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British Journal of Haematology Nov 2023Congenital fibrinogen disorders or CFDs are heterogenous, both in clinical manifestation and array of culprit molecular lesions. Correlations between phenotype and... (Review)
Review
Congenital fibrinogen disorders or CFDs are heterogenous, both in clinical manifestation and array of culprit molecular lesions. Correlations between phenotype and genotype remain poorly defined. This review examines the genetic landscape discovered to date for this rare condition. The question of a possible oligogenic model of inheritance influencing phenotypic heterogeneity is raised, with discussion of the benefits and challenges of sequencing technology used to enhance discovery in this space. Considerable work lies ahead in order to achieve diagnostic and prognostic precision and subsequently provide targeted management to this complex cohort of patients.
PubMed: 37583269
DOI: 10.1111/bjh.19039 -
International Journal of Clinical... Oct 2023We describe a case of acute pancreatitis (AP) and hypofibrinogenemia associated with drug treatment with the aim to increase awareness of uncommon yet possibly...
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 was detected in the blood and sputum, the patient was treated with tigecycline from the 14 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 33 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.
Topics: Male; Humans; Aged; Tigecycline; Anti-Bacterial Agents; Afibrinogenemia; Furosemide; Minocycline; Acute Disease; Pancreatitis; Fibrinogen; Acinetobacter baumannii
PubMed: 37548456
DOI: 10.5414/CP204337 -
Hamostaseologie Dec 2023Our study aimed to analyze the phenotype and genotype of a pedigree with inherited dysfibrinogenemia, and preliminarily elucidate the probable pathogenesis.
OBJECTIVE
Our study aimed to analyze the phenotype and genotype of a pedigree with inherited dysfibrinogenemia, and preliminarily elucidate the probable pathogenesis.
METHODS
The one-stage clotting method was used to test the fibrinogen activity (FIB:C), whereas immunoturbidimetry was performed to quantify the fibrinogen antigen (FIB:Ag). Furthermore, DNA sequence analysis was conducted to confirm the site of mutation. Conservation analysis and protein model analysis were performed using online bioinformatics software.
RESULTS
The FIB:C and FIB:Ag of the proband were 1.28 and 2.20 g/L, respectively. Gene analysis revealed a heterozygous c.293C > A (p.BβAla68Asp) mutation in . Bioinformatics and modeling analysis suggested that the missense mutation could potentially have a deleterious effect on fibrinogen.
CONCLUSION
The BβAla68Asp mutation in exon 2 of may account for the reduced FIB:C levels observed in the pedigree. To our knowledge, this point mutation is the first report in the world.
Topics: Humans; Fibrinogen; Afibrinogenemia; Genotype; Mutation, Missense; Mutation; Hemostatics; Pedigree
PubMed: 37516116
DOI: 10.1055/a-2116-8957 -
Transfusion Aug 2023Cryoprecipitate (CRY) is widely used for treating acquired hypofibrinogenemia. During our study to determine an optimal preparation method, we noticed that the...
BACKGROUND
Cryoprecipitate (CRY) is widely used for treating acquired hypofibrinogenemia. During our study to determine an optimal preparation method, we noticed that the measurement of fibrinogen concentration in CRY had a risk of overestimation. We analyzed this condition and mechanism.
STUDY DESIGN AND METHODS
CRY was prepared from fresh frozen plasma (FFP) under four conditions: A, 30 h thawing time, 2 cycles; B, 24 h thawing time, 2 cycles; C, 30 h thawing time, 1 cycle; and D, 24 h thawing time, 1 cycle. Then, fibrinogen concentrations in CRY and cryosupernatant (CS) were measured by the Clauss method.
RESULTS
Purification (CRY/CRY+CS) and recovery (CRY/FFP) rates in CRY prepared under 2-cycle conditions were higher than those under 1 cycle. However, recovery rates often exceeded 100%, particularly in the case of CRY prepared under A condition, and fibrinogen concentrations calculated by direct measurement were higher than those indirectly calculated from FFP and CS, suggesting an overestimation of fibrinogen values. The level of soluble fibrin monomer complex was considerably higher in CRY prepared under A than under D condition, indicating that CRY adopted a hypercoagulated state. We further found that repeated thawing/freezing increased fibrinogen values as measured by the Clauss method while mechanical vortexing did not.
DISCUSSION
Our findings suggest that direct assessment of fibrinogen contents in CRY prepared by repeated freeze-thawing with a longer thawing period presents a higher risk of overestimation. For the purpose of quality control, we propose an alternative method to indirectly estimate fibrinogen concentrations in CRY from those of CS and FFP.
