Tigecycline-associated hypofibrinogenemia: A single center, retrospective, controlled study.

BACKGROUND: Tigecycline-associated hypofibrinogenemia has been reported as an important adverse effect in recent years, but controlled studies minimizing confounding factors are needed. The objective of our study was to assess changes in fibrinogen levels in patients for hospitalization, comparing two antibiotic episodes (tigecycline and other) within the same patients. METHODS: The retrospective, self-controlled case series study was conducted at our University Hospitals. The study compared the change in fibrinogen levels during the patient's hospitalization for tigecycline (TigePer) and another antibiotic period (OtherPer). In addition, bleeding events, bleeding risk (determined by the IMPROVE bleeding risk score), as well as 15- and 30-day mortality rates between TigePer and OtherPer were compared. RESULTS: The study enrolled 50 patients with 100 episodes of antibiotic treatment. The median age (interquartile range) of the patients was 68.5 (21.5) years, and 38 % were female. As compared to OtherPer, TigePer had a statistically significant reduction in fibrinogen levels (p < 0.001), with a hypofibrinogenemia rate of 40 % in TigePer as compared to 2 % in OtherPer (p < 0.001). TigePer demonstrated a significantly higher 15-day mortality rate (p = 0.006). No significant differences were observed between the two periods in terms of bleeding risk, rate of bleeding events, and 30-day mortality rate (p > 0.05). CONCLUSION: Hypofibrinogenemia and other coagulopathies, without associated bleeding events, are more frequently observed in patients receiving tigecycline. Therefore, it is crucial for clinicians to monitor fibrinogen levels during tigecycline use.

Clinical observation of hypofibrinogenemia induced by the treatment of tocilizumab in rheumatic diseases and exploration of risk factor for hypofibrinogenemia.

OBJECTIVE: The objective of this study was to analyze the changes in plasma fibrinogen (FIB) levels during tocilizumab (TCZ) treatment in patients with rheumatic diseases, to clarify the incidence of hypofibrinogenemia and its possible risk factors, and to establish a nomogram model for predicting the probability of hypofibrinogenemia in rheumatoid arthritis (RA) patients treated with TCZ. METHODS: Clinical data of patients treated with TCZ at the Department of Rheumatology and Immunology, the First Affiliated Hospital of Xi'an Jiaotong University from January 2014 to October 2021 were retrospectively analyzed to observe the incidence of hypofibrinogenemia in several rheumatic diseases at different time points. The risk factor of hypofibrinogenemia in RA patients treated with TCZ was determined by using Cox regression analysis. Based on the results of Cox regression analysis, a nomogram for predicting the probability of hypofibrinogenemia in rheumatoid arthritis (RA) patients treated with TCZ was established and validated through RStudio software. RESULTS: A total of 83 TCZ-treated patients were enrolled in this study, and 32 (38.55%) patients developed hypofibrinogenemia during TCZ treatment. There were 8 males and 24 females in the FIB-reduced group, with an average age of 44.88 ± 18.39 years. Hypofibrinogenemia was most common in TCZ-treated patients with takayasu arteritis (TA) and RA. Hypofibrinogenemia typically occured within 3 months after TCZ treatment. In RA patients treated with TCZ, platelet distribution width, parathyroid hormone, bone mineral density, tender joint count, and swollen joint count were independent risk factors for the occurrence of hypofibrinogenemia. The nomogram based on the above risk factors could effectively predict the probability of hypofibrinogenemia in RA patients receiving TCZ. CONCLUSION: Although bleeding symptoms were not observed in this study, the incidence of hypofibrinogenemia remained high after TCZ treatment, usually occurring within 3 months of treatment. Therefore, it is necessary to monitor FIB levels during TCZ treatment. In addition, clinicians can use the nomogram model developed from this study to predict the incidence of hypofibrinogenemia after TCZ treatment in RA patients. Key Points • Hypofibrinogenemia often occurs during TCZ treatment for rheumatic diseases. • PDW, PTH, BMD, tender joint count, and swollen joint count are risk factors for the occurrence of hypofibrinogenemia. • It is necessary to monitor FIB levels during TCZ treatment to avoid bleeding tendency.

The prevalence and risk factors of coagulopathy in pediatric patients undergoing surgery for epilepsy.

