Rajaa Marouf

Avascular necrosis of the femoral head in adult Kuwaiti sickle cell disease patients.

While sickle cell disease (SCD) is generally mild in most Kuwaitis, because of their elevated fetal Hb levels, avascular necrosis of the femoral head (AVNFH) appears to be a common complication. It was recently documented in 26.7% of Kuwaiti children with SCD. There have, however, been no previous studies of adult patients. This is a 1-year study of consecutive, steady-state SCD patients seen in the hematology clinic of Mubarak Al-Kabeer Hospital. The patients’ charts were reviewed for frequency of hospitalizations, any documented complications and steady-state complete blood count (CBC). MRI was performed using T1- and T2-weighted FATSAT sequences in coronal and axial planes with 4-mm-thick slices on a 1.5-tesla GE super-conducting magnet. Thirty-five patients were studied, consisting of 25 SS and 10 Sβ⁰Thal patients aged between 17 and 44, with a mean age of 26.7 ± 9.3 years. Seventeen (48.6%) had varying degrees of AVNFH; among the 70 hips examined, 29 (41.1%) were affected. Of the 17 patients affected, 11 (64.7%) were SS, while 6 (35.3%) were Sβ⁰Thal. There were 14 (82.4%) males and 3 (17.6%) females (χ2 = 8.6, p < 0.01). The mean age of those affected, 27.5 ± 10.7 years, was not significantly higher than that of the unaffected (26.3 ± 8.0 years). Eleven (64.7%) of those affected had a history of frequent vaso-occlusive crisis. No significant differences could be demonstrated in the mean CBC and Hb F values of the two groups; coexistent α-thal trait was not a factor in the SS group. Male gender was the only significant predisposing factor identified. While more patients with frequent vaso-occlusive crises were affected, the difference was not significant. AVNFH is, indeed, quite common among Kuwaiti SCD patients and there is a need for early institution of preventive and therapeutic protocols.

Comparison of renal function markers in Kuwaiti patients with sickle cell disease

Background: Proteinuria is a common manifestation of renal disease which is a significant cause of morbidity in patients with sickle cell disease (SCD). Objective: To evaluate and compare cystatin C, β2-microglobulin, and creatinine as markers of renal disease in relation to the degree of proteinuria and other complications of SCD. Methods: 24 h urine collections were used for estimation of urine protein and creatinine clearance in 59 patients with SCD. Results were correlated with plasma cystatin C, β2-microglobulin, creatinine, glomerular filtration rate (GFR; derived from plasma creatinine by Cockcroft-Gault, MDRD formulae, and calculated cystatin C clearance), and clinical and haematological variables. Results: Comparing the different methods of GFR, the proportion of patients with hyperfiltration (GFR >140 ml/min) were 30.5% (MDRD), 44.1% (Cockcroft-Gault), and 10.2 % (calculated cystatin C clearance). Cystatin C was the most consistent marker of hyperfiltration. The endogenous markers of GFR showed an increasing trend with increasing proteinuria, but haematological variables were not correlated with cystatin C, β2-microglobulin, or plasma creatinine. Urine protein excretion was correlated with age (r = 0.33) and significant proteinuria was present in 13.6% of patients. Patients with proteinuria had lower haemoglobin concentration (p = 0.027) than those without proteinuria but HbF was not related to the degree of proteinuria or to markers of GFR. Conclusions: Markers of GFR show variable ability to identify hyperfiltration in patients with SCD, but cystatin C is the best endogenous marker. Proteinuria is associated with age, haemoglobin, and abnormalities of GFR. Routine screening is recommended to allow for early detection and intervention.

