A Generic Version of Recombinant FVIIa Is Similar to the Branded Product (NovoSeven)

Abstract Background: Commercially available recombinant factor VIIa (Novoseven) is widely used in the management of hemophilia patients with inhibitors. Recently several generic versions of recombinant VIIa (rFVIIa) have become available. The generic versions of rFVIIa are claimed to be biosimilar to the barnded Novoseven (Novo Nordisk, Copenhagen, Denmark). The purpose of this study is to compare the US and European Novoseven products with a generic version of rFVIIa namely, Aryoseven (Aryogen, Tehran, Iran). Methods: Four commercially available random lots of Novoseven were obtained from the US and European sources. Four different batches of Aryoseven were obtained from Aryogen. All individual rFVIIa preparations were diluted to obtain working concentrations of 100, 10, 1 and 0.1 ug/ml. Protein content (Lowry's method), molecular profile using surface enhanced laser desorption ionization (SELDI), gel electrophoretic profile (GEP), factor VII related antigen level (FVII:Ag), factor VII correction studies in depleted plasma and thrombin generation (TG) studies were carried out. In addition, VIIa/tissue factor mediated thrombin generation studies were carried out in various prothrombin complex concentrates such as Beriplex and Prothromplex. Results: The protein content and SELDI mass spectrophotometric profile of all 4 rFVIIa preparations were comparable. There was no differences in the Novoseven obtained from the US and European sources. The GEP of the two groups of agents showed a comparable profile with distinct peaks at 50 KDa and 25 KDa. The FVII related antigen levels were also comparable in the Novoseven and Aryoseven preparations. Supplementation of both the Novoseven and Aryoseven preparations at 10 and 100 ug/ml resulted in a comparable correction of the factor VII deficient plasma as measured by PT(INR). Thrombin generation was comparable in the branded and generic product. Conclusions: These results demonstrate that the US and European Aryoseven are comparable. Four batches of Novoseven and 4 individual clinical batches of Aryoseven were found to be comparable. When the US purchased Novoseven preparation was compared with the European Novoseven product, no differences were noted. Thus, the generic Aryoseven is biosimilar to barnded Novoseven and warrant in vivo validation studies. Disclosures No relevant conflicts of interest to declare.

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Feedback Activation of Factor XI by Thrombin Is Essential for Hemostasis In Vivo.

Blood ◽

10.1182/blood.v114.22.2127.2127 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2127-2127

Author(s):

Henri M. H. Spronk ◽

Sabine Wilhelm ◽

Rene Van Oerle ◽

Menno L. Knetsch ◽

David Gailani ◽

...

Keyword(s):

Thrombin Generation ◽

Conflicts Of Interest ◽

Factor Viia ◽

Fibrin Clot ◽

Intrauterine Death ◽

Factor Xii ◽

Dependent Manner ◽

Factor Xi ◽

Feedback Activation

Abstract Abstract 2127 Poster Board II-102 Background: The revised model of coagulation proposes that factor XI (FXI) can be activated by thrombin, which is generated upon activation of the tissue factor (TF) pathway. This concept, however, has not been tested in vivo. A recent study questioned the existence of this feedback loop and suggested that factor XII (FXII) is the sole activator of FXI. Here, we analyze the feedback activation of FXI in plasma and in genetically altered mice. Methods and results: Fluorescence-based assays indicated that particle-bound thrombin caused thrombin generation in plasma both in the absence of TF and in the presence of active site inhibited factor VIIa. Thrombin failed to activate FXII and thrombin generation was almost completely abolished by an anti-FXIa antibody and in FXI-deficient plasma. Surface bound thrombin induced complex formation of FXI, with its major inhibitor C1 inhibitor, even in FXII-deficient plasma in a time and dose dependent manner. To determine if thrombin-driven FXI activation is important for hemostasis in vivo we used TF deficient mice (low TF), which have severely reduced thrombin formation. Low TF mice were crossed with mice deficient in one of the intrinsic pathway proteases FXII, FXI, or FIX. Double deficiency in TF and either FIX or FXI resulted in the intrauterine death of embryos due to hemorrhage. In contrast low TF/FXII-null mice were viable and the bleeding phenotype was unchanged from low TF animals. Conclusions: Surface-bound thrombin, a model for fibrin clot-protected thrombin, generates thrombin in a FXI dependent manner, independently from FXII. In addition to corroborating an amplifying role of FXI in thrombin generation, we provide the first evidence that at low TF levels FXI is essential in generating a sufficient ambient level of thrombin to permit embryonic development. Disclosures: No relevant conflicts of interest to declare.