OBJECTIVE: Hematological consequences of novel antiseizure medications (ASMs) or combined therapies are rarely reported, especially in pediatric patients undergoing surgery for epilepsy. This study aimed to assess the prevalence and risk factors of coagulation dysfunction in this population and evaluate their relationship with intra- and postoperative bleeding. METHODS: Three hundred ninety children who underwent surgery for epilepsy and 104 children without epilepsy who underwent nonepilepsy surgery at the authors' center were included in the study. The authors retrospectively collected and analyzed the following clinical data: sex, age, weight, course of epilepsy, antiseizure therapy, first laboratory data after admission, and transfusion-related data. RESULTS: ASMs were responsible for the higher incidence of coagulation dysfunction in pediatric epilepsy surgery patients. Low body weight (OR 0.95, 95% CI 0.92-0.98) and valproic acid (VPA) therapy (OR 5.13, 95% CI 3.25-8.22) were the most relevant factors leading to coagulation dysfunction. The most common hematological side effects of VPA were thrombocytopenia and hypofibrinogenemia, whereas low body weight was only associated with hypofibrinogenemia. Both VPA and low body weight increased the need for intra- or postoperative transfusion (p < 0.001). CONCLUSIONS: Pediatric epilepsy surgery patients often take multiple ASMs, resulting in an increased incidence of coagulopathy. VPA levels and low body weight were found to be the main influential factors associated with an increased risk of coagulation dysfunction. Platelet and fibrinogen levels were the main indices that were affected. Both VPA and low body weight were relevant to additional surgery-related transfusion, necessitating the need for increased awareness of preoperative coagulopathy before pediatric epilepsy surgery. Clinical trial registration no.: NCT05675254 (ClinicalTrials.gov).

Safety of Tigecycline in Patients on Antithrombotic Therapy: A Single-Center Retrospective Study.

INTRODUCTION: The aims of the study were to investigate the risk factors of tigecycline-induced hypofibrinogenemia and to evaluate the safety of tigecycline with concomitant antithrombotic drugs. METHODS: We performed a retrospective analysis of patients who received tigecycline for more than 3 days between January 2015 and June 2019. Clinical and laboratory data were collected including fibrinogen concertation, tigecycline dose, duration of treatment, disease severity, complete blood count, indicators of infection, liver and renal function. Risk factors of hypofibrinogenemia were analyzed by univariate and multivariate analysis. To evaluate the safety of tigecycline and concomitant antithrombotic drugs, bleeding events were assessed by comparing the decline in hemoglobin and the amount of red blood cell transfusion in patients with antithrombotic drugs and those without. RESULTS: This study included a total of 68 cases, 20 of which experienced hypofibrinogenemia while receiving tigecycline treatment. Duration of treatment, cefoperazone/sulbactam combination therapy, and fibrinogen levels prior to initiation of tigecycline were risk factors associated with tigecycline-induced hypofibrinogenemia. There were 26 recorded bleeding incidents, 25 of which happened before the start of tigecycline. Antithrombotic and non-antithrombotic patients did not differ in their hemoglobin decline or need for red blood cell transfusions while taking tigecycline. CONCLUSION: A longer treatment duration, cefoperazone/sulbactam combination therapy, and a lower level of fibrinogen before tigecycline were associated with an increased risk of tigecycline-induced hypofibrinogenemia. A combination of antithrombotic drugs and tigecycline did not aggravate the bleeding events during tigecycline treatment.

Acute pancreatitis caused by tigecycline and furosemide combination treatment and hypofibrinogenemia caused by tigecycline: A case report.

OBJECTIVE: We describe a case of acute pancreatitis (AP) and hypofibrinogenemia associated with drug treatment with the aim to increase awareness of uncommon yet possibly life-threatening adverse reactions of tigecycline and furosemide. CASE SUMMARY: A 75-year-old Chinese male was hospitalized for acute non-ST-elevation myocardial infarction and acute heart failure. The patient underwent successful percutaneous coronary intervention and MitraClip. Furosemide was taken since admission. Because Acinetobacter baumannii was detected in the blood and sputum, the patient was treated with tigecycline from the 14th day of hospitalization. Abnormal pancreatitis parameters were observed, and pancreatic CT was undertaken 12 days after the treatment of tigecycline. AP was diagnosed and symptomatic treatment was carried out, but no significant improvement was observed. On the 33rd day of hospitalization, the patient presented with acute upper gastrointestinal bleeding and decreased levels of fibrinogen and platelets. After withdrawal of tigecycline, the coagulation and pancreatitis parameters improved significantly. However, the pancreatitis parameters increased again after stopping somatostatin. Therefore, somatostatin was given again for 1 day, and furosemide was discontinued. After that, the pancreatitis parameters returned to baseline levels after a slight recovery. CONCLUSION: Clinicians should pay attention to clinical signs, symptoms, and pancreatic enzymes during tigecycline or furosemide treatment, especially when used in combination. In addition, regular monitoring of fibrinogen and platelet count during tigecycline treatment is suggested.

