Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
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This study was designed to check whether lowering plasma homocysteine concentration resulting from treatment is associated with decreased thrombotic activity in haemodialyzed patients. The study group included 38 patients undergoing chronic haemodialysis. Blood was collected after an overnight fast after two days of weekend intervals in haemodialysis. Tests were performed before and after eight weeks of combined treatment with vitamin B6 (100 mg/day, oral), vitamin B12 (1 mg s.c. once a week) and folic acid (15 mg/day, oral). Homocysteine, vitamin B12 and folic acid concentrations in serum, antithrombin, fibrinogen and protein C activity in plasma and thromboxane B2 levels in activated platelets were determined before and after treatment. Combined treatment resulted in a statistically significant decrease in plasma homocysteine concentration. No influence of this finding on parameters of thrombotic activity was found. The following conclusions were drawn: (1) Treatment with physiological doses of vitamin B12, B6 and folic acid effectively decreases homocysteine concentration in haemodialyzed patients with chronic renal failure. (2) Monitoring of treatment with concentrations of folic acid and vitamin B12 is unfounded as no significant correlations with homocysteine were revealed. (3) The decrease in homocysteine concentration in haemodialyzed patients does not affect thrombotic activity. Therefore, treatment with physiological vitamin doses should not be recommended for routine use.
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PMID:[The effect of lowering plasma homocysteine levels on some parameters of thrombotic activity in haemodialyzed patients with chronic renal failure]. 1687 47

Thirty-six patients with stroke, aged from 8 months to 15 years, and 28 control children, aged 1-15 years, were studied. In both groups, the evaluation of anamnesis, neurologic status and genotyping for 11 most common prothrombotic polymorphisms were carried out. Coagulogram tests and measurement of homocysteine were performed before the anticoagulant therapy in the main group. The total frequency of prothrombin gene mutations (G20210A, factor V Leiden, MTHFR C677T and MTRR A66G) was 2.8 times higher in the main group compared to the control one. The most frequent genotypes were 677TT (8.3% of cases) and 66GG (30.6%). In patients with stroke, the homocysteine level exceeded the upper limit of normal age and also was significantly elevated in carriers of abovementioned risk genotypes: 10.29 +/- 1.55 mcmol/l vs 7.33 +/- 0.6 mcmol/l (p = 0.018). The coagulogram revealed disorders of anticoagulant system, including the decrease of protein C activity (22.7% of cases), protein S activity (13.6%) and antithrombin III (12.5%) and the increase of D-dimer level (21% of cases). It has been suggested to screen for common prothrombotic states and measure homocysteine levels in children with ischemic stroke and to lower homocysteine levels by using vitamins B6 and B12' and diet.
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PMID:[Prothrombotic disturbances in children after ischemic stroke]. 2087 2