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Comparison of Branded Enoxaparin (Lovenox) and a Biosimilar Version of Enoxaparin (Fibrinox)

Blood ◽

10.1182/blood.v116.21.4385.4385 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4385-4385

Author(s):

Walter Jeske ◽

Elizabeth McGeehan ◽

Omer Iqbal ◽

Debra Hoppensteadt ◽

Jeanine M. Walenga ◽

...

Keyword(s):

Molecular Weight ◽

Thrombin Generation ◽

Conflicts Of Interest ◽

Average Molecular Weight ◽

Molecular Profile ◽

Distribution Analysis ◽

Thrombin Time ◽

Plasma Samples ◽

Branded Product ◽

Inhibition Of Thrombin

Abstract Abstract 4385 Several biosimilar versions of branded enoxaparin (Lovenox, Sanofi-Aventis, Paris, France) have recently become available throughout the world. These biosimilar enoxaparin preparations are distributed by multiple suppliers in Asia and in North and South America. Enoxaparin represents a complex mixture of oligosaccharides obtained by alkaline depolymerization of porcine mucosal heparin. It is the most widely used low molecular weight heparin which has been validated for clinical use in multiple indications. While the molecular profile and anti-Xa potencies of some of the biosimilar versions of enoxaparin are comparable, product based differences have been reported amongst some of the biosimilar versions of enoxaparin. The purpose of this study was to compare the biochemical and pharmacologic profile of one biosimilar version of enoxaparin, namely Fibrinox (Sandoz SA, Buenos Aires, Argentina) with the branded product Lovenox. The products were compared in equigravimetric amounts, assuming equivalent potency (100 AXa U/mg). Both products exhibited comparable molecular weight profiles in terms of average molecular weight and oligosachharide distribution. Analysis of the antithrombin binding hexasaccharide fractions of Fibrinox and Lovenox indicated the presence of eight distinct hexasaccharides. The relative proportions these hexasaccharides differed between Fibrinox and Lovenox. The anti-Xa and anti-IIa activities were comparable. In the whole blood clot-based assays such as TEG and ACT, both agents produced similar anticoagulant effects. In the plasma based assays such as the APTT, Heptest and thrombin time, both products showed comparable anticoagulant effects in the normal human pooled plasma samples. However, in plasma samples collected from patients with liver disease who were apparently anticoagulant free, the two products showed differences in their anticoagulant effects in the APTT assay (p<0.05). In the TF mediated thrombin generation assay, Fibrinox produced a stronger inhibition of thrombin generation compared to Lovenox (IC50; Fibrinox, 1.6 μ g/ml, Lovenox 2.2 μ g/ml). No differences were observed between the two products in the agonist induced platelet aggregation assays. However in the 14C serotonin release study, Fibrinox produced a stronger HIT serum mediated 14C release (p<0.05). Differences in the fibrinokinetic profile and the inhibition of thrombin activatable fibrinolytic inhibitor activation were observed with these LMWHs. These studies suggest while both the molecular profile and the pharmacopoeial potency of Fibrinox is similar to the branded product, these drugs can be differentiated in some of the other assays and should be evaluated in terms of additional pharmacologic mechanisims to demonstrate bioequivalence. Disclosures: No relevant conflicts of interest to declare.

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Pharmacodynamic Differences in the Two Generic Brands of Enoxaparin

Blood ◽

10.1182/blood.v118.21.1251.1251 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1251-1251

Author(s):

Debra Hoppensteadt ◽

Walter Jeske ◽

Angel Gray ◽

Jeanine M. Walenga ◽

Rakesh Wahi ◽

...

