defect is associated with an altered catabolism.

Coagulation studies in patients with acute infectious hepatitis.

SummaryCoagulation studies were performed on 104 hospital inpatients with acute infectious hepatitis. Patients with clinical evidence of liver failure were studied separately from those without liver failure.A coagulation defect was found in 57 of the 78 patients without liver failure. This consisted of a prolonged prothrombin time and reduced levels of factors V, VII and X, and plasminogen. The defect was mild in most patients and was not associated with bleeding. A severe coagulation defect was found in all 26 patients with liver failure. Factors II, V, VII and X were markedly reduced. Plasminogen was reduced in all patients, and a low plasma fibrinogen concentration and thrombo‐cytopenia were found in half. One third of the patients studied showed an increase in serum fibrin/ fibrinogen degradation products. It is suggested that in some of these patients disseminated intravascular thrombosis contributed to the coagulation defect. Two patients had evidence of increased fibrinolytic activity.Bleeding occurred in 15 patients with liver failure and required treatment in 10. Fifteen patients with liver failure died. Nine patients with liver failure were treated with exchange transfusions during which a significant improvement of the prothrombin time and a slight reduction in platelet count was observed. Bleeding stopped during exchange transfusions in six of eight patients. It is possible that the improvement of the coagulation defect during exchange transfusions contributed to improved haemostasis.