Interest in the new thromboelastometry device, Clot Pro®, for predicting thrombocytopenia and hypofibrinogenemia during lung transplantation.

INTRODUCTION: Lung transplantation is associated with high proportion of transfusion. Monitoring of coagulopathy using viscoelastic tests could aid in the perioperative management of bleeding. The aim of the study was to assess the predictive cut-off values for thrombocytopenia and hypofibrinogenemia using the new thromboelastography analyzer, ClotPro. METHODS: We retrospectively enrolled 65 patients who underwent lung transplantation and were sampled for both viscoelastic assays and conventional coagulation assays simultaneously during the procedure. We characterized the correlation between the EX-test (extrinsic pathway) and platelet count as well as between the FIB-test (extrinsic pathway after platelet inhibition) and fibrinogen concentration. Then, we used ROC curve analysis to determine the optimal EX-test and FIB-test values for predicting thrombocytopenia and hypofibrinogenemia. RESULTS: All the amplitude values of the EX-test (A5, A10, A20, MCF) showed correlation with platelets count (Spearman's rank correlation coefficient ranging from 0.75 to 0.77, all p < 0.0001). We also observed a strong correlation between the amplitude values of the FIB-test (A5, A10, A20 and MCF) and the fibrinogen concentration (Spearman's rank correlation coefficient ranging from 0.68 to 0.71, all p < 0.0001). The AUCs of the EX-test values for thrombocytopenia <100 G/L and <80 G/L ranged from 0.80 to 0.93. Similarly, the AUCs of the FIB-test values for hypofibrinogenemia <1.5 g/L and <2 g/L ranged from 0.74 to 0.83. These results indicate that only the five-minute parameter of thromboelastometry is sufficient for detecting thrombocytopenia and hypofibrinogenemia in patients undergoing lung transplantation. The proposed cut off values for the EX-test to predict thrombocytopenia <80 G/L showed high sensitivity (>86 %), high specificity (>89 %) and high negative predictive value (>95 %). FIB-test cut off values predictive of fibrinogen below 1.5 g/L showed sensitivity (>78 %), specificity (>55 %) and negative predictive value (>88 %). CONCLUSIONS: Our study provided preliminary results that are useful for developing a ClotPro-based algorithm to guide transfusion in lung transplantation. Future interventional studies will be necessary to validate these cut-off values of ClotPro for guiding transfusion.

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.

Etiology and management of hypofibrinogenemia in trauma.

PURPOSE OF REVIEW: Fibrin polymerization is essential for stable clot formation in trauma, and hypofibrinogenemia reduces hemostasis in trauma. This review considers fibrinogen biology, the changes that fibrinogen undergoes after major trauma, and current evidence for lab testing and treatment. RECENT FINDINGS: Fibrinogen is a polypeptide that is converted to fibrin by the action of thrombin. During trauma, fibrinogen levels are consumed and reduce within the first few hours because of consumption, dilution, and fibrinolysis. Fibrinogen levels usually rebound within 48 hours of injury and can contribute to thrombotic events. The Clauss fibrinogen assay is the gold standard test for fibrinogen levels, although viscoelastic hemostatic assays are often used when a lab delay is anticipated. An evidence-based threshold for fibrinogen replacement is not well established in the literature, but expert opinion recommends maintaining a level above 150 mg/dl. SUMMARY: Hypofibrinogenemia is an important cause of nonanatomic bleeding in trauma. Despite multiple pathologic causes, the cornerstone of treatment remains fibrinogen replacement with cryoprecipitate or fibrinogen concentrates.

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.

Congenital dysfibrinogenemia in major surgery: A description of four cases and review of the literature.

