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Hirudin, the first specific thrombin inhibitor, which was used clinically, stems from medicinal leeches and is produced today by recombinant technology. R-hirudins have been studied in many clinical trials. R-hirudin has been shown to be more effective than low molecular weight heparin in the prevention of deep venous thrombosis after total hip replacement. In acute coronary syndromes hirudin and the chimeric oligoaminoacid peptide bivalirudin have also been effective. In acute coronary syndromes and when administered together with aspirin high doses of hirudin were associated with an increased risk of bleeding. Hirudin and argatroban successfully prevented thrombotic episodes in patients with heparin-induced thrombocytopenia type II. Several new orally active specific thrombin inhibitors are in development. The combined use of subcutaneous and oral administration of ximelagatran in patients with hip or knee replacement has led to promising results. It seems likely that in the future oral thrombin inhibitors may replace vitamin K-antagonists in some indications. The pentasaccharide fondaparinux is an indirect inhibitor of F Xa. Its anticoagulant and antithrombotic effect depends on the activation of antithrombin. Fondaparinux has shown remarkable antithrombotic efficacy in patients with high risk orthopedic surgery and has been approved in the US and in Europe. Several new low molecular weight specific F Xa-inhibitors are in different stages of development for i.v. and oral use.

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Heparin-induced thrombocytopenia (HIT) syndrome is one of the more frequent and dangerous autoimmune complications of heparin therapy in clinical setting. It is now widely accepted that heparins are capable of complexing with endogenous chemokines and modify at molecular level to trigger the HIT-associated antibodies responsible for pathogenesis. Newer evidence suggests a functional heterogeneity in the HIT antibodies. Besides platelet factor IV (PF IV), there are several endogenous factors, which are responsible for the upregulation of HIT antibodies in various prophylactic and therapeutic regimens. While the pathophysiology and the mechanisms of action in HIT are rather complex, the role of IgG subtype antibodies is clearly established in mediating the pathogenesis. Currently available antithrombin drugs seem to be promising therapeutic modalities to combat the severe thrombotic episode and platelet activation associated with HIT. The clinical relevance of the pathologically nonfunctional HIT antibodies and the mechanism(s) of their formation, in terms of both correlative evidence and causal relationships, need further investigation.

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Fondaparinux (Arixtra®; Sanofi-Synthélabo/Organon) is the first of a new class of antithrombotic agents distinct from low molecular weight (LMW) heparins and heparin. It is a synthetic pentasaccharide mimicking the site of heparin that binds to antithrombin III (AT). It is homogeneous with a molecular weight of 1728 Da. It exhibits only factor (F) Xa inhibitor activity via binding to AT, which in turn inhibits thrombin generation. It does not inhibit thrombin, release TFPI, or possess other actions of heparin. Low AT levels can limit the efficacy of fondaparinux. There is nearly complete bioavailability subcutaneously, rapid onset of action, a prolonged half-life (15- 20 h) and no metabolism preceding renal excretion. Elderly and renal impaired patients have reduced clearance. The PT, aPTT and ACT are not affected by fondaparinux; anti-FXa assays are used if needed. Phase IIb clinical studies have identified a fixed dose of 2.5 mg once daily for prophylaxis of venous thrombosis without monitoring. Four phase III studies (n > 7000) demonstrated a combined 55% relative risk reduction of venous thromboembolic events in orthopedic surgery patients in comparison to the LMW heparin enoxaparin. Hemorrhagic complications for fondaparinux were either comparable to or higher than that for LMW heparin. The US FDA and the European CPMP have approved fondaparinux for prophylaxis of venous thrombosis after orthopedic surgery with limitations of use in elderly, low weight, renal impaired patients and in those receiving spinal anesthesia. Marketing is expected in Spring 2002. Clinical trials for treatment of established thrombosis, coronary syndromes and adjunct to thrombolytic therapy are in progress.

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The Haemoglobin Colour Scale was developed for WHO as a simple, cheap, pocket-sized device for providing a reading of haemoglobin within 1 g/dL of true value. It is intended for the clinician/health worker without easy access to a laboratory, and it thus has an important role in management of anaemia in peripheral health services, especially in under-resourced areas, as well as in antenatal and child health programmes, in screening blood donors and for point-of-care anaemia checks anywhere. An international validation trial and other studies have confirmed its reliabilty when tested against reference haemoglobinometry. It is much more reliable than clinical examination in assessing the severity of anaemia and it has advantages over copper sulphate in blood donor screening.

