The Inhibitor of Prothrombin Conversion in Plasma of Patients on Oral Anticoagulant Treatment

1981 ◽  
Vol 45 (03) ◽  
pp. 237-241 ◽  
Author(s):  
R M Bertina ◽  
M E J Westhoek-Kuipers ◽  
G H J Alderkamp
Keyword(s):  
Vitamin K ◽  
Spectrophotometric Assay ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X ◽  
Dilution Curve ◽  
Anticoagulant Treatment ◽  
Oral Anticoagulant Treatment ◽  
Coagulation Assays ◽  
Factor Ii

SummaryPooled plasma of patients under stable oral anticoagulation has been analysed with respect to the presence of the vitamin-K dependent factors (factors II, VII, IX and X). Of all factors 1.5-2 times more antigen than procoagulant activity was present. The concentration of factors II, X (measured spectrophotometrically) and VII is about 0.25 U/ml while factor IX is slightly higher. Coagulation assays of factor X always gave lower values than the spectrophotometric assay. This discrepancy was not influenced by the removal of either factor II-factor VII- or factor IX antigen. However, when the factor X antigen was replaced by normal factor X, all factor X assays gave identical results, indicating that PIVKA X is responsible for these discrepancies. Using the technic of the Thrombotest-dilution curve it was shown that PIVKA X is the factor that causes the abnormal prolongation of ox-brain prothrombin time in these plasmas.

PROTEIN C RESPONSE TO INDUCTION AND WITHDRAWAL OF ORAL ANTICOAGULANT TREATMENT

1987 ◽  
Author(s):  
K P Schofield ◽  
J M Thomson ◽  
L Poller
Keyword(s):  
Oral Anticoagulant ◽  
Protein C ◽  
Oral Anticoagulants ◽  
Factor Vii ◽  
Factor X ◽  
Anticoagulant Treatment ◽  
Oral Anticoagulant Treatment ◽  
Rate Of Increase ◽  
Long Term Treatment

Protein C (PC) activity and antigen levels have been related to clotting activities of factors VII and X during the induction and withdrawal periods of oral anticoagulant treatment. Both factor VII and PC activities fell rapidly during a gradual induction regime of nicoumalone in six consecutive patients but factor VII showed a more rapid and much more marked depression than PC. In contrast reductions in factor X were much slower. PC antigen although depressed rapidly at the initiation of treatment did not subsequently fall to the same degree as PC activity, The ratio of activity to antigen became progressively smaller.In six further serial patients discontinued from long-term treatment with nicoumalone (mean duration 12-6 months) there was a reversal of the pattern, but with two important differences. Firstly, there was evidence of an excessive rise (“rebound”) of factor VII compared with the steady state levels in these patients; and secondly there was an unexpectedly slow return of PC activity and antigen to normal levels after the oral anticoagulant was withdrawn (levels were still below normal on day 4). Factor X also showed a slow rate of increase, similar to PC activity recovery. These observations lend support to gradual withdrawal of oral anticoagulants after a period of long-term administration. The results suggest that after discontinuation of long-term oral anticoagulants patients may have increased coagulability up to four days.

ACUTE INTERRUPTION OF ORAL ANTICOAGULANT THERAPY: A THROMBOTIC RISK?

1987 ◽  
Author(s):  
J Rouvier ◽  
H Vidal ◽  
J Gallino ◽  
M Boccia ◽  
A Scazziota ◽  
...  
Keyword(s):  
Anticoagulant Therapy ◽  
Vitamin K ◽  
Oral Anticoagulant ◽  
Protein C ◽  
Oral Anticoagulant Therapy ◽  
Factor Vii ◽  
Factor X ◽  
Functional Protein ◽  
Thrombotic Risk ◽  
Factor Ii

