Transfusion of fibrinogen concentrate before dental extractions in patients with afibrinogenemia: a narrative review supported by a case report with a proposed treatment protocol.

Afibrinogenemia is a coagulation disorder that occurs with a frequency of 1-2 cases/1,000,000 population and is characterized by a lack of capacity to synthesize fibrinogen. The predominant symptoms related to fibrinogen deficiency are mucocutaneous bleeding, bleeding from the gastrointestinal tract, genital tract or other vascularized tissues as well as excessive bleeding after minor injuries or accidental cuts. Thromboembolic complications and impaired wound healing may also occur. Due to the rarity of the disease, there are no recommendations about fibrinogen substitution before dental procedures (including dental surgery). The purpose of this review is to discuss the indications for the transfusion of a coagulation factor in the preparation of a patient with afibrinogenemia for dental extraction. The article is a narrative review with a proposed management protocol for the dental procedure. The authors have included information from previously published case reports, research studies, and review papers as well as their own case report.

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.

Effect of hypofibrinogenemia on obstetrical disseminated intravascular coagulation in Japan in 2018: a multicenter retrospective cohort study.

Japanese obstetrical hemorrhage recommendations state that not only pregnant women with an obstetrical disseminated intravascular coagulation (DIC) score ≥ 8 points but also those with fibrinogen levels ≤ 1.5 g/L have a high risk of maternal death and warrant blood transfusion. Our aim was to demonstrate the potential of fibrinogen levels ≤ 1.5 g/L as predictors of a Japanese obstetrical DIC score of ≥ 8. We included 595 participants with blood loss ≥ 1000 mL during vaginal delivery or ≥ 2000 mL during cesarean delivery. The frequency and volume of red blood cell (RBC), fresh-frozen plasma, platelet concentrate (PC), and fibrinogen administration in women with a DIC score of ≥ 8 and fibrinogen levels of ≤ 1.5 g/L were significantly higher than controls (P < 0.0001). Multivariate analysis demonstrated that a score of ≥ 3 was associated with RBC or fibrinogen administration and a score of ≥ 5 was associated with PC transfusion. Fibrinogen levels ≤ 1.89 g/L and ≤ 2.44 g/L were associated with PC transfusion and fibrinogen administration, respectively. Fibrinogen levels ≤ 1.5 g/L may have similar potential to a DIC score of ≥ 8 points for detecting obstetrical DIC in Japan.

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.

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.

Bleeding characteristics and management of minor surgeries in rare bleeding disorders: report from a Turkish Pediatric Hematology Center.

BACKGROUND AND OBJECTIVES: In this retrospective report the aim was to present the experience about bleeding characteristics and management of minor surgeries in rare bleeding disorders (RBDs). METHODS: Twenty-six patients were included; with Factor (F) V, FV+VIII, VII, FXI deficiency and afibrinogenemia. Six of the patients were asymptomatic. RESULTS: Fifty-three percent of the patients suffered from mucosal bleeding. Life-threatening bleedings were observed only in the patients with afibrinogenemia and good hemostatic control could only be provided with plasma-derived (pd)-fibrinogen concentrate. Twelve of the patients had undergone 17 minor surgeries. In the patients with FVII and FXI deficiencies with plasma F:C activity between 20-47%, there was a history of uneventful tooth extractions, circumcisions and a pilonidal sinus operation performed without any replacement treatment, whereas one patient with plasma F:C activity of FVII 47% had a history of poor hemostatic control during an adeno-tonsillectomy operation. Although some of these patients were asymptomatic to be on the safe side, minor operations were performed with preoperative administration of one dose of (pd)-fibrinogen concentrate to one afibrinogenemia patient, recombinant active FVII (rFVIIa) to 2 FVII deficient patients and fresh frozen plasma (FFP) to 3 FXI deficient and 1 FVII deficient patients plus postoperatively tranexamic acid (TXA) for 5-7 days. Only with one dose of the replacement therapy just before surgeries good hemostatic control was achieved and none of them had bleeding neither during nor after the surgeries. CONCLUSION: We suggest that minor operations must be performed with preoperative replacement therapies plus 5-7 days of antifibrinolytics under close observation of the hematologist and the surgeon.

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.

Hemostasis management and therapeutic plasma exchange: Results of a practice survey.