BACKGROUND: Congenital dysfibrinogenemia is characterized by qualitatively abnormal fibrinogens with resultant blood coagulation dysfunction. The clinical manifestations are high heterogeneity. Treatment for dysfibrinogenemia should be personalized. Here, we reported four congenital dysfibrinogenemia patients with the major surgery, in order to discuss the treatment and diagnosis of congenital dysfibrinogenemia. METHODS: We reported four asymptomatic congenital dysfibrinogenemia patients with the major surgery (valve replacement, brain surgery, tumorectomy, hysterectomy) in our study. Routine coagulation tests, hepatorenal function and gene analysis, thrombelastogram were performed. RESULTS: Four congenital dysfibrinogenemia patients all showed prolonged TT, low level of activity fibrinogen and normal fibrinogen antigen. Case1 showed a heterozygous mutation in exon 2 of the FGA, c.1223G > C, which turns the codon for residue Aα Gly13 into Arg (p. Gly13Arg). DNA sequencing of case2 showed that a heterozygous mutation in exon 8 of the FGG (c.5877G > A) with being responsible for the Arg â†’ His substitution at position 301 of the γ chain (p. Arg301His). Case3 and case 4 failed to do genetic testing for other reason. Four congenital dysfibrinogenemia patients were asymptomatic in the daily life. Personal and family history revealed no abnormal bleeding or thrombotic events. These four patients did not receive special treatment and management before surgery. They all had a smooth operation. CONCLUSIONS: Misdiagnosis and unnecessary infusion bring huge health risks to patients. Correct diagnosis of congenital dysfibrinogenemia is the key to avoid misdiagnosis or unnecessary infusion. Asymptomatic patients with congenital dysfibrinogenemia do not need cryoprecipitate or fibrinogen input before major surgery.

Acquired hypofibrinogenemia in a patient with multiple myeloma.

We report a case of acquired hypofibrinogenemia with multiple myeloma presenting λ-type IgG monoclonal protein. The patient had anemia and renal deficiency, and also developed bleeding tendency due to severe coagulopathy. Her fibrinogen level was under the detectable limits in a functional assay. Enzyme-linked immunosorbent assay (ELISA) and immunoblotting analysis results were consistent with functional assay results, and deficiency patterns observed in cross-mixing tests for PT and aPTT confirmed the diagnosis of hypofibrinogenemia. To determine the cause of hypofibrinogenemia, we purified the patient's immunoglobulin via protein A agarose, and confirmed that fibrinogen was included in the bound fraction, strongly indicating paraprotein interference with fibrinogen. As accelerated removal of fibrinogen was indicated, we incubated the patient's plasma up to 48 h, but did not observe significant loss of fibrinogen. In sharp contrast, fibrinogen returned to below the detection level 12 h after infusion of fresh frozen plasma. These findings support leukocyte-mediated fibrinogen removal, rather than paraprotein-triggered fibrinogen instability. Surprisingly, the patient's paraprotein was IgG2, but we speculate the amount of paraprotein (IgG 5346 mg/dL) compensated for lower affinity to Fcγ receptors.

How I treat dysfibrinogenemia.

Congenital dysfibrinogenemia (CD) is caused by structural changes in fibrinogen that modify its function. Diagnosis is based on discrepancy between decreased fibrinogen activity and normal fibrinogen antigen levels and is confirmed by genetic testing. CD is caused by monoallelic mutations in fibrinogen genes that lead to clinically heterogenous disorders. Most patients with CD are asymptomatic at the time of diagnosis, but the clinical course may be complicated by a tendency toward bleeding and/or thrombosis. Patients with a thrombosis-related fibrinogen variant are particularly at risk, and, in such patients, long-term anticoagulation should be considered. Management of surgery and pregnancy raise important and difficult issues. The mainstay of CD treatment remains fibrinogen supplementation. Antifibrinolytic agents are part of the treatment in some specific clinical settings. In this article, we discuss 5 clinical scenarios to highlight common clinical challenges. We detail our approach to establishing a diagnosis of CD and discuss strategies for the management of bleeding, thrombosis, surgery, and pregnancy.

Use of Fibrinogen Determination Methods in Differential Diagnosis of Hypofibrinogenemia and Dysfibrinogenemia.

BACKGROUND: Fibrinogen plays an important role in hemostasis. The normal concentration of fibrinogen in blood plasma is between 1.8 - 4.2 g/L. Decreased fibrinogen levels are observed in congenital afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, disseminated intravascular coagulation, fibrinolytic therapy, some more severe hepatic parenchymal disorders, and increased blood loss. Elevated fibrinogen levels occur in inflammatory diseases and neoplastic diseases, in pregnancy, and postoperative conditions. Functional fibrinogen measurement is also one of the basic coagulation screening tests. The fibrinogen antigen assay is used to distinguish between qualitative and quantitative fibrinogen disorders. METHODS: The aim of the study was the use of fibrinogen determination methods in differential diagnosis of hypofibrinogenemia and dysfibrinogenemia, statistical evaluation and determine the relationship of fibrinogen Clauss assay, prothrombin time (PT) derived fibrinogen assay, and fibrinogen antigen in the group of 60 patients with congenital fibrinogen disorders (n = 40 dysfibrinogenemia; n = 20 hypofibrinogenemia). RESULTS: The results measured by the PT-derived fibrinogen assay were approximately four times higher compared to the fibrinogen Clauss assay in the group of patients with dysfibrinogenemia. In patients with hypofibrinogenemia, there is a correlation (r = 0.9016) between the fibrinogen Clauss assay and PT-derived fibrinogen assay with a statistical significance of p < 0.0001. Using a linear or quadratic interpolation function, we were able to determine the fibrinogen Clauss assay and the fibrinogen antigen assay before analysis. CONCLUSIONS: The higher level of the PT-derived fibrinogen assay compared to the fibrinogen Clauss assay in the group of patients with dysfibrinogenemia may pose a greater risk to asymptomatic patients who require diagnosis and treatment in case of bleeding. The fibrinogen value using the PT-derived fibrinogen assay could erroneously give a normal level. The use of the interpolation function is important to estimate the value of fibrinogen activity and antigen before the analysis itself by the Clauss assay or analysis by the fibrinogen antigen assay.

