Replacement therapy for congenital Factor × deficiency

We studied a young woman with severe (less than 1%) congenital factor X deficiency during a 2-year period in order to document the levels of factor X required to provide hemostasis for vaginal bleeding, epistaxis, and hemarthroses, as well as during surgery. Factor X levels of 9 to 17 percent, achieved with fresh-frozen plasma (FFP) were satisfactory for minor bleeding. Hemostasis was achieved during emergency surgery for hemoperitoneum by increasing the factor X level to 35 percent with a Factor IX concentrate, followed with infusions of FFP to maintain levels between 10 and 20 percent for 6 days postoperatively. These data suggest that factor X levels of 10 to 20 percent are sufficient for hemostasis in factor X-deficient patients even in the immediate postoperative period.     

Efficacy and tolerability of a pasteurised human fibrinogen concentrate in patients with congenital fibrinogen deficiency.

The efficacy and tolerability of a pasteurised human fibrinogen concentrate were assessed in an open, multi-centre, non-controlled retrospective study in patients with congenital fibrinogen deficiency. Haemostatic efficacy was assessed by laboratory investigation and clinical observation. The study included 12 patients (afibrinogenaemia, n = 8; hypofibrinogenaemia, n = 3; dysfibrinogenaemia combined with hypofibrinogenaemia, n = 1). Fibrinogen substitution was indicated: to stop an ongoing bleed; as prophylaxis before surgery; or for routine prophylaxis to prevent spontaneous bleeding. In total, 151 fibrinogen infusions were recorded. The median single dosage was 63.5mg/kg body weight for bleeding events or surgery and 76.9 mg/kg for prophylaxis. The median total dose per event for bleeding events or surgery was 105.6 mg/kg. Fibrinogen was administered in 26 bleeding episodes; 11 surgical operations; and 89 prophylactic infusions, of which 86 were received by one patient. The median response (n = 8) was 1.5 mg/dl per substituted mg of fibrinogen per kg body weight (0.8-2.3). The median in vivo recovery (n = 8) was 59.8% (32.5-93.9). Clinical efficacy was very good in all events with the exception of one surgical procedure, where it was moderate. No intercurrent bleeding occurred during prophylaxis. All but one infusion was well tolerated; the patient, who was administered 86 prophylactic infusions, experienced an anaphylactic reaction after the 56th infusion. In addition, one patient developed deep vein thrombosis and non-fatal pulmonary embolism with treatment for osteosynthesis after collum femoris fracture. Fibrinogen substitution could not be excluded as a contributing factor in this high-risk patient. Substitution with pasteurised human fibrinogen concentrate in patients with congenital fibrinogen deficiencies is efficient and generally well tolerated.     

Fibrinogen as a therapeutic target for bleeding: a review of critical levels and replacement therapy

Fibrinogen plays a critical role in achieving and maintaining hemostasis and is fundamental to effective clot formation. There is increasing awareness of the important role of fibrinogen as a key target for the treatment and prevention of acquired bleeding. Fibrinogen is the first coagulation factor to fall to critically low levels (<1.0 g/L) during major hemorrhage (normal plasma fibrinogen levels range from 2.0 to 4.5 g/L), and current guidelines recommend maintaining the plasma fibrinogen level above 1.5 g/L. Fibrinogen supplementation can be achieved using plasma or cryoprecipitate; however, there are a number of safety concerns associated with these allogeneic blood products and there is a lack of high‐quality evidence to support their use. Additionally, there is sometimes a long delay associated with the preparation of frozen products for infusion. Fibrinogen concentrate provides a promising alternative to allogeneic blood products and has a number of advantages: it allows a standardized dose of fibrinogen to be rapidly administered in a small volume, has a very good safety profile, and is virally inactivated as standard. Administration of fibrinogen concentrate, often guided by point‐of‐care viscoelastic testing to allow individualized dosing, has been successfully used as hemostatic therapy in a range of clinical settings, including cardiovascular surgery, postpartum hemorrhage, and trauma. Results show that fibrinogen concentrate is associated with a reduction or even total avoidance of allogeneic blood product transfusion. Fibrinogen concentrate represents an important option for the treatment of coagulopathic bleeding; further studies are needed to determine precise dosing strategies and thresholds for fibrinogen supplementation.     