Tocilizumab-induced hypofibrinogenemia in patients with systemic-onset juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (SJIA) is a chronic inflammatory disease of childhood with elevated serum IL-6 levels. As an inhibitor of IL-6R, tocilizumab (TCZ) has been approved to treat SJIA patients. TCZ-induced hypofibrinogenemia has been only reported in adult cases and limited small case series with rheumatoid arthritis or giant cell arteritis. Here, we describe the incidence of TCZ-induced hypofibrinogenemia in SJIA patients and its possible influence on bleeding risk. SJIA patients with TCZ treatment in Shenzhen Children's hospital were retrospectively reviewed. Only those with the data on serum fibrinogen levels were included. Data on clinical manifestations, laboratory parameters, management, and sJADAS10-ESR score were collected. Laboratory data were extracted following the start of TCZ therapy at 2, 4, 8, 12, and 24 weeks thereafter. Seventeen SJIA patients with TCZ treatment were included. Thirteen (76.47%, 13/17) had hypofibrinogenemia. The lowest serum fibrinogen levels were even below 1.5 g/L in seven (41.17%, 7/17) patients. Among four patients without MTX treatment, two had obvious hypofibrinogenemia. Although five patients had already stopped steroid treatment 24 weeks after TCZ treatment, three of them still had hypofibrinogenemia. Only P14 had mild nasal mucosal bleeding occasionally. Coagulation tests were regularly performed in eight patients, of these, six had hypofibrinogenemia, which occurred following one to four doses of TCZ; continuation of TCZ treatment hadn't further aggravated hypofibrinogenemia. Serum fibrinogen levels were not decreased consistently with the improvement of sJADAS10-ESR score in more than half of these eight patients. Factor XIII was detected in six patients and none was identified with Factor XIII deficiency. TCZ alone may induce hypofibrinogenemia in SJIA patients. Continuation of TCZ treatment may be safe for most SJIA patients. But for SJIA patients with indications of surgery or complicated with MAS, the risk of hemorrhage should be regularly evaluated during TCZ treatment. The association between TCZ-induced hypofibrinogenemia and factor XIII deficiency remains uncertain.Trial registration: Not applicable; this was a retrospective study.

Cost-effectiveness of Fibrinogen Concentrate vs Cryoprecipitate for Treating Acquired Hypofibrinogenemia in Bleeding Adult Cardiac Surgical Patients.

