Clauss Fibrinogen Research Articles

Relationship between the dual platelet-inhibited ROTEM® Sigma FIBTEM assay and Clauss fibrinogen during postpartum haemorrhage.

Relationship between the dual platelet-inhibited ROTEM® Sigma FIBTEM assay and Clauss fibrinogen during postpartum haemorrhage.

TEG® 6s coagulation testing with a novel heparin neutralization cartridge: Technical validation and determination of normal reference ranges.

We sought to establish normal reference ranges (NRRs) for a novel TEG 6s cartridge (TEG 6s Citrated: K, KH, RTH, FFH [Global Hemostasis]) (Haemonetics Corporation, Boston, MA, US). Healthy volunteers (≥18 years of age) included in this single-arm study provided single samples of whole blood. Primary end points included TEG parameters in the citrated kaolin (CK), CK with heparinase (CKH), RapidTEG with heparinase (CRTH), and functional fibrinogen with heparinase (CFFH) assays. Evaluable data were contributed by 164 volunteers (48.8% female; 62% White/Caucasian). The following NRRs were established: CK maximum amplitude (MA), 51.0 to 67.6mm; CKH-MA, 51.8 to 67.9mm; CRTH-MA, 53.0 to 68.9mm; CFFH-MA, 15.3 to 34.4mm; CK reaction time, 5.0 to 9.1 minutes; CKH reaction time, 4.9 to 9.4 minutes; CKH lysis 30 minutes after MA, 0% to 3.2%. Duplicate measurements demonstrated high reproducibility. CFFH-MA correlated with Clauss fibrinogen concentration (Pearson correlation coefficient, 0.74). Laboratory-based studies demonstrated maintenance of the relationship between CFFH-MA and fibrinogen up to 1344mg/dL (hyperfibrinogenemic samples) and acceptability of heparin neutralization up to concentrations of low molecular weight and unfractionated heparin of 1.3 IU/mL and 5 IU/mL, respectively. This study established NRRs for the Global Hemostasis cartridge and serves as a proof of concept for the validity of results obtained using this cartridge.

Trauma-induced dysfibrinogenemia: the von Clauss assay does not accurately measure fibrinogen levels after injury

AbstractTrauma patients who sustain severe tissue injury and hemorrhage often receive fibrinogen repletion to avert coagulopathy and achieve hemostasis. However, fibrinogen supplementation has not shown a benefit in trauma patients with coagulopathy. The von Clauss functional fibrinogen assay is the primary indication for fibrinogen transfusion. This assay, however, infers fibrinogen levels optically via in vitro clot formation time and does not directly measure the quantity or quality of plasma fibrinogen. We hypothesized that the Clauss fibrinogen activity assay does not accurately reflect true fibrinogen levels in severely injured patients. Here, we demonstrate normal baseline plasma fibrinogen levels as measured by mass spectrometry despite coagulopathic Clauss values in severely injured patients. This discrepancy is most significant in patients with coagulopathy (international normalized ratio of >1.3) or with high shock, and persists even after fibrinogen repletion. These data highlight the need to reevaluate clinical testing of fibrinogen activity and transfusion criteria for the critically injured, and indicate that correcting shock and the oxidative, inflammatory milieu of trauma may be more effective at improving fibrinogen activity. This trial was registered at www.ClinicalTrials.gov as #NCT01838863.

A comparative in vitro study of the anticoagulant effect of branded versus generic rivaroxaban

BackgroundSeveral generic formulations of rivaroxaban were recently marketed to be used interchangeably with their branded equivalent. However, there have been no previously published studies that directly compared the in vitro anticoagulant effect of branded vs. generic rivaroxaban. The aim of this in vitro study was to compare the effects of three raw rivaroxaban materials, obtained from the branded (Xarelto®) and two generic (Rivarolto® and Rivaroxaban Sandoz®) rivaroxaban formulations on an array of coagulation assays. MethodsA pool of normal plasma was spiked with several concentrations of the three rivaroxaban (range 50–750 ng/ml). The concentrations were assessed with a rivaroxaban calibrated anti-Xa assay and confirmed by ultra-high-performance liquid chromatography-mass spectrometry coupled with tandem mass spectrometry (UHPLC-MS/MS). The following assays were performed: Prothrombin time (PT), activated Partial Thromboplastin time (aPTT), Diluted Russell's Viper Venom Test (dRVVT), Thrombin time (TT), Clauss Fibrinogen, Factor VII, VIII and IX assays, and thromboelastography. ResultsThe results obtained by the three rivaroxaban at similar concentrations were comparable. Increasing concentrations of the three rivaroxaban showed a strong positive correlation with the PT, aPTT and dRVVT assays (r > 0.95, p < 0.01 for all), and a strong negative correlation with the Factors assays (r < −0.95, p < 0.01 for all). TT and Clauss Fibrinogen were not affected by rivaroxaban. No significant difference was identified in the mean assays' results obtained by the three rivaroxaban. ConclusionThis study showed that the branded and generic rivaroxaban exert an identical in vitro anticoagulant effect across a wide range of concentrations.