Factor VIIa replacement therapy in factor VII deficiency.

Factor (F)VII deficiency is an autosomal recessive disorder for which a replacement therapy is not universally available; recombinant FVIIa has been utilized as a therapeutic substitute. As FVII competes with FVIIa for binding to tissue factor in initiating the extrinsic pathway of blood coagulation, a lower dose of FVIIa replacement in cross-reacting material-negative (CRM-) individuals can achieve hemostasis. Three coagulation models (computational, synthetic and in vitro whole blood) were used to predict the FVIIa levels needed to provide apparent hemostasis in a non-bleeding state. Our whole blood results show that a 'normalized' coagulation profile for FVII-deficient individuals has an initiation phase that ends at 5.8 +/- 0.5 min (clot time) and the propagation phase of thrombin generation (thrombin-antithrombin III) yields a maximum concentration of 380 +/- 29 nmol L(-1). When CRM- FVII-deficient subjects were infused with a prophylactic dose of 23 micro g kg(-1) of recombinant FVIIa, 6-8 h postinfusion resulted in a comparable normalized whole blood profile. This FVIIa concentration (0.3-0.7 nmol L(-1)/equivalent dose: 0.8-1.8 micro g kg(-1)) is approximately 1/10 that currently used in treating FVII-deficient individuals and suggests that therapies should be altered relative to the concentration of the FVII zymogen.     

Pharmacokinetics,clot strength and safety of a new fibrinogen concentrate: randomized comparison with active control in congenital fibrinogen deficiency

Essentials

• Congenital afibrinogenemia causes a potentially life‐threatening bleeding and clotting tendency.
• Two human fibrinogen concentrates (HFCs) were compared in a randomized pharmacokinetic study.
• Bioequivalence was not shown for AUC_norm, which was significantly larger for the new HFC.
• Increases in clot strength were comparable, and no thromboses or deaths occurred in the study.

Summary

Background

Human fibrinogen concentrate (HFC) corrects fibrinogen deficiency in congenital a‐/hypofibrinogenemia.

Objectives

To assess pharmacokinetics (PK), effects on thromboelastometry maximum clot firmness (MCF), and safety of a new double virus‐inactivated/eliminated, highly purified HFC vs. active control.

Patients/Methods

In this multinational, randomized, phase II, open‐label, crossover study in 22 congenital afibrinogenemia patients aged ≥ 12 years, 70 mg kg^?1 of new HFC (FIBRYGA, Octapharma AG) or control (Haemocomplettan^® P/RiaSTAP?, CSL Behring GmbH) were administered, followed by crossover to the other concentrate. Fibrinogen activity, PK and MCF in plasma were assessed.

Results

The concentrates were not bioequivalent for the primary endpoint, AUC_norm (mean ratio, 1.196; 90% confidence interval [CI], 1.117, 1.281). Remaining PK parameters (C_maxnorm, IVR, t_1/2, MRT) reflected bioequivalence between concentrates, except for clearance (mean ratio, 0.836; 90% CI, 0.781, 0.895) and V_ss (mean ratio, 0.886; 90% CI, 0.791, 0.994). Mean AUC_norm was significantly larger for the new HFC (1.62 ± 0.45 vs. 1.38 ± 0.47 h kg g L^?1 mg^?1, P = 0.0001) and mean clearance was significantly slower (0.665 ± 0.197 vs. 0.804 ± 0.255 mL h^?1 kg^?1, P = 0.0002). Mean MCF increased from 0 mm to 9.68 mm (new HFC) and 10.00 mm (control) 1‐hour post‐infusion (mean difference, ?0.32 mm; 95% CI, ?1.70, 1.07, n.s.). No deaths, thromboses, viral seroconversions or serious related adverse events occurred.

Conclusions

Bioequivalence was not demonstrated for AUC_norm, clearance and V_ss. Larger AUC_norm and slower clearance were observed for the new HFC. Remaining pharmacokinetic parameters reflected bioequivalence to control. Safety profiles and increases in clot strength were comparable between concentrates.