Importance: Excessive bleeding requiring fibrinogen replacement is a serious complication of cardiac surgery. However, the relative cost-effectiveness of the 2 available therapies-fibrinogen concentrate and cryoprecipitate-is unknown. Objective: To determine cost-effectiveness of fibrinogen concentrate vs cryoprecipitate for managing active bleeding in adult patients who underwent cardiac surgery. Design, Setting, and Participants: A within-trial economic evaluation of the Fibrinogen Replenishment in Surgery (FIBERS) randomized clinical trial (February 2017 to November 2018) that took place at 4 hospitals based in Ontario, Canada, hospitals examined all in-hospital resource utilization costs and allogeneic blood product (ABP) transfusion costs incurred within 28 days of surgery. Participants included a subset of 495 adult patients from the FIBERS trial who underwent cardiac surgery and developed active bleeding and acquired hypofibrinogenemia requiring fibrinogen replacement. Interventions: Fibrinogen concentrate (4 g per dose) or cryoprecipitate (10 units per dose) randomized (1:1) up to 24 hours postcardiopulmonary bypass. Main Outcomes and Measures: Effectiveness outcomes included number of ABPs administered within 24 hours and 7 days of cardiopulmonary bypass. ABP transfusion (7-day) and in-hospital resource utilization (28-day) costs were evaluated and a multivariable net benefit regression model built for the full sample and predefined subgroups. Results: Patient level costs for 495 patients were evaluated (mean [SD] age 59.2 [15.4] years and 69.3% male.) Consistent with FIBERS, ABP transfusions and adverse events were similar in both treatment groups. Median (IQR) total 7-day ABP cost was CAD $2280 (US dollars [USD] $1697) (CAD $930 [USD $692]-CAD $4970 [USD $3701]) in the fibrinogen concentrate group and CAD $2770 (USD $1690) (IQR, CAD $1140 [USD $849]-CAD $5000 [USD $3723]) in the cryoprecipitate group. Median (interquartile range) total 28-day cost was CAD $38 180 (USD $28 431) $(IQR, CAD $26 350 [USD $19 622]-CAD $65 080 [USD $48 463]) in the fibrinogen concentrate group and CAD $38 790 (USD $28 886) (IQR, CAD $26 180 [USD $19 495]-CAD $70 380 [USD $52 409]) in the cryoprecipitate group. After exclusion of patients who were critically ill before surgery (11%) due to substantial variability in costs, the incremental net benefit of fibrinogen concentrate vs cryoprecipitate was positive (probability of being cost-effective 86% and 97% at $0 and CAD $2000 (USD $1489) willingness-to-pay, respectively). Net benefit was highly uncertain for nonelective and patients with critical illness. Conclusions and Relevance: Fibrinogen concentrate is cost-effective when compared with cryoprecipitate in most bleeding adult patients who underwent cardiac surgery with acquired hypofibrinogenemia requiring fibrinogen replacement. The generalizability of these findings outside the Canadian health system needs to be verified.

Analysis of the clinical characteristics of tigecycline-induced hypofibrinogenemia.

Knowledge regarding the association between hypofibrinogenemia and tigecycline is based mainly on case reports. However, the clinical features of tigecycline-induced hypofibrinogenemia are unclear. We collected 20 patients (16 males and 4 females) with tigecycline-induced hypofibrinogenemia by searching the Chinese and English databases from June 2005 to May 2021, with a median age of 63.5 years (range 39∼90 years). Hypofibrinogenemia developed at a median of 9 days (range 2∼35 days). Most patients had no typical clinical manifestations, and only a few patients had bleeding and ecchymosis. Fibrinogen levels gradually decreased from 3.98 ± 2.05 g/L to 0.87 ± 0.45 g/L (P = 0.000), and the activated partial thromboplastin time (APTT) increased from 38.26 ± 8.80 s to 83.43 ± 47.23 s (P = 0.002). Fibrinogen levels in all patients recovered to the normal range within a median of 4 days (range 1∼12 days) after tigecycline cessation. Our results suggest that fibrinogen levels should be closely monitored in patients treated with tigecycline, specifically patients who may have renal insufficiency or patients with long-term use.

Diagnostic Tests for Hypofibrinogenemia Resulting from Green Pit Viper (Trimeresurus albolabris) Envenomation: A Simulated In Vitro Study.

INTRODUCTION: The green pit viper (GPV) Trimeresurus albolabris is found in Southeast Asia. Its venom has a thrombin-like activity that can cause hypofibrinogenemia. Fibrinogen measurement is not always available. We aimed to establish a more available diagnostic tool indicating hypofibrinogenemia caused by GPV envenomation. METHODS: This was an in vitro study, in which healthy subjects aged 20 to 45 y were enrolled. There were 2 experiments. In Experiment 1, blood samples from 1 subject had varying amounts of T albolabris venom added to determine its effect on the fibrinogen level (FL). In Experiment 2, 3 sets of blood samples were obtained from another 25 subjects. The 2 venom doses established in Experiment 1 were used on 2 sets of the samples to simulate severe (FL <1.0 g·L-1) and mild hypofibrinogenemia (FL 1.0-1.7 g·L-1). The third set of samples was venom-free. All samples were used for platelet counts, prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT), and 2 bedside clotting tests. Diagnostic parameters were calculated against the target FL of <1.0 g·L-1 and <1.7 g·L-1. RESULTS: Twenty-five subjects were enrolled in Experiment 2. On referencing normal cutoff values (platelet count >150,000 cells/mm3, venous clotting time <15 min, normal 20-min whole blood clotting time, INR <1.2, aPTT <30), we found abnormalities of 5, 0, 0, 3, and 22%, respectively. The highest correlation with hypofibrinogenemia was provided by PT/INR. For an FL of <1.0 g·L-1, PT and INR revealed the highest areas under the receiver operating characteristic curve, 0.76 (95% CI, 0.55-0.97) and 0.76 (95% CI, 0.57-0.97), respectively. The highest accuracy and the highest sensitivity were provided by PT/INR. CONCLUSIONS: PT/INR could be used as a diagnostic test for severe hypofibrinogenemia in GPV envenomation because of its high accuracy and area under the receiver operating characteristic curve.