Investigation of acquired dysfibrinogenaemia in adult patients with sepsis using fibrinogen function vs. concentration ratios: a cross-sectional study.

Inherited or acquired molecular abnormalities form a clinically heterogeneous group of fibrinogen disorders called dysfibrinogenaemia. Apart from a pediatric case report and in contrast to other clinical conditions, acquired dysfibrinogenaemia has not been previously reported in septic patients. In an observational cohort study, 79 adult septic patients were investigated for the presence of acquired dysfibrinogenaemia at the time of their admission to the intensive care unit (ICU) of the University Hospital Frankfurt. Following established recommendations, fibrinogen clotting activity vs. antigen ratios were analyzed using Clauss fibrinogen, prothrombin-derived fibrinogen, and radial immunodiffusion (RID) fibrinogen concentration. Prothrombin-derived fibrinogen levels were highest (527 ± 182 mg/dL) followed by Clauss fibrinogen (492 ± 209 mg/dL) and radial immunodiffusion fibrinogen (426 ± 159 mg/dL). Very few cases demonstrated hypofibrinogenaemia making overt disseminated intravascular coagulation (DIC) unlikely in the cohort investigated. Clauss/RID fibrinogen ratios were lower (1.17 ± 0.19) compared to prothrombin time-derived/RID ratios (1.35 ± 0.33). Using the Clauss/RID dataset, 21% of patients (16/76 patients) demonstrated values below a threshold ratio for suspected acquired dysfibrinogenaemia arbitrarily set at 1.0. In contrast, prothrombin-derived ratios were below the threshold in only 7% (4/58 patients). The results point to the presence of acquired dysfibrinogenaemia in part of adult septic patients. If confirmed in further studies, this may form part of a specific laboratory signature of a sepsis-associated coagulation phenotype.

International council for standardisation in haematology recommendations on fibrinogen assays, thrombin clotting time and related tests in the investigation of bleeding disorders.

This guidance was prepared on behalf of the International Council for Standardisation in Haematology (ICSH) by an international working group of clinicians and scientists. The document focuses on tests and assays used for the assessment of fibrinogen function, particularly in the scenario of bleeding disorders. Thrombin clotting time (TT) is used as a screening test in some laboratories and also has some utility when direct anticoagulants are in use. The Clauss fibrinogen assay remains the method of choice for the assessment of fibrinogen function, but there are some situations where the results may be misleading. Prothrombin time derived fibrinogen assays are frequently used, but should be interpreted with caution; the results are not interchangeable between different methods and fibrinogen can be overestimated in certain clinical scenarios. Viscoelastic point of care methods may be helpful in emergency situations, while Reptilase time (and similar tests) are useful combined with TT in distinguishing heparin contamination of samples (i.e., if an incorrect blood draw is suspected) and the presence of direct thrombin inhibitors. Fibrinogen antigen assays should be used in the investigation of functional fibrinogen abnormalities; fibrinogen antigen and genetic testing are recommended in the confirmation of congenital fibrinogen disorders. The following recommendations for fibrinogen function assessment are based on published literature and expert opinion and should supplement local regulations and standards.

Dysfibrinogenemia: discrepant results following infusion of purified fibrinogen.

Inherited dysfibrinogenemias are molecular disorders of fibrinogen that affect fibrin polymerization. The majority of cases are asymptomatic, but a significant proportion suffer from increased bleeding or thrombosis. We present two unrelated cases of dysfibrinogenemia, both of whom showed a characteristic discrepancy between fibrinogen activity and the immunologic fibrinogen. In one patient, the dysfibrinogenemia was confirmed by molecular analysis; in the other case, the diagnosis was presumptive based upon laboratory studies. Both patients underwent elective surgery. Both received a highly purified fibrinogen concentrate preoperatively and demonstrated a suboptimal laboratory response to the infusion. Three methods for determining fibrinogen concentration (Clauss fibrinogen, prothrombin-derived fibrinogen, and the viscoelastic functional fibrinogen) were utilized in the case of one patient, and these techniques showed discrepant results with the classic Clauss method giving the lowest concentration. Neither patient experienced excessive bleeding during surgery. Although these discrepancies have been previously described in untreated patients, their manifestation after infusion of purified fibrinogen is less well appreciated.

