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Journal of Thrombosis and Haemostasis :... Apr 2023Postpartum hemorrhage (PPH) may be exacerbated by hemostatic impairment. Information about PPH-associated coagulopathy is limited, often resulting in treatment... (Observational Study)
Observational Study
BACKGROUND
Postpartum hemorrhage (PPH) may be exacerbated by hemostatic impairment. Information about PPH-associated coagulopathy is limited, often resulting in treatment strategies based on data derived from trauma studies.
OBJECTIVES
To investigate hemostatic changes associated with PPH.
PATIENTS/METHODS
From a population of 11 279 maternities, 518 (4.6%) women were recruited with PPH ≥ 1000 mL or placental abruption, amniotic fluid embolism, or concealed bleeding. Routine coagulation and viscoelastometric results were collated. Stored plasma samples were used to investigate women with bleeds > 2000 mL or those at increased risk of coagulopathy defined as placenta abruption, amniotic fluid embolism, or need for blood components. Procoagulant factors were assayed and global hemostasis was assessed using thrombin generation. Fibrinolysis was investigated with D-dimer and plasmin/antiplasmin complexes. Dysfibrinogenemia was assessed using the Clauss/antigen ratio.
RESULTS
At 1000 mL blood loss, Clauss fibrinogen was ≤2 g/L in 2.4% of women and 6/27 (22.2%) cases of abruption. Women with very large bleeds (>3000 mL) had evidence of a dilutional coagulopathy, although hemostatic impairment was uncommon. A subgroup of 12 women (1.06/1000 maternities) had a distinct coagulopathy characterized by massive fibrinolysis (plasmin/antiplasmin > 40 000 ng/mL), increased D-dimer, hypofibrinogenemia, dysfibrinogenemia, reduced factor V and factor VIII, and increased activated protein C, termed acute obstetric coagulopathy. It was associated with fetal or neonatal death in 50% of cases and increased maternal morbidity.
CONCLUSIONS
Clinically significant hemostatic impairment is uncommon during PPH, but a subgroup of women have a distinct and severe coagulopathy characterized by hyperfibrinolysis, low fibrinogen, and dysfibrinogenemia associated with poor fetal outcomes.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Afibrinogenemia; Antifibrinolytic Agents; Blood Coagulation Disorders; Cohort Studies; Embolism, Amniotic Fluid; Fibrinogen; Fibrinolysin; Hemostatics; Placenta; Postpartum Hemorrhage
PubMed: 36696216
DOI: 10.1016/j.jtha.2022.11.036 -
Scandinavian Journal of Immunology Mar 2006The complement system participates in both innate and acquired immune responses. Deficiencies in any of the protein components of this system are generally uncommon and... (Review)
Review
The complement system participates in both innate and acquired immune responses. Deficiencies in any of the protein components of this system are generally uncommon and require specialized services for diagnosis. Consequently, complement deficiencies are clinically underscored and may be more common than is normally estimated. As C3 is the major complement component and participates in all three pathways of activation, it is fundamental to understand all the clinical consequences observed in patients for which this protein is below normal concentration or absent in the serum. C3 deficiencies are generally associated with higher susceptibility to severe infections and in some cases with autoimmune diseases such as systemic lupus erythematosus. Here, we review the main clinical aspects and the molecular basis of primary C3 deficiency as well as the mutations in the regulatory proteins factor I and factor H that result in secondary C3 deficiencies. We also discuss the use of animal models to study these deficiencies.