It is still on discussion how oral anticoagulant therapy must be interrupted. A progressive diminution of drug intake have been proposed in order to avoid a MreboundM of vitamin K-dependent procoagulant factors. At the present, it is well known that coumarin drugs affect not only the biologic activity of factors II, VII, IX and X but also Protein C (PC), an inhibitor of coagulation kinetics, and their cofactor Protein S. With the aim to determine the recovery level of PC in relation with the others vitamin K-dependent factors, the effect of suppression of anticoagulant therapy in patients under chronic treatment with acenocoumarin was studied.Quick time, functional factors II, VII, X (one stage methods), functional PC (Francis method) and immunological Factor II and Protein C (Laurell) were determined before and 36 hours after suspension of acenocoumarin administration.Results showed that: 1) Recovery levels of functional Protein C (increased from 28.55% ±2.57 to 72.64% ±5.9) were significantly higer than functional Factor II (22.09% ±2.34 to 30.73% ±8.64), Factor VII (22.55% ±2.01 to 40.73% ±4.85) and Factor X (23.27% ±2.66 to 39.18% ±3.19). Statistical analysis (Newmann-Keuls test) showed at least a p<0.01 between PC increase and factors II, VII or X increment.2) No significant differences were seen between immunological levels of Factor II before and after suspension of acenocoumarin.3) Levels of immunological PC in patients under anticoagulant therapy were higer than functional PC. After acenocoumarin suppression, not correlation was seen between immunological and functional Protein C recovery.It is concluded that acute suppression of acenocoumarin does not induce a thrombotic tendency because the recuperation of functional Protein C is more important than factors II, VII and X recovery.

ANTICOAGULANT AND ANTIGENIC LEVELS OF PROTEIN C AND PROTEIN S IN PATIENTS ON STABILIZED ORAL ANTICOAGULANT TREATMENT

1987 ◽  
Author(s):  
A D'Angelo ◽  
F Gilardoni ◽  
M P Seveso ◽  
P Poli ◽  
R Quintavalle ◽  
...  
Keyword(s):  
Vitamin K ◽  
Oral Anticoagulant ◽  
Protein C ◽  
Protein S ◽  
Reference Interval ◽  
Factor Ix ◽  
Activity Levels ◽  
Anticoagulant Treatment ◽  
Oral Anticoagulant Treatment ◽  
Congenital Deficiency

Isolated deficiencies of protein C and protein S, two vitamin K-dependent plasma proteins, constitute about 70% of the congenital abnormalities of blood coagulation observed in patients with recurrent venous thrombosis beLow the age of 40. The laboratory diagnosis of congenital deficiency of these proteins represents a major problem since a large proportion of patients are on oral anticoagulation (OA) at the time the deficiencies are suspected.Under these circumstances the availability of a reference interval obtained in patients on stabilized OA has proven useful.Functional (C) and antigenic levels (Ag) of protein C, protein S, factor IX and II were estimated in 136 patients on stabilized OA, subdivided according to the degree of anticoagulation (Internatio nal Normalized Ratio, INR).The results indicate that with increasing anticoagulation the activity levels of all the vitamin K-dependent factors decrease to a greater extent than the corresponding antigenic levels. At variance with the other factors, total protein S antigen levels are only moderately reduced by OA with protein S anticoagulant activi ty comparing well to factor IX clotting activity. These data suggest the possibility of identifying both quantitative and qualita tive deficiencies of protein C and protein S in patients on oral anticoagulant treatment.

DEFECTS OF VITAMIN K-DEPENDENT FACTORS IN CA(11)-STABILI ZED STRUCTURE

1987 ◽  
Author(s):  
S R Poort ◽  
C Krommenhoek-van Es ◽  
I K van der Linden ◽  
N H van Tilburg ◽  
R M Bertina
Keyword(s):  
Vitamin K ◽  
Genetic Variants ◽  
Protein C ◽  
Conformational Transition ◽  
Oral Anticoagulants ◽  
Indirect Evidence ◽  
Coagulation Factors ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor Ii