P21 FIBTEM A5 correlates well with laboratory Clauss fibrinogen results in the obstetric population

P21 FIBTEM A5 correlates well with laboratory Clauss fibrinogen results in the obstetric population

Fibcare® shows correlation with fibrinogen levels by the Clauss method during cardiopulmonary bypass.

Central laboratory measurements are time consuming, while rapid fibrinogen level measurements within the operating room improve transfusion strategies. We aimed to clarify the correlation between fibrinogen concentrations (measured using Fibcare® and the Clauss fibrinogen assay in a central laboratory) during cardiovascular surgery with cardiopulmonary bypass. Data of patients whose Fibcare, traditional laboratory-based testing, and thromboelastographic results were measured using the same blood sample during cardiopulmonary bypass from February 2021 to January 2022 were retrospectively examined. We analyzed correlation in categories of body temperature during cardiopulmonary bypass: total cases, mild hypothermia (28-34°C), and moderate or severe hypothermia (<28°C). The Clauss fibrinogen assay was performed in 123 cases, Fibcare in 107, and thromboelastography in 91. For mild hypothermia, moderate or severe hypothermia, and overall, the root mean squared error and R-square in Fibcare were 16.1 and 0.86, 13.1 and 0.87, and 14.9 and 0.87, respectively, and for thromboelastography, they were 3.26 and 0.74, 2.70 and 0.79, and 3.08 and 0.75, respectively. A significant relationship was noted between Fibcare and Claus fibrinogen analysis regardless of body temperature during cardiopulmonary bypass. The measurement of fibrinogen levels using Fibcare allows for faster transfusion preparation than that of the traditional Clauss fibrinogen assay.

Potential for prolongation of fibrinogen concentrates post-reconstitution

Background and objectivesReconstituted fibrinogen concentrate is considered stable for 8–24 h based on product monographs. Given the long half-life of fibrinogen in vivo (3–4 days), we hypothesized that reconstituted sterile fibrinogen protein would remain stable longer than 8–24 h. Extending the expiry date for reconstituted fibrinogen concentrate could decrease wastage and facilitate reconstitution in advance to minimize turnaround times. We performed a pilot study to define the stability of reconstituted fibrinogen concentrates over time. Materials and methodsReconstituted Fibryga® (Octapharma AG) from 64 vials was stored in the temperature-controlled refrigerator (4 °C) for up to 7 days with functional fibrinogen concentration measured serially using the automated Clauss method. The samples were frozen, then thawed and diluted with pooled normal plasma in order for them to be batch tested. ResultsReconstituted fibrinogen samples stored in the refrigerator showed no significant reduction in functional fibrinogen concentration for the entire 7-day study period (p = 0.63). Duration of initial freezing had no detrimental effect on functional fibrinogen levels (p = 0.23). ConclusionFibryga® can be stored at 2–8 °C post-reconstitution for up to one week with no loss in functional fibrinogen activity based on Clauss fibrinogen assay. Further studies with other fibrinogen concentrate formulations and clinical in vivo studies may be warranted

Acute obstetric coagulopathy during postpartum hemorrhage is caused by hyperfibrinolysis and dysfibrinogenemia: an observational cohort study

BackgroundPostpartum hemorrhage (PPH) may be exacerbated by hemostatic impairment. Information about PPH-associated coagulopathy is limited, often resulting in treatment strategies based on data derived from trauma studies. ObjectivesTo investigate hemostatic changes associated with PPH. Patients/MethodsFrom a population of 11 279 maternities, 518 (4.6%) women were recruited with PPH ≥ 1000 mL or placental abruption, amniotic fluid embolism, or concealed bleeding. Routine coagulation and viscoelastometric results were collated. Stored plasma samples were used to investigate women with bleeds > 2000 mL or those at increased risk of coagulopathy defined as placenta abruption, amniotic fluid embolism, or need for blood components. Procoagulant factors were assayed and global hemostasis was assessed using thrombin generation. Fibrinolysis was investigated with D-dimer and plasmin/antiplasmin complexes. Dysfibrinogenemia was assessed using the Clauss/antigen ratio. ResultsAt 1000 mL blood loss, Clauss fibrinogen was ≤2 g/L in 2.4% of women and 6/27 (22.2%) cases of abruption. Women with very large bleeds (>3000 mL) had evidence of a dilutional coagulopathy, although hemostatic impairment was uncommon. A subgroup of 12 women (1.06/1000 maternities) had a distinct coagulopathy characterized by massive fibrinolysis (plasmin/antiplasmin > 40 000 ng/mL), increased D-dimer, hypofibrinogenemia, dysfibrinogenemia, reduced factor V and factor VIII, and increased activated protein C, termed acute obstetric coagulopathy. It was associated with fetal or neonatal death in 50% of cases and increased maternal morbidity. ConclusionsClinically significant hemostatic impairment is uncommon during PPH, but a subgroup of women have a distinct and severe coagulopathy characterized by hyperfibrinolysis, low fibrinogen, and dysfibrinogenemia associated with poor fetal outcomes.

