Post-authorization safety study of Clottafact® , a triply secured fibrinogen concentrate in congenital afibrinogenemia. A prospective observational study.

BACKGROUND AND OBJECTIVES: A new fibrinogen concentrate Clottafact® was developed according to European guidelines on plasma-derived products. A post-authorization safety study was set up in 2009 as part of the risk management plan. This was a non-interventional, prospective, non-comparative, multicenter study of the use of fibrinogen concentrate for congenital afibrinogenemia in real-life medical practice in France. MATERIALS AND METHODS: The analysis was descriptive and performed on 3 subgroups: prophylaxis vs. on-demand treatment, age (<6, <12 and ≥12) and severity of the deficiency. RESULTS: Fourteen patients [1-78 years] were included in 7 centres and followed for 1 year. Twenty-one adverse drug reactions (ADRs) classically reported with fibrinogen (pallor, chills, cough, vomiting, headache, urticaria and erythematous rash) were reported in 5 of 14 patients. Two ADRs were serious: an anaphylactic shock and a subclavian venous thrombosis with a favourable outcome without sequelae. In the nine patients under prophylaxis, 365 of 367 infusions were considered as successful (99·5%) and 2 as failures. For the five patients treated on-demand, the efficacy was rated as excellent for 27 of 48 infusions and good for the 21 others. CONCLUSION: This study confirms that the benefit/risk balance for this fibrinogen concentrate is favourable.

FEIBA in the treatment of acquired haemophilia A: results from the prospective multicentre French 'FEIBA dans l'hémophilie A acquise' (FEIBHAC) registry.

Factor VIII inhibitor bypass activity (FEIBA) is a recommended first-line bypassing agent for bleeding episodes in patients with acquired haemophilia A (AHA). Due to the low incidence of AHA, available clinical data on FEIBA treatment are limited. The study aim was to delineate practice patterns in FEIBA treatment of AHA patients, the haemostatic efficacy of FEIBA, including criteria for its assessment, and safety. A prospective registry was established of AHA patients receiving FEIBA for bleeding episodes or prophylaxis at the time of invasive procedures. Data were collected at 16 participating centres in France. Patients were followed up for 3 months. Haemostatic efficacy, FEIBA regimen and FEIBA-related adverse events were documented. Thirty-four patients averaging 81.8 years old with standard deviation (SD) 8.1 years were included in the study: 33 for acute bleeding and one for haematoma evacuation. The mean initial dose of FEIBA for acute bleeding was 75.4 U kg(-1) (SD, 7.7 U kg(-1) ), most often administered twice daily, and the median duration of FEIBA treatment was 4.0 days (interquartile range, 2.2-8.0 days). FEIBA was effective in managing 88.0% of bleeding episodes (95% confidence interval, 75.8-94.5%). No baseline variables influencing treatment response could be identified. The sensitivity and specificity of an objective haemostatic efficacy scale in predicting sequential investigator assessments of haemostatic efficacy were 45.3% and 84.1% respectively. Four patients experienced a total of six serious adverse events possibly related to FEIBA. In the first prospective study specifically focused on FEIBA treatment of patients with AHA, 88.0% of bleeding episodes were effectively managed.

Factor XI replacement for inherited factor XI deficiency in routine clinical practice: results of the HEMOLEVEN prospective 3-year postmarketing study.

Factor XI (FXI)-deficient patients may develop excessive bleeding after trauma or surgery. Replacement therapy should be considered in high-risk situations, especially when FXI levels are below 20 IU dL(-1) . HEMOLEVEN is a human plasma-derived factor XI concentrate available in France since 1992, but there are few data regarding its use by physicians. This prospective study assessed the use, efficacy and safety of HEMOLEVEN in common clinical practice. HEMOLEVEN was evaluated in FXI-deficient patients in 13 French centres in a 3-year postmarketing study. Forty-four patients (30 females, 14 males) received 67 treatments. The median age was 37 years (8 months-91 years). Basal FXI levels were <1 to 51 IU dL(-1) (median: 5.5); 29 patients were severely FXI-deficient (<20 IU dL(-1) ). FXI was administered prophylactically before 43 surgical procedures, 10 invasive procedures, 8 vaginal deliveries, or as curative treatment for six bleeds. The efficacy was assessed as excellent/good in 63, moderate in two and undetermined in two treatments. Seven patients experienced seven adverse effects, including two rated as serious: one sudden massive pulmonary embolism with fatal outcome and one case of inhibitor to FXI. HEMOLEVEN is effective for bleeding prevention in FXI deficiency. However, considering the benefit/risk ratio observed in relation to dosage in this study; firstly, it should be used sparingly due to its potential prothrombotic effect; secondly, new prescription procedures should be defined to adapt the dosage, especially in patients with intrinsic and/or acquired risk factors for thrombosis.