The Association of Skin Test Reactivity, Total Serum IgE Levels, and Peripheral Blood Eosinophilia with Asthma in Kuwait

There is evidence that elevated serum immunoglobulin E (IgE) and eosinophilia correlate well with allergic skin test reactivity. These parameters have been used as alternative methods to characterize atopic subjects. Skin test reactivity is the only measure used routinely in clinical practice in Kuwait to reflect atopy in asthma patients. This study examines the usefulness of the two other parameters of atopy in patients with asthma, and to determine the most common allergens involved in Kuwait. Between 1998 and 1999, 101 asthma patients and 33 healthy controls were recruited for this study. Skin sensitivity test, serum total and specific IgE, total blood eosinophil count (B-EOS), and eosinophil cationic protein (ECP) tests were performed in patients and controls. Nine allergens known to be prevalent in this environment were selected for the skin test and specific IgE test. Spirometry was also measured. These parameters were repeated after 4 weeks of therapy in the patients only. Skin test reaction was positive in 81% of the patients, while total IgE above 200 kU/L was obtained in 63% of cases. B-EOS above 300 ± 103/L was found in 75% of cases. House dust mite reactivity (positivity) was the most frequently encountered skin allergy, occurring in 28% of the patients. IgE correlated positively with B-EOS and ECP. B-EOS similarly correlated positively with ECP. There was a negative correlation between ECP and forced expiratory volume in 1 sec (FEV1) (% predicted) as expected. At least one positive parameter of atopy was found in 95% of the patients. In 48% of the patients, all three parameters of atopy were found to be positive. Skin test reactivity and elevated IgE were found together in 62% of the cases. This study reveals a significant degree of allergy among patients with asthma in this environment. Skin testing was found to be the most effective measure of atopy in this environment, and correlates well with the other more sensitive newer tests.

Transthoracic Echocardiography and 6-Minute Walk Test in Kuwaiti Sickle Cell Disease Patients

Objective: The aim of this study was to investigate cardiac abnormalities in Kuwaiti sickle cell disease (SCD) patients using markers such as tricuspid regurgitant jet velocity (TRJV), pulmonary artery systolic pressure (PASP), and the 6-minute walk (6MW) test and correlate these findings with clinical, hematological, and biochemical parameters. Materials and Methods: Seventy-three patients with SCD and 70 matched controls were studied. The cardiac status was investigated using transthoracic echocardiography in 57 patients; the 6MW test was carried out in patients and controls. Complete blood counts and hemolytic parameters were assessed. Results: Reticulocytes, bilirubin, and lactate dehydrogenase were significantly higher (p < 0.0001) in patients, while hemoglobin (Hb) and haptoglobin were lower (p < 0.0001) than in controls. The mean fetal Hb among patients was 15.85 ± 8.7%. Of the 57 patients, 14 (24.5%) and 15 (26%) had mild tricuspid and mitral regurgitation, respectively. The mean ejection fraction, TRJV, and PASP were 63.9 ± 6.3%, 1.7 ± 0.5 m/s, and 23.0 ± 7.3 mm Hg, respectively. Three (5.2%) patients had mildly raised TRJV (2.6-2.97 m/s, normal range <2.5 m/s) while 8 (14%) had high PASP (mean 35.3 ± 5.1 mm Hg, normal range <30 mm Hg). Hb, hematocrit, and reticulocytes were different (p = 0.010, p = 0.006, and p = 0.011, respectively) between patients with normal and high PASP. All 3 patients who had a high TRJV had a high PASP, and 2 of these patients died during follow-up. The systolic and diastolic blood pressure, oxygen saturation before and after the 6MW test, and distance walked were lower (p = 0.006, p = 0.000, p = 0.002, p = 0.000, and p = 0.000, respectively) in patients compared to controls. Conclusion: Raised PASP was common in Kuwaiti SCD patients while raised TRJV was not.

Determinants of plasma homocysteine in relation to hematological and biochemical variables in patients with acute myocardial infarction.

