Functional Promoter Polymorphism in the VKORC1 Gene is no Major Genetic Determinant for Vitamin K Dependent Coagulation Factor Activity

2008 ◽  
pp. 261-263
Author(s):  
M. Marinova ◽  
Ph. Westhofen ◽  
M. Watzka ◽  
B. Pötzsch ◽  
J. Oldenburg
2009 ◽  
Vol 102 (08) ◽  
pp. 418-420 ◽  
Author(s):  
Matthias Watzka ◽  
Philipp Westhofen ◽  
Moritz Hass ◽  
Milka Marinova ◽  
Bernd Pötzsch ◽  
...  

2017 ◽  
Vol 17 (3) ◽  
pp. 174-178
Author(s):  
Jufitriani Ismy

Abstrak. Acquired Prothrombin Complex Deficiency (APCD) merupakan perdarahan spontan yang disebabkan oleh penurunan aktivitas faktor koagulasi yang tergantung vitamin K (faktor II, VII, IX dan X), sedangkan aktivitas faktor koagulasi lain, kadar fibrinogen dan jumlah trombosit masih dalam batas normal. Insiden tertinggi APCD pada anak usia 3 – 8 minggu. Dilaporkan 2 kasus APCD di RS Zainoel Abidin Banda Aceh dengan hasil CT-Scan tampak adanya perdarahan Subaracnoid haemorhagic, Subdural haemorhagic, Intracranial Haemorhagic dan Edema cerebri. Pasien mengalami penyembuhan tanpa dilakukan intervensi bedah.Kata kunci : Acquired Prothrombin Complex Deficiency , vitamin K, Perdarahan Subaracnoid haemorhagic, Subdural haemorhagic, Intracranial Haemorhagic AbstractAcquired Prothrombin Complex Deficiency (APCD) is a spontaneous haemorrhage caused by decreased vitamin K-dependent coagulation factor activity (factor II, VII, IX and X), while other coagulation factor activity, fibrinogen levels and platelet counts are within normal limits. Highest incidence of APCD at age 3 - 8 weeks. Reported 2 cases of APCD in RS Zainoel Abidin Banda Aceh with CT-Scan result seen bleeding Subaracnoid haemorhagic, Subdural haemorhagic, Intracranial Haemorhagic and Edema cerebri. The patient is healed without surgical intervention.Key words : Acquired Prothrombin Complex Deficiency, child, vitamin K, Subaracnoid haemorhagic, Subdural haemorhagic, Intracranial Haemorhagic


2010 ◽  
Vol 6 (4) ◽  
pp. 64
Author(s):  
Jose L Merino ◽  
Jose López-Sendón ◽  
◽  

Atrial fibrillation (AF) is the most frequent sustained arrhythmia and its prevalence is increasing in developed countries. This progressive increase and the negative impact of this arrhythmia on the patient’s prognosis make AF one of the main healthcare problems faced today. This has led to intense research into the main aspects of AF, one of them being thromboembolism prevention. AF patients have a four to five times higher risk of stroke than the general population. Several factors increase thromboembolic risk in patients with AF and the use of risk scores, such as the Congestive Heart Failure, Hypertension, Age Greater than 75, Diabetes, and Prior Stroke or Transient Ischemic Attack (CHADS2), have been used to identify the best candidates for anticoagulation. Antithrombotic drugs are the mainstay of therapy for embolic prevention. The clinical use of these drugs is based on the risk–benefit ratio, where benefit is the reduction of stroke and systemic embolic events and risk is mostly driven by the increase in bleeding events. Generally, antiplatelets are indicated for low-risk patients in light of the fact anticoagulants are the drug of choice for moderate- or high-risk patients. Vitamin K antagonists have been the only option for oral anticoagulation for the last 50 years. However, these drugs have many pharmacodynamic and pharmacokinetic problems. The problems of anticoagulation with vitamin K antagonists have led to the investigation of new drugs that can be administered orally and have a better dose–response relationship, a shorter half-life and, in particular, higher efficacy and safety without the need for frequent anticoagulation controls. The drugs that have been studied most thoroughly in patients with AF are inhibitors of the activated coagulation factor X and inhibitors of coagulation factor II (thrombin), including ximelagatran and dabigatran. In addition, non-pharmacological therapies have been developed to prevent recurrent embolism in certain patient populations.


1981 ◽  
Vol 90 (5) ◽  
pp. 1387-1395 ◽  
Author(s):  
Yasuo OHNO ◽  
Hisao KATO ◽  
Takashi MORITA ◽  
Sadaaki IWANAGA ◽  
Katsumi TAKADA ◽  
...  