The Role of Thromboelastography during the Management of Postpartum Hemorrhage: Background, Evidence, and Practical Application.

Postpartum hemorrhage (PPH) is a common cause of significant maternal morbidity and mortality that can be associated with coagulopathy, especially hypofibrinogenemia. There is interest in point-of-care viscoelastic hemostatic assays (POC-VHA) in PPH because prompt knowledge of coagulation status can aid diagnosis, identify cases of severe coagulopathy, and allow ongoing monitoring during rapid bleeding. The incidence of coagulopathy in most cases of PPH is low because of the procoagulant state of pregnancy, including raised fibrinogen levels of around 4 to 6 g/L. A Clauss fibrinogen of >2 g/L or POC-VHA equivalent has been found to be adequate for hemostasis during PPH. POC-VHA has been used successfully to diagnose hypofibrinogenemia (Clauss fibrinogen of ≤2 g/L) and guide fibrinogen treatment which has reduced bleed size and complications of massive transfusion. There are uncertainties about the use of POC-VHA to direct fresh frozen plasma and platelet administration during PPH. Several POC-VHA algorithms have been used successfully incorporated in the management of many thousands of PPHs and clinicians report that they are easy to use, interpret, and aid decision making. Due to the relative cost of POC-VHA and lack of definitive data on improving outcomes, these devices have not been universally adopted during PPH.

Comparison between the Rotational Thromboelastometry (ROTEM) Delta device against the Cartridge-based Thromboelastography 6s and Quantra in a healthy third trimester pregnant cohort.

Rotational Thromboelastometry (ROTEM) Delta has been described in several postpartum hemorrhage algorithms, but this device requires pipetting and careful mixing of reagents to initiate the clotting reaction. In contrast, thromboelastography (TEG 6s) and the Quantra devices operate utilizing an automated pre-mixed cartridge that only requires a blood sample to start the clot strength analysis. We compared the correlation between 3 point of care viscoelastic testing (POCVT) devices to laboratory Clauss fibrinogen and platelets, their inter-device correlation, and the total running time difference between Quantra and ROTEM. A high correlation was noted between the Clauss fibrinogen and the fibrinogen parameters from ROTEM (r = 0.76-0.84, P < 0.0001), TEG6s (r = 0.71, P < 0.0001) and Quantra (r = 0.72, P = 0.0001). A moderate correlation between laboratory platelets and the ROTEM (r = 0.54;0.45, P < 0.0001; P = 0.0013) and Quantra (r = 0.66, P = 0.0001) parameters was noted. The inter-device correlation showed to be high when comparing the fibrinogen parameters of TEG6s and Quantra to that of ROTEM (r = 0.88 and 0.74, P < 0.0001, respectively). In contrast, a moderate correlation was noted between the platelet parameters of Quantra and ROTEM (r = 0.51, p = 0.0036). The Quantra device resulted 20.9min (95% CI -0.2 to 4.7, P = 0.07) faster than the ROTEM if the warming and pipetting of reagents of the latter were considered. All the POCVT devices demonstrated a high correlation to laboratory Clauss fibrinogen, making each beneficial for the early recognition and management of hypofibrinogenemia.

