Normal Fibrinogen Levels Research Articles

Dual guided heparin monitoring with anti-Xa and APTT during micro-axial flow pump support for cardiogenic shock

Abstract Background Precise management of unfractionated heparin (UFH) is key to avoid coagulopathic complications in patients on percutaneous mechanical circulatory support (pMCS) for cardiogenic shock (CS). While the activated partial thromboplastin time (APTT) is commonly used for this purpose, it can be affected by various laboratory factors during critical illness. Alternatively, the anti-Xa test directly measures UFH activity. We proposed a parallel anti-Xa/APTT-based protocol for UFH titration during pMCS. (1) Purpose We aimed to investigate the correlation between parallel anti-Xa/APTT measurements in a CS population on pMCS. We also evaluated mortality correlation in samples exhibiting prolonged APTT and in-range anti-Xa levels, based on fibrinogen levels and INR. Methods We assessed all CS patients with isolated left-sided ImpellaTM-support (>24h) and UFH anticoagulation monitoring per protocol at two pMCS-institutions from April-2017 to June-2022. Overall correlation between parallel anti-Xa/APTT samples was assessed by Pearson correlation coefficient (with ≤0.7 considered to confer a weak correlation). Anti-Xa levels were defined as 0.20-0.30IU/mL or 0.31-0.50IU/mL, with corresponding APTT values of 40-55s and 55-80s, respectively. Samples with prolonged APTT as compared to the in-range anti-Xa were stratified based on fibrinogen (<1.5g/dL or ≥ 1.5g/dL) and INR (<1.5 or ≥1.5) on the same day as the index sample. Mortality of patients with normal fibrinogen ànd INR was then compared to those with abnormal fibrinogen and/or INR via a Chi² test. Results Ninety-three ImpellaTM-runs (77 men, 83%) with a median age of 56 years (IQR 46-66) were analyzed. Median support was 6 days (IQR 4-12). In 2447 parallel anti-Xa/APTT samples, the Pearson correlation coefficient was 0.50 (p<0.001). Among the 1914 in-range anti-Xa samples, APPT was shortened in 460 (24%), in-range in 986 (52%) and prolonged in 468 (24%) samples. In the 59 patients with samples with prolonged APTT, two patients (with 80 samples) were excluded due to absence of fibrinogen and/or INR measurements on the same day. The mortality in patients with prolonged APTT but normal fibrinogen levels and normal INR (N=29; APTT prolongation due to FXI/FXII-consumption) was significantly lower compared to the remaining 28 patients who showed samples with reduced fibrinogen levels and/or prolonged INR (suffering from concomitant conditions) (10% vs. 32%; p=0.043). Conclusion We highlight a weak correlation between anti-Xa and APTT in an anti-Xa guided UFH anticoagulated CS population during left-sided ImpellaTM support. Patients with APTT-prolongation due to concomitant conditions with INR prolongation and/or fibrinogen shortage are at highest mortality risk. The APTT/Anti-Xa coefficient can serve as an independent risk factor whilst managing critically CS patients.

A novel γ-chain mutation p.Asp318His in a Chinese family with dysfibrinogenemia.

Congenital dysfibrinogenemia is characterized by reduced fibrinogen activity, but normal immunoreactive fibrinogen levels. Here, we present a novel case with an elevated risk of thrombosis. Coagulation assays, gene analysis, in silico tools, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), fibrin polymerization, thrombin generation assay, and electron microscopy scanning were utilized to elucidate the pathogenic mechanism. The proband manifested with a normal immunologic fibrinogen (2.13 g/l) but reduced functional fibrinogen (0.39 g/l). Subsequent genetic analysis unveiled a novel heterozygous mutation, c.1030G>C (p.Asp318His), in the γ-chain D domain of fibrinogen, which was highly conserved in homologous species and led to enhanced thrombin generation capability. The ability of the proband's fibrinogen to polymerize was significantly impaired, with decreased final turbidity. Scanning electron microscopy indicated that the fibers of the proband were thinner than normal, with smaller pores. Thromboelastography (TEG) results demonstrated prolonged K time, decreased angle value, and a normal confidence interval value in the proband. We present a novel case displaying the γAsp318His mutation, which resulted in dysfibrinogenemia.

Evaluation of tocilizumab-induced hypofibrinogenemia in rheumatology practice: a retrospective, real-life, single-center experience.