Keyword(s):

Thrombin Generation ◽

Conflicts Of Interest ◽

Molecular Profile ◽

Thrombin Time ◽

Time Period ◽

Pharmacodynamic Profile ◽

The Us ◽

Fibrinolysis Inhibitor ◽

Tissue Factor Pathway

Abstract Abstract 1251 Several generic versions of enoxaparin have recently become available. While these generic versions of enoxaparin exhibit similar molecular profiles and comparable anti-Xa activities; product specific differences in global anticoagulant (APTT, Heptest and thrombin generation inhibition) have been reported. The purpose of this study was to compare a generic version of enoxaparin Sandoz from Argentina (Fibrinox lot 002) and from the US (enoxaparin lot 914786) in various in vitro whole blood and plasma based clotting tests. Despite comparable molecular profile and anti-Xa potency, product specific differences were noted between the products and the US generic enoxaparin showed a cumulatively stronger activity in most of the assays. To further test the pharmacodynamic profile of these products, individual groups of monkeys (n=4–8) were administered with each product at a 1 mg/kg SC and blood samples were collected for up to 28 hours. Clot based assays such as the APTT, Heptest, thrombin time, amidolytic anti-Xa and anti-IIa activities were carried out. In addition, tissue factor pathway inhibitor (TFPI) antigen, thrombin activatable fibrinolysis inhibitor (TAFI) activity and thrombin generation assays were also performed. Variable differences were noted in the clot based and amidolytic assays. Interestingly, the US generic product exhibited a lower release in the TFPI antigen whereas in the thrombin generation assays it produced a stronger inhibition of thrombin in terms of the AUC. TAFI activity profile also showed wide variations. These differences were more prevalent during the 1–4 hour time period. No differences were noted at >6 hours. The hysterisis PK/PD plots revealed marked differences between the two products. These results indicate that the products for the same generic suppliers may exhibit variations according to market places. Moreover, these observations underscore the need for a more stringent pharmacodynamic profile to demonstrate product equivalence. Disclosures: No relevant conflicts of interest to declare.

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The Role of Factor VII in Haemostasis: Infusion Studies of Factor VIIa in a Canine Model of Factor VIII Deficiency

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647270 ◽

1990 ◽

Vol 64 (01) ◽

pp. 138-144 ◽

Cited By ~ 16

Author(s):

Koen Mertens ◽

Ernest Briët ◽

Alan R Giles

Keyword(s):

Factor Viii ◽

Thrombin Generation ◽

Factor Viia ◽

Intrinsic Factor ◽

Canine Model ◽

Factor Vii ◽

Factor Viii Deficiency ◽

Post Infusion

SummaryThe role of factor VIIa in haemostasis has been studied using a canine model of factor VIII deficiency. Highly purified human factor VIIa was administered to dogs at a dosage of 0.5 μg/kg. At selected times pre- and post-infusion, haemostasis was evaluated by the cuticle bleeding time. Plasma was collected for the assay of various parameters, including fibrinopeptide A (FPA) as a marker for thrombin generation in vivo. Factor VIIa infusion resulted in a 6-fold increase of factor VII clotting activity with z t1/2 of 2 h. FPA levels which were 1.4 ng/ml before infusion, did not increase significantly in haemophilic dogs. In normal dogs, however, FPA levels rose to a mean value of 190 ng/ml 30 min post-infusion. It appeared that thrombin generation by factor VIIa infusion had occurred mainly via the intrinsic, factor VIIIdependent pathway. In factor VIII-deficient dogs, factor VIIa infusion did not correct cuticle bleeding, but an inconsistent haemostatic effect was observed 15–30 min post-infusion. Similar results were obtained in haemophilic dogs with circulating antibodies against factor VIII. The haemostatic effectivity could not be improved by increasing the factor VIIa dosage up to 40-fold. Although these data suggest that the extrinsic, factor VIIdependent factor X activation provides only a minor pathway of thrombin generation in vivo, it is possible that the suboptimal haemostatic effect noted may be promoted in bleeding situations where tissue factor availability is less limited. As such, factor VIIa may prove useful in the treatment of haemophilia A patients with acquired inhibitors to factor VIII.

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The Effect of Active Site-inhibited Factor VIIa on Tissue Factor-initiated Coagulation Using Platelets before and after Aspirin Administration

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657715 ◽

1997 ◽

Vol 78 (04) ◽

pp. 1202-1208 ◽

Cited By ~ 18

Author(s):

Marianne Kjalke ◽

Julie A Oliver ◽

Dougald M Monroe ◽

Maureane Hoffman ◽

Mirella Ezban ◽

...