Heterogeneity of congenital afibrinogenemia, from epidemiology to clinical consequences and management.

Fibrinogen is a complex protein playing a major role in coagulation. Congenital afibrinogenemia, characterized by the complete absence of fibrinogen, is associated with major hemostatic defects. Even though the clinical course is unpredictable and can be completely different among patients, severe bleeding is the prominent symptom. Patients are also at increased risk of thrombosis and sometimes suffer from spontaneous spleen rupture, bone cysts and defective wound healing. Due to the relative rarity of afibrinogenemia, there are no evidence-based strategies for helping physicians in care of these patients. Fibrinogen supplementation is the keystone to prevent or treat bleeding events. In addition, fibrinogen, a pleiotropic protein with numerous physiological roles in immunity, angiogenesis and tissue repair, is involved in many diseases. Indeed, depletion of fibrinogen in animal models of infections, tumors and neurological diseases has an effect on the clinical course. The consequences for patients with afibrinogenemia still need to be investigated.

Screening method for congenital dysfibrinogenemia using clot waveform analysis with the Clauss method.

INTRODUCTION: Congenital fibrinogen disorders (CFDs) are classified as afibrinogenemia or hypofibrinogenemia (Hypo), dysfibrinogenemia (Dys), or hypodysfibrinogenemia (Hypodys), according to functional and antigenic fibrinogen concentrations. However, in routine laboratory tests, plasma fibrinogen levels are mostly measured using the functional Clauss method and not as an antigenic level. Therefore, it is difficult to discriminate CFD from acquired hypofibrinogenemia (aHypo). To establish a screening method for CFD, we investigated the parameters of clot waveform analysis (CWA) from the Clauss method. METHODS: We compared fibrinogen concentrations determined using Clauss and prothrombin time (PT)-derived methods for 67 aHypo and CFD cases (19 Dys, 4 Hypodys, and 1 Hypo determined using antigen levels and DNA sequence analysis) with a CS-2400 instrument, and the CWA parameters, dH and Min1, were analyzed automatically with an on-board algorithm. dH and Min1 are the maximum change in transmittance at the end of coagulation and the maximum velocity of transmittance change during coagulation, respectively. RESULTS: Clauss/PT-derived ratios detected 18 cases of Dys and Hypodys but no Hypo cases, whereas Clauss/dH plus Clauss/Min1 ratios were calculated from fibrinogen concentration using the Clauss method and CWA parameters detected 21 cases of Dys and Hypodys and one Hypo case. Moreover, the Clauss/PT-derived ratio and Clauss/dH plus Clauss/Min1 ratio detected 22 cases of Dys and Hypodys cases and one Hypo case. CONCLUSION: This report demonstrates that CWA parameters of the Clauss method, Clauss/dH plus Clauss/Min1 ratio, screened Dys patients with a higher rate, whereas Clauss/PT-derived ratios did not.

Detection of hypofibrinogenemia during cardiac surgery: a comparison of resonance-based thrombelastography with the traditional Clauss method.