Topics: Humans; Fibrinogen; Freezing; Hemostatics; Afibrinogenemia; Plasma; Hematologic Agents
PubMed: 37450885
DOI: 10.1111/trf.17483 -
Hamostaseologie Dec 2023Inherited dysfibrinogenemia is a qualitative defect of fibrinogen caused by various mutations among three fibrinogen genes. Dysfibrinogenemia can be associated with...
INTRODUCTION
Inherited dysfibrinogenemia is a qualitative defect of fibrinogen caused by various mutations among three fibrinogen genes. Dysfibrinogenemia can be associated with an increased risk of thrombosis, bleeding, or both. Here, we report a 36-year-old female with dysfibrinogenemia who experienced two successful pregnancies under thromboprophylaxis after cerebral venous sinus thrombosis (CVST).
PATIENTS AND METHODS
In addition to plasmatic coagulation tests, fibrinogen genes , , and were screened using direct genomic DNA sequencing. The structural-functional implications of the detected mutation were analyzed in silico.
RESULTS
Inherited dysfibrinogenemia was diagnosed in an index patient after CVST in a risk situation. Anticoagulation with warfarin was stopped after 12 months when the first pregnancy was planned. Pregnancy and spontaneous delivery (2020) was uncomplicated. A second pregnancy was interrupted because of acute cytomegalovirus infection and the third pregnancy was successful in 2022. Pregnancies were accompanied by thromboprophylaxis with enoxaparin 40 mg once daily until 6 weeks postpartum. Substitution of fibrinogen has not become necessary in the index patient so far. Genetic analysis revealed a novel missense mutation (p. Arg510Cys) in the gene ("fibrinogen Bonn") in the index patient, as well as an asymptomatic sister, and their father who experienced recurrent pulmonary embolism. Surface exposure of wild-type Arg510 suggested the mutated Cys510 to form nonnative disulfide bonds with surface-exposed reactive cysteines from other plasma proteins like albumin leading to formation of aggregates and impaired fibrinolysis.
CONCLUSIONS
Fibrinogen Bonn might be associated with an increased risk of thrombosis, possibly due to impaired polymerization.
Topics: Pregnancy; Female; Humans; Adult; Fibrinogen; Anticoagulants; Venous Thromboembolism; Afibrinogenemia; Venous Thrombosis; Mutation; Thrombosis; Hemostatics
PubMed: 37442158
DOI: 10.1055/a-2094-7191 -
Blood Coagulation & Fibrinolysis : An... Jul 2023Inherited dysfibrinogenemias are molecular disorders of fibrinogen that affect fibrin polymerization. The majority of cases are asymptomatic, but a significant...
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.
Topics: Humans; Fibrinogen; Afibrinogenemia; Thrombosis; Hemorrhage; Hemostatics
PubMed: 37395199
DOI: 10.1097/MBC.0000000000001237 -
The Journal of Pediatric Pharmacology... 2023Fibrinogen deficiencies in neonates can lead to bleeding complications. In this report, we describe a case of congenital afibrinogenemia in a newborn with critical...
Fibrinogen deficiencies in neonates can lead to bleeding complications. In this report, we describe a case of congenital afibrinogenemia in a newborn with critical pulmonary stenosis who presented with bilateral cephalohematomas after an uncomplicated delivery. The initial use of cryoprecipitate was followed by administration of fibrinogen concentrate. We estimated a half-life of 24 to 48 hours with the concentrate product. This patient received fibrinogen replacement and had a subsequent successful cardiac repair. The drug's shorter half-life in this neonate contrasts with prior reports of longer half-life in older patients and is important to note in treating future neonatal patients with this diagnosis.
PubMed: 37303762
DOI: 10.5863/1551-6776-28.3.268 -
Scientific Reports Jun 2023Systemic 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)...
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.
Topics: Child; Adult; Humans; Arthritis, Juvenile; Retrospective Studies; Afibrinogenemia; Factor XIII Deficiency; Disseminated Intravascular Coagulation; Fibrinogen; Treatment Outcome
PubMed: 37270663
DOI: 10.1038/s41598-023-36246-6 -
Journal of Thrombosis and Haemostasis :... Oct 2023Conventional clotting tests are not expeditious enough to allow timely targeted interventions in trauma, and current point-of-care analyzers, such as rotational...
BACKGROUND
Conventional clotting tests are not expeditious enough to allow timely targeted interventions in trauma, and current point-of-care analyzers, such as rotational thromboelastometry (ROTEM), have limited sensitivity for hyperfibrinolysis and hypofibrinogenemia.