Keyword(s):

Tissue Factor ◽

Active Site ◽

Large Scale ◽

Thrombin Generation ◽

Factor Viia ◽

Dependent Manner ◽

Antithrombotic Agent ◽

Before And After ◽

Ic50 Values

SummaryActive site-inactivated factor VIIa has potential as an antithrombotic agent. The effects of D-Phe-L-Phe-L-Arg-chloromethyl ketone-treated factor VIla (FFR-FVIIa) were evaluated in a cell-based system mimicking in vivo initiation of coagulation. FFR-FVIIa inhibited platelet activation (as measured by expression of P-selectin) and subsequent large-scale thrombin generation in a dose-dependent manner with IC50 values of 1.4 ± 0.8 nM (n = 8) and 0.9 ± 0.7 nM (n = 7), respectively. Kd for factor VIIa binding to monocytes ki for FFR-FVIIa competing with factor VIIa were similar (11.4 ± 0.8 pM and 10.6 ± 1.1 pM, respectively), showing that FFR-FVIIa binds to tissue factor in the tenase complex with the same affinity as factor VIIa. Using platelets from volunteers before and after ingestion of aspirin (1.3 g), there were no significant differences in the IC50 values of FFR-FVIIa [after aspirin ingestion, the IC50 values were 1.7 ± 0.9 nM (n = 8) for P-selectin expression, p = 0.37, and 1.4 ± 1.3 nM (n = 7) for thrombin generation, p = 0.38]. This shows that aspirin treatment of platelets does not influence the inhibition of tissue factor-initiated coagulation by FFR-FVIIa, probably because thrombin activation of platelets is not entirely dependent upon expression of thromboxane A2.

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Injection of recombinant activated factor VII can induce transient increase in circulating procoagulant microparticles

Thrombosis and Haemostasis ◽

10.1160/th03-05-0301 ◽

2004 ◽

Vol 91 (05) ◽

pp. 873-878 ◽

Cited By ~ 21

Author(s):

Bénédicte Hugel ◽

Benoit Guillet ◽

Catherine Trichet ◽

Anne Rafowicz ◽

Thierry Lambert ◽

...

Keyword(s):

Short Duration ◽

Platelet Activation ◽

Thrombin Generation ◽

Transient Increase ◽

Factor Vii ◽

Recombinant Activated Factor Vii ◽

Activated Factor Vii ◽

Therapeutic Doses

SummaryRecombinant activated factor VII (rFVIIa) is an effective haemostatic treatment in haemophiliacs with inhibitors. In vitro, FVIIa concentrations corresponding to those obtained with therapeutic doses of rFVIIa have been shown to induce normal thrombin generation and platelet activation in the absence of factors VIII or IX. To further study the in vivo haemostatic changes induced by rFVIIa, circulating procoagulant microparticles (MP) were measured in patients treated with discontinuous injections of Novoseven®. In 6 out of 15 patients, a transient peak of procoagulant MP was observed after injection, occurring 15 min to 2 h after infusion. It was composed primarily of platelet-derived MP and was of very short duration. This peak was not observed in haemophiliacs without inhibitor, who were treated with conventional replacement therapies. Our results provide further in vivo evidence that rFVIIa specifically activates platelets, either directly or as a consequence of a burst of thrombin generation that could account for its haemostatic efficacy.

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Plasma elimination kinetics for factor VII are independent of its activation to factor VIIa and complex formation with plasma inhibitors

Thrombosis and Haemostasis ◽

10.1160/th08-10-0699 ◽

2009 ◽

Vol 101 (05) ◽

pp. 818-826 ◽

Cited By ~ 20

Author(s):

Torben Elm ◽

Mirella Ezban ◽

Thomas Krogh ◽

Ditte Karpf ◽

Anne Steinø ◽

...