: Bleeding after cardiac surgery is associated with significant morbidity and mortality. Hypofibrinogenemia is a crucial factor for bleeding in this setting and may be rapidly detected using point-of-care viscoelastic tests (POC-VET). However, the correlation of POC-VET with conventional coagulation assays is still unclear. The current study aimed to correlate resonance-based POC-VET assays (Haemonetics TEG 6s) with the traditional nonrapid Clauss method. Another aim was to identify a cut-off value for the detection of hypofibrinogenemia (fibrinogen plasma level below 150 mg/dl) focusing on the maximum amplitude of the TEG 6s citrated functional fibrinogen (CFF) assay. Adult patients undergoing cardiac surgery were screened for inclusion in this single-centre retrospective cohort study. Inclusion criteria were the availability of a TEG assay and timely corresponding laboratory results. Calculation of a CFF-maximum amplitude (CFF-MA) cut-off value was performed using receiver operating curve analysis in the baseline cohort and validated in the control cohort. The best correlation with the Clauss method was observed for the CFF-MA (r = 0.77; P < 0.0001) compared with the citrate kaolin maximum amplitude assay (r = 0.57; P < 0.0001) and the citrate kaolin heparinase maximum amplitude assay (r = 0.67; P < 0.0001). A cut-off value of 19.9 mm for the CFF-MA was calculated [area under the curve 0.87 (95% confidence interval: 0.82-0.92; P < 0.0001)]. This cut-off value had a sensitivity of 81.8% and a specificity of 71.1% for identification of hypofibrinogenemia in the control cohort. The resonance-based thrombelastography analyser can identify hypofibrinogenemia. Future clinical studies should investigate whether cut-off value guided coagulation therapy with POC-VET may improve patient outcomes in patients who suffer from bleeding complications.

Diagnostic accuracy of viscoelastic point-of-care identification of hypofibrinogenaemia in cardiac surgical patients: A systematic review.

Hypofibrinogenaemia during cardiac surgery may increase blood loss and bleeding complications. Viscoelastic point-of-care tests provide more rapid diagnosis than laboratory measurement, allowing earlier treatment. However, their diagnostic test accuracy for hypofibrinogenaemia has never been reviewed systematically. We aimed to systematically review their diagnostic test accuracy for the identification of hypofibrinogenaemia during cardiac surgery. Two reviewers assessed relevant articles from seven electronic databases, extracted data from eligible articles and assessed quality. The primary outcomes were sensitivity, specificity and positive and negative predictive values. A total of 576 articles were screened and 81 full texts were assessed, most of which were clinical agreement or outcome studies. Only 10 diagnostic test accuracy studies were identified and only nine were eligible (ROTEMdelta 7; TEG5000 1; TEG6S 1, n = 1820 patients) (ROTEM, TEM International GmbH, Munich, Germany; TEG, Haemonetics, Braintree, MA, USA). None had a low risk of bias. Four ROTEM studies with a fibrinogen threshold less than 1.5-1.6 g/l and FIBTEM threshold A10 less than 7.5-8 mm had point estimates for sensitivity of 0.61-0.88; specificity 0.54-0.94; positive predictive value 0.42-0.70; and negative predictive value 0.74-0.98 (i.e. false positive rate 30%-58%; false negative rate 2%-26%). Two ROTEM studies with higher thresholds for both fibrinogen (<2 g/l) and FIBTEM A10 (<9.5 mm) had similar false positive rates (25%-46%), as did the two TEG studies (15%-48%). This review demonstrates that there have been few diagnostic test accuracy studies of viscoelastic point-of-care identification of hypofibrinogenaemia in cardiac surgical patients. The studies performed so far report false positive rates of up to 58%, but low false negative rates. Further diagnostic test accuracy studies of viscoelastic point-of-care identification of hypofibrinogenaemia are required to guide their better use during cardiac surgery.

Congenital dysfibrinogenaemia presented with preterm premature rupture of the membranes and vaginal bleeding.

A 26-year-old woman was found to have congenital dysfibrinogenaemia after presenting to our hospital with premature rupture of the membranes and vaginal bleeding. Given the absence of clear guidelines for the management of pregnancy complicated by dysfibrinogenaemia, we followed expert consensus that exists among published works, with some modifications. This case was managed by a multidisciplinary team of obstetrics-gynaecology, haematology and paediatric haematology. Here we review how the patient presented, the investigations that led to the diagnosis and the treatment options.

Congenital dysfibrinogenemia as a rare cause of recurrent gastrointestinal bleeding.

<b>Introduction: </b>Gastrointestinal bleeding is a common disease that surgeons encounter in everyday clinical practice. It is most often easy to diagnose and treat. However, rare causes of bleeding can lead to delayed diagnosis and ineffective treatment. Dysfibrinogenemia is a qualitative fibrinogen disorder in which functional fibrinogen level is reduced with normal antigenic level. <br><b> Case report:</b> Herein we present the case of a 59-year-old female with recurrent gastrointestinal bleeds, that turned out to be an unusual manifestation of congenital dysfibrinogenemia. Detailed imaging and endoscopic diagnostics revealed portal hypertension with a non-bleeding 1-cm gastrointestinal stromal tumor and multiple angiodysplastic lesions in close proximity.