Outcome of acquired haemophilia in France: the prospective SACHA (Surveillance des Auto antiCorps au cours de l'Hémophilie Acquise) registry.

Although extremely rare, acquired haemophilia A (AHA) can cause severe bleeding, which may be fatal. The underlying causes of autoantibody development are not fully understood. Treatment goals are bleeding control and autoantibody eradication. At the time of our study, there was no consensus on a standard treatment strategy for AHA. Previous data were mainly retrospective or from single-centre cohorts. We conducted a prospective, controlled, registry-based study of patients with AHA in France. The prospective French registry (Surveillance des Auto antiCorps au cours de l'Hémophilie Acquise [SACHA]) collected data on prevalence, clinical course, disease associations and outcomes for haemostatic treatment and autoantibody eradication in 82 patients with a 1-year follow-up. Similar to earlier studies, the prevalence of AHA was higher in the elderly, with two thirds of patients aged >70 years. Around half of AHA cases were associated with underlying disease, most commonly autoimmune disease and cancer in younger and older patients respectively. Haemostatic treatment was initially administered to 46% of patients. Complete resolution or improvement of initial bleeding occurred in 22/27 (81%) rFVIIa-treated patients and in all six cases receiving pd-aPCC. The majority of patients (94%) received immunosuppressive therapy, with complete remission at 3 months in 61% (36/59) and in 98% (50/51) at 1 year. Overall mortality was 33%: secondary to bleeding in only three patients but to sepsis in 10. Bypassing agents were effective at controlling bleeding in patients with AHA. Immunosuppressive therapy should be used early but with caution, particularly in elderly patients.

Characterizing hospital pathways for the care of acquired hemophilia in France using comprehensive national health data.

PURPOSE: Acquired hemophilia (AH) is a rare, serious bleeding disorder most often associated with older age and life-threatening complications. The patient care pathway for AH is complex because of the different types of bleeding, the presence of comorbidities, and the heterogeneity of medical specialists who care for these patients. METHODS: This observational study used the French national PMSI (Programme de médicalisation des systèmes d'information) database to characterize patients with AH in real-life practice and analyze their hospital pathway. In total, 180 patients with AH were identified over a 5-year study period (January 2010 to December 2014), based on three criteria: bypassing agent use, International Classification of Diseases, 10th revision code allocation, and aged over 65 years. Comparison of the incidence rate of AH versus registry data validated the PMSI as an epidemiological database. RESULTS: Rituximab was prescribed more often (60/180; 33.3%) than expected following guidelines and was associated in half of cases to early infections (32/60; 53.3%), surgery procedures were frequently performed during the year before AH onset (29/159; 18.2%), which may suggest a triggering effect, extended hospital stays (median: 20 days) and mortality remaining high (66/180; 36.7%) that occurred mainly during the first month after AH diagnosis. Median costs and number of injections were comparable between recombinant activated factor VII and plasma-derived activated prothrombin complex concentrate. CONCLUSION: These findings could inform future medico-economic approaches in this AH population (duration of stays, bypassing agents, rituximab use, comorbidities, hospitalizations with infections).

[Anticoagulation clinics for outpatients: a 5-year experience]. / Expérience d'un centre de suivi et de conseil des traitements anticoagulants oraux en médecine de ville: résultats à cinq ans.