Many pathophysiological process components are known to be implicated in lower limb ulcerations, among which vascular lesions have a major role. Vasculitis denotes a heterogeneous group of clinical entities which all are characterized by the inflammatory process of arterial and venous walls of any size and in any organ, quite frequently in the skin. Vasculopathy, on the other hand, refers to vascular and capillary lesions caused by, for example, some medications. The classification of vasculitides according to the size of the blood vessels involved serves for proper understanding the issue among clinicians and researchers, and not as a diagnostic tool. According to histologic finding obtained by examination of blood vessel biopsy specimen, vasculitides are divided into three groups: lymphocytic, leukocytoclastic and granulomatous. Livedoid vasculitis (livedo reticularis) most commonly affects women and is generally localized on lower extremities. The etiology oflivedoid vasculitis may imply autoimmune diseases, capillary obstruction with cryoglobulins, or antiphospholipid syndrome. Livedoid vasculopathy is a hyalinization disease of the vasculature, with thromboses and ulcerations on lower extremities, and of unknown etiology. Livedoid vasculopathy has been singled out as a separate disease that usually does not occur consequentially to other primary diseases. Livedoid vasculopathy typically affects women (71%) at a mean age of 45 (range 10-85) years; bilateral involvement of both lower limbs is present in 80.8%, disease manifested with ulcerations in 68.9%, ulcerations followed by development of atrophie blanche in 71.1%, transcutaneous oximetry reduction is found in 74.1%, factor V mutation (Leiden heterozygotes) in 22.2%, reduced protein C activity in 13.3%, prothrombin gene mutation (G20210A) in 8.3%, positive lupus anticoagulant in 17.9%, positive anticardiolipin antibodies in 28.6%, and elevated homocysteine level in 14.3% cases; blood vessel histology shows intraluminal thrombosis in 97.8% of patients, while direct immunofluorescence of blood vessel specimen shows immunoglobulins and complement components in blood vessels on the surface, in the mid-dermis as well as deep in the dermis. The immunofluorescence pattern differs from that found in immune complex diseases. Some of the agents tried in the treatment of livedoid vasculopathy include pentoxifylline, low-molecular heparin, hyperbaric oxygen therapy, methylprednisolone i.v. with pentoxifylline, recombinant tissue plasminogen activator, intravenous immunoglobulins, phenformin (biguanide) and ethylestrenol (anabolic steroid) combination, warfarin, heparin, systemic photochemotherapy (PUVA with oral psoralen), and low-molecular dextran. Infected ulcerations are treated with antibiotics. Combined therapy with folic acid, vitamin B12 and vitamin B6 can also be used.
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PMID:[Vasculitis and vasculopathy]. 2319 16

To explore the clinical manifestations, diagnosis and treatment of pulmonary thromboembolism associated with protein C (PC)/protein S (PS) deficiency. Two male patients 29 and 26 years old diagnosed with PC deficiency and/or PS deficiency were retrospectively analyzed and related literatures were reviewed. The most common symptoms were pain in the lower limbs with chest pain or decreased vision. Color dopper flow imaging (CDFI) showed lower deep venous phlebothrombosis. Multislice CT angiography (CTA) revealed pulmonary embolism. The level of serum homocysteine (HCY) increased and the level of plasma PC/PS content decreased to PC 57.4%, and PS 28.9% in patient 1, while PS 33.4% in patient 2. Poor routine anticoagulant response was observed. After the diagnosis of PC/PS deficiency, vitamin B6 and B12 anticoagulant therapy was added, and the symptoms in the patients improved significantly. Congenital thrombophilia should be taken into consideration for young patients with lower deep venous thrombosis and pulmonary embolism which occur recurrently without obvious predisposing causes before 40. Plasma PC/PS concentrations or activity help a lot in the diagnosis and treatment.
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PMID:[Two cases of pulmonary thromboembolism associated with protein C and protein S deficiency and literature review]. 2407 97

We evaluated the promoter methylation levels of the APC, MGMT, hMLH1, RASSF1A and CDKN2A genes in 107 colorectal cancer (CRC) samples and 80 healthy adjacent tissues. We searched for correlation with both physical and pathological features, polymorphisms of folate metabolism pathway genes (MTHFR, MTRR, MTR, RFC1, TYMS, and DNMT3B), and data on circulating folate, vitamin B12 and homocysteine, which were available in a subgroup of the CRC patients. An increased number of methylated samples were found in CRC respect to adjacent healthy tissues, with the exception of APC, which was also frequently methylated in healthy colonic mucosa. Statistically significant associations were found between RASSF1A promoter methylation and tumor stage, and between hMLH1 promoter methylation and tumor location. Increasing age positively correlated with both hMLH1 and MGMT methylation levels in CRC tissues, and with APC methylation levels in the adjacent healthy mucosa. Concerning gender, females showed higher hMLH1 promoter methylation levels with respect to males. In CRC samples, the MTR 2756AG genotype correlated with higher methylation levels of RASSF1A, and the TYMS 1494 6bp ins/del polymorphism correlated with the methylation levels of both APC and hMLH1. In adjacent healthy tissues, MTR 2756AG and TYMS 1494 6bp del/del genotypes correlated with APC and MGMT promoter methylation, respectively. Low folate levels were associated with hMLH1 hypermethylation. Present results support the hypothesis that DNA methylation in CRC depends from both physiological and environmental factors, with one-carbon metabolism largely involved in this process.
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PMID:Gene promoter methylation in colorectal cancer and healthy adjacent mucosa specimens: correlation with physiological and pathological characteristics, and with biomarkers of one-carbon metabolism. 2450 May

