Coagulation Induced by Dilute Tissue Factor Depends More Critically on Factor II and X Concentration Than on FVII or FIX

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4084-4084
Author(s):  
Brynja R. Gudmundsdottir ◽  
Alexia M Bjornsdottir ◽  
Pall T. Onundarson
Keyword(s):  
Prothrombin Time ◽  
Vitamin K ◽  
Platelet Rich Plasma ◽  
Coagulation Factor ◽  
Maximum Velocity ◽  
Coagulation Factors ◽  
Factor X ◽  
Platelet Poor Plasma ◽  
Stabilization Phase ◽  
Maximum Clot Firmness

Abstract Prothrombin time based tests used to monitor coumarin anticoagulation measure the initiation phase of fibrin formation (clotting time, CT) in platelet poor plasma. Additional information can be obtained using computerized rotational thromboelastometry (ROTEM) which also measures the consequent propagation phase (measured as maximum velocity, Vmax), and the stabilization phase (maximum clot firmness, MCF). We used ROTEM to study the effect of individual vitamin K dependent (VK) coagulation factor (F) concentration on clotting induced by dilute thromboplastin in platelet poor and platelet rich plasma (PPP and PRP). As expected, FII, FVII and FX in PPP equally affected the prothrombin time whereas FIX did not. In PPP the ROTEM CT, however, was affected more by the concentration of FII and FX than by FVII (data not shown). To imitate physiological clotting better, factor deficient platelet poor plasma was repleted by adding frozen platelets in an optimal concentration corresponding to 100 × 109/L.. In the PRP the ROTEM CT was more dependent on the concentration of FII than of FVII, more dependent on FX than on FII and not dependent on FIX at all (left figure). The Vmax (reflecting the propagation phase) was also more dependent on FII and factor X than on the concentration of FVII or FIX which both may demonstrate a threshold effect (right figure). The stabilization phase or maximum clot firmness (MCF, not shown) was influenced similarly by FII and FX but was not influenced by FVII or FIX. Figure Figure Conclusion: During deficiency of vitamin K dependent coagulation factors the concentration of FII and FX may be more critical for hemostasis than FVII or FIX concentration. This may have practical implications for the appropriate choice of monitoring assays during coumarin administration.

Critical Role of Factors II and X During Coumarin Anticoagulation and Their Combined Measurement with a New Prothrombin Time Variant (Fiix-PT),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3354-3354
Author(s):  
Pall T. Onundarson ◽  
Brynja R. Gudmundsdottir ◽  
Charles W. Francis
Keyword(s):  
Prothrombin Time ◽  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Critical Role ◽  
Patent Application ◽  
Maximum Velocity ◽  
Coagulation Factors ◽  
Clot Formation ◽  
Normal Platelet ◽  
Anticoagulated Patients

Abstract Abstract 3354 Introduction: Vitamin K antagonists (VKA) are monitored with prothrombin time (PT) based assays that are equally sensitive to reductions in factors II, VII or X. However, previous studies suggest that the anticoagulant effect of VKA depends primarily on reductions in factors II and X and not VII. Aim and methods: We compared the effect of vitamin K dependent (VKD) coagulation factors on PT (Quick and Owren methods) and also on rotational thromboelastometric (ROTEM) parameters. The experiments used normal platelet poor plasma (PPP) and PPP selectively immunodepleted of individual VKD factors, with and without added platelet phospholipid or washed platelets. Results: The PT was equally sensitive to reductions in factors II, VII or X. However, ROTEM parameters correlated poorly with the PT in anticoagulated patients` plasmas. ROTEM experiments showed that the clotting time, maximum velocity of clot formation and the maximum clot firmness were more affected by reductions in FII or FX than by FVII or FIX concentrations which had little influence except at very low concentrations. We developed a modified PT that was sensitive only to reductions in factors II and X by using factor II and X (Fiix) depleted plasma in the PT system. The Fiix-PT (Fiix-INR) correlated well with PT (INR) but the Fiix-INR fluctuated less than the INR in anticoagulated patients reflecting its insensitivity to FVII. Conclusion: The ROTEM results suggest that mild to moderate reductions in factors II or X are more important in clot formation than factors VII or IX at therapeutically relevant factor concentrations. Reductions in FII and X may therefore better reflect anticoagulation with VKA than FVII or IX. FVII may be a confounding source of unwanted variation in PT-INR. The new Fiix-PT that is sensitive only to FII and FX may more accurately reflect the degree of therapeutic anticoagulation in patients treated with VKA than do the current PT assays which may overestimate the fluctuation in anticoagulation. Disclosures: Onundarson: See i. other: Patent application for Fiix method in process. Gudmundsdottir:Other, see i: patent applicaiton filed for Fiix method.