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The development of acquired inhibitors against the factor VIII protein in childhood period, is a very rare disorder in nonhemophiliac persons but may be clinically important condition due to potential serious bleedings. We have investigated acquired hemophilia development frequency in children with potential high risk groups. Totally 483 nonhemophiliac children including healthy controls were enrolled the study. Age range was 2 to 20 years and mean age was 11 ± 5.4 years. Risk groups for acquired hemophilia were selected among sick children with transfusion dependent ß- thalassemia major (n= 75), children with malignancy (n= 55), asthma bronchiale (n= 65), type I insulin dependent diabetes mellitus (n= 63), collagen tissue disorders (n= 35). Age-matched 190 healthy children were selected as for healthy control group. Inhibitor tests were performed by the method of Bethesda assay. We have found only two patients who had acquired factor VIII inhibitor among 483 children. These two patients were solid tumor (osteosarcoma) and type I insulin dependent diabetes mellitus. Other risk groups and healthy controls have not inhibitor positivity. As a conclusion, acquired inhibitors should be considered for the differential diagnosis of unusual bleeding episodes in patients who had risk factors of all age groups including childhood period.

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Genetic and nutritional factors are determinants of total plasma homocysteine (tHCy) whose increased levels play a pathogenic role in atherothrombosis and cardiovascular disease. This study investigated the influence of sex, age, creatinine, serum folate, vitamin B12 and vitamin B6 (pyridoxal- 5-phosphate, PLP) on fasting (FtHCy) and two hour postmethionine loading levels of tHCy in 147 apparently healthy subjects (M/F= 82/65, age range: 14-94 y). FtHCy was higher in men than women (9.89 vs 8.00 μmol/L, p< 0.01). In males, the main determinants of FtHCy were age and folate levels, respectively explaining 20.5% and 19.0% of FtHCy variance. In women, besides age (22.6%), vitamin B12 (17.8%) rather than folate was a major determinant of FtHCy. Two hour postload tHCy, expressed both as absolute value (PML) and as the difference between 2 hour postload tHCy and FtHCy (delta tHCy) was negatively correlated with folate in both sexes, and with vitamin B12 and age in women only. In males folate was the main determinant, explaining 20% of the variance of postload values, while in females vitamin B12 and PLP were predominant, explaining respectively 40% and 20% of that variance. Age was not among the main determinants of postload values in either sex. These results demonstrate that age and vitamin status differently influence both the fasting and the postmethionine plasma homocysteine levels in normal subjects.

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Erythromelalgia is the main, pathognomonic and presenting symptom in patients with Essential Thrombocythemia and thrombocythemia associated with Polycythemia Vera. Complete relief of erythromelalgic and acrocyanotic pain is obtained with the cyclooxygenase inhibitors aspirin and indomethacin, but not with sodiumsalicylate, dipyridamol, sulfinpyrozone and ticlopedine indicating that platelet-mediated cyclooxygenase metabolites are necessary for erythromelalgia to develop. Local platelet consumption in erythromelalgic areas became evident by the demonstration of arteriolar fibromuscular intimal proliferation and occlusions by platelet-rich thrombi in skin biopsies, by the findings of shortened platelet survival times, significant higher levels of platelet activation markers ß-thromboglobulin (ß-TG), thrombomoduline and increased urinary thromboxane B2 excretion in thrombocythemia patients suffering from erythromelalgia. Aspirin treatment of erythromelalgia in thrombocythemia patients resulted in disappearance of the erythromelalgic, thrombotic signs and symptoms, correction of the shortened platelet survival times, and significant reduction of the increased levels of ß-TG, PF IV, thrombomodulin and urinary T x B2 excretion to normal. Erythromelalgia is frequently preceded or followed by atypical transient neurologic, ocular or coronary ischemic symptoms, which specifically responds to low-dose aspirin or reduction of platelet counts to normal. The broad spectrum of acropareshesias, erythromelalgia and acrocyanotic ischemia together with the episodic and transient atypical TIAs and ocular or coronary ischemic symptoms all are the consequence of one underlying disorder of aspirin-responsive and platelet-mediated arterial thrombophilia precipitated by spontaneous activation and aggregation of hypersensitive platelets in the endarteial microvasculature involving the peripheral, cerebral and coronary circulation of thrombocythemia patients.