INTRODUCTION: Anticoagulation clinics and computerized management of chronic oral anticoagulation increase the time spent in the therapeutic range with both mortality and morbidity reduction. Usually, anticoagulation clinics are hospital-based medical care centers. We report the five-year results from a general medicine center (CSCTA) using a computer-assisted management. METHODS: A prospective cohort observational study of 530 primary care patients that were receiving long term oral anticoagulation. RESULTS: Cardiac arrhythmia (55%), heart valve disease and venous thrombo-embolic disease (30%) represented the most common indications of oral anticoagulation. Patients received fluindione, warfarin and acenocoumarol in 80%, 13% and 7%, respectively. The duration of treatment was at least one year in 54% of the cases, and was at least three years in 25% of the cases. The rate of patients that were in average within the therapeutic range (INR 2-3) was 72%, while 12% were under and 16% over the therapeutic range. Corresponding rates were 82, 17 and 1% respectively for all anticoagulation targets (INR 1.5-4.5). Twenty-six bleeding events (4.9 per 100 patient-years) and four thrombotic complications (0.75 per 100 patient-years) occurred. Life-threatening hemorrhage occurred in 1.3 per 100 patient-years. After the equilibration of the anticoagulation, the average delay of control between two consecutive INR was 19 days. CONCLUSION: The results obtained with CSCTA were similar to those reported by other anticoagulation clinics regarding hemorrhagic complications and time spent in the therapeutic range. In contrast, thrombotic events were less frequent. Because of the absence of a control group, a medico-economic analysis could not be performed.

The G79A polymorphism of protein Z gene is an independent risk factor for cerebral venous thrombosis.

BACKGROUND AND PURPOSE: Protein Z (PZ), a vitamin Kdependent protein, plays a role in inhibiting coagulation. Its plasma level or PZ gene polymorphisms have been discussed as risk factors for stroke with conflicting results reported between various studies. Only one of these polymorphisms was studied in a cohort of patients suffering from cerebral venous thrombosis (CVT). METHODS: We performed a retrospective genetic study comparing 100 healthy controls to 54 patients referred to our hemostasis unit after CVT occurrence. We compared the distribution of three PZ gene polymorphisms that may influence PZ plasma levels: A-13G in the promoter and G79A in intron F were tested using previously described techniques, and we developed a technique to evaluate the G-103A in intron A. RESULTS: The G79A polymorphism was significantly more frequent in patients than in controls (p = 0.012): the presence of at least one A allele led to an odds ratio of 2.57 with a 95 % confidence interval of 1.23-5.34. The A-13G polymorphism also showed a nonsignificant trend towards a higher prevalence in patients. CONCLUSION: The G79A polymorphism of the PZ gene was shown to be a new independent risk factor for cerebral venous thrombosis. Nevertheless, these results have to be confirmed by a prospective study including plasma PZ evaluation.

Thromboembolic disease due to thermolabile conformational changes of antithrombin Rouen-VI (187 Asn-->Asp)

A new variant of antithrombin (Rouen-VI, 187 Asn-->Asp) with increased heparin affinity was shown to have normal inhibitory activity which decreased slowly at 4 degrees C and rapidly at 41 degrees C. On electrophoresis the freshly isolated variant had an anodal shift relative to native antithrombin due to the mutation. A further anodal transition occurred after either prolonged storage at 4 degrees C or incubation at 41 degrees C due to the formation of a new inactive uncleaved component with properties characteristic of L-form (latent) antithrombin. At the same time, polymerization also occurred with a predominance of di-, tri-, and tetra-mers. These findings fit with the observed mutation of the conserved asparagine (187) in the F-helix destabilizing the underlying A-sheet of the molecule. Evidence of A-sheet perturbation is provided by the increased rate of peptide insertion into the A-sheet and by the decreased vulnerability of the reactive loop to proteolysis. The spontaneous formation of both L-antithrombin and polymers is consistent with our crystal structure of intact antithrombin where L-form and active antithrombin are linked together as dimers. The nature of this linkage favors a mechanism of polymerization whereby the opening of the A-sheet, to give incorporation of the reactive center loop, is accompanied by the bonding of the loop of one molecule to the C-sheet of the next. The accelerated lability of antithrombin Rouen-VI at 41 versus 37 degrees C provides an explanation for the clinical observation that episodes of thrombosis were preceded by unrelated pyrexias.

Proposed heparin binding site in antithrombin based on arginine 47. A new variant Rouen-II, 47 Arg to Ser.