International Normalized Ratio Versus Plasma Levels of Coagulation Factors in Patients on Vitamin K Antagonist Therapy

2011 ◽  
Vol 135 (4) ◽  
pp. 490-494 ◽  
Author(s):  
Gene Gulati ◽  
Megan Hevelow ◽  
Melissa George ◽  
Eric Behling ◽  
Jamie Siegel
Keyword(s):  
Vitamin K ◽  
Warfarin Therapy ◽  
Clinical Laboratory ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
International Normalized Ratio ◽  
Activity Levels ◽  
Factor X ◽  
Life Threatening ◽  
Average Factor

Abstract Context.—The key question when managing patients on warfarin therapy who present with life-threatening bleeding is how to use the international normalized ratio (INR) to best direct corrective therapy. The corollary question for the clinical laboratory is at what level will the INR reflect a critical value that requires notifying the clinician. Objective.—To determine the levels of vitamin K–dependent factors over a range of INR values. Design.—Evaluation of the vitamin K–dependent coagulation factor levels on plasma remnants from patients in whom a prothrombin time and INR was ordered to monitor warfarin therapy. There were a total of 83 specimens evaluated with an INR range from 1.0 to 8.26. Results.—The mean activity levels of all 4 factors remained near or above 50% when the INR was less than 1.5. The average factor X level was 23% when the INR range was 1.6 to 2.5, but levels of factors II, VII, and IX did not drop below the hemostatic range until the INR was greater than 2.5. At an INR of 3.6 or more, the activity levels of all 4 factors were less than 30% in more than 90% of the specimens. Conclusion.—Levels of factors II, VII, IX, and X declined with increasing INR but not at the same rate and not to the same level at a given INR. However, most of the values were below the hemostatic value once the INR was 3.6 or more, the level that was also considered critical for physician notification.

scholarly journals INR and Vitamin K Dependent Coagulation Factor Fluctuation during Warfarin Initiation and Stable Therapy in Patients Dosed with the Fiix-Prothrombin Time or the Quick Prothrombin Time. the Fiix Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4278-4278 ◽  
Author(s):  
Brynja R. Gudmundsdottir ◽  
Petur I. Jonsson ◽  
Pall T. Onundarson
Keyword(s):  
Prothrombin Time ◽  
Vitamin K ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Target Range ◽  
Startup Company ◽  
Warfarin Treatment ◽  
Monitoring Group ◽  
Equity Ownership ◽  
Patent Applications