Vitamin K-dependent (anti)coagulation factors (factor II, VII, IX, X protein C and S) undergo a conformational transition upon binding of Ca(II), which is a prerequisite for their normal function. Abnormalities in these properties occur during vitamin K deficiency or treatment with anti vitamin K drugs and in some genetic variants of coagulation factors. Immunological assays utilizing antibodies against the Ca(II)-stabilized structure are useful to detect such abnormalities.Starting from specific rabbit antisera antibody populations specific for the Ca(II)-dependent conformation of factor II, VII, IX, X and protein C and S were isolated using immuno-affinity procedures. Subsequently immunoradiometric assays specific for the Ca(II)-dependent (Ca(II)Ag) and Ca(II)-independent (NonCa(II)Ag) conformations of the different proteins were developed. These assays were used for the analysis of plasmas of patients stably treated with oral anticoagulants; Ca(II)Ag, NonCa(II)Ag and their ratio were measured as function of the intensity of the treatment (INR 2.4 to 4.8). The same parameters were measured in plasmas of patients with hereditary coagulation disorders. After treatment with oral anticoagulation with an antivitamin K drug reduced ratios of Ca(II)Ag/-NonCa(II)Ag were observed for factor II, VII, IX, protein C and protein S. However, the actual degree of reduction and its dependence on the intensity of treatment varied for the different vitamin K-dependent proteins. In general Ca(II)Ag levels correspond nicely with the procoagulant activity of the concerning proteins. These data provide indirect evidence for the existence of abnormal (non and/or subcarboxylated) forms of the vitamin K-dependent proteins during oral anticoagulant treatment.Genetic variants with a mutation in one of the sites involved in the formation of the Ca(II)-s tab i1ized structure could be detected for factor IX, factor VII and factor II. However, the extent of reduction of the ratio Ca(II)Ag/-NonCa(II)Ag differed considerably in those variants.

Intrauterine Subdural Hemorrhage Associated with Profound Deficiency of the Vitamin K Dependent Clotting Factors in an Infant Homozygous for a Common Polymorphism in the Vitamin K Epoxide Reductase Complex 1 (VKORC1) Promoter.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2152-2152
Author(s):  
Nadav Schwartz ◽  
Johannes Oldenburg ◽  
David Hart ◽  
Michael Nardi ◽  
Ori Langer Most ◽  
...  
Keyword(s):  
Vitamin K ◽  
Gestational Age ◽  
Subdural Hematoma ◽  
Factor Ix ◽  
Factor Vii ◽  
Dietary Vitamin ◽  
Subdural Hemorrhage ◽  
Factor X ◽  
Clotting Factors ◽  
Complete Sequencing

Abstract Hemorrhage in newborn infants who have not received vitamin K supplementation is a well recognized entity, but hemorrhage occurring prenatally due to deficiency of the vitamin K dependent factors is not. We report a subdural hemorrhage in a fetus at 29 weeks of gestation associated with very low levels of vitamin K dependent factors. The pregnancy was monitored by periodic ultrasound because of a previous near term stillbirth to this mother for which no etiology was identified. At 29 weeks a 4.6 × 7.7 × 8.8 cm left subdural hematoma was detected. There is no history of bleeding in this Hispanic family and no known consanguinity. His mother was not taking coumadin or any other medication, and her coagulation studies were normal. The baby was delivered by cesarean section, blood drawn for coagulation studies and 1mg Vitamin K given intramuscularly. The baby oozed from the injection and venipuncture sites. The hematocrit was 19% (mean for gestational age = 40.88) and packed red blood cells were given followed by fresh frozen plasma (10ml/kg). Platelets were 284,000/cmm. At six hours of life coagulation studies were greatly improved, the factor levels now being in the normal range for 29 weeks gestational age. Results at birth, 6 hours and 6 months are shown in the table. At 6 hours the baby no longer oozed from venipuncture sites. He received 1mg vitamin K daily for 3 days and no further supplementation thereafter other than that contained in infant formula. The subdural hematoma was drained on day 1 of life. Growth and development at 20 months are normal. Complete sequencing of the VKORC1 gene showed a homozygous functional promoter polymorphism: VKORC1:c.[1–1639&gt;A]+[1–1639&gt;A] (VKORC1*2/*2). This A allele is associated with 25% less VKORC1 expression and protein (50% less for homozygotes) compared to the G allele. Complete sequencing of the gamma-glutamyl carboxylase gene revealed no functional abnormalities. Individuals homozygous for this VKORC1 polymorphism have a relatively low capacity to regenerate reduced vitamin K and should require more vitamin K intake than others. They are known to require less warfarin. We hypothesize that insufficient vitamin K was available in utero to this fetus to compensate for the relatively low reductase level, and he became severely factor deficient. In the extra uterine environment sufficient dietary vitamin K was available to compensate for his relatively low reductase level. It is possible that the previous unexplained stillbirth was due to hemorrhage because of a similar factor deficiency. A reason for an intrauterine paucity of vitamin K has not been determined but must be rare as 17% of Europeans and a larger number of Chinese are homozygous VKORC1*2/*2, and intrauterine hemorrhage due to this cause is not reported. Birth 6 hours 6 months Values in parentheses are ELISA assays. Other assays are functional. nd = not done PT (sec) &gt;120 17.6 13.7 PTT (sec) 176 50.3 35.2 Fibrinogen (mg/dL) 194 196 287 % Factor II 1 39 96 % Factor V 81 nd 116 % Factor VII 3 61 99 % Factor IX 1 nd 108 % Factor X 2 (33) nd 107 % Protein C &lt;1 (18) 27 nd