Antithrombin Rouen-II, a new inherited variant of antithrombin-III, was found in two members of a family with no definite history of thrombosis. The subjects had normal antigenic concentrations of antithrombin and normal progressive inhibitory activity. However, the variant had defective heparin and heparan sulfate cofactor activities, and was not activated by a synthetic pentasaccharide representing the minimum heparin sequence. The abnormal antithrombin was isolated using heparin-Sepharose chromatography, and on electrophoresis at pH 8.6 migrated more anodally than normal. Two-dimensional peptide mapping of tryptic and Staphylococcus aureus V8 protease digests was performed and the abnormal peptide was located by tryptophan staining. Amino acid sequence studies demonstrated a substitution of arginine at residue 47 by a serine. Evidence strongly suggests that arginine 47 is a prime heparin binding site in antithrombin and that it forms part of a proposed positively charged linear site (to which heparin binds) that stretches across the surface of the molecule from the A to the D helix.

Antithrombin Rouen-IV 24 Arg----Cys. The amino-terminal contribution to heparin binding.

A variant antithrombin with reduced heparin affinity was shown by mass spectrometry sequencing and DNA amplification to have a substitution of a cysteine for an arginine at residue 24. The position of Arg-24 can be fixed within a 12 A radius from the bridge at Cys-21. This is compatible with findings in the homologous protease nexin-1 which indicate an extension of the binding site of heparin from the D-helix to under the adjacent amino-terminal pole.

New carbohydrate site in mutant antithrombin (7 Ile----Asn) with decreased heparin affinity.

A mutant antithrombin was isolated from the plasma of a patient with pulmonary embolism. The new protein, which accounted for 55% of the antithrombin, had decreased heparin affinity and contained two components when analysed on the basis of either charge or molecular mass. Sialidase and endo-beta-N-acetylglucosaminidase F treatment suggested that this heterogeneity was due to a partial glycosylation occurring at a new carbohydrate attachment sequence. Peptide mapping by reverse-phase HPLC showed that the abnormality involved the N-terminal tryptic peptide. Sequence analysis demonstrated that the underlying mutation was 7 Ile----Asn which introduces a new Asn-Cys-Thr glycosylation sequence. This new oligosaccharide attachment site occupies the base of the proposed heparin-binding site, and the finding explains the consequent decrease in heparin affinity.

Evaluation of sensitivity and specificity of a standardized procedure using different reagents for the detection of lupus anticoagulants. The Working Group on Hemostasis of the Société Française de Biologie Clinique and for the Groupe d'Etudes sur I'Hémostase et la Thrombose.

This study was designed to test the sensitivity and specificity of a combination of 3 phospholipid-dependent assays performed with various reagents, for the detection of lupus anticoagulant (LA). Plasmas containing an LA (n = 56) or displaying various confounding pathologies [58 intrinsic pathway factor deficiencies, 9 factor VIII inhibitors, 28 plasmas from patients treated with an oral anticoagulant (OAC)] were selected. In a first step, the efficiency of each assay and reagent was assessed using the Receiving Operating Characteristic (ROC) method. Optimal cut-offs providing both sensitivity and specificity > or = 80% were determined. The APTT assay and most of the phospholipid neutralization assays failed to discriminate factor VIII inhibitors from LA. In a second step, using the optimal cut-offs determined above, the results of all the possible combinations of the 3 assays performed with 4 different reagents were analyzed. Thirteen combinations of reagents allowed > or = 80% of plasmas of each category (LA, factor deficiency or OAC) to be correctly classified (3/3 positive test results in LA-containing plasmas and 0/3 positive results in LA-negative samples).

Five novel mutations of the protein S active gene (PROS 1) in 8 Norman families.

To further elucidate the molecular basis for hereditary thrombophilia, we screened the protein S active gene in 11 families with type I deficiency, using a strategy based on denaturing gradient gel electrophoresis (DGGE) of all the coding sequences. Fragments with an abnormal DGGE pattern were sequenced, and 5 novel mutations were identified in 8 families. The mutations were a 7-nucleotide deletion in exon II, a 4-nucleotide deletion in exon III, a T insertion in exon VII, a C to T transition transforming Leu 259 into Pro and a T to C transition transforming Cys 625 into Arg in 4 families. These mutations were the only sequence variations found in the propositus' gene exons and co-segregated with the plasma phenotype. A total of 28 members of these 8 families were heterozygous for one of the 5 mutations. Twenty-four (58,5%) of the 41 deficient subjects over 18 years of age had clinical thrombophilia, whereas the 13 subjects under 18 were asymptomatic. Of the 28 subjects, 6 (21,5%) were also found to bear the factor V Arg 506 Gln mutation.