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Plasma levels of thrombin activatable fibrinolysis inhibitor (TAFI) and total plasminogen activator inhibitor-1 (PAI-1) and tissue type plasminogen activator (tPA)/PAI-1 complex in patients with disseminated intravascular coagulation (DIC) to examine the relationship between hypofibrinolysis and the pathogenesis with DIC. We examined 39 patients with DIC, 23 with pre-DIC, 181 without DIC and 17 healthy volunteers. Both plasma levels of total PAI-1 and tPA/PAI-1 complex were significantly high in patients with DIC. Those levels were also high in patients with organ failure, especially sepsis. Both TAFI activity and antigen levels in the plasma were significantly low in patients with DIC. TAFI activity in plasma was correlated with TAFI antigen. TAFI activity and antigen levels were negatively correlated with TAT and D-dimer. The TAFI activity in plasma was significantly low in patients with infection and in those with organ failure, suggesting that TAFI may play an important role in the mechanism of organ failure in DIC-associated sepsis. Regulation of fibrinolysis by TAFI and PAI-1 may play an important role in the pathogenesis of DIC and organ failure.

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Ninetysix untreated patients with Malignant lymphoma’s, 81 Hodgkin’s disease and 15 Burkitt’s lymphoma were studied for zinc (Zn) and selenium (Se) status. Plasma and hair Zn, and Se levels were measured by atomic absorption spectrophotometry. Chronic Zn and Se deficiencies (low plasma and low hair Zn and Se levels together) were found to be associated with Malignant lymphoma’s in Turkish children. This was most likely due to poor “nutritional environment” of the patients since majority of the Malignant lymphoma cases were from low socioeconomic class. Supplemention of the patients with physiological doses of Zn and Se, in addition to standard chemo radiotherapy regimen was proposed.

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To evaluate the role the coagulation and fibrinolysis abnormalities in the pathogenesis of ischemic stroke of undetermined etiology, we assayed plasma concentration of fibrinopeptide-A and thrombin-antithrombin III complex, both sensitive markers for thrombin activation and fibrin formation, and D-dimer, a marker of plasmin activity and fibrinolysis. Hemostatic markers were measured in 32 patients with acute stroke and 20 patients with chronic stroke, and compared with 21 normal subjects. Fibrinopeptid-A and thrombin-antithrombin III complex levels were not elevated significantly, whereas the D-dimer level was markedly raised in acute (p< 0.001) and chronic (p< 0.05) phases of ischemic stroke in comparison with the control group. Prolonged elevation of D-dimer concentration suggests that hemostatic abnormalities have a primary role in the pathogenesis of ischemic stroke. The measurement of D-dimer concentration may help to better decide the indications for therapy of the patients with ischemic stroke of undetermined etiology.

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Various studies have shown that 17ß-estradiol (E2), has acute effects on cardiovascular system in addition to its genomic effect. Acute administration of E2 had been shown to increase intracellular free calcium concentration (Ca+2)i in human umbilical vein endothelial cells (HUVEC). The present study investigates the signalling pathway responsible for Ca+2 response to E2. In the study, the effect of E2 on phosphoinositide turnover was investigated by use of Dowex-1 anion-exchange columns after labeling cells with myo(3H)inositol. Additionally, the effects of tyrosine phosphorylation inhibitor genistein and protein kinase C activator 4ß-phorbol-12ß-myristate-13-acetate (PMA) on the Ca+2 response to E2 and ATP were investigated and compared in fura-2 loaded HUVEC. The data demonstrates that E2 treatment causes 45% increase in inositol phosphate production in parallel to increases in (Ca+2)i. Genistein and PMA inhibit the Ca+2 response to E2 ~75%, 49%, while they inhibit the response to ATP ~62%, 73% respectively. Our data suggests the involvement of PLC in the signaling stimulated by E2 and indicate the involvement of tyrosine phosphorylation and PKC. Differences in the effect of the inhibitors on E2- and ATPinduced responses suggest that there may be differences in the upstream signaling initiated by E2 and ATP, such as different roles for tyrosine phosphorylation.