Tocilizumab (TCZ) which is a humanized interleukin (IL)-6 receptor antibody has been increasingly widespread used in rheumatology practice. TCZ-related hypofibrinogenemia is a not well-described side effect, but awareness seems to be incresing as publications on this topic are also becoming more frequent. Our aim in this study was to determine the frequency, timing, and approach to TCZ-related hypofibrinogenemia in rheumatic diseases. We retrospectively screened our patients who received TCZ for inflammatory rheumatic diseases and studied serum fibrinogen at least once before and/or after drug administration. We recorded and analyzed demographic features (age, gender, diagnosis), comorbidities, laboratory parameters, management, and outcome data. 30 patients who received TCZ due to rheumatological diseases and had at least one fibrinogen level were included in this study. 73.3% were female and median age was found to be 65 (42-82) years, with median disease duration of 148 (36-500) months. 90% of the patients received TCZ for RA and 10% for GCA. We examined the fibrogen levels at an average of 24 months (min 1 max 108) following the start of TCZ treatment. The study group was divided into those with normal fibrinogen levels (normal fibrinogen group) and those with low fibrinogen levels (lowfibrinogen group). In total, hypofibrinogenemia was found in 14 (46.6%) patients. Median serum fibrinogen level in the low fibrinogen group after TCZ was calculated to be 151.5mg/dl (min 92 max 171). Most patients were asymptomatic (71.4%). Ecchymoses were in seen 4 (28,6%) patients. No major bleeding were seen. TCZ was discontinued in 5 out of 14 patients (35.7%), while 9 out of 14 patients (64.3%) were closely followed. Outcomes regarding fibrinogen levels (11 out of 14) were as follows: increase in 4 and not checked in one after cessation of the drug, 3 spontaneous increases under the drug, and 3 persistently low levels on TCZ treatment. We found no difference in terms of gender (p = 0.417), platelets (p = 0.343), ESR (p = 0.448), and CRP (p = 0.660) at the time of TCZ initiation between groups. TCZ-related hypofibrinogenemia is more frequent than expected with occurence in both the early and late stages of treatment. Further research is required to determine whether to regularly measure fibrinogen levels in patients using TCZ and how to treat patients with hypofibrinogenemia.

The utility of the prehospital shock index, age shock index, and modified shock index for predicting hypofibrinogenaemia in trauma patients: an observational retrospective study

PurposeReduced fibrinogen levels are associated with worse outcomes in bleeding trauma patients. The purpose of this study was to evaluate the potential of the prehospital shock index (SI) and its derivatives, the age shock index (aSI) and the modified shock index (mSI), as predictors of hypofibrinogenaemia in trauma patients.MethodsThis retrospective study included 2383 patients who presented to a regional trauma center. We reviewed the plasma fibrinogen levels upon admission to the trauma center and patients were divided into two groups: the hypofibrinogenaemia group and the normal group. The predictive performances of the SI, aSI, and mSI were assessed by the area under the receiver operating characteristic curve (AUC).ResultsOf the 2383 patients, 235 (9.9%) had hypofibrinogenaemia. Patients with hypofibrinogenaemia were more likely to receive transfusions within 4 h and had significantly greater in-hospital mortality than patients with normal fibrinogen levels. The AUCs of prehospital SI, prehospital aSI, and prehospital mSI for the prediction of hypofibrinogenaemia were 0.75 (95% confidence interval [CI] 0.73–0.77), 0.70 (95% CI 0.68–0.72), and 0.75 (95% CI 0.73–0.77), respectively.ConclusionPrehospital SI and prehospital mSI demonstrated moderate performance for identifying trauma patients with hypofibrinogenaemia. The prehospital aSI had poor predictive performance. In the prehospital setting, the use of prehospital SI or prehospital mSI as the sole predictor of hypofibrinogenaemia in trauma patients is not recommended.

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.

Successful Recanalization by Mechanical Thrombectomy in a Child with Arterial Thrombotic Stroke Involving Posterior Circulation: A Case Report with Review of the Literature