BACKGROUND: Patients undergoing therapeutic plasma exchange (TPE) may present with risks for hemorrhage or thrombosis. Use of replacement fluids devoid of coagulation factors will decrease factor levels and platelet levels. There are no established guidelines for hemostasis management in these situations. MATERIALS AND METHODS: A survey to evaluate current hemostasis management practice during TPE was conducted using online survey software. One response per institution was analyzed based on a hierarchical algorithm, excluding membrane filtration users, resulting in a maximum of 107 respondents. Descriptive analysis was performed with results reported as the number and frequency (%) of respondents to each question. RESULTS: Apheresis Medicine physicians, alone (59.4%) or jointly with the requesting provider (29.2%), choose the replacement fluid. Based on a theoretical patient case receiving five TPEs approximately every other day, the percent of respondents who would use albumin with or without normal saline was 94.7% with no history of a bleeding or clotting disorder, 1.1% with active bleeding, and 8.8% with hypofibrinogenemia (<100 mg/dL) due to recent TPE. More respondents would use albumin with or without normal saline for replacement fluid when a minor invasive procedure (49.5%) vs a major surgery (8.9%) was performed 1 day before TPE. Replacement fluid selection varied among respondents for several other clinical conditions. The most frequent use for cryoprecipitate by respondents (14.3%) was hypofibrinogenemia. CONCLUSIONS: These survey results demonstrate wide interinstitutional variation in replacement fluid selection to manage hemostasis in patients undergoing TPE. Further studies are needed to guide optimal hemostasis management with TPE.

Clinical Features and Management of Congenital Fibrinogen Deficiencies.

Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenemia and hypofibrinogenemia) or the quality (dysfibrinogenemia) or both (hypodysfibrinogenemia) of plasmatic fibrinogen. Afibrinogenemia is often diagnosed at birth following prolonged umbilical cord bleeding and is characterized by spontaneous bleeding in all tissues, while hypofibrinogenemic patients are more often asymptomatic. Spontaneous spleen ruptures, painful bone cysts, cardiovascular events, and intrahepatic inclusions can complicate the clinical course of patients with quantitative fibrinogen disorders. Clinical manifestations of dysfibrinogenemia are very heterogeneous, from absence of symptoms to major bleeding or thrombosis, chronic thromboembolic pulmonary hypertension, and renal amyloidosis. Hypodysfibrinogenemic patients can suffer from both major bleeding and recurrent thrombosis. Pregnancy of women with congenital fibrinogen disorders is a high-risk situation. Owing to the absence of controlled randomized studies, clinical management is mainly based on expert consensus. For the treatment and/or the prevention of bleeding, plasma-derived fibrinogen concentrates are the optimal choice. Treatment of thrombosis may be challenging. More specifically, management strategies should be tailored to each patient, taking the personal and familial history of bleeding and thrombosis, the genotype, and the specific clinical situation into account.

Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management.

Congenital dysfibrinogenemia is a qualitative congenital fibrinogen disorder characterized by normal antigen levels of a dysfunctional fibrinogen. The diagnosis is usually based on discrepancies between fibrinogen activity and antigen levels, but could require more specialized techniques for the assessment of fibrinogen function, owing to some limitations in routine assays. Molecular abnormalities, which are frequently heterozygous missense mutations localized in exon 2 of FGA and exon 8 of FGG, lead to defects in one or more phases of fibrinogen to fibrin conversion, fibrin network formation, and other important functions of fibrinogen. The clinical phenotype is highly heterogeneous, from no manifestations to bleeding and/or thrombotic events. Asymptomatic propositi and relatives with the predisposing genotype are at risk of developing adverse outcomes during the natural course of the disease. Correlations between genotype and phenotype have not yet been clearly established, with the exception of some abnormal fibrinogens that severely increase the risk of thrombosis. Functional analysis of polymerization and fibrinolysis, structural studies of the fibrin network and the viscoelastic properties of fibrin clot could help to predict the phenotype of congenital dysfibrinogenemia, but have not yet been evaluated in detail. The management is essentially based on personal and family history; however, even individuals who are still asymptomatic and without a family history should be carefully assessed and monitored. Particular situations, such as pregnancy, delivery, and surgery, require a multidisciplinary approach.

[The cryoprecipitate: that old unknown]. / El crioprecipitado: ese viejo desconocido.

Cryoprecipitate is a plasma derivative rich in fibrinogen and other procoagulant factors. It has been successfully used for decades in the treatment of the coagulopathy of trauma patients, cardiovascular surgery, liver failure and disseminated intravascular coagulation. Although cryoprecipitate is routinely used in many western countries, most of the Spanish regional blood banks stopped its production in the late 1990's. Moreover, in recent years there is a movement to replace cryoprecipitate with manufactured fibrinogen concentrate. As a consequence, many of the younger anaesthesiologists did not have any direct experience with cryoprecipitate. This article aims to describe the characteristics of cryoprecipitate since it is a different product from manufactured fibrinogen concentrate, with its own specific indications that deserve to be further studied in clinical trials.