Serum concentration as a predictor of tigecycline-induced hypofibrinogenemia in critically ill patients: A retrospective cohort study.

OBJECTIVES: This study aimed to determine the thresholds of serum concentration as a predictor of tigecycline (TGC)-induced hypofibrinogenemia (HF) in critically ill patients. METHODS: A retrospective cohort study was conducted in intensive care unit patients treated with TGC. The clinical data and serum concentration were extracted from the patients' electronic medical records. Patients were divided into an HF group and a normal group according to fibrinogen value. The receiver operating characteristic curves and logistic regression were used to derive serum concentration thresholds and quantify the association between exposure thresholds and HF while adjusting for confounders. RESULTS: In total, 100 patients were included. The receiver operating characteristic curves analysis showed that TGC concentration parameters were strongly predictive of HF. Adjusting for duration of TGC, serum concentration at the 6 hours after the dosing (C1/2) ≥ 0.645 mg/l, area under the concentration-time curve over a 24-hour period (AUC 0-24) ≥ 20.76 mg·h/l, and serum concentration of 30 minutes before next dose (Cmin) ≥ 0.455 mg/l were associated with a three- to five-fold increased risk of TGC-induced HF in logistic regression. CONCLUSION: The findings from this study provide evidence that TGC exposure is highly predictive of HF, with an approximately three- to five-fold increased risk. Serum concentration at the 6 hours after the dosing (C1/2) ≥ 0.645 mg/l with best area under the receiver operating characteristic curve and negative predictive value appears to be the most appropriate toxicity threshold.

[Acquired hypofibrinogenemia in patients with leukemia during steroid therapy].

Acquired hypofibrinogenemia is observed in patients with severe liver disease, disseminated intravascular coagulation, and high-volume perioperative fluid replacement. In lymphoblastic leukemia, hypofibrinogenemia is most frequently caused by the administration of L-asparaginase. Here we report the cases of two patients with acquired hypofibrinogenemia that occurred during steroid-containing chemotherapy treatment against lymphoblastic blast crisis of chronic myeloid leukemia in the first case and acute lymphoblastic leukemia in the second case. Administration of steroids repeatedly and promptly caused hypofibrinogenemia, irrespective of the products (prednisolone, dexamethasone, or methylprednisolone) or routes (oral or intravenous) that were used. Monitoring of the fibrinogen levels, especially during the first course of steroid therapy, would be useful for early diagnosis.

Rare severe hypofibrinogenemia induced by tissue plasminogen activator in stroke patients: Case report.

RATIONALE: Severe hypofibrinogenemia after intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) is rare and easily overlooked, but hypofibrinogenemia increases the risk of major bleeding. However, it is unclear when hypofibrinogenemia reaches the peak and when hypofibrinogenemia is resolved. PATIENT CONCERNS: Case 1 was of a 66-year-old man who was hospitalized due to sudden onset of vague speech and right hemiplegia for 4 hours. Case 2 was of an 84-year-old woman who was hospitalized for sudden onset of left hemiplegia and vague speech for 4 hours. In case 1, fibrinogen levels decreased from normal values to <0.25 g/L within 4.5 hours after commencing IVT and returned to normal at 35 hours later. In case 2, fibrinogen levels decreased from 1.1 to <0.25 g/L within 2 hours after commencing IVT and normalized 36.5 hours later. DIAGNOSES: Both patients were diagnosed with rt-PA-related hypofibrinogenemia. INTERVENTIONS: No antiplatelet or symptomatic treatment was administered during the period of hypofibrinogenemia. OUTCOMES: Fibrinogen levels gradually recovered. In case 1, the patient did not experience cerebral hemorrhage during hypofibrinogenemia. His symptoms improved significantly within 1 week. In case 2, repeat computed tomography revealed minor cerebral hemorrhage, but no deterioration in her condition was noted until she was discharged. LESSONS: Rapid, severe, and prolonged hypofibrinogenemia may occur after IVT with rt-PA, which may increase the risk of massive hemorrhage and affect the related therapy. Prompt diagnosis of hypofibrinogenemia is important for preventing complications. We recommend checking the fibrinogen levels routinely after IVT. Fibrinogen replacement therapy and platelet transfusion are the main management routes for rt-PA-related symptomatic intracranial hemorrhage.