Congenital afibrinogenemia in a 4-year-old girl complicated with acute lymphoblastic leukemia.

BACKGROUND: Congenital fibrinogen deficiency is one of the rare inherited coagulation disorders. Congenital fibrinogen deficiency complicated with a hematological malignancy can be life threatening. CASE: We present a four-year-old girl with congenital fibrinogen deficiency complicated with acute lymphoblastic leukemia. CONCLUSION: This case aims to highlight therapeutic approaches for the management of afibrinogenemia patients with acute leukemia.

Trials and Tribulations of Viscoelastic-Based Determination of Fibrinogen Concentration.

Acquired fibrinogen deficiency is a major determinant of severe bleeding in different clinical conditions, including cardiac surgery, trauma, postpartum hemorrhage, liver surgery, and transplantation. The existing guidelines recommend to supplement fibrinogen in patients with severe bleeding when the fibrinogen concentration is <1.5 g/L. Viscoelastic tests (VETs) provide a fast determination of the fibrinogen contribution to clot firmness and allow prompt treatment of acquired fibrinogen deficiency. However, different VET devices are presently available on the market, based on different technologies and different activators and platelet inhibitors. The available tests are the functional fibrinogen (FF, thromboelastography), the fibrinogen contribution to clot firmness (fibrinogen determination [FIBTEM], thromboelastometry), and the fibrinogen contribution to clot strength (FCS, sonorheometry). All these tests have a moderate to very good correlation with the Clauss fibrinogen assays; however, when comparing VET-based fibrinogen contribution to clot firmness with Clauss fibrinogen concentration, strong differences occur within the same test under different conditions and between different tests. The most widely studied test is the thromboelastometric FIBTEM; the best predictor of a Clauss fibrinogen <1.5 g/L is placed at a maximum clot firmness around 8 mm of amplitude. Fewer data are available for thromboelastographic FF, but the correspondent value is in the range of 12 mm. Overall, due to an incomplete inhibition of platelet contribution, FF overestimates the fibrinogen contribution with respect to FIBTEM. Data on sonorheometry FCS are limited and conflicting. When addressing the correlation between different tests, it is good in general, but no fixed conversion factors can be proposed, due to a considerable dispersion of the experimental points. In conclusion, VET-based fibrinogen tests are certainly powerful tools that are presently suggested by the existing guidelines; however, when using them for clinical decision-making, users should consider the possible sources of bias, which include the different level of platelet inhibition, the role of platelet count and function, the possible different degrees of blood activation with tissue factor, the important role of factor XIII in stabilizing the fibrin clot, and others.

Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients.

BACKGROUND: Congenital fibrinogen deficiency is an ultra-rare disorder in which patients can experience severe and/or frequent bleeding episodes (BEs). Here, we present the largest prospective study to date on the treatment of this disorder. METHODS: Hemostatic efficacy of human fibrinogen concentrate (HFC; FIBRYGA® , Octapharma AG) for treatment of bleeding or surgical prophylaxis was assessed by investigators and adjudicated by an independent data monitoring and endpoint adjudication committee (IDMEAC) according to a four-point scale, using objective criteria. Thromboelastometry maximum clot firmness (MCF) was also determined. RESULTS: Twenty-five afibrinogenemia patients were treated with HFC: 24 for on-demand treatment of 89 BEs, and nine as prophylaxis for 12 surgeries. For BEs, treatment success (rating of excellent or good) evaluated by investigators was 96.6% (90% confidence interval [CI], 0.92-0.99; two missing ratings, classified as failures) and by the IDMEAC was 98.9% (90% CI, 0.95-0.999). Mean ± standard deviation (SD) increase in MCF was 5.8 ± 2.5 mm one hour after the first HFC infusion (mean ± SD dose, 61.88 ± 11.73 mg/kg). For the 12 surgeries (median [range] HFC dose/surgery, 85.80 mg/kg [34.09-225.36]), intraoperative and postoperative treatment success were both rated 100% (90% CI, 0.82-1.00) by investigators and the IDMEAC. Three adverse events were possibly treatment related, including a moderate case of thrombosis. There were no deaths, no severe allergic or hypersensitivity reactions, and no clinical evidence of neutralizing antifibrinogen antibodies. CONCLUSIONS: Human fibrinogen concentrate was efficacious for on-demand treatment of bleeding and as surgical prophylaxis, with a favorable safety profile, in patients with congenital afibrinogenemia.