Background: Mechanical thrombectomy (MT) for arterial ischemic stroke, although established in adults, is not endorsed routinely for children. The procedure is even rare in children with stroke involving posterior circulation. Here we describe, a child with ischemic stroke due to thrombotic occlusion in the posterior circulation, which was successfully treated with MT. Clinical Description: A 12-year-old boy presented with sudden-onset vertigo, imbalance, slurring of speech, inability to stand, associated with headache and vomiting for 8 hours, without any associated fever, trauma, or seizures. On initial examination, his National Institute of Health Stroke Scale (NIHSS) score was 8. Other systems were within normal limits and there was no cutaneous rash. Management and Outcome: Investigations revealed a normal complete hemogram, lipid profile, serum homocysteine, fibrinogen, and D-dimer levels along with a normal hemoglobin electrophoresis profile. The electrocardiography, two-dimensional echocardiography were normal and even antinuclear antibodies, antiphospholipid antibodies were negative. Magnetic resonance imaging (MRI) of the brain demonstrated multiple acute infarcts in bilateral cerebellar hemispheres, pons, and right anterior thalamus. Noncontrast MR angiography (MRA) of the head and digital subtraction angiography showed distal basilar artery cutoff and right vertebral artery dominance. As the NIHSS score worsened to 10, a MT with solitaire was done (after 12 hours of onset of symptoms), and reperfusion was achieved in two passes. The child showed remarkable improvement in NIHSS score to 2 by 5 days. At discharge, the child had residual mild ataxia. Despite investigations, the cause of thrombosis remained unknown. Conclusion: Our case highlights that in case of significant large arterial occlusion with rapid worsening of symptoms, MT may be considered, even if it involves posterior circulation, and the child presents beyond the usual window of 4–6 hours.

Anti-Xa/APTT discrepancy in heparinized ImpellaTM-supported cardiogenic shock patients can predict mortality

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fonds Wetenschappelijk Onderzoek Flanders. Background Meticulous management of unfractionated heparin (UFH) is important to avoid complications in patients receiving percutaneous mechanical circulatory support (pMCS) for cardiogenic shock (CS). Whereas the anti-Xa assay directly measures UFH activity, the activated partial thromboplastin time (APTT) remains the most frequently used test. The APTT covers the intrinsic and common coagulation pathway and can be influenced by various confounding (laboratory) factors during critical illness, unrelated to the patient’s (anti)coagulation state. Purpose We investigated a CS population supported with isolated left-sided Impella™ and UFH-anticoagulation. UFH-levels were guided by anti-Xa with APTT in parallel. Here, we focus on those samples with anti-Xa in-range and discrepantly prolonged parallel APTT-measurements. We differentiated the APTT-prolongation according to reduced fibrinogen levels and/or prolonged INR (factor XI/XII consumption vs. concomitant conditions) and correlated this with mortality during Impella™-support. Methods Between April-2017 and June-2022, all CS patients with isolated left-sided ImpellaTM-support (>24h) and UFH anticoagulation monitored by anti-Xa with APTT in parallel were assessed at two high-volume tertiary institutions. In-range anti-Xa samples (between 0.20-0.30IU/mL or 0.31-0.50IU/mL based on the patient’s profile) were selected. In-range APTT values were considered between 40-55s and 55-80s respectively. Samples with prolonged APTT as compared to the in-range anti-Xa were allocated in 4 groups based on fibrinogen (<1.5g/dL or ≥ 1.5g/dL) and INR (<1.5 or ≥1.5) on the same day as the sample with prolonged APTT. Mortality of patients with normal fibrinogen ànd INR was then compared to those with abnormal fibrinogen and/or INR via a Chi² test. Results Ninety-three ImpellaTM-runs (77 men, 83%) with a median age of 56 years (IQR 46-66) were analyzed. Median support was 6 days (IQR 4-12). Among the 1914 in-range anti-Xa samples, parallel APTT was prolonged in 468 samples (24%) across 59 patients. 80 Samples from 2 patients were excluded due to absence of fibrinogen and/or INR measurements on the same day. The mortality in patients with prolonged APTT but normal fibrinogen levels and normal INR (N=29; due to FXI/FXII-consumption) was significantly lower compared to the remaining 28 patients who showed samples with reduced fibrinogen levels and/or prolonged INR (10% vs. 32%; p=0.043). Conclusions Fibrinogen-levels and INR uncover the underlying etiology in discrepant APTT-prolongation as compared to an in-range anti-Xa value in a CS population during left-sided ImpellaTM support. In patients with prolonged APTT and reduced fibrinogen (<1.5 g/dL) and/or prolonged INR (≥1.5), the risk of mortality is significantly elevated. This is due to concomitant conditions with high mortality (liver failure, sepsis, DIC,…). We advocate to monitor such patients carefully and treat them in a patient/disease tailored approach.

Development of biosensors for detection of fibrinogen: a review.