Abstract Introduction: The Quick prothrombin time (PT) is equally sensitive to the influence of factors (F) II, VII and X but experiments suggest that it is mainly the influence of warfarin on factors (F) II and X that cause its anticoagulant effect. The new Fiix prothrombin time (Fiix-PT) differs from the PT in it being sensitive only to factors (F) II and X and not being sensitive at all to FVII activity in the test plasma. The Fiix-trial has demonstrated increased stability of warfarin anticoagulation and possibly improved efficacy when monitored with Fiix-PT compared to PT monitoring (unpublished data). However, as very low levels of vitamin K dependent (VKD) factors not measured with the Fiix-PT could possibly have deleterious effect on anticoagulation (AC) outcome, we measured the VKD coagulation factors in plasma obtained from patients on stable warfarin anticoagulation and during the first 30 days of warfarin treatment monitored either with the Fiix-PT or the PT. Methods: In order to define stable anticoagulation in terms of coagulation factor activity, samples from patients enrolled in the Fiix trial and monitored either with Fiix-PT or PT were used. Frozen samples from 20 patients were obtained from each monitoring group. All the samples had been drawn from patients during very stable warfarin treatment (INR within range 2-3 for over 10 months by serial monitoring). Serial samples were also obtained from 10 patients in each group during days 1-30 of warfarin initiation. PT, Fiix-PT and VKD coagulation factors were measured. An INR was calculated for both PT and Fiix-PT. Results: During stable AC, the median INR (range) was 2.5 (2.1-3.0) in the Fiix-group vs 2.4 (2.0-3.0) in the PT group (p=ns). The median (95% range) VKD factor percent coagulant activity was as follows in the stable Fiix-group vs the stable PT-group: FII 28 (19-40) vs 25 (18-40), FVII 48 (30-88) vs 42 (23-85), FIX 66 (41-85) vs 61 (36-79), and FX 15 (11-17) vs 15 (10-22). Although the medians tended to be higher in the Fiix group except for FX, p was n.s. for all. In patients starting on warfarin a stable Fiix-INR (defined as two INRs within target range) was reached on day 14 (median) in the Fiix group vs a stable PT-INR on day 11 in the PT controls. Following this, however, the PT-INR fluctuates more out of the INR target range than the Fiix-INR does. As shown in the figures, the earlier rise in INR in the PT group is mainly a reflection of a rapid fall in FVII activity. The FVII level decreases to a nadir of 20% in the Fiix group compared to a nadir of 30% in the PT monitoring group. Subsequently FII, FVII and FX fluctuate less in the Fiix-PT group than in the PT group. During the first 30 days 46% of Fiix-INRs in the Fiix-group were within target range vs 29% of INRs in the controls (p=0.06). Also during the initiation period FII was 47% vs. 30% within the 95% stable range established for the PT method (p=0.06), FVII 60% vs. 73% (p=0.13), FIX 41% vs 36% (p=0.69), and FX 51% vs 38% (p=0.20), respectively. The more fluctuating INR in the PT group is also reflected by a rollercoaster like pattern of warfarin dosing as opposed to the more cascade like pattern that is observed in the Fiix group. Figure 1 Figure 1. Figure 2 Figure 2. Conclusion: During stable warfarin AC VKD factors are similarly reduced with Fiix-PT or PT monitoring.During initiation of warfarin monitored with the Fiix-PT, FVII decreases initially more than with PT monitoring but subsequently stabilizes and fluctuates less. Fiix-PT leads to smoother reduction in FII and X which stabilize faster than during PT monitoring. The smoother anticoagulant effect is also reflected by the warfarin dose pattern during initiation. The results may suggest that the Quick-PT confounds warfarin management during initiation and dose changes. Disclosures Gudmundsdottir: Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties. Onundarson:Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties.

USE OF ALBUMIN AND TWEEN AS STABILIZERS TO PREVENT ACTIVITY LOSS DURING CLOTTING ASSAYS OF COAGULATION FACTOR IX AND X CONCENTRATES

1987 ◽  
Author(s):  
Shirley I Miekka
Keyword(s):  
Vitamin K ◽  
Surface Adsorption ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Test Tube ◽  
Factor Ix ◽  
Tween 20 ◽  
Factor X ◽  
Bovine Albumin ◽  
Activity Loss

Assays for clotting activities of Vitamin K-dependent coagulation factors in Factor IX complex concentrates are IcnovTn to give variable results depending on the composition of the sample diluent. Higher potency values are obtained when deficient plasma is used for sample pre-dilution compared with dilution in buffer. This discrepancy is more pronounced in assays of higher purity Factor IX (FIX) or Factor X (FX) concentrates. We have found that addition of a mixture of bovine albumin (0.1% w/v) and Tween 20 (0.01% v/v) (BAT) to the dilution buffer can eliminate the discrepancy, giving clotting times and plot slopes equal to chose obtained upon dilution in deficient plasma. Less protection was obtained with either albumin or Tween added separately. Polyethylene glycol 8000 (0.1% w/v), commonly used to stabilize thrombin solutions, gave variable results. BAT had no effect on clotting times of whole plasma or of FIX or FX samples pre-diluted in deficient plasma. Neither deficient plasma nor BAT had any effect when added after sample dilutions were prepared: activity of a FIX concentrate was 137 U/ml when pre-diluted in Factor IX-deficient plasma and 1312 U/ml diluted in BAT, compared with 49 U/ml diluted in buffer alcne; addition of deficient plasma or BAT to the dilutions of sample in buffer gave activities of only 36 a).id 34 U/ml, respectively. Similar results were obtained with FX samples. Furthermore, when a solution of FX (pre-diluted to 1 U/ml in buffer without stabilizer) was merely transferred from one test tube to another without further dilution, clotting times increased progressively and activity decreased by 85% after 8 transfers. By contrast, an identical sample diluted to 1 U/ml with BAT remained essentially unchanged after 8 serial transfers. These results indicate that Vitamin K-dependent coagulation factors are very susceptible to surface adsorption or inactivation after dilution of concentrates, and that either BAT or deficient plasma will prevent this loss. The use of albumin and Tween as stabilizers provides a simpler, .less expensive alternative to prevent nonspecific surface adsorption and achieve more accurate measurement of clotting activities.