Keyword(s):

Complex Formation ◽

Antithrombin Iii ◽

Factor Viia ◽

Factor Vii ◽

Elimination Kinetics ◽

Inhibitor Complex ◽

Α2 Macroglobulin ◽

Clearance Mechanism ◽

Deficient Mice

SummaryThe mechanism for the elimination of factor VII (FVII) from the circulation is unknown, just as it is unclear how activation of FVII to FVIIa and subsequent complex formation with antithrombin III (AT) or α2-macroglobulin (α2M) affects clearance. The possibility that the clearance mechanism involves activation and inhibitor complex formation as obligatory intermediate reactions is examined in this study. Human and murine sera were spiked with human FVIIa in the absence and presence of heparin and analysed for complex formation. Complex formation in vivo was studied after intravenous injection of 125I-VIIa in mice; and the pharmacokinetics (PK) of human and murine FVIIa was studied in normal mice. Furthermore, comparative PK studies were performed with FVII, FVIIa, active site blocked FVIIa and a preformed FVIIa-AT complex in normal and α2M-deficient mice. The data demonstrated that FVIIa-AT complexes and to a much lesser extent FVIIa-α2M-complexes accumulated in vivo after FVIIa administration. FVIIa-AT accounted for about 50% of total FVIIa antigen left in the circulation after 3 hours. All FVII derivatives studied including FVII, FVIIa and FVIIa-AT were cleared with similar rates suggesting an elimination kinetics which is unaffected by FVII activation and subsequent inactivation by plasma inhibitors.

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Prothrombin Activation Is Increased among Asymptomatic Carriers of the Prothrombin G20210A and Factor V Arg506Gln Mutations

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614034 ◽

2000 ◽

Vol 84 (09) ◽

pp. 396-400 ◽

Cited By ~ 15

Author(s):

Steve Humphries ◽

Belinda Smillie ◽

Lily Li ◽

Jacqueline Cooper ◽

Samad Barzegar ◽

...

Keyword(s):

Factor Viia ◽

Conclusive Evidence ◽

Factor Ix ◽

Factor Vii ◽

Prothrombin G20210a ◽

Factor V ◽

Factor X ◽

Coagulation Proteins ◽

Prothrombin Activation

SummaryThe risk of venous thrombosis is increased in individuals who carry specific genetic abnormalities in blood coagulation proteins. Among Caucasians, the prothrombin G20210A and factor V Arg506Gln (FV R506Q) mutations are the most prevalent defects identified to date. We evaluated their influence on markers of coagulation activation among participants in the Second Northwick Park Heart Study, which recruited healthy men (aged 50–61 years) from nine general medical practices in England and Wales. They were free of clinical vascular disease and malignancy at the time of recruitment. Genotypes for the two mutations were analyzed using microplate array diagonal gel electrophoresis, and coagulation markers (factor XIIa; activation peptides of factor IX, factor X, and prothrombin; fibrinopeptide A) were measured by immunoassay. Factor VII coagulant activity and factor VIIa levels were determined by a functional clotting assay. Among 1548 men genotyped for both mutations, 28 (1.8%) and 52 (3.4%) were heterozygous for prothrombin G20210A and FV R506Q, respectively. The only coagulation marker that was significantly associated with the two mutations was prothrombin activation fragment F1+2 [mean ± SD, 0.88 ± 0.32 nmol/L in men with prothrombin G20210A (p = 0.002) and 0.89 ± 0.30 in men with FV R506Q (p = 0.0001) versus 0.72 ± 0.24 among non-carriers for either mutation]. This data provides conclusive evidence that heterozygosity for the prothrombin G20210A as well as the FV R506Q mutations in the general population leads to an increased rate of prothrombin activation in vivo.

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Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of hemophilia A by factor VIIa

Blood ◽

10.1182/blood.v95.4.1330.004k28_1330_1335 ◽

2000 ◽

Vol 95 (4) ◽

pp. 1330-1335 ◽

Cited By ~ 98

Author(s):

Cornelis van 't Veer ◽

Neal J. Golden ◽

Kenneth G. Mann

Keyword(s):