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After various earlier attempts with different radiotracers 51chromium and finally ^IndiumoKİne became the tracers of choice for the radiolabeling of human platelets and the subsequent monitoring of in vivo kinetics. Data on clinical application of platelet survival in atherosclerotic vascular disease and a variety of risk factors are presented. Furthermore, a new approach to use nonradioactive material (rubidium) as label for platelets allowing application in children and pregnants, where only the information on platelet survival is necessary, are discussed. The application of 111lndium-oxine and cold rubidium is an underused reiiable methodology for the assessment of lifespan of human platelets for clinical diagnosis and treatment monitoring.

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Activated protein C (APC) resistance has been found to be an important cause of venous thrombosis. The prevalence of F V Leiden (FVL) in general population is variable according to the region and the ethnic group. The aim of this study was to determine the prevalence of APC resistance and FVL in healthy population in Edirne as a representative sample of province of Edirne. Total 467 healthy subjects were studied. There were 238 males (50.96%) and 229 females (49.04%). APC resistance was studied by functional and DNA methods. There were a total 22/476 subjects (4.7%) were APC resistance. There were 20/476 subjects (4.28%) who had FVL by DNA test. Of these, there were 18 heterozygous and 2 homozygous FVL and other two subjects have no FVL mutation but have the high levels of FVIII to explain acquired APC resistance. The coexistence of FVL and the deficiencies of protein C (1/22), protein S (2/22) and antithrombin (1/22) were also studied. No one of subjects had prothrombin gene mutation. The data showed that the prevalence of APC resitance and FVL in healthy Turkish population were similar to the previously reported publications in Turkey and Europe. One thing is a keeping in mind to be the coexistence of FVL and the other known thrombophilic risk factors.

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This study intends to describe growth and endocrine disorders secondary to chemotherapy among long-term survivors of pediatric acute leukemia. Sixteen patients including 14 ALL and 2 AML entered the study. Four were females and 12 were males with the mean age of 17.38 ± 3.81 years. Following the completion of their therapy, the mean follow up period of the patients was 62.43 ± 41.11 months. Somatic growth, sexual maturation, hypothalamic- pituitary-thyroid axis and hypothalamic-pituitary-gonadal axis were evaluated in all the patients. Two out of 16 had pathologic short stature (12.5%) and 3 patients had enuchoid status (18.75%) with antrophometric measurements. Eleven patients had normal thyroid gland dimensions and homogeneous thyroid tissue on ultrasonographic examination. One patient had Ia and another four patients had Ib diffuse goitre according to WHO criteria. Two out of 16 patients were diagnosed as subclinic primary hypothyroidism (12.5%), and three of them were diagnosed as subclinic central hypothyroidism (18.75%) according to TRH testing. Three patients were subclinic subtle central hypothyroidism. Thyroid auto-antibodies were in normal range in all patients. Eight patients (66.6%) out of 12 male subjects revealed impaired HHG axis. Hypergonadotropic hypogonadism (Leydig and Sertoli dysfunction) were observed in five of them and isolated Sertoli dysfunction was detected in three of them. Azoospermia was encountered in all patients with isolated Sertoli dysfunction. Testicular biopsy was obtained from only one of them and atrophic testicular tissue was detected. Female patients show normal pubertal development and gonadal functions. CONCLUSION: Subclinic subtle primary and subclinic central hypothyroidism were found in 31.2%, impaired Sertoli and Leydig with Sertoli cell function in 66.66% of long-term survivors pediatric acute leukemia and testicular tissue was more sensitive to adverse effects of chemotherapy than ovarian tissue.

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Deformability of density-separated red blood cells (RBC) was determined in individuals, in three different age groups. The "young" group was composed of eight individuals between 22-30 years of age; there were eight individuals between 35-45 years of age in the "mid-age" group and 8 individuals between 60-85 years of age in the "old" group. Density separation was performed using discontinuous, Iodixanol (Optiprep®) density gradients. Five layers of Iodixanol with densities between 1.075 and 1.115 g/mL were used. The density distribution of RBC was estimated by determining the hemoglobin concentration in each layer, after centrifugation. The RBC deformability was measured by ektacytometry in least and most dense RBC fractions. In all age groups, the RBC were mostly accumulated in the layers with 1095 and 1105 g/mL densities. In the "young" group, about 80% of RBC were distributed in each of these gradients almost equally. In the "old" group, 50% of RBC were in 1095 g/mL density layer, while 28% was present in the 1105 g/mL layer. The values for "mid-age" group were in between "young" and "old" groups. In all age groups, EI of denser RBC were smaller, in comparison with the RBC in less dense layers. However, the difference between the EI of less and more dense RBC was more pronounced in the "old" group. RBC aggregation was found to be higher in denser RBC fraction, but the difference was less pronounced in "old" group. These results suggest that, RBC circulating in the vasculature of "aged" individuals exhibit more pronounced rheological alterations, during the aging process of RBC.