Transfusion-related acute lung injury in a patient diagnosed with hypofibrinogenemia after a cesarean section--case report and review of the literature.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a rare, but potentially fatal, complication of blood product transfusion, manifesting as acute respiratory distress syndrome. In most cases, TRALI is associated with massive transfusion of fresh frozen plasma and platelets. CASE REPORT: A 38-year-old-woman at 40 weeks gestation was admitted to hospital with spontaneous labor contractions. A cesarean section was performed due to feto-pelvic disproportion and a male infant (Apgar 10) was delivered. After 37 hours low hemoglobin level and growing subfascial hematoma were detected. Urgent relaparotomy was carried out. The blood loss was over 1500 ml and a massive transfusion (6 units of red cell concentrate, 8 units of fresh frozen plasma and 6 units of cryoprecipitate) was necessary. The patient developed symptoms of acute respiratory distress 10 hours after relaparotomy. No pathological findings were shown in echocardiography and ECG. Chest CT revealed pulmonary edema. Low fibrinogen levels were observed in laboratory tests, decreasing in time after transfusion of the blood products to 1.0/L. Oxygen therapy with facial mask was initiated, furosemide was administered and continued for three days until symptom resolution. A series of hematological tests performed after the patient was discharged from hospital confirmed the diagnosis of TRALI and congenital hypofibrinogenemia. CONCLUSION: Congenital hypofibrinogenemia may be responsible for the development of subfascial hematoma, a complication of cesarean section, necessitating relaparotomy. The following massive transfusion of blood products resulted in a potentially fatal complication in a form of TRALI.

Intraosseous pseudotumor in a child with hypofibrinogenemia.

Intraosseous pseudotumor (i.e. chronic, encapsulated, hemorrhagic fluid collection that can be seen in any portion of the tubular bones) is an uncommon complication of severe hemophilia; however, it can occur with other rare bleeding disorders. We present the case of an 11-year-old girl with hypofibrinogenemia who had multiple intramedullary lesions that were consistent with intramedullary pseudotumor associated with this rare bleeding disorder. Percutaneous biopsy of a pseudotumor is contraindicated due to the high prevalence of complications, including life-threatening bleeding. Therefore, radiologists should make the diagnosis with characteristic MR imaging findings in a patient with a severe coagulation disorder.

Fibrinogen concentrate reduces intraoperative bleeding when used as first-line hemostatic therapy during major aortic replacement surgery: results from a randomized, placebo-controlled trial.

OBJECTIVES: We assessed whether fibrinogen concentrate as targeted first-line hemostatic therapy was more effective than placebo or a standardized transfusion algorithm in controlling coagulopathic bleeding in patients undergoing major aortic surgery. METHODS: In this single-center, prospective, double-blind study, adults undergoing elective thoracic or thoracoabdominal aortic replacement surgery involving cardiopulmonary bypass were randomized to intraoperative fibrinogen concentrate (n = 29) or placebo (n = 32). Study medication was given if patients had clinically relevant coagulopathic bleeding, measured by 5-minute bleeding mass, after cardiopulmonary bypass removal, protamine administration, and surgical hemostasis. Fibrinogen concentrate dosing was individualized using the thromboelastometric FIBTEM test. If bleeding continued, a standardized transfusion algorithm was followed. In the placebo group, all 32 patients received 1 transfusion cycle of fresh-frozen plasma/platelets, and 30 patients required a second transfusion cycle; none of these patients received any other procoagulant therapy. Change in bleeding rate after treatment was compared using t tests. RESULTS: Mean change in bleeding rate after fibrinogen concentrate was -48.3 g/5 min, compared with 0.4 g/5 min after placebo (P < .001), -16.1 g/5 min after 1 transfusion cycle (fresh-frozen plasma or platelets; P = .003), and -28.0 g/5 min after 2 transfusion cycles (fresh-frozen plasma and platelets; P = .11). Reductions in bleeding rate were greater for patients with higher bleeding rates before treatment, especially with fibrinogen concentrate. CONCLUSIONS: FIBTEM-guided intraoperative hemostatic therapy with fibrinogen concentrate is more effective than placebo in controlling coagulopathic bleeding during major aortic replacement surgery. Fibrinogen concentrate is also more effective than 1 cycle of fresh-frozen plasma/platelets and is more rapid than--and at least as effective as--2 cycles of fresh-frozen plasma/platelets.