Topics: Afibrinogenemia; Animals; Autoimmune Diseases; Complement Activation; Complement C3; Complement Factor H; Fibrinogen; Humans; Immunologic Deficiency Syndromes; Infections; Models, Animal
PubMed: 16499568
DOI: 10.1111/j.1365-3083.2006.01729.x -
Journal of Thrombosis and Haemostasis :... Sep 2011This review of published studies was conducted to derive data on patients with congenital fibrinogen deficiency (CFD), including dosing of fibrinogen replacement... (Review)
Review
This review of published studies was conducted to derive data on patients with congenital fibrinogen deficiency (CFD), including dosing of fibrinogen replacement therapy, outcome, and adverse events, either temporally related or distant to fibrinogen replacement, in order to assist clinicians in developing treatment plans for patients with CFD. A systematic review was performed of case reports identified by a MEDLINE search between 1961 and 2010. Eligible studies included subjects with a diagnosis of CFD who received fibrinogen replacement. An attempt was made to extract dose, frequency, duration, hemostatic efficacy and adverse events such as thrombosis or allergic reactions. Reported thrombotic events distant from fibrinogen replacement were also recorded. From 104 papers reviewed, a total of 50 cases were identified: afibrinogenemia (35), hypofibrinogenemia (6), and dysfibrinogenemia (9). Fibrinogen replacement therapy was generally effective in preventing or treating bleeding in doses adequate to achieve and maintain fibrinogen activity above 50-100 mg dL(-1) (non-surgical and obstetric use) or 100-200 mg dL(-1) (surgical prophylaxis). Increased fibrinogen clearance was observed with massive hemorrhage, major surgery, and advanced pregnancy. Obstetric outcomes were optimized when fibrinogen replacement was initiated prior to conception. Uncontrolled hemorrhage, allergic reactions and antibody formation were rare events. However, thromboses, both related and unrelated to fibrinogen replacement, occurred in 15 of 50 (30%) patients overall, and in eight of 12 (67%) adult non-obstetric patients with afibrinogenemia. Published fibrinogen replacement regimens are presented for 50 CFD patients. Fibrinogen replacement therapy requires careful monitoring of fibrinogen levels. Afibrinogenemia is associated with thromboembolic complications with or without treatment.
Topics: Adolescent; Adult; Afibrinogenemia; Child; Child, Preschool; Female; Fibrinogen; Hemorrhage; Hemostasis, Surgical; Humans; Infant; Infant, Newborn; Male; Pregnancy; Pregnancy Complications, Hematologic; Thrombosis; Young Adult
PubMed: 21711446
DOI: 10.1111/j.1538-7836.2011.04424.x -
BMC Pregnancy and Childbirth Sep 2023Preeclampsia complicated with hypofibrinogenemia is a rare disorder. We report two cases of severe preeclampsia complicated with hypofibrinogenemia followed by... (Review)
Review
BACKGROUND
Preeclampsia complicated with hypofibrinogenemia is a rare disorder. We report two cases of severe preeclampsia complicated with hypofibrinogenemia followed by postpartum haemorrhage (PPH).
CASE
Two women diagnosed as preeclampsia and hypofibrinogenemia developed severe PPH after undergoing Cesarean sections. Besides supplement with fibrinogen concentrate and supportive treatment, the second patient got administration of heparin after delivery and bleeding was stopped. The haemorrhage in case 1 didn't disappear until an hysterectomy. The two patients both recovered and were discharged soon.
CONCLUSIONS
Severe preeclampsia patients with hypofibrinogenemia could suffer PPH. It's necessary to detect and master coagulation function. Heparin could be considered to balance hypercoagulation and hypocoagulation to avoid catastrophic haemorrhage and hysterectomy.
Topics: Pregnancy; Humans; Female; Afibrinogenemia; Pre-Eclampsia; Fibrinogen; Postpartum Hemorrhage; Heparin
PubMed: 37658306
DOI: 10.1186/s12884-023-05965-z -
Clinical Case Reports Oct 2022This is a case of congenital afibrinogenemia with multiple thrombotic and hemorrhagic events. His fibrinogen concentration was negatively correlated with thrombin time...
This is a case of congenital afibrinogenemia with multiple thrombotic and hemorrhagic events. His fibrinogen concentration was negatively correlated with thrombin time and prothrombin time and abnormally negatively correlated with plasma D-dimer levels. The individualized standard for fibrinogen concentration may help to balance thrombotic and hemorrhagic events for this disease.
