Natural inhibitors of coagulation and markers of coagulation activation: the hypercoagulable state in sickle cell disease

This study was designed to clarify abnormalities of the natural coagulation inhibitors and of the markers of thrombin generation in patients with homozygous sickle cell disease [HbSS] in the steady-state, and to evaluate their role in the contribution of the increased thrombotic risk in these patients that could result in new therapeutic interventions. This study was carried out on 50 subjects. They were divided into two groups. Group [A] included 30 patients with homozygous sickle cell disease [HbSS]. Group [B] included 20 apparently healthy age- and sex-matched control subjects; with normal baseline hematologic parameters and haemoglobin electrophoresis as well as no apparent increased thrombotic risk. All patients were tested during steady-state phase with no symptoms or signs of crises or infection for at least 8 weeks and had not had any blood transfusion during the preceding two weeks. They were not on medications other than folic acid 5mg tablets. HbSS was diagnosed by family studies and haemoglobin electrophoresis on cellulose-acetate at pH 8.6. Both patients and control groups were subjected to initial laboratory investigations including complete blood count [CBC], bleeding time [BT], prothrombin time [PT] and INR, activated partial thromboplastin time [aPTT] and haemoglobin electrophoresis. Then, both groups were tested for: [1] Natural coagulation inhibitors including Protein C [antigen and activity], Protein S [total and free levels], Antithrombin-III activity, Heparin cofactor II level, and Tissue factor pathway inhibitor [TFPI] and [2] Markers of coagulation activation; Prothrombin fragments 12 [Fl.2] and Thrombin-antithrombin complex [TAT]. HbSS patients had significantly higher leukocytic count [x 10 [3]/cmm] than control subjects [10.4 +/- 2.8 compared to 6.2 +/- 2.4, p < 0.01]. There was no significant difference between both groups regarding platelet count, bleeding time, prothrombin time [and INR] and activated partial prothrombin time. HbSS patients had significantly lower values than the control group regarding the level of protein C antigen, protein C activity, protein S total and protein S free as well as heparin cofactor TI [p < 0.001, each]. Although FIbSS had lower antithrombin-III activity and tissue factor pathway inhibitor than the control group, the difference was not significant. On the other hand, markers of coagulation activation [namely prothrombin fragments 1.2 and thrombin-antithrombin complex] were significantly higher in HbSS patients compared to the control group [p < 0.001, each]. Comparative studies showed no significant correlation between the level of haemoglobin SS and any of the studied coagulation inhibitors or markers of activation. These data shows that steady state SCD is associated with significant reduced level and/or function of the majority of naturally occurring anticoagulants as well as increased markers of thrombin generation denoting a state of chronic hypercoagulability with increased thrombotic and vasoocclusive tendency. Such changes might justify the prophylactic use of low dose coumadin and/or antiplatelet drugs in HbSS

Erythro-thrombocytopoiesis in hemodialysis patients: possible interaction between thrombopoietin and erythropoietin? is there a role for arterio-venous fistula?