     

Treatment of congenital fibrinogen disorders

Background: The goal of the coagulation pathway is the conversion of fibrinogen to fibrin and formation of an insoluble clot. Although relatively rare, congenital fibrinogen disorders are interesting and pose several challenges that can serve as paradigms for many diseases. An impressive body of knowledge has accumulated recently, particularly thanks to international collaborative clinical and genetic studies allowing the molecular characterization of these disorders. However, apart from the possibility of developing safer fibrinogen concentrates and the availability of prenatal diagnosis, the basic therapeutic approach has changed little. Objective: We need to better understand the clinical phenotype of patients in order to administer fibrinogen preparations or other treatments more appropriately. Methods: We discuss current therapeutic options and others that could be available in the near future. Results/conclusion: Patients with congenital fibrinogen deficiencies require better predictive tests for clinical complications and more efficient and available fibrinogen concentrates. Global hemostasis tests in combination with routine assays could help to individually tailor therapeutic protocols.     

Fibrinogen Philadelphia. A hereditary hypodysfibrinogenemia characterized by fibrinogen hypercatabolism

A new, autosomally inherited abnormal fibrinogen associated with hypofibrinogenemia has been described in several members of a family. Plasma fibrinogen measured either as thrombin-clottable protein or by immunodiffusion revealed a fibrinogen level ranging between 60 and 90 mg/100 ml. The thrombin time of plasma or purified fibrinogen was prolonged and only partially corrected by the addition of calcium. Purified fibrinogen prolonged the thrombin time of normal plasma. Fibrinopeptide release by thrombin was normal in rate and amount, but fibrin monomer aggregation was grossly disturbed, especially in a high ionic strength medium. We have designated this fibrinogen "fibrinogen Philadelphia." Acrylamide gel electrophoresis of mixtures of [121I]normal and [125I]abnormal fibrinogens revealed a slight increase in the anodal mobility of fibrinogen Philadelphia. Similarly, DEAE-cellulose chromatography showed slightly stronger binding of fibrinogen Philadelphia than normal. To elucidate the mechanism responsible for the low plasma fibrinogen concentration, simultaneous metabolic studies of autologous (patient) and homologous (normal) fibrinogen, labeled with 125I and 121I, respectively, were performed in two affected subjects. Autologous fibrinogen half-life was short and the fractional catabolic rate was markedly increased in both family members. In contrast, homologous fibrinogen half-life and fractional catabolic rate were normal. These metabolic studies demonstrate that rapid degradation of fibrinogen Philadelphia is largely responsible for the depressed levels of a plasma fibrinogen. This represents the first example of a mutant plasma protein in which the molecular defect is associated with an altered catabolism.     

Fibrinogen levels during trauma hemorrhage,response to replacement therapy,and association with patient outcomes

Summary. Background: Low fibrinogen levels are known to occur in trauma. However, the extent of fibrinogen depletion during trauma hemorrhage, the response to replacement therapy and association with patient outcomes remain unclear. Objectives: The study aims were to: characterize admission fibrinogen level and correlate it with factors associated with injury; describe the time course of fibrinogen depletion and response to replacement therapy; determine the correlation of fibrinogen level with rotational thromboelastography (ROTEM) parameters; evaluate the effect of fibrinogen supplementation ex vivo; and establish the association between fibrinogen level and clinical outcomes. Methods: This was a prospective cohort study of 517 patients. Blood samples were drawn on admission and after admistration of every 4 units of packed red blood cells. Fibrinogen levels were determined with the Clauss method, and global hemostatic competence was assessed with thromboelastometry. The effect of fibrinogen supplementation was assessed in a subgroup of coagulopathic patients. Results: Low admission fibrinogen level was independently associated with injury severity score (P < 0.01), shock (P < 0.001), and prehospital fluid volume (P < 0.001). Fibrinogen supplementation during transfusion maintained but did not augment fibrinogen levels. Administration of cryoprecipitate was associated with improved survival. ROTEM parameters correlated with fibrinogen level, and ex vivo fibrinogen administration reversed coagulopathic ROTEM parameters. Fibrinogen level was an independent predictor of mortality at 24 h and 28 days (P < 0.001). Conclusions: Fibrinogen level is decreased in injured patients on admission and is associated with poor outcomes. ROTEM is a rapid means of assessing hypofibrinogenemia. Earlier administration of specific fibrinogen replacement may improve outcomes, and prospective controlled trials are urgently needed.