Fibrinogen as a major inflammation marker and blood coagulation factor has a direct impact on the health of humanity. The variations in fibrinogen content lead to risky conditions such as bleeding and cardiovascular diseases. So, accurate methods for monitoring of this glycoprotein are of high importance. The conventional methods, such as the Clauss method, are time consuming and require highly specialized expert analysts. The development of fast, simple, easy to use, and inexpensive methods is highly desired. In this way, biosensors have gained outstanding attention since they offer means for performing analyses at the points-of-care using self-testing devices, which can be applied outside of clinical laboratories or hospital. This review indicates that different electrochemical and optical sensors have been successfully implemented for thedetection of fibrinogen under normal levels of fibrinogen in plasma. The biosensors for thedetection of fibrinogen have been designed based on the quartz crystal microbalance, field-effect transistor, electrochemical impedance spectroscopy, amperometry, surface plasmon resonance, localized surface plasmon resonance, and colorimetrictechniques. Also, this review demonstrates the utility of the application of nanoparticles in different detection techniques.

Fibrinogen Levels in Patients with Metastatic Renal Cell Carcinoma Treated with Nivolumab: Results of a Multicenter Prospective Trial

Background: Introduction of immune checkpoint inhibitors in the standard of care for metastatic renal cell carcinoma (mRCC) requires robust but yet simple biomarkers to predict efficacy of immunotherapy. Objective: The aim of this study was to evaluate the association between fibrinogen levels and efficacy of second-line therapy with nivolumab in mRCC. Methods: This is a prospective multicenter biomarker study. Fibrinogen levels were measured one week prior to second-line nivolumab therapy and six times monthly. A high fibrinogen level was defined as ≥5 g/L. Patients were divided into two cohorts: high (H) and normal (N) fibrinogen levels. The primary endpoint was overall survival (OS). Results: The median OS was 31.5 months (95% confidence interval [CI], 27.9 to 35.1) in cohort N vs. 20.9 months (95% CI, 18.1 to 23.7) in cohort H (hazard ratio [HR], 0.39; 98.5% CI, 0.21 to 0.7; P = 0.002). The median progression-free survival was 9.4 months (95% CI, 5.5 to 14.1) in cohort N and 4.0 months (95% CI, 2.9 to 5.1) in cohort H (HR, 0.65; 95% CI, 0.51 to 0.72; P < 0.001). The objective response rate was higher in N cohort (33% vs. 17% ; P = 0.012). No statistically significant changes of fibrinogen concentration during nivolumab therapy were found. Conclusion: The study demonstrated an association of hyperfibrinogenemia with worse clinical outcomes of second-line nivolumab monotherapy in patients with mRCC. Further validation of fibrinogen as a predictive biomarker for immunotherapy efficacy in patients with mRCC is warranted.

The predictive value of the preoperative albumin-to-fibrinogen ratio for postoperative hospital length of stay in liver cancer patients.

Hepatocellular carcinoma (HCC) is a significant global health burden, with postoperative hospital length of stay (LOS) impacting patient outcomes and healthcare costs. Existing nutritional, inflammatory, and coagulation indices can predict LOS, with particular interest in albumin, fibrinogen, and D-dimer. This study investigates the predictive value of preoperative albumin-to-fibrinogen ratio (AFR) and albumin-to-D-dimer ratio (ADR) for postoperative LOS in HCC patients. This retrospective study involved 462 adult HCC patients who underwent partial hepatic lesion excision between February 2016 and August 2022. We analyzed demographic and clinical data, including preoperative blood samples, surgical approach, and LOS. The primary outcome measure was LOS, calculated from the date of surgery to the date of hospital discharge. Preoperative AFR and ADR were calculated. The ROC curves determined optimal cutoff points. The Cox proportional hazards model, Kaplan-Meier method, and the log-rank test were used for statistical analysis. The study established an optimal AFR cutoff value of 15.474, with a higher AUC value than ADR, indicating superior predictive potential for postoperative LOS. Participants with high-AFR (AFR > 15.474) had a shorter median LOS (13 vs. 15 days, p < 0.001) compared to those with low-AFR (AFR ≤15.474). Multivariate analysis revealed high-AFR (HR: 1.99; p < 0.001) as a positive influence on LOS reduction, whereas Child-Pugh rated as B (HR: 0.49; p < 0.001), laparotomy (HR: 0.37; p < 0.001) and total bilirubin >20.5 μmol/L (HR: 0.58; p < 0.001) negatively impacted LOS reduction. Subgroup analysis confirmed AFR's predictive ability for patients experiencing reduced or prolonged LOS due to Child-Pugh score, surgical methods, and total bilirubin concentrations. Even within normal albumin and fibrinogen levels, patients with high-AFR exhibited a shorter LOS (all p < 0.001). Our findings underscore the value of the AFR as a reliable predictor of LOS in HCC patients. An AFR greater than 15.474 consistently correlated with a shorter LOS, suggesting its potential clinical utility in guiding perioperative management and resource allocation in HCC patients.