Quantification of lupus anticoagulants in clinical samples using anti-beta2GP1 and anti-prothrombin monoclonal antibodies.

Quantification of lupus anticoagulant (LA) in clinical samples is hampered by the lack of a suitable standard of activity. We evaluated the use of mAbs displaying LA activity for this purpose. As most patient samples contain both beta2Glycoprotein I (beta2GP1) and prothrombin dependent LA, a combination of two mAbs, one of each specificity, was added to normal plasma in a concentration from 0 to 60 microg/ml. Eight assay systems using different reagents and instruments were used. The calibration curves were linear for all but one, with marked differences between the responsiveness to each mAb. A panel of plasmas from 69 patients with persistent LA diagnosed using the SSC-ISTH criteria was tested. An antiphospholipid syndrome (APS) was present in 40, whereas 29 were asymptomatic. LA activities of individual plasmas varied between assays (p < 10(-4)), but homogeneous subgroups were identified. In a majority of samples, LA activity displayed a prothrombin-dependent profile, with a variable contribution of beta2GP1-dependent activity. The latter was associated to beta2GP1 antibodies detected by solid-phase immunoassay. By using 3 dilute Russell viper venom time assays, higher LA titers were found in APS, compared to asymptomatic patients (p <0.05).

Analysis of biological phenotypes from 42 patients with inherited factor VII deficiency: can biological tests predict the bleeding risk?

BACKGROUND AND OBJECTIVES: Inherited factor VII (FVII) deficiency is a rare bleeding disorder characterized by a poor relationship between reported FVII clotting activity (FVII:C) and bleeding tendency. Our study was aimed at defining biological parameters that are possibly predictive for bleeding risk in this condition. DESIGN AND METHODS: Forty-two FVII-deficient patients (FVII:C <30%) were classified into two opposite clinical groups defined as severe and non-or-mild bleeders. For each patient, plasma samples were collected and then investigated for FVII:C (using a sensitive method and human recombinant thromboplastin as the reagent), FVII antigen, activated FVII coagulant activity (FVIIa:C) and the free-form of tissue factor pathway inhibitor. RESULTS: None of these tests could be used as highly accurate predictors of bleeding. Nevertheless, both FVII:C and FVIIa:C differed significantly between the two clinical groups. Using ROC-curve analysis, two critical values of 8% and 3mIU/mL for FVII:C and FVIIa:C, respectively, could be proposed to discriminate between severe bleeders and non-or-mild bleeders. INTERPRETATION AND CONCLUSIONS: A highly accurate diagnostic test for predicting bleeding tendency in inherited FVII deficiency still eludes definition, highlighting the fact that factors other than FVII itself interfere with the expression of bleeding phenotypes in this condition. Nevertheless, potential critical values using sensitive FVII:C and FVIIa:C methods may be useful in clinical laboratories for FVII-deficient patients. Those patients with FVII:C levels higher than 8% FVII:C or FVIIa:C higher than 3 mIU/mL, with no other hemostatic defect, seem to have a minimal risk of severe bleeding. Extended clinical studies are needed to support these findings.

Decision analysis for use of platelet aggregation test, carbon 14-serotonin release assay, and heparin-platelet factor 4 enzyme-linked immunosorbent assay for diagnosis of heparin-induced thrombocytopenia.

The value of the platelet aggregation test, carbon 14-labeled serotonin release assay (SRA), and heparin-platelet factor 4 enzyme-linked immunosorbent assay (H-PF4 ELISA) for the diagnosis of heparin-induced thrombocytopenia was evaluated by studying blood samples from 100 patients with suspected heparin-induced thrombocytopenia, and categorized into 4 clinical groups: unlikely (n = 22), possible (34), probable (36), and definite (8) thrombocytopenia. Results of the platelet aggregation test were positive in 40 of 44 patients with probable or definite heparin-induced thrombocytopenia (sensitivity 91%) and in 5 of 22 unlikely to have heparin-induced thrombocytopenia (specificity 77%). The SRA exhibited sensitivity of 88% and negative predictive value of 81%, close to those values for the platelet aggregation test; specificity and positive predictive value were 100%. The sensitivity of the heparin-PF4 ELISA was 97%, with specificity 86%, and a positive correlation was recorded between the level of antibodies to H-PF4 and clinical score (P = 0.66). When ELISA was used with the platelet aggregation test or SRA, positive predictive value and specificity were 100% when both tests yielded positive results, and negative predictive value was 100% when both tests yielded negative results. A biologic flow chart was designed that presented a choice based on the results of the platelet aggregation test or SRA in association with ELISA, and enabled more accurate and specific identification of heparin-induced thrombocytopenia.