Factor Viii ◽

Tissue Factor ◽

Thrombin Generation ◽

Hemophilia A ◽

Factor Viia ◽

Plasma Concentrations ◽

Factor Xa ◽

Factor Vii ◽

Lag Phase ◽

Single Chain

Factor VII circulates as a single chain inactive zymogen (10 nmol/L) and a trace (∼10-100 pmol/L) circulates as the 2-chain form, factor VIIa. Factor VII and factor VIIa were studied in a coagulation model using plasma concentrations of purified coagulation factors with reactions initiated with relipidated tissue factor (TF). Factor VII (10 nmol/L) extended the lag phase of thrombin generation initiated by 100 pmol/L factor VIIa and low TF. With the coagulation inhibitors TFPI and AT-III present, factor VII both extended the lag phase of the reaction and depressed the rate of thrombin generation. The inhibition of factor Xa generation by factor VII is consistent with its competition with factor VIIa for TF. Thrombin generation with TF concentrations >100 pmol/L was not inhibited by factor VII. At low tissue factor concentrations (<25 pmol/L) thrombin generation becomes sensitive to the absence of factor VIII. In the absence of factor VIII, factor VII significantly inhibits TF-initiated thrombin generation by 100 pmol/L factor VIIa. In this hemophilia A model, approximately 2 nmol/L factor VIIa is needed to overcome the inhibition of physiologic (10 nmol/L) factor VII. At 10 nmol/L, factor VIIa provided a thrombin generation response in the hemophilia model (0% factor VIII, 10 nmol/L factor VII) equivalent to that observed with normal plasma, (100% factor VIII, 10 nmol/L factor VII, 100 pmol/L factor VIIa). These results suggest that the therapeutic efficacy of factor VIIa in the medical treatment of hemophiliacs with inhibitors is, in part, based on overcoming the factor VII inhibitory effect.

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Thrombin Generation in Pediatric Patients Treated with L-asparaginase.

Blood ◽

10.1182/blood.v114.22.3983.3983 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3983-3983

Author(s):

Katerina Tousovska ◽

Ondrej Zapletal ◽

Sona Vytiskova ◽

Martina Slanska ◽

Petra Ruzickova ◽

...

Keyword(s):

Thrombin Generation ◽

Pediatric Patients ◽

Fibrinogen Level ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Coagulation Cascade ◽

Induction Treatment ◽

Bleeding Episodes ◽

Almost All

Abstract Abstract 3983 Poster Board III-919 Introduction Treatment with L-asparaginase is associated with an disturbance of coagulation cascade. Increased thrombin generation is the most frequently cited coagulation anomaly associated with L-asparaginase treatment. Until now, almost all studies aimed on estimation of thrombin generation, have used circulating procoagulant markers such are thrombin/antithrombin complexes(TAT),D dimers(DD),prothrombin fragments (F1,F2).Calibrated automated thrombogram (CAT) allows the precise estimation of the whole amount of thrombin generated in vivo at present time. We show the first data on thrombin generation measured by CAT among pediatric patients with acute lymphoblastic leukemia treated with L-asparaginase. Patients and methods Thrombin generation was measured in platelet poor plasma of 18 patients (age 7-17years) by means of CAT. Samples were obtained at pre-defined time points during the induction and reinduction phase of protocol ALL-IC BFM 2000. We simultaneously checked the APTT,PT,AT III,fibrinogen and DD from each blood sample. Detailed patientsx data were collected prospectively. Results We collected 22 series of CAT measurements from 18 patients. The average endogenous thrombin potential (ETP) value was 1237,64±334,49nM/min during protocol I(PI) and 892,31±405,03 during protocol II resp.III(PII/III) (p .000013). Maximum ETP was reached on day 24 in PI (1310,15±256,3nM/min) and on day 15 in PII/III (978,20±262,30 nM/ min). The average ETP value in 20 healthy controls was 1218,12±129,00 nM/min. Three patients developed deep venous thrombosis (DVT) during the study period, all of them on PI. Their average ETP value on the last measurement before thrombosis was 1510,54±78,6 nM/min. Four patient had an infection gr. III/IV, according WHO, during the study period. Their average ETP value after the infection was 1711,43±106,0 nM/min. Two of those four patient developed DVT within 5 resp.8 days after the first sign of infection. Fibrinogen level <1g/l was detected in 19 samples out of 104. From those 19 samples with fibrinogen < 1,0,the ETP value from the same sample was normal in 14 cases and low in 5 cases. There were no bleeding episodes in that time. Conclusions Thrombin generation is preserved in majority of patients treated with L-asparaginase in accordance with ALL-IC BFM 2000 protocol, despite the associated hypofibrinogenemia. Patients on induction treatment generate significantly more thrombin than patients on reinduction treatment. Our results show the sharp increase in ETP right after the infection with risk of DVT. Our data should be proved on larger group of patients. Disclosures: No relevant conflicts of interest to declare.

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