A Sri Lankan child with hypersplenism secondary to pre-hepatic portal hypertension, successfully managed with partial splenic artery embolization: a case report and review of the literature

BackgroundHypersplenism, one of the major complications of portal hypertension, is traditionally treated by splenectomy. However, partial splenic artery embolization is an evolving minimally invasive intervention to treat these patients effectively.Case presentationA 13-year-old girl was referred for further evaluation of isolated splenomegaly with pancytopenia. She did not have bleeding manifestations or features of anemia. She never had hematemesis or melena. On examination, she was pale. Abdominal examination revealed massive splenomegaly of 10 cm below the costal margin without hepatomegaly. Rest of the examination was unremarkable. Her investigations revealed a white cell count of 1700/mm3 (neutrophils 9.8% and lymphocytes 88.7%), hemoglobin 9.5 g/dL and platelet count 42,000/mm3. Blood picture showed pancytopenia without abnormal cells. Her reticulocyte count was 1.9%. Complete liver profile was normal. Abdominal ultrasonography revealed massive splenomegaly with the oblique length of 17 cm and normal echogenic liver with normal size. Cavernous transformation of portal vein with portal hypertension was evident. Mesenteric angiogram showed portal vein thrombosis and markedly tortuous splenic artery. Anti-nuclear antibodies and double-stranded DNA were negative. Ham test and urine for hemosiderin were negative. Clauss fibrinogen assay was normal. Hemoglobin high performance liquid chromatography for hemoglobin subtypes was normal. Anti-phospholipid antibodies were negative. JAK2 V617F mutation was not identified. Diagnosis of pre hepatic portal hypertension was made. Her upper gastrointestinal endoscopy was normal. Partial splenic artery coil embolization was done by interventional radiology team. Vaccines against capsulated organisms were given. Post-procedure contrast abdominal computed tomography revealed infarction of approximately 70% of the spleen and blood counts were improved. Index case is in the follow up for 3 years. She is on penicillin prophylaxis with regular blood count and annual upper gastrointestinal endoscopy monitoring.ConclusionsMinimally invasive interventions such as partial splenic artery embolization should be considered in managing the patients with hypersplenism secondary to portal hypertension.

Fibrinogen Deficiency with Thrombotic Manifestations.

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.LEARNING POINTSFunctional 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.

An audit of the diagnostic accuracy of the ROTEM®sigma for the identification of hypofibrinogenaemia in cardiac surgical patients.

The ROTEM®delta (TEM Innovations GmbH, Munich, Germany) has been used extensively worldwide for the assessment of coagulation in cardiac surgical patients. Recently, a new cartridge-based ROTEM device (ROTEM®sigma, TEM Innovations GmbH, Munich, Germany) has become available. In this paper we report an audit of the diagnostic accuracy of the ROTEM sigma for the identification of hypofibrinogenaemia in cardiac surgical patients. We hypothesised that the diagnostic accuracy of the ROTEMsigma for the identification of hypofibrinogenaemia would be in a similar range to that previously reported for the ROTEMdelta. Simultaneous blood samples for Clauss laboratory fibrinogen and ROTEMsigma FIBTEM measurements were obtained immediately after heparin reversal post-cardiopulmonary bypass in 200 adult cardiac surgical patients. The sensitivity, specificity, and positive and negative predictive values for FIBTEM A5 and A10 for the identification of hypofibrinogenaemia (Clauss fibrinogen <1.5 g/l) were calculated. The prevalence of hypofibrinogenaemia across the 200 patients was 8%. The mean sensitivity and specificity of FIBTEM A10 ≤8 mm for the identification of hypofibrinogenaemia were 0.75 and 0.90 respectively, which are in a similar range to that reported in several previous studies using the ROTEMdelta. For FIBTEM A5 ≤6 mm the values were 0.63 and 0.98 respectively. The predictive values were also in a similar range to those previously reported for the ROTEMdelta, with low false negative rates (2% for A10 ≤8 mm; 3% for A5 ≤6 mm). These findings support the use of the ROTEMsigma as an alternative to the ROTEMdelta for the identification of hypofibrinogenaemia post-cardiopulmonary bypass in cardiac surgical patients. However, further studies are required in other settings.

Using Machine Learning to Detect Theranostic Biomarkers Predicting Respiratory Treatment Response.

Background: Theranostic approaches—the use of diagnostics for developing targeted therapies—are gaining popularity in the field of precision medicine. They are predominately used in cancer research, whereas there is little evidence of their use in respiratory medicine. This study aims to detect theranostic biomarkers associated with respiratory-treatment responses. This will advance theory and practice on the use of biomarkers in the diagnosis of respiratory diseases and contribute to developing targeted treatments. Methods: We performed a cross-sectional analysis on a sample of 13,102 adults from the UK household longitudinal study ‘Understanding Society’. We used recursive feature selection to identify 16 biomarkers associated with respiratory treatment responses. We then implemented several machine learning algorithms using the identified biomarkers as well as age, sex, body mass index, and lung function to predict treatment response. Results: Our analysis shows that subjects with increased levels of alkaline phosphatase, glycated haemoglobin, high-density lipoprotein cholesterol, c-reactive protein, triglycerides, hemoglobin, and Clauss fibrinogen are more likely to receive respiratory treatments, adjusting for age, sex, body mass index, and lung function. Conclusions: These findings offer a valuable blueprint on why and how the use of biomarkers as diagnostic tools can prove beneficial in guiding treatment management in respiratory diseases.