Increased Activity of Vitamin K-Dependent Clotting Factors in Human Hyperlipoproteinaemia – Association with Cholesterol and Triglyceride Levels

1977 ◽  
Vol 38 (02) ◽  
pp. 0465-0474 ◽  
Author(s):  
M Constantino ◽  
C Merskey ◽  
D. J Kudzma ◽  
M. B Zucker
Keyword(s):  
Vitamin K ◽  
Plasma Lipids ◽  
Coagulation Factors ◽  
Clotting Factor ◽  
Factor X ◽  
Clotting Factors ◽  
Blood Coagulation Factors ◽  
Cholesterol Levels ◽  
Type V ◽  
Increased Activity

SummaryLevels of blood coagulation factors, cholesterol and triglyceride were measured in human plasma. Prothrombin was significantly elevated in type Ha hyperlipidaemia; prothrombin and factors VII, IX and X in type lib; and prothrombin and factors VII and IX in type V. Multiple regression analysis showed significant correlation between the levels of these plasma lipids and the vitamin K-dependent clotting factors (prothrombin, factors VII, IX and X). Higher cholesterol levels were associated with higher levels of prothrombin and factor X while higher triglyceride levels were associated with higher levels of these as well as factors VII and IX. Prothrombin showed a significant cholesterol-triglyceride interaction in that higher cholesterol levels were associated with higher prothrombin levels at all levels of triglyceride, with the most marked effects in subjects with higher triglyceride levels. Higher prothrombin levels were noted in subjects with high or moderately elevated (but not low) cholesterol levels. Ultracentrifugation of plasma in a density of 1.21 showed activity for prothrombin and factors VII and X only in the lipoprotein-free subnatant fraction. Thus, a true increase in clotting factor protein was probably present. The significance of the correlation between levels of vitamin K-dependent clotting factors and plasma lipids remains to be determined.

ABNORMALITIES OF PLATELET AGGREGATION AND ENHANCED FACTOR X ACTIVATOR ACTIVITY OF WASHED PLATELETS IN SICKLE CELL DISEASE

1987 ◽  
Author(s):  
D A F Chamone ◽  
A Y Hoshikawa-Fujimura ◽  
C Massumoto ◽  
G Bellotti ◽  
F Arashiro ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Endothelium ◽  
Platelet Rich Plasma ◽  
Coagulation Factors ◽  
Factor X ◽  
Cell Disease ◽  
Normal Volunteers ◽  
Pathologic Features

The occurence of microvascular occlusion is one of the most prominent pathologic features of sickle cell anemia. The mechanism of vaso occlusion has generally been attributed to the abnormal shape and reduced deformability of the sickled erithrocy tes. However, the involvement of vascular endothelium, platelets and their interactions with coagulation factors may also be of pathogenic significance in microvascular occlusive crises.We investigated the interaction between vascular endothelium, platelets and blood coagulation factors in 23 patients with Sickle Cell Disease (SCD) and in normal volunteers.Factor X activator activity in washed platelets was performed according to Semeraro and Vermylen (1977), thromboxane B2 (TXB2) and 6-keto-PGF1β were determined using specific radioimmunoassays.. PAF-acether from platelets was determined according to Chignard et al (Nature, 1979, 279:799). Platelet aggregation was performed with a Chrono-Log Aggregometer (Model 440) on platelet rich plasma (PRP) using the Born method. Prostacyclin release from endothelium was performed according to Mon-cada et al (Lancet i:18, 1977).Our results showed that platelets from patients with SCD ha ve enhanced factor X activator activity (p < 0.0001), produce mo re PAF-acether than controls (p < 0.02) and showed hyperaggregability in these patients as compared to normal volunteers (p < 0.00001).We concluded that platelets from homozygous sicklers have enhanced factor X activator activity as well as increased capacity for PAF-acether production. These abnormalities may contribute to the incidence of vaso occlusive crises in these patients.