Factor IX Complex Linked to Disseminated Intravascular Coagulation in Patients with Cirrhosis: A Single Center Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2286-2286
Author(s):  
Maitri Kalra ◽  
Ashish Aggarwal ◽  
Vikas Kalra ◽  
Laura Caragol ◽  
Marwan Ghabril ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Liver Disease ◽  
Meld Score ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X ◽  
Post Dose ◽  
Decompensated Liver Cirrhosis ◽  
Factor Ii ◽  
Higher Doses

Abstract Background: Decompensated cirrhosis is associated with both bleeding and thrombotic complications. These patients, especially those undergoing liver transplant evaluations, often receive multiple blood products for correction of coagulopathy prior to invasive procedures or in the setting of acute bleeding. Profilnine SD, a non-activated purified Factor IX Complex containing Factor IX, Factor II, Factor X, and low levels of Factor VII is often used off-label in these patients to promote hemostasis. However, its safety in this clinical setting is not well known. Aim: To evaluate safety of Factor IX complex use in patients with decompensated liver cirrhosis. Methods: This is a retrospective study that included all patients who were hospitalized in a tertiary care liver transplant center and received Factor IX complex (Profilnine SD) between November 2011 and October 2013. Demographic, clinical, laboratory, procedural and outcome data were collected from manual review of electronic medical records. The primary endpoint of our study was to determine the safety of Factor IX complex in decompensated cirrhotic patients. Disseminated Intravascular Coagulation (DIC) was diagnosed based upon ISTH criteria and included a constellation of laboratory markers in the appropriate clinical setting. SPSS software was used for data analysis. Results: 69 doses of Factor IX complex were given to 41 patients with decompensated liver cirrhosis on 43 occasions. Mean age was 53.5 +/- 13.5 years (54% females, 76% Caucasians), weight was 88 +/- 25 kg and mean BMI was 29.8 +/- 7.7. Mean MELD score was 32 +/- 9 and 95% patients had Child Pugh Class C cirrhosis. Median follow up was 43 days (IQR 8, 150). Mean dose of Factor IX complex was 3269 Units +/- 3055 Units. Most common etiologies of liver cirrhosis included alcoholic liver disease (19.5%), Hepatitis C (17%), non-alcoholic fatty liver disease (17%), combined Hepatitis C and alcohol liver disease (24.4%) and others (21.6%). Five patients (12.2%) had Hepatocellular cancer. Common indications for the use of Profilnine included bleeding (33.8%), prior to catheter placement (dialysis or cardiac catheterization, 20.6% ), paracentesis or thoracentesis (13.2%), and others including endoscopic procedures (26.5%). Mean prothrombin time (PT) was 33.4+/- 15.2 s before Factor IX complex infusion as compared 34.9 +/- 32.4 s after Factor IX complex infusion, (p=0.001). Mean pre dose partial thromboplastin time (PTT) was 68.7 +/-33s and mean post dose PTT was 62.7+/- 56.5, (p=0.002). Mean pre dose hemoglobin (Hgb) was 8.2+/- 1.4 gm/dL and post dose Hgb was 7.1+/- 1.3 gm/dL, (p=0.001). Eight patients (18.6%) developed DIC related complications likely related to Factor IX complex use, based upon clinical and laboratory data. Patients developing DIC complications had received significantly higher doses of Factor IX complex (mean 6601 +/- 4591 units vs. 2507 +/- 1995 units, p= 0.04), had higher MELD score (mean MELD 37 +/- 5.7 vs. 30 +/- 8.2, p = 0.03). Development of complication did not depend upon age, gender, presence of HCC, indication of the procedure, or pre procedure laboratory variables including platelet count, Hemoglobin, PT, PTT or INR. Patients who developed DIC also required more transfusions of platelets (4.4 vs. 1.8, p=0.014), cryoprecipitate (9.6 vs. 2.4, p=0.008) and fresh frozen plasma (12.5 vs. 4.5, p=0.008). Seven out of eight patients who developed DIC died and five of them (62.5%) died within 10 days of Factor IX complex administration. In contrast, out of the 33 patients who did not develop DIC, 7 (21.2%) died within 10 days of receiving Factor IX complex (p=0.02). Conclusions: DIC is a serious but under-recognized complication of Factor IX complex use in patients with decompensated liver cirrhosis, affecting 18% of patients. Risk increases with higher doses of the Factor IX complex. Thus its use in decompensated liver cirrhosis can lead to serious outcomes, as compared to Factor IX complex use to reverse warfarin overdose in patients with intracranial hemorrhage where it has a better safety profile. Awareness regarding the use of this product in patients with liver failure and its potential for serious side effects should be evaluated further. Disclosures Off Label Use: Factor IX Complex, Profilnine® SD, Solvent Detergent Treated, is a sterile, lyophilized concentrate of Factor IX (antihemophilic factor B), Factor II (prothrombin), Factor X (Stuart-Prower Factor), and low levels of Factor VII (proconvertin) derived from human plasma. Factor IX Complex, Profilnine SD is indicated for the prevention and control of bleeding in patients with Factor IX deficiency due to hemophilia B.