PubMed: 36276905
DOI: 10.1002/ccr3.6395 -
Journal of Thrombosis and Haemostasis :... Dec 2009Although fibrinogen concentrate has been available for the treatment of congenital fibrinogen deficiency for years, knowledge of its pharmacokinetics comes from only two...
BACKGROUND
Although fibrinogen concentrate has been available for the treatment of congenital fibrinogen deficiency for years, knowledge of its pharmacokinetics comes from only two small studies.
OBJECTIVES
To assess the pharmacokinetic (PK) profile, clot integrity and safety of fibrinogen concentrate (human) (FCH) in patients with afibrinogenemia.
PATIENTS AND METHODS
A multinational, prospective, open-label, uncontrolled study of patients with afibrinogenemia > or = 6 years of age was conducted in the USA and Italy. Plasma was collected before and after infusion for PK analyses and evaluation by rotational thromboelastometry of maximum clot firmness (MCF) to assess clot integrity. Safety was assessed on the basis of adverse events and laboratory parameters.
RESULTS
After a single dose of 70 mg kg(-1) body weight (b.w.) FCH in 14 patients, median incremental in vivo recovery was a 1.7 mg dL(-1) increase per mg kg(-1) b.w., and median levels were 1.3 g L(-1) for fibrinogen activity and antigen 1 h after infusion. Median half-life (t(1/2)) was 77.1 h for fibrinogen activity and 88.0 h for antigen. Plasma recovery in children < 16 years old was similar to that in adults aged 16 to < 65 years, but the t(1/2) and area under the curve were decreased, with an increased steady-state volume and clearance. MCF increased by a mean of 8.9 mm from baseline to 1 h after infusion of FCH (P < 0.0001). All four adverse events reported were mild, and none was serious or related to study drug.
CONCLUSIONS
These PK findings confirm a rapid increase in plasma fibrinogen levels after infusion with FCH. Together with the clot integrity and safety data and published data on efficacy, the results support the idea that FCH substitution can restore hemostasis with a good safety profile.
Topics: Adolescent; Adult; Afibrinogenemia; Age Factors; Blood Coagulation Tests; Child; Drug-Related Side Effects and Adverse Reactions; Female; Fibrinogen; Humans; Italy; Male; Middle Aged; Pharmacokinetics; Thrombelastography; United States; Young Adult
PubMed: 19804533
DOI: 10.1111/j.1538-7836.2009.03633.x -
Experimental and Clinical... Oct 2019Liver transplant is a life-saving procedure in patients with end-stage liver disease. However, this procedure may be associated with transmission of various deficiencies...
Liver transplant is a life-saving procedure in patients with end-stage liver disease. However, this procedure may be associated with transmission of various deficiencies of proteins synthesized by the liver. Factor I (fibrinogen) deficiency is one of the rare inherited coagulation disorders with an extremely low risk of transmission by liver transplant. We report a case of a patient with no inherited coagulation disorders but who demonstrated disturbance of fibrinogen after liver transplant. This case highlights the ever-present risk of donor-to-recipient disease transmission during transplant and emphasizes the difficulty in procuring organs from donors in which standard blood tests are insufficient to determine the likelihood of this event.
Topics: Afibrinogenemia; Humans; Liver Transplantation; Male; Middle Aged; Postoperative Complications
PubMed: 28952920
DOI: 10.6002/ect.2016.0338 -
Blood Advances Mar 2024Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD...
Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, FGA, FGB, and FGG were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (FGG, p.Arg301Cys/His and FGA, p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.
Topics: Humans; Female; Fibrinogen; Afibrinogenemia; Prospective Studies; Retrospective Studies; Hemorrhage; Hemostatics
PubMed: 38286442
DOI: 10.1182/bloodadvances.2023012186 -
International Journal of Molecular... Jan 2021Venous thrombosis occurs in patients with quantitative and qualitative fibrinogen disorders. Injury-induced thrombosis in zebrafish larvae has been used to model human...