A case of acquired dysfibrinogenemia in multiple myeloma treated with therapeutic plasma exchange.

A 70 year old Caucasian woman with IgG lamda multiple myeloma presented with uncontrollable bleeding from a bone marrow biopsy site which started days after the procedure. The patient was hyperviscous, and coagulation tests showed elevated activated partial thromboplastin time (aPTT) which was not corrected with a mixing study, elevated thrombin time and reptilase time, and possible inhibitors to Factors VIII and IX. Therapeutic plasma exchange was performed using plasma with corrections of plasma viscosity (1.6 to 1.1 centipoise) and aPTT (50 to 42.1s) observed. The bleeding was controlled, and purified IgG demonstrated dysfibrinogenemic effects of the patient's paraprotein.

Epidemiology and treatment of congenital fibrinogen deficiency.

Congenital fibrinogen deficiency is a rare bleeding disorder, affecting either the quantity (afibrinogenemia, hypofibrinogenemia) or quality (dysfibrinogenemia) of circulating fibrinogen. There is a strong association between fibrinogen activity levels and clinical bleeding severity. Patients with afibrinogenemia experience frequent, often severe, spontaneous bleeds into the muscles and joints and are at significant risk of intracranial hemorrhage. Patients with hypofibrinogenemia are usually asymptomatic; however, they are vulnerable to bleeding after trauma. Dysfibrinogenemia is associated with both spontaneous bleeding and a relatively high risk of thrombosis. Fibrinogen replacement therapy is effective in treating bleeding episodes in congenital fibrinogen deficiency. Fibrinogen concentrates are the preferred treatment option and guidelines now exist for their on-demand use and to manage surgery. Prophylaxis may benefit patients with afibrinogenemia and others with a severe bleeding tendency. The dose and frequency of administration should be adjusted to maintain a fibrinogen activity level >0.5-1.0 g/L. Pregnant women with afibrinogenemia require prophylactic factor replacement as early as possible during pregnancy, continuing throughout pregnancy, and after the birth. Fibrinogen replacement should also be considered in pregnant women with other fibrinogen deficiencies. The risk of thrombosis presents an additional management challenge in these patients, often necessitating the concurrent use of anticoagulants and fibrinogen. Although basic guidelines have been developed, further studies are needed to help optimize treatment in different patient groups under different clinical circumstances and to improve our understanding of thrombotic events.

Recurrent massive hemoperitoneum due to ovulation as a clinical sign in congenital afibrinogenemia.

Massive hemoperitoneum due to ovulation is a rare but serious and life-threatening complication for women with coagulation disorders, and may lead to surgical interventions and even oophorectomy. Congenital afibrinogenemia is an uncommon coagulation disorder usually discovered during childhood. Intraabdominal bleeding due to ovulation is very rare in these patients and only a few cases of corpus luteum rupture and hemoperitoneum in afibrinogenemic patients have been described. In all women, the diagnosis was known since childhood. We report on a 24-year-old woman with congenital afibrinogenemia with recurrent massive intraabdominal bleeding due to ovulation as the presenting clinical sign. Exploratory laparotomy and excision of the ruptured follicle was performed at the first bleeding episode; the second episode was managed with fresh frozen plasma and blood transfusions. Conservative management is crucial for these patients. If surgery cannot be avoided, a conservative surgical approach should be chosen to preserve ovarian function.

[A rare coagulation disorder. Diagnostics and management in cases of hereditary dysfibrinogenemia]. / Seltene Ursache einer hämorrhagischen Diathese. Diagnostik und perioperatives Management bei hereditärer Dysfibrinogenämie.

Before elective surgery, it is mandatory that a precise history be taken to detect increased hemorrhagic diathesis and that thrombocytes, Quick/INR, and aPTT be determined. If pathological levels are found, further laboratory tests are necessary after frequent causes (e.g., liver cirrhosis) have been excluded. Single-factor analysis for the von Willebrand's factor antigen and if necessary further tests to check for von Willebrand's syndrome (multimeric analysis) as well as platelet function tests should be performed.Dysfibrinogenemia is a rare coagulation disorder, which causes elevated INR. It shows a wide spectrum of clinical manifestations including thrombophilia, excessive bleeding, and even asymptomatic cases. We present a 72-year-old patient with asymptomatic dysfibrinogenemia who needed hip replacement due to arthrosis. Lowered fibrinogen levels were substituted prior to operation and the clinical course afterwards was uneventful under additional prophylactic anticoagulation in order to prevent thrombosis. The case report illustrates the interdisciplinary teamwork which is very important in the management of patients with coagulation disorders.