This study was carried out to evaluate the thrombopoietic status of patients with ESRD, to postulate possible causes of altered thrombopoiesis [if any], to verify the clinical significance of endogenous thrombopoietin on both erythropoiesis and thrombopoiesis as well as to assess the contribution of arteriovenous fistula on TPO activity. It included 60 subjects divided into two groups. Group [A] included 40 patients with ESRD on regular hemodialysis three times a week. All included patients had no history of thrombosis [local or systemic, arterial or venous] or a hemorrhagic event within the previous 6 months and they were negative for hepatitis B antigen [HBsAg] and for hepatitis C virus RNA [HCV-RNA] and have normal aminotransferases for the previous 6 months. Patients with a history of malignancy, autoimmune disease, or a documented infection were not included in this study. None of the patients received medication known to interfere with haemostasis [i.e. oral contraceptives, anticoagulants] except for heparin administered during hemodialysis as well as antihypertensives [but not angiotensin-converting enzyme inhibitor or angiotensin II-receptor antagonist] when indicated. Group [A] patients were further subdivided into two subgroups according to their need to rHu-Epo therapy; group [AI] included 19 hemodialysis patients treated with recombinant erythropoietin at a dose of 170 +/- 30 U/kg/sc per week, and group [AII] included 21 patients treated only with oral iron supplementation. Group [B] included 20 age-and sex-matched healthy as the control group. Both patients and control groups were subjected to the following tests: Complete blood count [including blood smear], BUN, serum creatinine, ALT, AST, serum iron, total iron binding capacity [TIBC], serum ferritin, serum erythropoietin [EPO], serum thrombopoietin [TPO] and absolute reticulated platelets count. Furthermore, serum TPO was measured from both the venous return of the AVF and the contra-lateral peripheral vein in each patient with ESRD. Serum erythropoietin was significantly lower [p < 0.01] in HD patients [7.6 +/- 0.8] than in the control group [10.1 +/- 1.3]. Also, serum thrombopoietin was significantly lower [p < 0.001] in the HD patients [60.6 +/- 6.9] than in the control group [120.7 +/- 50.9]. Furthermore, the absolute count of reticulated platelets [x10 [3]/cmm] was significantly lower [p < 0.01] in the HD patients [9.4 +/- 3.7] than in the control group [2 1.7 +/- 4.3]. Hemoglobin and hematocrit were slightly higher in Group AII [10.2 +/- 0.8, 32.7 +/- 5.2, respectively] than in group AI [10.1 +/- 0.9, 32.5 +/- 4.3, respectively]. Such difference was not significant. Platelet count [x10 [3]/cmm] was significantly higher [p < 0.01] in group AI [190 +/- 24.6] than in group AII [150 +/- 30.8]. On the other hand, the absolute count of reticulated platelets [x10 [3]/cmm] was lower in group AI [8.8 +/- 1.5] than group AII [9.3 +/- 1.1], and such difference was not significant. Furthermore, serum TPO was significantly higher [p < 0.05] in group AII [64.7 +/- 5.9] than group AI [55.6 +/- 6.8]. The serum EPO level was significantly higher [p < 0.01] in group AI [8.3 +/- 1.1] than in group AII [6.3 +/- 0.7]. In hemodialysis patients, comparative studies showed significant positive correlation between s. TPO and hematocrit and reticulated platelet count particularly group AII [p < 0.02 and p < 0.01 respectively]. But there was insignificant inverse correlation between s. TPO and platelet count in HD patients. On the other hand, there was significant inverse correlation between s. TPO and endogenous s. EPO in dialysis patients [p < 0.01]. In ND patients, s. TPO concentrations in AVF samples were significantly lower than in the peripheral veins [60.6 +/- 6.9 vs 40.4 +/- 3.9, p < 0.01]. These data confirm the presence of impaired erythro-thrombocytopoiesis in HD patients. This could be partly due to impaired thrombopoietin production and/or increased thrombopoietin destruction and partly due to impaired bone marrow response to the endogenous thrombopoietin. Thrombopoietin appears to induce marrow erythropoiesis either directly or indirectly by augmenting the action of endogenous erythropoietin. Also, it suggests possible involvement of the arteriovenous fistula in the production and/or catabolism of this growth factor. These findings serve as a starting point for further studies to determine the regulatory mechanisms of TPO levels and its precise erythrothrombocytopoietic role in end-stage renal disease

Rapid venous lactate: new parameter for diagnostic and prognostic utility in acute chest pain

