Thrombophilia in patients with cryptogenic stroke

Cryptogenic stroke means stroke with unexplained aetiology, in many cases the cause of stroke remains undetermined in spite of full investigations. Those patients are thought to have hypercoagulable state, the purpose of study is to unmask some of the pathogenic mechanisms underlying cryptogenic stroke through assessment of some genetic disorders including C677T mutation in methylenetetrahydrofolate reductase gene and activated protein C [APC] resistance, and the role of thrombin anti-thrombin complex concentration in plasma as indicator of hypercoagulable state. The study is case-control study that was conducted on 20 Egyptian patients who were classified into 2 groups; group I includes 10 patients with cryptogenic stroke who are less than 50 years and group II that includes 10 age and sex-matched patients with non-cryptogenic stroke. They were subjected to a panel of investigations including all routine labs and imaging studies in order to exclude any conventional risk factors for stroke in group I patients and to determine the risk factors for stroke in group II, then both groups are investigated for C677T mutation in methylenetetrahydrofolate reductase gene, activated protein C [APC] resistance and thrombin anti-thrombin complex concentration in plasma. Revealed no statistical significant difference was found between the two groups as regard C677T mutation in methylenetetrahydrofolate reductase gene, activated protein C [APC] resistance, and thrombin anti-thrombin complex concentration [TAT] in plasma [P value >0.05], TAT level was positively correlated with clinical severity in non-cryptogenic stroke [P value <0.05]. C677T mutation in methylenetetrahydrofolate reductase gene, activated protein C [APC] resistance and thrombin anti-thrombin complex concentration in plasma are not independent risk factors for cryptogenic stroke, thrombin anti-thrombin complex concentration [TAT] could be used as indicator of clinical severity and prognosis in patients with non-cryptogenic stroke

Platelet glycoprotein [GPIIIA] gene polymorphism and aspirin resistance in patients with cerebrovascular accidents

Several large clinical trials have found that 30% to 40% of patients who had stroke were taking ASA at the time of their event. Several theories have been studied which offer possible explanation for aspirin resistance. A common T/C polymorphism at position 1565 in exon 2 of the GPIIIa gene has been implicated in increased prevalence of thrombosis and decreased responsiveness to aspirin. The aim of this study was to determine GPIIIa genotype and the degree of platelet activation in Egyptian patients with clinical aspirin resistance as evidenced by occurrence of cerebrovascular stroke in spite of taking aspirin for primary or secondary prevention using soluble P-selectin as a measure for the degree of platelet activation. Twenty nine patients with cerebrovascular stroke were enrolled from Kasr Eleini Hospital between Feb. 2006 and Jan. 2007. The enrollment criteria included documented ischemic stroke by radiological evidence [CT or MRI brain] in spite of regular aspirin use for the last month [75-325mg]. Twenty nine apparently healthy volunteers who are age and sex matched served as control. They were taking no medications. All patients and the control were subjected to clinical examination and routine labs for the estimation of blood sugar, lipid profile in addition to P-selectin level and determination of platelet glycoprotein IIIa T/C gene polymorphism. A significant difference was found in the frequency of GPIIIa gene polymorphism between patients and control; PL[A1A2] present in [55.1%] of patients and [17.2%] of control with odds ratio 5.9 CI95% 1.7-19.8 There was only one patient with PL[A1A2] genotype. The prevalence of PL[A1A2] in females was significantly higher 90% [9/10] than males 36.8% [7/19] [p 0.007] Odds ratio 15.4 [CI 95%1.13-53.62]. P-selectin levels were not significantly different between patients and control when done on the groups as a whole; however, when the groups were compared according to their platelet glycoprotein Ilia gene T/C polymorphism. Significant difference was found between groups, higher levels of P selectin was associated with GPIIIa gene polymorphism. P-selectin level was significantly higher in the heterozygous PL[A1]/ PL[A2] group of patients than homozygous PL[A1]/ PL[A2] group [p 0.000]. P-selectin was significantly lower in homozygous PL[A1]/ PL[A1] patients than in homozygous PL[A1]/ PL[A2] control [p 0.000] which may indicate better and partial, though not enough, response to aspirin. These findings indicate that patients who carry PLA2allele are less aspirin sensitive. In conclusion, aspirin prophylaxis should be individualized, taking the genotype, sex and cholesterol level in consideration. Further larger and prospective studies are needed to decide the optimal dose in variable conditions and the best test/s for follow-up of the effect of the drug

Expression of the multidrug resistance protein MDR1/P-glycoprotein in acute leukemia patients

Therapeutic resistance is a major obstacle in the treatment of acute leukemia which has been closely associated with treatment failure. One of the mechanisms of drug resistance involves over expression of the multidrug resistance gene product, P glycoprotein [MDR1/pgp]. In this study the extent of MDR1/Pgp expression in patients suffering from acute leukemia and its possible prognostic role were evaluated. Twenty -five leukemia patients with mean age of 22.3 +/- 19.6 years were evaluated for percentage cells expressing MDR1/Pgp and mean fluorescence index reflecting intensity of expression using flow cytometry. Evaluation was performed at diagnosis and 21 days after induction chemotherapy to assess possible prognostic role of Pgp expression. 10 age matched control subjects were enrolled in the study. At diagnosis, mean percentage of cells expressing MDR1/Pgp were significantly higher in acute leukemia patients compared to controls [P < 0.05]. Further significant elevation of both percentage cells expressing Pgp and Mil was noted comparing patient results before and after induction chemotherapy [P < 0.05 for each]. On comparing percentage of cells expressing Pgp and MF1 in responders and non responders to standard therapy protocols, there was no significant difference before initiation of therapy, while after induction chemotherapy both parameters showed a statistically significant higher values in non-responders compared to responders [P < 0.05 for each]. Thus, increased expression of MDR1/Pgp is noted in acute leukemia cases with more evident over-expression after use of chemotherapy. Enhanced Pgp expression can affect the response of acute leukemia patients to chemotherapy opening the way for a possible role of MDR1 modulating drugs