OBJECTIVES
To evaluate the performance of a recently developed global fibrinolysis capacity (GFC) assay in identifying fibrinolysis and hypofibrinogenemia in trauma patients.
METHODS
Exploratory analysis of a prospective cohort of adult trauma patients admitted to a single UK major trauma center and of commercially available healthy donor samples was performed. Lysis time (LT) was measured in plasma according to the GFC manufacturer's protocol, and a novel fibrinogen-related parameter (percentage reduction in GFC optical density from baseline at 1 minute) was derived from the GFC curve. Hyperfibrinolysis was defined as a tissue factor-activated ROTEM maximum lysis of >15% or LT of ≤30 minutes.
RESULTS
Compared to healthy donors (n = 19), non-tranexamic acid-treated trauma patients (n = 82) showed shortened LT, indicative of hyperfibrinolysis (29 minutes [16-35] vs 43 minutes [40-47]; p < .001). Of the 63 patients without overt ROTEM-hyperfibrinolysis, 31 (49%) had LT of ≤30 minutes, with 26% (8 of 31) of them requiring major transfusions. LT showed increased accuracy compared to maximum lysis in predicting 28-day mortality (area under the receiver operating characteristic curve, 0.96 [0.92-1.00] vs 0.65 [0.49-0.81]; p = .001). Percentage reduction in GFC optical density from baseline at 1 minute showed comparable specificity (76% vs 79%) to ROTEM clot amplitude at 5 minutes from tissue factor-activated ROTEM with cytochalasin D in detecting hypofibrinogenemia but correctly reclassified >50% of the patients with false negative results, leading to higher sensitivity (90% vs 77%).
CONCLUSION
Severe trauma patients are characterized by a hyperfibrinolytic profile upon admission to the emergency department. The GFC assay is more sensitive than ROTEM in capturing hyperfibrinolysis and hypofibrinogenemia but requires further development and automation.
Topics: Adult; Humans; Fibrinolysis; Afibrinogenemia; Thromboplastin; Prospective Studies; Blood Coagulation Disorders; Thrombelastography; Wounds and Injuries
PubMed: 37207863
DOI: 10.1016/j.jtha.2023.05.005 -
Thrombosis Research Jun 2023Hypofibrinogenemia is often associated with excessive bleeding and requires immediate treatment. The qLabs FIB® is a handheld and easy-to-use point-of-care (POC) device...
The qLabs® FIB system, a novel point-of-care technology for a rapid and accurate quantification of functional fibrinogen concentration from a single drop of citrated whole blood.
Hypofibrinogenemia is often associated with excessive bleeding and requires immediate treatment. The qLabs FIB® is a handheld and easy-to-use point-of-care (POC) device designed for the rapid measurement of functional fibrinogen concentration from a single drop of citrated whole blood. The aim of this study was to evaluate the analytical performances of the qLabs FIB system. Fibrinogen concentrations from 110 citrated whole blood specimen were measured by both the qLabs FIB and the Clauss laboratory reference methods (STA®-Liquid Fib assay on STA-R® Max from Stago). A three-laboratories comparison study was conducted to assess reproducibility and repeatability of the qLabs FIB using plasma quality control material. In addition, single-site assays were conducted to assess the repeatability from citrated whole blood specimen covering the qLabs FIB reportable range. A very strong correlation between the qLabs FIB and the Clauss laboratory reference method was observed (r = 0.95). Using a clinical cut-off value of 2.0 g/L, the area under the receiver operating characteristic curve (ROC) of citrated whole blood was 0.99 and sensibility and specificity were 100 % and 93.5 %, respectively. Percent CVs for reproducibility and repeatability assessed from quality control material, were both <5 %. Repeatability assessed from citrated whole blood specimen showed a CV of 2.6 to 6.5 %. In conclusion, the qLabs FIB system enables a rapid and reliable measurement of functional fibrinogen levels from citrated whole blood and exhibits a strong prediction power at the 2 g/L clinical cut-off when compared to the Clauss laboratory reference. Further clinical studies should demonstrate its ability to quickly confirm the diagnosis of acquired hypofibrinogenemia and help identify patients who may benefit from targeted hemostatic treatment.
Topics: Humans; Fibrinogen; Point-of-Care Systems; Afibrinogenemia; Reproducibility of Results; Hemostatics; Citrates; Citric Acid; Quality Control
PubMed: 37178638
DOI: 10.1016/j.thromres.2023.03.018