Hypofibrinogenemia induced by high-dose tigecycline-case report and review of literature.

RATIONALE: Extensive off-label use may affect the safety profile of tigecycline. Tigecycline-associated hypofibrinogenemia is potentially life threatening, although the frequency of life-threatening reactions is unknown and their incidence is easily overlooked. We report a case of 2 instances of treatment with high-dose tigecycline, each of which presented with hypofibrinogenemia. PATIENT CONCERNS: An 86-year-old male patient was treated twice with high-dose tigecycline and presented with hypofibrinogenemia both times. The decrease in fibrinogen occurred within 3 to 7 days of tigecycline treatment. Other coagulation parameters had slightly prolonged values. DIAGNOSES: Coagulopathy and hypofibrinogenemia. INTERVENTIONS: We discontinued the tigecycline. OUTCOMES: The fibrinogen level normalized within 5 days after the withdrawal of tigecycline. Following 80 days of hospitalization, the patient was transferred to the rehabilitation hospital for further treatment. LESSONS: We suggest routine strict monitoring of coagulation parameters, particularly fibrinogen. Attention should be paid to below-normal fibrinogen levels due to increased bleeding risk and severity of reaction at fibrinogen levels below 1 g/L.

Risk factors for tigecycline-induced hypofibrinogenaemia.

WHAT IS KNOWN AND OBJECTIVE: Hypofibrinogenaemia is major treatment-related adverse event associated with tigecycline therapy, which in some cases can result in treatment termination. We aimed to identify the risk factors for tigecycline-induced hypofibrinogenaemia. METHODS: We retrospectively retrieved 426 Chinese patients who were undergoing tigecycline therapy ≥ 3 days. RESULTS AND DISCUSSION: There were 426 patients treated with tigecycline. The mean age was 60.31 ± 19.23 years, and 299 (70.19%) patients were male. Of the patients, 50.5% developed hypofibrinogenaemia and 10.1% of patients developed bleeding. Compared with before treatment, fibrinogen (FIB) significantly decreased after tigecycline was used while prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT) significantly increased (all P < .001). There was no statistically significant difference in platelet count, hepatic function, and renal function before and after tigecycline treatment (all P > .05). In analysing relevant risk factors, extension of the tigecycline treatment course was found to be the main risk factor for tigecycline-induced hypofibrinogenaemia. Regardless of whether patients received the standard dose or high dose of tigecycline, the long treatment course group (>14 days) had more patients with hypofibrinogenaemia than the routine treatment course group (52.21% vs 40.74%, 48.81% vs 19.44%, all P < .05). Renal failure (whether requiring or not requiring dialysis) is also a risk factor for tigecycline-induced hypofibrinogenaemia (OR [95% CI]: 2.450 [1.335-4.496]). WHAT IS NEW AND CONCLUSION: Tigecycline administration has been related to hypofibrinogenaemia, especially patients with renal failure and when long treatment course of tigecycline are used. We recommend that coagulation function be closely monitored in patients with the aforementioned risk factors for tigecycline-induced hypofibrinogenaemia to ensure patient safety.

Hypofibrinogenemia Caused by Hemocoagulase Injection: A Retrospective Study on Clinical Laboratory Findings.