scholarly journals Reduction of salivary tissue factor (thromboplastin) activity by warfarin therapy

Blood ◽  
1979 ◽  
Vol 53 (3) ◽  
pp. 366-374 ◽  
Author(s):  
LR Zacharski ◽  
R Rosenstein
Keyword(s):  
Tissue Factor ◽  
Vitamin K ◽  
Coagulation Factors ◽  
Human Saliva ◽  
Factor Vii ◽  
Clotting Factor ◽  
Activate Factor ◽  
Total Protein Content ◽  
Factor X ◽  
Clotting Factors

Abstract The coagulant of normal human saliva has been identified as tissue factor (thromboplastin, TF) by virtue of its ability to cause rapid coagulation in plasmas deficient in first-stage coagulation factors and to activate factor x in the presence of factor VII and by virtue of the fact that its activity is expressed only in the presence of factor VII and is inhibited by an antibody to TF. The TF is related to cells and cell fragments in saliva. Salivary TF activity has been found to be significantly reduced in patients taking warfarin. The decline in TF activity during induction of warfarin anticoagulation occurs during the warfarin-induced decline in vitamin-K-dependent clotting factor activity, as judged by the prothrombin time. The decrease in TF activity is not related to a reduction in salivary cell count or total protein content or to a direct effect of warfarin on the assay. It is hypothesized that the mechanism by which warfarin inhibits TF activity may be related to the mechanism by which it inhibits expression of the activity of the vitamin-K-dependent clotting factors. Inhibition of the TF activity may be involved in the antithrombotic effect of warfarin.

scholarly journals Dose-dependent antithrombotic effect of warfarin in rabbits

Blood ◽  
1983 ◽  
Vol 61 (3) ◽  
pp. 435-438 ◽  
Author(s):  
SN Gitel ◽  
S Wessler
Keyword(s):  
Vitamin K ◽  
Coagulation Factors ◽  
Progressive Increase ◽  
Drug Dose ◽  
Mean Value ◽  
Factor X ◽  
Antithrombotic Effect ◽  
Tissue Thromboplastin ◽  
Dose Dependent Decrease ◽  
Dose Dependent

Abstract One-hundred and fifty-one rabbits, divided into controls and animals treated with varying daily doses of warfarin, were subjected to the stasis assay, and the amount of thrombosis quantitated after intravascular coagulation was initiated either by activated factor X or tissue thromboplastin. Following 8–10 days of warfarin administration, there was a significant dose-dependent decrease in the vitamin-K- dependent coagulation factors paralleled by an increase in the prothrombin time ratio. Whether thrombosis was initiated by activated factor X or tissue thromboplastin, there was, with increasing drug dose, a progressive increase in the inhibition of stasis thrombosis. This significant antithrombotic effect occurred even when the vitamin-K- dependent coagulation activities were at a mean value of 50%.

Genetic Polymorphism of Factor IX Gene in Greek Patients with Thrombophilia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4121-4121
Author(s):  
Pantelis P.E. Makris ◽  
Michel M. Iskas ◽  
Rigini R. Papi ◽  
Dimitrios D.K. Kiriakidis
Keyword(s):  
Vitamin K ◽  
Polyacrylamide Gel Electrophoresis ◽  
Control Sample ◽  
Coagulation Factor ◽  
Factor Ix ◽  
University Hospital ◽  
Activate Factor ◽  
Factor X ◽  
Coagulation Factor Ix ◽  
Pcr Products