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ß-thalassemia, a-thalassemia and sickle cell anemia are the three most common hemoglobinopathies in Turkey. ß-thalassemia major makes up 73%, sickle cell anemia 23% and Hb H disease 4% of total patients with hemoglobinopathy. The overall frequency of ß-thalassemia is 2%. However, the frequency shows regional variations and in some areas it is as high as 13%. Molecular studies indicated the presence of more than 35 different mutations associated with ß-thalassemia. In this study it was shown that five different mutations, namely IVSI-110 (G-A), IVSI- 6 (T-C), IVSII-1 (G-A), IVSII-745 (C-G) and IVSI-1 (G-A) make up 71% of all ß-thalassemia mutations. The rate of consanguineous marriage in families with thalassemia major is %63. However, in 11% of these families, parents carry two different thalassemia mutations. The IVSI-1 (GÆA) mutation is most prevalent in the Aegean Region and it seemed that this mutation moved from this region toward Marmara, Black Sea, Middle, East and South- eastern Anatolia. The IVSII-745 (C-G) is most prevalent in the Mediterranean region and it moved toward Central Anatolia, Black Sea and South-eastern Anatolia. Contrary to these two mutations FSC8 (-AA), IVSII-1 (GA) and -30 (T-A) mutations are most prevalent in Eastern Anatolia and they moved from this region to South-eastern Anatolia, Mediterranean Region, Central Anatolia and Aegean Region. The frequency of various mutations in Central Anatolia is very close to the mean figures given for Turkey indicating that these mutations are well mixed in this region. Sickle cell anemia and sickle cell ß-thalassemia are almost exclusively seen in eastern coast of Mediterranean Sea and in Thrace.

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At our institution 94 transplantations have been performed in an 8 year period up to December 2001. Forty-three females and 49 males with ages ranging from 14 to 61 years received 67 allogeneic (allo) and 27 autologous (auto) transplants; 2 patients were transplanted twice. The diagnosis of allo transplants were AML (27 patients-pts), CML (17 pts), ALL (16 pts) and AA (5 pts); those of auto transplants were NHL (13 pts), HD (10 pts), MM (3 pts) and AML (l pt). Of the patients with acute leukemia 69.7% were in first CR and ali but öne of the patients with CML were in first chronic phase. Source of hematopoetic stem cells were bone marrow (BM) in 61.9% (allo 81.5%, auto 14.8%) and peripheral blood (PB) in 38.1% (allo 18.5%, auto 85.2%). Ail donors were HLA-full matched siblings with öne exception. Conditionİng regimens were BU-CY (31 pts), TBI-CY (28 pts) and Flag-lda (öne pî) for leukemia, CY-ATG for AA, CBV for lymphoma and Mel-200 for MM. Median 2.69 x 108 nucieated celIsAg (BM) and 21.7 x 106 CD34 + celIsAg (PB) were infused to allo transplant recipients; 4 patients faiied to engraft and öne patient was inevaluable due to early death. Acute GVHD was observed in 11 patients (16.9% - grade ll-IV in 10.7%) and chronic GVHD was documented in 18 patients (33.9%- extensive in 9.43%). VOD was seen in 8 patients (12.3%). Early response was CR in 91.6% in patienîs wîth leukemia; patients with lymphoma showed a 73.1% response (CR & PR) rate and 23.1% had resistant disease. So far 27.6% of the patients have relapsed ör showed progression and 45.7% have died (disease-related 27.2%, transplant-related 18.5%). At a median follow-up time of 32 months (range 0.6-96) DFS is 50.8% and OS is 53.9% in the allo transplant group. With a shorter follow-up (median 16 months, range 1-65) the same figures for the auto transplant group are 51.9 and 55.5%, respectively, in this cohort overall, OS and DFS are significantly superior in patients with early-stage disease: 71.7% vs. 26.7% in advanced-stage disease for OS and 71.4% vs. 36.8% for DFS, respectively and this trend applies to both transplant groups (p< 0.001 for ali comparisons).

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