Protein C: Rouen, a new hereditary protein C abnormality with low anticoagulant but normal amidolytic activities.

A family is described in which venous thrombo-embolic disease is associated with reduced plasma protein C anticoagulant activity but normal levels of protein C amidolytic activity and antigen. The partial characterization of the heterozygous defect is described using crossed immunoelectrophoresis (CIE) with or without calcium and seven functional assays which differ by activators (thrombin-thrombomodulin complex, bovine thrombin and Protac snake venom) and by an eventual preliminary adsorption on insoluble salts. PC activity was thereafter determined either by chronometric or amidolytic assays. The results indicate that this abnormal protein C (PC) is normally activated and at least partially carboxylated. Three hypothesis are proposed to explain the discrepancy between normal amidolytic and low anticoagulant activities.

Resistance to activated protein C: evaluation of three functional assays.

Resistance to Activated Protein C (APC) was evaluated using 3 different methods: two of them were based on the prolongation of the Activated Partial Thromboplastin Time (APTT) using 2 different APTT reagents in the presence of APC, whereas the third method was based on the prolongation of prothrombin time when APC is added. The three methods were significantly correlated. APTT-based assays were sensitive to factor XII deficiency, whereas thromboplastin-based assay was sensitive to factor VII deficiency (< 0.5 UI/ml), which surestimates the response to APC. In contrast, an increase in factor VIII (F. VIII) level is associated with a decreased response to APC, when APTT-based assays are used, whereas thromboplastin-based assay is unmodified. During pregnancy, a decreased response to APC is observed, which is not only due to the increase in F. VIII, since thromboplastin-based assay is also modified. In Protein S (PS) immuno-depleted plasma, the low response to APC is corrected by addition of free PS: the thromboplastin-based assay was the most sensitive one to PS deficiency. However, in patients with congenital PS deficiency, there was no correlation between APC-resistance and free PS level. In patients with lupus anticoagulant, discrepancies were observed between the 3 methods, but with a high frequency of low response to APC. For the 3 assays, there was a good differentiation and correlation between normal and pathological results, the thromboplastin-based assay being perhaps the most discriminating. However, 3 unrelated thrombophilic patients showed normal results using thromboplastin-based assay, although they were APC-resistant using APTT-based assays. For 2 patients, this discrepancy can be explained by high levels of F. VIII. For the last patient, an abnormal F. VIII, resistant to APC can be suspected.

Functional antithrombin-III variant (41 Pro----Leu) identified by liquid secondary ion mass spectrometry.

A genetic variant of antithrombin with impaired heparin cofactor activity was identified in 4 members of a French family. Both the variant and normal antithrombin component were purified by affinity chromatography on heparin Sepharose. Reverse phase peptide mapping revealed a single altered peak when tryptic digests of both antithrombins were compared. After further purification of the aberrant peptide, amino acid analysis indicated a substitution of 41 Leu----Pro (antithrombin Basel). This result was confirmed by liquid secondary ion mass spectrometry which gave a measured mass of 816.4655 Da for the new peptide compared to a calculated mass of 800.3579 Da for the normal peptide and 816.4579 for the Leu----Pro substitution.

Potent activity of peripheral blood lymphocytes in inducing hepatocyte stimulating factor and urokinase in monocytes.

As fibrinogen is an independent risk factor for arterial thrombosis we were interested in analysing the mechanism controlling fibrinogen biosynthesis. In this work, we showed that incubation of monocytes with lymphocytes increased hepatocyte stimulating factor (HSF) production. Different mechanisms are involved and our results demonstrated that this effect is in part mediated by an increase in interleukin 6 (IL-6) production. However, IL-6 cannot account for the whole effect and other cytokines could be implicated. In addition, we observed a stimulation of urokinase-type plasminogen activator (u-PA) associated with monocytes when these cells were incubated with lymphocytes for 18 h at 37 degrees C. By producing fragment D (fibrinogen degradation product) and D-dimer (fibrin degradation product) this fibrinolytic activity might also contribute to fibrinogen biosynthesis by hepatocytes.