This study included 75 patients, 10 of them were critically ill, with a lactate level of 12.4 +/- 2.5 mmol/dl, this could be a predictor of death or critical illness and for the need of ICU admission. Twenty-one cases of acute myocardial infarction had a lactate level of 3.4 +/- 1.1 mmol/dl. The overall sensitivity of a positive lactate finding for acute myocardial infarction [AMI] was 92%. The specificity was 50%. The mean lactate level for patients not requiring ICU admission was 1.4 +/- 0.7 mmol/dl. The study showed that hyperlactemia correlates with the critical illness and mortality in the Emergency Department [ED] patients presenting with chest pain. Patients who have a normal lactate, normal history and normal ECG should be considered at a low risk for AMI and should be referred for the appropriate test than admitting them for the 24-hour rule out procedure. The admission lactate levels are immediately available and highly sensitive markers of AMI in patients with chest pain. A false positive lactate finding is useful as a prognostication of other critical illness and the need for resuscitation and early admission. The rapid venous lactate diagnostic and prognostic value should be confirmed by incorporation into large multicenter trials

Hyperhomocysteinemia in end stage renal disease: a risk factor for atherosclerotic and/or thromboembolic complications?

To clarify the association of hyperhomocysteinemia with the increased risk of atherosclerotic and thromboembolic vascular complications in patients with end stage renal disease [ESRD] independent of other traditional risk factors, this study was performed. It included 150 patients with established ESRD scheduled on chronic ambulatory peritoneal dialysis [CAPD] or regular hemodialysis using high-flux membrane. All patients were supplemented with multivitamins including B12, B6 and folic acid. These patients were divided into two groups: Group A included 26 patients with clinically documented peripheral vascular events [ten with deep venous thrombosis and 16 with peripheral arterial disease] and group B included 124 patients without any clinically or laboratory documented vascular disease. In addition, 30 apparently healthy individuals were included as a control group. Total fasting plasma homocysteine as well as other risk factors were determined including hypertension, obesity, smoking, diabetes mellitus, hyperuricemia, dyslipidemia, prolonged recumbency and recent operations or trauma. Biochemical analyses were done including blood glucose levels [fasting and 2-hour postprandial], lipid profile [total cholesterol, triglycerides, HDL, LDL], serum uric acid, BUN and creatinine. Hematological analyses were also done including complete blood count, prothrombin time and concentration, aPTT, protein C, protein S, antithrombin III as well as fibrinogen. Imaging was also performed in the form of duplex ultrasound for peripheral arterial and/or venous systems and/or angiography in the selected cases. It was concluded that hyperhomocysteinemia is frequently seen in ESRD patients and it represents an independent risk factor for the atherosclerotic and thrombotic vascular disorders which occur frequently in these patients. It is higher in hemodialysis patients than in those on chronic ambulatory peritoneal dialysis [CAPD]

value of transfferrin receptors assay and erythrocyte zinc protoporphrin in diagnosis of iron deficiency in hemodialysis patients.

This study aimed to evaluate the clinical usefulness of serum transferrin receptor and erythrocytes zinc protoporphyrin as possible markers of iron deficiency anemia in dialysis patients. This cross sectional study included 50 patients undergoing regular hemodialysis treatment, three times weekly. None of these patients received intravenous iron therapy, blood transfusion or recombinant human erythropoietin [rHuEpo] within three months before the study. Patients who had factors affecting serum ferritin and transferrin receptor [TR] levels as well as other causes of iron deficiency anemia were excluded. All patients were subjected to complete blood count [including hemoglobin concentration, hematocrit and MCV] and routine biochemical profile including blood urea and serum creatinine, sodium, potassium, calcium, phosphorus and albumin. Iron studies included serum transferrin, serum iron, total iron binding capacity [TIBC], serum ferritin, transferrin saturation index, erythrocyte zinc protoporphyrin and serum transferrin receptors. Iron status was evaluated by bone marrow examination by a biopsy from the posterior iliac crest or sternal bone marrow aspiration. Sections were examined for iron with Prussian blue stain and graded according to scale described by Ho-Yen. The study concluded that TR is more sensitive than s. ferritin as an indicator of iron deficiency, while s. ferritin is more specific screening test for iron store deficiency. ZPP also gives low sensitivity and specificity as an indicator of iron store deficiency. It may be predicted that these measurements are likely to replace the conventional parameters. They would be especially used in the outpatient clinics, where bone marrow examination is either not available or regarded as an invasive mean