Objective Hemocoagulase injection based on the venom of Agkistrodon halys Pallas is widely used in the treatment of hemorrhagic disorders. This study aimed to characterize the clinical laboratory findings of hemocoagulase-induced hypofibrinogenemia as the associated adverse reaction of hemocoagulase injection.Methods We retrospectively enrolled 27 in-patients who were treated with hemocoagulase injection for hemoptysis and developed hypofibrinogenemia during the period of January 1, 2015 to March 31, 2018. Clinical data were collected and investigated, including clinical manifestations, hemostatic and fibrinolytic parameters, dosage of hemocoagulase, the medication time, and the cryoprecipitate blood product infusion. Differences in fibrinogen, D-dimer, and fibrin/fibrinogen degradation products (FDP) before, during, and after the application of hemocoagulase injection were analyzed statistically.Results Plasma fibrinogen level during medication of hemocoagulase injection decreased significantly compared to that before the treatment (F=1.80, P<0.001), with the average decrease of 2.28 g/L (0.63-3.9 g/L). After withdrawal, fibrinogen level increased significantly compared to that during the medication (F=-1.20, P<0.001), but was still lower than that before the medication (F=0.59, P=0.03). The D-dimer level and the FDP level after withdrawal decreased significantly compared to the levels during the medication (F=0.83, P=0.002; Wilcoxon-test, Z=-4.54, P<0.001). Spearman's correlation analyses did not find either fibrinogen change during-before the administration or FDP change after-during the administration was associated with the dosage of hemocoagulase (r=-0.17, P=0.40; r=-0.28, P=0.15; respectively) and the time of recovery from hypofibrinogenemia (r=-0.45, P=0.05; r=0.13, P=0.61; respectively).Conclusion Monitoring both clotting and fibrinolysis parameters is essential in the management of hemoptysis patients treated with hemocoagulase injection. Clinicians should be aware of hypofibrinogenemia and consider discontinuation of the administration of hemocoagulase whenever necessary.

Unpredicted late-, new-onset thrombocytopenia and hypofibrinogenemia in Fab antivenom-treated rattlesnake envenomation.

The use of Fab antivenom (Crotalidae Polyvalent Immune Fab (Ovine) (CroFab); Boston Scientific) against North American Crotalidae envenomation is associated with the development of late- (≥4 days post-envenomation), new-onset of hematological abnormalities. Although attempts have been made to identify predictive indicators during the acute phase of an envenomation, of patients who are not at-risk of late-, new-onset of hematological abnormalities, there has been at least one prior report of a patient who developed thrombocytopenia that was unpredicted by current indicators. We add three cases of unpredicted, late-, new-onset of hematological abnormalities in patients with Fab-treated rattlesnake bite.

Tigecycline-associated hypofibrinogenemia in a real-world setting.

Background Tigecycline is a broad-spectrum antibiotic used to treat infections that do not respond to first-line treatments. High-doses and extended treatments are common; therefore, adverse events might be more frequent and severe than those observed in clinical trials. Several case-reports have referred hypofibrinogenemia in patients who received tigecycline. Objective To analyse the impact of tigecycline use on coagulation parameters, and identify which variables could be related with this. Setting The study was performed at Hospital Universitari Vall Hebron, in Barcelona, Spain. Method Observational, retrospective study. All patients older than 18, who received tigecycline for > 72 h from January 2016 to March 2018 were included. Clinical and laboratory data from before, during and at the end of tigecycline treatment were retrospectively collected. Differences between means were analyzed using the paired-sample Student's t-test. Binary logistic regression was performed to identify risk factors for hypofibrinogenemia. Main outcome measure Mean difference in fibrinogen plasma concentration and INR, before and at the end of tigecycline treatment. Results 78 patients (mean age 65; SD ± 15.5 years) were identified. The most common indications for tigecycline treatment were abdominal (66%), respiratory tract (16%) and skin&soft tissue (10%) infections. High-dose tigecycline was used in 62% of cases and the median duration of treatment was 12 days. Hypofibrinogenemia occurred in 12 patients, 5 bleeding events were observed and 4 of them required fibrinogen administration. Tigecycline caused significant alterations in fibrinogen plasma concentration (mean decrease 1.76 g/L; IC 95% 1.36 to 2.15) as well as INR (mean increase 0.11; IC 95% 0.05 to 0.17). Both were recovered after treatment cessation. We identified duration of treatment > 4 weeks (OR = 6.6), high-dose tigecycline (OR = 4.75) and high protein C levels (OR = 4.2) as independent variables associated with fibrinogen decrease, but not renal impairment. Conclusions Tigecycline administration has been related with hypofibrinogenemia, especially when high-doses of tigecycline are used. Health professionals should be aware of the potentially severe tigecycline-associated hypofibrinogenemia and monitor coagulation during treatment, especially when high-doses of tigecycline are used.

Clinical characteristics and risk factors of tigecycline-associated hypofibrinogenaemia in critically ill patients.