Structure of the Human Factor VII Gene

1987 ◽  
Author(s):  
Patrick J O'hara ◽  
Frank A Grant ◽  
A Betty ◽  
J Haldmen ◽  
Mark J Murray
Keyword(s):  
Serine Protease ◽  
Vitamin K ◽  
Protein C ◽  
Tandem Repeats ◽  
Human Factor ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X ◽  
X Protein ◽  
Additional Exon

Factor VII is a member of a family of vitamin K-dependent, gamma-carboxylated plasma protein which includes factor IX, factor X, protein C, protein S and prothrombin. Activated factor VII (factor Vila) is a plasma serine protease which participates in a cascade of reactions leading to the coagulation of blood. Two overlapping genomic clones containing sequences encoding human factor VII were isolated and characterized. The complete sequence of the gene was determined and found to span 12.8 kilobases. The mRNA for factor VII as demonstrated by cDNA cloning is polyadenylated at multiple sites but contains only one AAUAAA poly-A signal sequence. The mRNA can undergo alternative splicing forming one transcript containing eight segments as exons and another with an additional exon which encodes a larger pre-pro leader sequence. The portion of the pre-pro leader coded for by the additional exon has no known counterpart in the other vitamin K-dependent proteins. The positions of the introns with respect to the amino acid sequence encoded by the eight essential exons of factor VII are the same as those present in factor IX, factor X, protein C and the first three exons of prothrombin. These exons code for domains generally conserved among members of this gene family, including a pre-pro leader (the essential exon la and alternative exon lb), a gamma-carboxylated domain (exons 2 and 3) a growth factor domain (exons 4 and 5) an activation region (exon 6) and a serine protease (exon 8). The corresponding introns in these genes are dissimilar with respect to size and sequence, with the exception of the third intron in factor VII and protein C. Four introns and a portion of exon 8 in factor VII contain regions made up of tandem repeats of oligonucleotide monomer elements. More than a quarter of the intron sequences and more than a third of the 3' untranslated portion of the mRNA transcript consist of these minisatellite tandem repeats. This type of structure is responsible for polymorphisms due to allelic variation in repeat copy number in other areas of the human genome. Tandem repeats can evolve as a result of random crossover in DNA whose sequence is not maintained by selection. This suggests that much of the sequence information present in the introns and untranslated portion of the message is dispensable.