1987 ◽  
Author(s):  
J Rosing ◽  
H Speijer ◽  
J W P Govers-Riemslag ◽  
R F A Zwaal

It is generally thought that procoagulant phospholipid surfaces that promote the activation of vitamin K-dependent coagulation factors should have a net negative charge in order to promote calcium-dependent binding of the enzymes (FVIIa, FIXa and FXa) and substrates (prothrombin and FX) of the coagulation factor-activating complexes. Two models have been proposed to explain calcium-mediated association of vitamin K-dependent proteins with phospholipid: a) an electrostatic model, in which a positively-charged protein-calcium complex is attracted by a negatively-charged phospholipid surface and b) a chelation model in which a coordination complex is formed between calcium ions, γ-carboxyglutamic acids of the proteins and negatively-charged membrane phospholipids. To study the effect of the electrostatic potential of phospholipid vesicles on their activity in the pro-thrombinase complex the net charge of vesicles was varied by introduction of varying amounts of positively-charged stearylamine in the membrane surface. Introduction of 0-15 mole% stearylamine in phospholipid vesicles that contained 5 mole% phosphatidylseri-ne (PS) hardly affected their activity in prothrombin activation. Electrophoretic analysis showed that vesicles with > 5 mole% stearylamine had a net positive charge. The procoagulant activity of vesicles that contained phosphatidic acid, phosphatidylglyce-rol, phosphatidylinositol or phosphatidyl-glactate (PLac) as acidic phospholipid was much more effected by incorporation of stearylamine. Amounts of stearylamine that compensated the negative charge of acidic phospholipid caused considerable inhibition of the activity of the latter vesicles in prothrombin activation. The comparison of vesicles containing PS and PLac as acidic phospholipid is of special interest. PS and PLac only differ by the presence of NH+ 3-group in the serine moiety of PS. Thus, in spite of the fact that vesicles with PLac are more negatively charged than vesicles with PS, they are less procoagulant. Our results show that a) although procoagulant membranes have to contain acidic phospholipids there is no requirement for a net negative charge, b) the amino group of phosphatidylserine has an important function in the interaction of procoagulant membranes with vitamin K-dependent proteins and c) the chelation model can satisfactorily explain calcium-mediated lipid-protein association.


2006 ◽  
Vol 96 (07) ◽  
pp. 73-78 ◽  
Author(s):  
Roslyn Bonar ◽  
Elizabeth Duncan ◽  
Gail Earl ◽  
Joyce Low ◽  
Margaret Aboud ◽  
...  

SummaryWe have assessed the proficiency of diagnostic haemostasis facilities to correctly identify coagulation factor abnormalities and inhibitors. Forty-two laboratories participating in the external Quality Assurance Program (QAP) conducted by the RCPA agreed to participate and were each sent a set of eight sample (each 3x1ml) for evaluation. They were asked to blind test these samples for the presence or absence of inhibitors, and wher identified, to perform further analysis (including specific inhibitor analysis). In order to make the exercise more challenging, in addition to true factor inhibitors, samples were provided that reflected potential pre-analytical variables that might arise and complicate inhibitor detection or lead to false inhibitor identification. In brief, the sample set comprised a true high level factor (F)V inhibitor, a true moderate level FVIII inhibitor (but sample was defibrinogenated),a true lupus anticoagulant (LA),a normal (but slightly aged) plasma sample, a normal serum sample, a normal EDTA sample, an oral anticoagulant/vitamin K deficiency sample, and a gross heparin (∼10U/ml) contaminated sample. Sixty-three percent of participants correctly identified the true FV inhibitor as such, although the reported range varied greatly [10 to >250 Bethesda units (BU/ml)] and 46% correctly identi fied the true FVIII inhibitor, despite the complication of the sample presentation, although the reported range also varied (7 to 64 BU/ml). Some laboratories either failed to identify the inhibitor present, or misidentified the inhibitor type. The LA, the oral anticoagulant/vitamin K deficiency, the normal serum sample, and the normal (aged) sample were also correctly identified by most laboratories, as was the absence of specific factor inhibitors in these samples. However, a small subset of laboratories incorrectly identified the presence of specific factor inhibitors in some of these samples. The heparin sample was also correctly identified by most (68%) laboratories. In contrast, the normal EDTA sample was misidentified as a FV and/or FVIII inhibitor by most (68%) laboratories, and only one laboratory correctly identified this as an EDTA sample. Thus, we conclude that although laboratories are able, in most cases, to identify the presence of true factor inhibitors, there is a large variation in identified inhibitor levels and there are also some significant errors in identification (i.e. false negatives and misidentifications). In addition, there is a significant false positive error rate where some laboratories will identify the presence of specific factor inhibitors where no such inhibitor exists (i.e. false positives).


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4121-4121
Author(s):  
Pantelis P.E. Makris ◽  
Michel M. Iskas ◽  
Rigini R. Papi ◽  
Dimitrios D.K. Kiriakidis

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


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