#6934 INFLAMMATORY STATUS PRIOR TO THE CREATION OF ARTERIOVENOUS FISTULAS FOR HEMODIALYSIS: IS IT DETERMINING?

Abstract Background and Aims Clinical practice guidelines recommend an arteriovenous fistula (AVIF) as the preferred vascular access for hemodialysis and is associated with a lower incidence of morbidity and mortality. However, primary vascular access (VA) failure is not uncommon. Low-grade inflammation is present in ERCT. We identified the inflammatory parameters that influence the primary patency of the vascular access for hemodialysis. Method Cross-sectional study; We included all VAs made between October 2009 and April 2022. We evaluated the initial performance after the creation of the VAs. Demographic variables (age, sex), CKD etiology, and associated comorbidity were collected. Statistical analysis with SPSS 25.0. Categorical variables are expressed as percentages and compared using the Chi2 test. Quantitative variables are expressed as mean ± standard deviation and the t-student test was used to compare them. Statistical significance for a value of p&amp;lt;0.05. Results 712 VA performed in 546 patients were reviewed between October 2009 and April 2022. 617 autologous VA (86.7%) and 95 prosthetic VA (13.3%) were performed. The mean age of the patients was 65.4 ± 14.1 years and 67.4% were male. The most frequent etiology of CKD was diabetic nephropathy (30.5%), followed by unknown (17.3%) and glomerulonephritis (16.4%). 91.4% of the patients presented arterial hypertension (HTA), diabetes mellitus (DM) 47.5%. 72.6% of the VA presented primary permeability. In the univariate analysis using Chi2 and T student, AHT (p&amp;lt;0.001), treatment with statins (p&amp;lt;0.001), antiaggregation (p&amp;lt;0.001), normal fibrinogen levels (p = 0.003), and CRP (p&amp;lt;0.001) reached statistical significance. = 0.039). When recoding the PCR in relation to its normal values, the pathological levels were associated with primary failure after the creation of AVFs. Conclusion In our study, inflammatory states with elevated CRP and ferritin were associated with primary failure in initial functioning after the creation of AVFs. On the contrary, arterial hypertension and treatment with statins prior to the creation of AVFs are associated with their primary permeability.

Nivolumab as second-line treatment of patients with metastatic renal cell carcinoma with high or normal fibrinogen levels: A prospective, cohort study.

e16510 Background: In a number of coagulation-related studies, elevated fibrinogen levels were found in patients with renal cell carcinoma (RCC) and correlated with more advanced disease. The impact of hyperfibrinogenemia on the clinical outcomes of immunotherapy remains uncertain. Methods: In this prospective cohort study, fibrinogen levels were measured one week prior to the second-line nivolumab therapy (240 mg or 480 mg every 2 or 4 weeks) and then monthly until disease progression or unacceptable toxicity. High fibrinogen level was defined as ≤5 g/L. Key eligibility criteria included metastatic clear cell RCC resistant to the first-line targeted therapy, ≤3 MSKCC risk factors, ECOG PS 0-2, platelet count &lt;400×10(9)/L, no heart diseases, no anticoagulation therapy, and age 40-65 years. The primary endpoint was overall survival (OS) in cohorts with high (H) and normal (N) fibrinogen levels. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and fibrinogen levels during therapy. Results: Between November 2018 and January 2021, 82 patients were enrolled, of whom 41 and 41, respectively, were recruited in H and N cohorts. The groups were well balanced at baseline. The median follow-up time was 32.4 months. Compared to patients in N cohort, patients in H cohort had shorter OS (P=0.001), shorter PFS (P&lt;0.01), and lower ORR (P=0.012). In H cohort, a below-median fibrinogen level was associated with longer observed OS (median, 23.7 vs. 19.4 months; P=0.03). In N cohort, 6 (15%) patients with stable disease had an increase in fibrinogen levels during nivolumab therapy. Patient characteristics and clinical outcomes are summarized. Conclusions: High fibrinogen levels affect the clinical outcomes in patients with metastatic renal cell carcinoma treated with second-line nivolumab. These findings require large-scale prospective validation. Clinical trial information: KCRB0181209 . [Table: see text]

Evaluation of indicators of coagulation hemostasis and endothelial dysfunction in covid-19 convalescents