Venous thrombosis occurs in patients with quantitative and qualitative fibrinogen disorders. Injury-induced thrombosis in zebrafish larvae has been used to model human coagulopathies. We aimed to determine whether zebrafish models of afibrinogenemia and dysfibrinogenemia have different thrombotic phenotypes. Laser injuries were used to induce venous thrombosis and the time-to-occlusion (TTO) and the binding and aggregation of fluorescent thrombocytes measured. The larvae failed to support occlusive venous thrombosis and showed reduced thrombocyte binding and aggregation at injury sites. The larvae were largely unaffected. When genome editing zebrafish to produce fibrinogen Aα R28C, equivalent to the human Aα R35C dysfibrinogenemia mutation, we detected in-frame skipping of exon 2 in the fga mRNA, thereby encoding Aα. This mutation is similar to Fibrinogen Montpellier II which causes hypodysfibrinogenemia. Aα fish had prolonged TTO and reduced thrombocyte activity, a dominant effect of the mutation. Finally, we used transgenic expression of fga R28C cDNA in fga knock-down or mutants to model thrombosis in dysfibrinogenemia. Aα R28C expression had similar effects on TTO and thrombocyte activity as Aα. We conclude that thrombosis assays in larval zebrafish can distinguish between quantitative and qualitative fibrinogen disorder models and may assist in anticipating a thrombotic phenotype of novel fibrinogen mutations.
Topics: Animals; Base Sequence; Biomarkers; Blood Coagulation; Blood Platelets; Disease Models, Animal; Exons; Fibrinogen; Gene Editing; Gene Expression; Plasmids; Platelet Activation; Sequence Deletion; Venous Thrombosis; Zebrafish; RNA, Guide, CRISPR-Cas Systems
PubMed: 33440782
DOI: 10.3390/ijms22020655 -
Polish Archives of Internal Medicine Dec 2019Congenital qualitative and quantitative fibrinogen disorders represent heterogeneous rare abnormalities caused by mutations in one of the 3 genes encoding individual...
Congenital qualitative and quantitative fibrinogen disorders represent heterogeneous rare abnormalities caused by mutations in one of the 3 genes encoding individual fibrinogen polypeptide chains, located on chromosome 4q28. It is estimated that congenital fibrinogen disorder accounts for 8% of rare coagulation factor deficiencies. Most of congenital fibrinogen disorders are suspected in individuals with bleeding tendency or coincidentally discovered, for instance prior to surgery. Fibrinogen disorders could be also found in patients with thrombotic events, impaired wound healing, and recurrent spontaneous abortions. Afibrinogenemia manifests as mild to severe bleeding, while hypofibrinogenemia is often asymptomatic. Dysfibrinogenemia, a qualitative fibrinogen disorder, is associated with bleeding, thrombosis, or with no symptoms. Recent recommendations issued by the International Society on Thrombosis and Haemostasis in 2018 do not encourage routine evaluation of thrombin time or other coagulation tests in patients with suspected congenital fibrinogen disorders, highlighting the value of fibrinogen antigen measurement and genetic analysis, added to the key finding, that is, reduced fibrinogen concentration determined with a coagulometric assay. The current review summarizes practical issues in diagnostic workup and clinical management of patients with afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia from a perspective of internists who may encounter patients with reduced fibrinogen concentration in everyday practice. Despite the fact that hematologists are in front line for the management of patients with bleeding tendency, internists should be aware of the clinical and laboratory findings in patients with inherited fibrinogen disorders including the risk of thromboembolism and management prior to invasive procedures.
Topics: Adult; Afibrinogenemia; Blood Coagulation Tests; Female; Fibrinogen; Genetic Predisposition to Disease; Genetic Testing; Hemorrhage; Humans; Male; Middle Aged; Poland; Thrombosis; Young Adult
PubMed: 31797863
DOI: 10.20452/pamw.15082