PURPOSE: To analyze the clinical features and risk factors of tigecycline-associated hypofibrinogenaemia and study whether cefoperazone/sulbactam combined with tigecycline aggravates coagulopathy or hypofibrinogenaemia. METHODS: A retrospective case-control study of patients with severe infection who were treated with tigecycline was conducted. Patients were assigned to the hypofibrinogenaemia group (< 2.0 g/L) and normal fibrinogen (normal) group (≥ 2.0 g/L) to assess the clinical features of patients with tigecycline-associated hypofibrinogenaemia. The traits of patients treated with cefoperazone/sulbactam in the hypofibrinogenaemia group were also analyzed. RESULTS: In total, 127 patients were enrolled in the study, including 71 patients with hypofibrinogenaemia and 56 patients with normal fibrinogen levels. Hypofibrinogenaemia developed at a median of 6 (4-8) days after tigecycline treatment, and the fibrinogen level returned to normal at a median of 3 (3-5) days after tigecycline discontinuation. In the multivariate analysis, intra-abdominal infection (p = 0.005), fibrinogen level at tigecycline initiation (p < 0.001), maintenance dose (p = 0.039), and treatment duration (p = 0.002) were found to be related to hypofibrinogenaemia. Treatment with cefoperazone/sulbactam was not associated with hypofibrinogenaemia (p = 0.681), but patients treated with cefoperazone/sulbactam had a higher incidence of coagulopathy (p = 0.009) and needed more blood products (p = 0.003) than those treated without cefoperazone/sulbactam. CONCLUSION: Tigecycline-associated hypofibrinogenaemia often developed on the 6th (4th-8th) day of tigecycline use and was associated with intra-abdominal infection, fibrinogen level at tigecycline initiation, maintenance dose, and treatment duration of tigecycline but not cefoperazone/sulbactam.

Is it required to routinely check fibrinogen level in patients with rheumatic diseases on tocilizumab? Case-based review.

Tocilizumab (TCZ) may rarely cause hematological side effects including neutropenia and thrombocytopenia. TCZ is essentially expected to lower the fibrinogen levels to stay within the normal range, but TCZ-induced hypofibrinogenemia has been rarely reported in literature. Although it may remain asymptomatic, hypofibrinogenemia has clinical significance owing to the tendency of the condition to result in bleeding. A 65-year-old female patient with known polymyositis was, approximately 20 years after the diagnosis was made, examined due to elevated acute phase reactants leading to the diagnosis of giant cell arteritis (GCA) and TCZ treatment was initiated as she had former steroid-induced osteoporotic fractures. 1 month after the initial dose of intravenous (IV) TCZ, she presented with ecchymosis and was detected to have hypofibrinogenemia. Following the administration of the second dose, hypofibrinogenemia was detected again. In this review, we have analyzed this patient in addition to the cases in six other articles of TCZ induced hypofibrinogenemia which we found out based on our search strategy. Our aim is to point out a rare side effect of TCZ, hypofibrinogenemia, thus to emphasize a possible bleeding disorder and discuss probable underlying mechanisms.

Human Fibrinogen Concentrate and Fresh Frozen Plasma in the Management of Severe Acquired Hypofibrinogenemia in Children With Acute Lymphoblastic Leukemia: Results of a Retrospective Survey.

OBJECTIVE OF THE STUDY: In this study we aimed to retrospectively evaluate how centers, belonging to the Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP), manage severe acquired hypofibrinogenemia in children with acute lymphoblastic leukemia, particularly evaluating the therapeutic role of human fibrinogen concentrate (HFC) and fresh frozen plasma (FFP). METHODS: We conducted a survey among AIEOP centers; thereafter, we collected and analyzed data with regard to the treatment of episodes of severe acquired hypofibrinogenemia occurring during the induction and reinduction phases of the AIEOP-BFM ALL 2009 protocol. RESULTS: In total, 15 of the 37 AIEOP centers invited to join the survey agreed to collect the data, with 10 and 5 centers declaring to react to severe acquired hypofibrinogenemia (<70 mg/dL) by administering HFC or FFP, respectively. Of the 150 episodes of severe hypofibrinogenemia occurring in 101 patients, 47.3% were treated with HFC and 52.7% with FFP, with a normalization of fibrinogen levels achieved in greater proportion and in a shorter amount of time in the HFC group as compared with the FFP group. None of the patients presented with bleeding or thrombosis during the observation period. CONCLUSIONS: Even with the limitations of the retrospective nature of this study, HFC seems to be a safe and effective alternative to FFP for replacement therapy in case of severe hypofibrinogenemia in children with acute lymphoblastic leukemia.