Purpose: Evaluation of indicators of coagulation hemostasis and humoral markers of endothelial dysfunction in COVID-19 convalescents. Material and methods: 105 COVID-19 convalescents were examined. Patients were included in the study after suffering COVID-19 after 4-6 months. The average age of the surveyed was 51.8±6.7 years. Women made up - 64 (60.95%), men - 41 (39.05%). Hemostasis indicators were assessed by coagulogram parameters - fibrinogen level, determination of D-dimer by enzyme immunoassay, humoral factors of endothelial dysfunction - endothelin-1, von Willebrand factor, thrombomodulin by enzyme immunoassay. Results: In the group of patients with elevated fibrinogen levels (more than 400 mg/dl), these values were significantly higher in terms of humoral markers of endothelial dysfunction than in patients with normal fibrinogen levels. Similarly, in patients with elevated levels of D-dimer, these values were significantly higher than in patients with normal levels of this indicator. When studying the levels of fibrinogen and D-dimer in the blood of COVID-19 convalescents, a direct correlation between them was established in relation to endothelin-1, VWF and thrombomodulin. There was a strong correlation between D-dimer and humoral factors endothelin-1 (r=0.88) and VWF (r=0.61), while thrombomodulin had a moderate correlation (r=0.56). Conclusions: In the blood of COVID-19 convalescents, there was a significant increase in the level of fibrinogen and D-dimer. In COVID-19 convalescents, an increase in the level of markers of endothelial dysfunction was associated with indicators of the clinical course and indicators of fibrinogen and D-dimer.

Abstract 143: Differential Suppression Of Arterial Versus Venous Thrombosis But Preserved Hemostasis In Mice Expressing Fibrinogen That Cannot Support Fibrin Formation

Elevated circulating fibrinogen correlates with increased risk for both cardiovascular and venous thromboembolic diseases. In vitro studies show that formation of a highly dense fibrin matrix is a major determinant of clot structure and stability. However, the precise contribution of fibrin matrix to occlusive arterial and venous thrombus formation in vivo remains largely undefined. To determine the contribution of fibrinogen versus fibrin to arterial thrombosis, venous thrombosis, and hemostatic potential in vivo , arterial and venous thrombotic challenges as well as hemostatic tests were performed in wildtype ( Fga WT ) and Fga EK mice that express normal levels of fibrinogen “locked” in the monomeric form. In a model arterial thrombosis, a 10% FeCl 3 injury to the carotid artery resulted in similar times to occlusion between Fga WT/WT , Fga WT/EK and Fga EK/EK mice, while Fga -/- mice were completely protected. However, when injured with 5% FeCl 3 , Fga EK/EK mice were partially protected from occlusion but had increased embolic events. These results suggest that fibrinogen can contribute to arterial thrombus formation independent of fibrin formation. Consistently, fibrinogen-dependent platelet aggregation and intraplatelet fibrinogen content in Fga WT/WT , Fga WT/EK and Fga EK/EK mice were similar. In an inferior vena cava stasis model of venous thrombosis, Fga EK/EK had near complete protection from thrombus formation. Intriguingly, Fga WT/EK mice also displayed significant reduction in thrombus frequency and mass relative to Fga WT/WT mice. Plasma from Fga WT/EK mice produced prolonged prothrombin and thrombin times with reduced fibrin formation based on turbidity assay. In bleeding models, Fga WT/EK and, Fga EK/EK mice had preserved hemostasis in contrast to Fga -/- mice that presented with significantly impaired hemostasis. These findings show that selective prevention of fibrin polymerization significantly reduces venous thrombosis and suppresses arterial thrombosis based on the severity of injury with minimal disruption to hemostasis. Moreover, the data suggests that administration of non-polymerizable fibrinogen may be a therapeutic strategy against thrombosis.

The indicators for early blood transfusion in patients with placental abruption with intrauterine fetal death: a retrospective review

BackgroundPlacental abruption (PA) with intrauterine fetal death (IUFD) is associated with a high risk of postpartum hemorrhage (PPH) resulting from severe disseminated intravascular coagulation (DIC). Therefore, blood products that are sufficient for coagulation factor replacement must be prepared, and delivery should occur at referral medical institutions that are equipped with sufficient blood products and emergency transfusion protocols. We retrospectively reviewed the records of patients with PA and IUFD (PA-IUFD) to identify possible factors that may indicate the need for early blood transfusion and investigated whether the Japanese scoring system for PPH can be applied in such cases.MethodsWe used a database of 16,058 pregnant patients who delivered at Yokohama City University Medical Center between January 2000 and February 2016. Thirty-three patients were diagnosed with PA-IUFD before delivery and categorized into two groups–blood transfusion and non-transfusion–to compare the maternal characteristics and pregnancy outcomes.ResultsIn patients with PA-IUFD, the transfusion group exhibited significantly more blood loss; lower fibrinogen levels and platelet counts; higher levels of fibrin degradation products (FDP), D-dimer, and prothrombin time; and a tendency for tachycardia on admission, compared to the non-transfusion group. Many patients in the transfusion group had normal fibrinogen levels on admission but later displayed markedly decreased fibrinogen levels. The Japan Society of Obstetrics and Gynecology (JSOG) DIC score was significantly higher in the transfusion than in the non-transfusion group.ConclusionsIn PA-IUFD, the fibrinogen level, platelet count, D-dimer, FDP, heart rate, and JSOG DIC score on admission may indicate the need for blood transfusion. However, even with normal fibrinogen levels on admission, continuous monitoring is indispensable for identifying progressive fibrinogen reductions in patients with PA-IUFD.