scholarly journals A High Factor II/Factor X Functional Ratio Is Not a Useful Predictor of the FII G20210A Gene Mutation in Thromboembolic Patients Undergoing Oral Anticoagulant Treatment

2000 ◽  
Vol 46 (6) ◽  
pp. 886-887
Author(s):  
Angel José González Ordóñez ◽  
José Manuel Fernández Carreira ◽  
María Victoria Alvarez ◽  
Leoncio Martín Sánchez ◽  
Jesús María Medina Rodríguez ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Oral Anticoagulant ◽  
Factor X ◽  
Anticoagulant Treatment ◽  
Oral Anticoagulant Treatment ◽  
Factor Ii

CLOTTING FACTOR DEPENDENCY OF PROTHROMBINASE ACTIVITY IN DICOUMAROL PLASMA. THE IMPORTANCE OF A FACTOR IX DEPENDENT PATHWAY IN EXTRINSIC COAGULATION

1987 ◽  
Author(s):  
Ma Xi ◽  
S Béguin ◽  
H C Hemker ◽  
P P Devilée
Keyword(s):  
Thrombin Generation ◽  
Factor Ix ◽  
Factor Vii ◽  
Coagulation System ◽  
Clotting Factor ◽  
Factor X ◽  
Oral Anticoagulant Treatment ◽  
Anticoagulated Patients ◽  
Dependent Pathway ◽  
Prothrombinase Activity

We determined the generation of prothrombinase activity in plasma using a mathematical analysis of the thrombin generation curve (H. C. Hemker, G. M. Willems, S. Béguin. Thromb. Haemostas. 56, 9-17, 1986).Addition of the purified factor VII, IX or X to plasma from deeply anticoagulated patients (<15% level >10%) did not influence the rate and amount of prothrombinase formed. Only the amount of prothrombin in the starting plasma determined the course of thrombin generation. Adding increasing amounts of purified human clotting factor preparations to deficient plasmas showed that the treshold concentration under which factor VII, and IX start to have an effect on prothrombinase activity are 5% or lower. For factor X it is lower than 10%.From this it can be concluded that only the changes in prothrombin level must be held responsible for the anti thrombotic effect of oral anticoagulation. These conclusions are not modified if different types and concentrations of thromboplastin are used.We were able to show that at dilutions of human brain thromboplastin higher than 1:50, a factor IX and factor VIII dependent pathway plays an increasingly important role. This directly demonstrates the Josso pathway. The concentration of factor IX necessary for full activity is again <5%.We conclude that the antithrombotic effect of oral anticoagulant treatment, if it is mediated via the coagulation system, works via modification of the prothrombin level only.

scholarly journals Acquired Vitamin K Deficiency as Unusual Cause of Bleeding Tendency in Adults: A Case Report of a Nonhospitalized Student Presenting with Severe Menorrhagia

2017 ◽  
Vol 2017 ◽  
pp. 1-3 ◽  
Author(s):  
Omid Reza Zekavat ◽  
Gholamreza Fathpour ◽  
Sezaneh Haghpanah ◽  
Seyed Javad Dehghani ◽  
Maryam Zekavat ◽  
...  
Keyword(s):  
Vitamin K ◽  
Coagulation Factor ◽  
Energy Drinks ◽  
High Energy ◽  
Factor Ix ◽  
Factor Vii ◽  
Bleeding Tendency ◽  
Factor X ◽  
Vitamin K Deficiency ◽  
K Deficiency

We report a rare case of acquired vitamin K deficiency presenting with severe menorrhagia and without any gynecological problem. Partial thromboplastin time (59.2 seconds) and prothrombin time (33.1 seconds, INR: 5.97) were considerably prolonged in laboratory evaluations. A complete coagulation factor assay test was performed for the patient: factor IX, 24%; factor II, 41%; factor VII, 3%; and factor X, 52%. She had been taking many high-energy drinks and she had inadequate dietary intake for the past 6 months. Given that she had vitamin K deficiency (VKD), a course of vitamin K therapy was started for her in the hospital. This case showed the potential for menorrhagia due to VKD with use of high-energy drinks and the value of a complete and detailed history in early diagnosis.

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