Impact of Fibrinogen Infusion on Thrombin Generation and Fibrin Clot Structure in Patients with Inherited Afibrinogenemia.

Inherited afibrinogenemia is a very rare disease characterized by complete absence of fibrinogen in the circulation and an increased risk in both thrombosis and bleeding. Infusion of fibrinogen concentrate (FC) is the main approach for prevention and management of bleeding; however, it has been reported to carry a thrombotic risk. We investigated the impact of a standard dose (40-100 mg/kg) of FC infusion on the thrombin generation (TG) parameters and the fibrin clot structure formed in plasma samples of patients with afibrinogenemia. Blood samples were collected from 20 patients before (T0) and 1 hour after infusion of FC (T1). TG was studied with calibrated automated thrombography. Fibrin clot structure was assessed with turbidimetry and scanning electron microscopy. FC infusions (mean Clauss fibrinogen plasma level: 1.21 g/L at T1) led to a statistically significant increase in endogenous thrombin potential (ETP) (p < 0.0001) and thrombin peaks (p = 0.02). Nevertheless, when compared with healthy controls, patients' T1 lag times were longer (p = 0.002), ETP values were lower (p = 0.0003), and thrombin peaks were lower (p < 00001). All fibrin polymerization parameters (turbidimetry) obtained at T1 were comparable to those of patients with inherited hypofibrinogenemia matched for fibrinogen plasma levels. In summary, fibrinogen infusion with a standard dose of FC increased but did not correct TG and led to formation of fibrin clots similar to those of patients with hypofibrinogenemia. All in all, our results do not support the biological evidence of hypercoagulability induced by FC in patients with afibrinogenemia.

Development and validation of a novel qualitative test for plasma fibrinogen utilizing clot waveform analysis

Plasma fibrinogen is commonly examined by Clauss fibrinogen assay, which cannot distinguish between quantitative and qualitative fibrinogen anomalies. However, our previously reported Clauss fibrinogen assay utilizing clot waveform analysis (Clauss-CWA) provides additional information that contributes to the classification of fibrinogen anomalies. In this study, we adopted the Clauss-CWA method for an autoanalyzer to automatically measure the antigenic estimate (eAg) of fibrinogen in addition to the functional amount (Ac), and to thus provide the Ac/eAg ratio as a qualitative indicator. Performance was validated by receiver operating characteristics (ROC) and precision recall (PR) curve analyses using a patient cohort, consisting of a training cohort (n = 519) and a validation cohort (n = 523), both of which contained cases of congenital (hypo)dysfibrinogenemia as qualitative defects. We obtained an optimal cutoff of 0.65 for Ac/eAg by ROC curve analysis of the training cohort, offering superior sensitivity (> 0.9661) and specificity (1.000). This cutoff was validated in the validation cohort, providing positive predictive value > 0.933 and negative predictive value > 0.998. PR curve analysis also showed that Clauss-CWA provided excellent performance for detecting qualitative fibrinogen anomalies. The Clauss-CWA method may represent a useful approach for detecting qualitative fibrinogen abnormalities in routine laboratory testing.

Thromboelastography demonstrates progressive hypercoagulability in COVID-19 patients admitted to ICU with respiratory failure.

Thromboembolic complications are associated with COVID-19 owing to the hypercoagulable nature of the disease. Although patients with COVID-19 often have higher levels of fibrinogen and D-dimers, hypercoagulability has been attributed to various other factors too. In this prospective observational study conducted between April 2020 and June 2020, we compared coagulation parameters using thromboelastography in COVID-19 patients to non-COVID-19 patients admitted to ICU with respiratory failure. This study demonstrated a significant difference between the cohorts in functional fibrinogen (CFF) progressively from third day of ICU admission whilst there was no difference in the Clauss fibrinogen levels. COVID-19 patients also demonstarted supranormal R time indicating hypocoagulability. These mixed coagulation changes suggest targeting fibrinogen or platelets may prevent thromboembolic complications in COVID-19.