Preoperative fibrinogen level and postcardiac surgery morbidity and mortality rates.

High preoperative fibrinogen levels are associated with reduced bleeding rates after cardiac surgery. Fibrinogen is directly involved in inflammatory processes and is a cardiovascular risk factors. Whether high fibrinogen levels before cardiac surgery are a risk factor for mortality or morbidity remains unclear. This study aimed to examine the association between preoperative fibrinogen levels and mortality and morbidity rates after cardiac surgery. This is a single-center retrospective study. Patients (n = 1628) were divided into high (HFGr) and normal (NFGr) fibrinogen level groups, based on the cutoff value of 3.3 g/L, derived from the receiver operating characteristic (ROC) curve analysis. The primary outcome was the 30-day mortality rate. The rates of postoperative complications, including postoperative bleeding and transfusion rates, were examined. Between-group comparisons were performed with the Mann-Whitney U test and Chi-squared test, as suitable. Model discriminative power was examined with the area under the ROC curve. The HFGr and NFGr included 1103 and 525 patients, respectively. Mortality rate was higher in the HFGr than in the NFGr (2.7% vs. 1.1%, P = 0.04). The 12-h bleeding volume (280 mL [195-400] vs. 305 mL [225-435], P = 0.0003) and 24-h bleeding volume values (400 mL [300-550] vs. 450 mL [340-620], P &lt; 0.0001) were lower in the HFGr than in the NFGr. However, the rate of red blood cell transfusion during hospitalization was higher in the HFGr than in the NFGr (21.7% vs. 5.9%, P = 0.0103). Major complications were more frequent in the HFGr than in the NFGr. High fibrinogen levels were associated with reduced postoperative bleeding volume and increased mortality and morbidity rates.

Fulfillment status of hypertriglyceridemia and hypofibrinogenemia in children with hemophagocytic lymphohistiocytosis and risks of multiple organ dysfunction syndrome and early mortality

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder. How to stratify high risk patients is one of the current challenges for the treatment of HLH. HLH patients usually fulfill multiple but not all eight diagnostic criteria. Different combinations of the fulfilled criteria may naturally cluster into previously undescribed subsets or phenotypes that may have different pathophysiology and demonstrate different risks for a poor outcome. The objectives of this study were to identify HLH subgroups according to the fulfillment of diagnostic criteria and evaluate the risk of multiple organ dysfunction syndrome (MODS) and 30-day mortality for subgroups. We retrospectively collect medical records of patients with discharge diagnosis of HLH between June 2015 and October 2018 from a tertiary children’s hospital in China. Latent class analysis was used to identify class defining variables from HLH diagnostic items, and subgroups were defined according to different combinations of the class defining variables.ResultsTriglyceride and fibrinogen were identified as the class defining variables. When evaluated in combinations, patients with hypertriglyceridemia and normal fibrinogen levels during hospitalization had the lowest risks for MODS (27.8%, OR = 1) and 30-day mortality (18.8%, OR = 1), and patients with normal triglyceride and hypofibrinogenemia had the highest risks for MODS (86.2%, OR = 16.24, P = 0.0002) and 30-day mortality (57.1%, OR = 5.78, P = 0.0187). The fulfillment status of hypertriglyceridemia and hypofibrinogenemia within 72 h of hospital admission was also associated with the risk of adverse outcomes.ConclusionsThe fulfillment status of hypertriglyceridemia and hypofibrinogenemia were associated with the risks of MODS and 30-day mortality among pediatric HLH patients. Further studies are needed to validate this association and investigate its clinical utility in the severity evaluation for HLH.