Abstract Introduction. Coagulation factor IX plays an important intermediate role in the activation of blood coagulation. It is located within the blood plasma as a zymogen, in its inactivated state. Factor IX is dependent on the presence of Vitamin K. The structure of factor IX closely resembles the structures of many other Vitamin K dependent plasma proteins, such as prothrombin, factor X and protein C. After being activated, Factor IX forms a complex with calcium ions, membrane phospholipids and coagulation factor VIIIa to activate factor X. The exact locus of the coagulation factor IX gene was found to exist in the Xq26-q27 region of the X chromosome. The FIX gene spans 34 kb and contains eight exons. Over 300 different mutations have been identified in the FIX gene, all of which result in the production of inactive FIX, causing hemophilia B. Aim. In this study we searched for mutations in the FIX gene which result in an increased activity of FIX thus being the cause of thrombophilia syndromes. Material: A total of 108 individuals from unrelated families were involved in this study, presenting thrombophilic syndromes. A control sample from a healthy non-thrombophilic individual was also used. Total DNA from the above individuals was supplied to us by the Haemostasis and Thrombosis Unit of AHEPA University Hospital, Thessaloniki, Greece. According to HAT (Heparin Antithrombin Test, Makris, Van Dreden 1998) method a mixture of human antithrombin and heparin is added in the plasma and partial thromboplastin time is estimated. 97% of normal individuals exhibit prolonged time values in this test, whereas in our patients the time was significantly reduced. However, after the addition of recombined human FIX (rhFIX) in the mixture, prolongation of PTT is noted. Methods: The promoter region and the eight exons of the FIX gene were amplified by PCR using seven labelled primer pairs specific for these regions, that were described previously in literature. The amplification reactions were performed in a MJ Research P200 thermal cycler while the Tm of each primer pair was optimised as shown in the table. PCR products were analyzed using LI-COR DNA analyzer which is based on fragment separation by polyacrylamide gel electrophoresis. With this method PCR products presenting up to a 1 bp difference in their molecular weight create distinct bands on the gel and thus an insertion, or deletion of a base can be detected. However, no such differentiation was present among the samples examined. Assuming that the potential mutations could involve point mutations and thus be undetectable by the above method, the samples were sequenced and compared with the control. Sequencing the promoter and the 8 exons sites of the FIX gene of the most high risk cases. A point mutation was detected in four of the samples. The mutation was a single base change (ACT →GCT) located at the 21975 bp of the FIX gene, in exon 6. This mutation causes a significant change, replacing the Thr194 residue with an Ala residue (T194A). The sequencing pattern of one of these patients and the control is shown in the figure. Figure Figure

Immunoaffinity purification of factor IX from commercial concentrates and infusion studies in animals

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1269-1277
Author(s):  
KJ Smith
Keyword(s):  
Replacement Therapy ◽  
Vitamin K ◽  
Disease Transmission ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Ix ◽  
Heat Treated ◽  
Coagulation Factor Concentrates ◽  
Risk Of Disease ◽  
Factor Ix Deficiency

Thrombosis and transmission of viral diseases are the principal adverse effects of current replacement therapy for factor IX deficiency when using heat-treated concentrates of vitamin K-dependent coagulation factors. More highly purified factor IX preparations could decrease the risk of disease transmission, reduce patient exposure to allogeneic proteins, and reduce the risk of thrombosis. In this study, two immunoaffinity-purified factor IX preparations from commercial vitamin K-dependent coagulation factor concentrates had specific activities of 134 and 155 U/mg. Crude concentrates and purified factor IX preparations were tested for thrombogenicity in rabbits. One of two crude concentrates tested in the stasis-thrombosis assay caused large thrombi at doses of 50 U/kg. Purified factor IX from this concentrate was not thrombogenic at 106 to 234 U/kg. A heparin-treated concentrate that was not active in the stasis model at 100 U/kg caused significant (P less than .05) delayed consumption of rabbit fibrinogen, platelets, antithrombin III antigen, and factor VIII activity at the same dose. Factor IX prepared from this concentrate caused no consumption of coagulation factors at 214 to 243 U/kg despite the presence of trace amounts of activated factor IX. These results indicate that more highly purified preparations could reduce the risk of thrombosis in replacement therapy for hemophilia B. Also, at least for the preparations tested, factor IX and factor IXa were not the thrombogenic components of the crude concentrates.

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