Dear Editor, Thrombophilia is the tendency to form blood clots both in arteries and veins [1]. Inherited and acquired high plasma homocysteine (HHcy) levels are judged as thrombophilic agents because can induce both arterial and venous thrombosis [2-5]. But, the association of hHHcy with Venous Thromboembolism (VTE) has been studied less extensively than that with arterial thrombosis. Some causes are responsible for this, such as Endothelial Dysfunction (ED). Several mechanisms have been suggested explaining HHcy-induced ED. Among these are included: nitric oxide (NO) inhibition due to the suppression of NO. The inhibition is caused by Asymmetric-D-Methyl-Arginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS). ED is also dependent on the endothelin-1 induction, angiotensin II activation and oxidative stress [6]. Other factors involved in the induction of arterial thrombosis are: impaired DNA methylation, vascular smooth muscle cells proliferation, and platelet's activation [7]. On the contrary, a direct correlation between HHcy and venous thrombosis is substantially less known [8]. In this context, some AA. Reports show that HHcy promotes venous thrombosis by disturbing the procoagulant-anticoagulant balance [9]. But, a significant increase of VTE risk also happens in patients contemporary suffering of inherited HHcy and factor V Leiden gene mutation. In addition, venous thrombosis can be evident when HHcy is present in association with other thrombophilic factors, such as prothrombin G 20210A, protein C deficiency, protein C deficiency or antithrombin deficiency [10]. On view of these evidences, to prevent both arterial and venous thrombosis in HHcy-patients, an antiplatelet drug should be added to an anticoagulant compound. The combination of two antithrombotics seems to be effective to antagonize the risk of arterial and venous thrombi formation, even if this treatment increases the risk of major bleeding [11]. Antiplatelet therapy should consist of Aspirin or Clopidogrel, whereas anticoagulant treatment will require an acecumarol. But, conventional anticoagulants, such as acecumarol, also called Vitamin K Antagonists (VKAs), have multiple negative effects as: delayed onset of action, need to coagulation monitoring performed through the evaluation of International Normalized Ratio (INR), frequent dosage adjustments and numerous drugs and foods interaction [12]. Thus, a combination of an antiplatelet drug with a DOAC should be used in HHcy-patients. Specifically, likewise to the Cardiovascular OutcomMes for People uSing Anticoagulation StrategieS (COMPASS) Study [13], Aspirin or Clopidogrel at full dosage + half dose of a DOAC could be administered. The choice of DOACs, as above referred, added to an antiplatelet treatment can be associated with risk of major bleeding. For this reason, DOAC should be given at reduced dose. Conclusively, HHcy is certainly associated with atherosclerosis, while its association with venous thrombosis is controversial. On the contrary, its presence in association with factor V Leiden and/or other coagulative factors could likely increase VTE [14]. In that case, the association of an antiplatelet drug with reduced doses of DOAC seems to be an attractive and rational treatment to antagonize both arterial and venous thromboembolism induced by HHcy. Interestedly, the supplementation with water soluble vitamins (folate, Vit. B6, Vit. B12) reducing the high Hcy levels, can also decrease the severity of HHcy-related thrombophilia [4, 15].
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PMID:What could be the most advantageous therapeutic approach to avoid both arterial and venous thrombosis in hyperhomocysteinemia? 3239 17


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