Slow It Down: A Case Report Of Microangiopathic Hemolytic Anemia In A Heartmate III Patient

<h3>Introduction</h3> Incidence of hemolysis in left ventricular assist devices (LVADs) is reported from 13-18%, but with HeartMate 3 (HM3) LVAD has been decreased to <1%. Typically, hemolysis is associated with LVAD thrombosis with subsequent decreased survival rate at 1 year (38.9% vs. 89.3%). We present a case of microangiopathic hemolytic anemia (MAHA), not related to pump thrombosis in a recent implanted HM3 LVAD patient which resolved by decreasing LVAD speed. <h3>Case Report</h3> A 44 year-old man with status post LVAD HM3 4 months prior complicated with right ventricular (RV) failure, pulmonary hypertension and CKD Stage III was admitted for mixed vasodilatory and cardiogenic shock. Patient required dual inotropes, vasopressors and temporary renal replacement therapy in an effort to stabilize him and continue his evaluation for heart and kidney transplant. Meanwhile, patient developed acute, severe thrombocytopenia (platelet count of 26K) and mild anemia. Disseminated intravascular coagulation was unlikely (normal fibrinogen level). Heparin-induced thrombosis (HIT) antibody testing was non-reactive. No active sepsis. There were no power spikes or suspected LVAD thrombosis (Table 1). Intrinsic bone marrow disease was thought to be unlikely. LDH was elevated and haptoglobin level undetectable (Table 2), blood smear showed schistocytes, raising suspicious for MAHA, therefore LVAD speed was decreased to 5100 RPM to diminish red blood cell (RBC) fragmentation and maintained in systemic unfractionated heparin infusion. This resulted in recovery of platelets and hemolysis parameters (Table 2). Ultimately, patient underwent dual organ transplantation without complications. <h3>Conclusions</h3> Per our knowledge, this is the first case reported of MAHA in a LVAD HM3 patient, not related to pump thrombosis that resolves with decrease in LVAD speed. MAHA is caused by mechanical injury of RBCs. The effective treatment in this scenario was to decrease the speed of the LVAD, hypothetically to decrease excessive shear in circulation. Further research should be done to delineate efficacy of reducing LVAD speed in these patients.

Acquired Factor XIII Deficiency in a Patient with Metastatic Lung Cancer

Acquired factor XIII (FXIII) deficiency can result in life-long bleeding tendency and can be caused by enhanced consumption, impaired synthesis, or as an immune-mediated process. The latter can be related with solid neoplasms, through neutralizing or non-neutralizing antibodies. The relationship between FXIII activity and non-small cell lung cancer (NSCLC) is not well established. This case report is about a patient with NSCLC and acquired FXIII deficiency. Materials and Methods: Clinical records were obtained through the electronic process analysis, and the confidentiality of the patient was always assured. Results and Discussion: A 70-year-old male with no relevant past medical history and a recently diagnosed metastatic NSCLC was admitted for priapism. Five days later, a he developed a bleeding disorder, with slightly elevated coagulation times and normal fibrinogen levels and platelets count. FXIII level was found to be decreased (0.24 IU/mL) and FXIII plasma mixing studies did not confirm the presence of a neutralizing inhibitor. The FXIII level correction with standard plasma mixing studies was in favour of a non-neutralizing antibody. Despite treatment, haemorrhage control was not achieved and the patient died. Conclusion: This clinical report describes a rare case of a patient with metastatic NSCLC presenting a severe haemorrhagic event caused by FXIII deficiency immune-mediated by non-neutralizing antibodies and subsequent increased clearance.

A Case of Late-Onset Vitamin K Deficiency Bleeding in an Exclusively Breastfed Infant Emphasizing the Need for Revision of Vitamin K Prophylaxis Policy

A 4-month-old male child presented with a history of seizure and vomiting. There was no history of fever, fall, or any other trauma. On examination, there was anisocoria, and anterior fontanelle was bulging and nonpulsating. Computerized tomography revealed an acute on chronic bilateral subdural hematoma (left &gt; right) with a midline shift. He had no relevant past or family history suggestive of any bleeding disorder. Blood investigations revealed anemia with prolonged prothrombin time (PT)/international normalized ratio/and activated partial thromboplastin time (APTT). Mixing study was done and it showed a correction with pooled normal plasma. The possibility of coagulation factor deficiency was confirmed. Further, mixing studies and factor assays revealed normal levels of fibrinogen and Factor VIII, with a reduced level of Factor IX. Since both PT and APTT were prolonged and Factor IX level was low, a deficiency of Vitamin K-dependent coagulation factors was suspected. The child was immediately given intravenous Vitamin K injection. The diagnosis of Vitamin K deficiency bleeding (VKDB) was confirmed by protein induced by Vitamin K absence testing. Unfortunately, the child succumbed to the complications of the intracranial bleed.