Background: Elevated plasma total homocysteine (tHcy) is a risk factor for coronary artery disease (CAD), but the mechanism is not known. This study evaluates the determinants and associations of tHcy in patients presenting with acute myocardial infarction (AMI). Methods: Plasma concentration of tHcy, protein C, protein S, and antithrombin were measured in 210 (177 males and 33 females) patients with first AMI and 167 (87 males and 80 females) controls. Serum vitamin B12, folate, creatinine, lipid profile, fasting glucose, full blood count and red cell folate were determined. Creatinine clearance was calculated using the modification of diet in renal disease formula. Univariate and multivariate analyses were used to determine the associations of tHcy. Results: Mean tHcy was higher in male than female patients. On logistic regression analysis, the most important determinants of tHcy in the patients were age, creatinine, creatinine clearance, vitamin B12 and red cell folate. When study patients were compared with the controls, tHcy, fasting glucose and serum creatinine were significantly higher, while creatinine clearance and HDL cholesterol were significantly lower in the study patients. Logistic regression analysis showed significant association of tHcy with AMI, odds ratio = 1.39, in the presence of other confounding factors. Conclusions: Our results show that tHcy is a significant risk factor for CAD in our patient population. The determinants in the patients are age, glomerular filtration rate and the status of vitamins B12 and folate. The above determinants should be kept in mind when using tHcy as a risk factor for CAD.

Pattern of Bone Mineral Density in Sickle Cell Disease Patients with the High-Hb F Phenotype

Low bone mineral density (BMD) is common in sickle cell disease (SCD) patients of all ages due to erythropoietic stress and consequent bone marrow hyperplasia. Kuwaiti SCD patients have a mild clinical phenotype because of their high Hb F level. There has been no previous documentation of BMD in this population of patients. SCD patients (n = 81) and controls (n = 67) were recruited from hematology clinics of Mubarak Hospital, Kuwait. BMD was measured using dual X-ray absorptiometry (Hologic) in the lumbar spine and the hip (left femoral neck). Among the 53 adult patients, the prevalence of low BMD was 67.4% in the spine and 33.3% in the hip while among controls, the figures were 23.1 and 11.3%, respectively. These differences are significant (p < 0.01). In SCD children, the figures were 17.9% (in the lumbar spine) and 3.6% (in the hip), while in controls the figures were 13.3 and 0%, respectively. The differences are not significant (p > 0.05). Patients with frequent vaso-occlusive crisis had significantly lower mean BMD, but those with MRI evidence of avascular necrosis of the femoral head were more likely to have normal or osteosclerotic BMD. Our study showed that osteopenia/osteoporosis is uncommon among Kuwaiti children with SCD but quite common in adults.

Hypercoagulable State and Methylenetetra- hydrofolate Reductase (MTHFR) C677T Mutation in Patients with Beta-Thalassemia Major in Kuwait

Introduction: Patients with thalassemia major often present with a hypercoagulable state, the pathogenesis of which is still not understood. Materials and Methods: This study evaluates the risk factors for hypercoagulability in 50 β-thalassemia major patients and 50 healthy controls. Fasting total homocysteine, protein C (PC), protein S (PS), antithrombin (AT), activated protein C resistance (APCR) and lupus anticoagulant (LA) were assessed. MTHFR C677T mutation was determined. Results: Significant reductions in PC, PS and AT were noted in patients. Only 4% of the patients had hyperhomocysteinemia. Thirty-two percent of the patients were heterozygous and 4% were homozygous for MTHFR C677T mutation. Conclusion: The natural coagulation inhibitors PC, PS and AT were significantly reduced in patients with β-thalassemia major and were thus important risk factors for the hypercoagulable state, but hyperhomocysteinemia and MTHFR mutation do not seem to be significant risk factors for thromboembolic events.

Cryoglobulinemic vasculitis in pregnancy.

Gasbarrini G. Recurrent spontaneous abortion and intrauterine fetal growth retardation as symptoms of coeliac disease. Lancet 2000;356(9227):399–400. [7] Salvatore S, Finazzi S, Radaelli G, Lotzniker M, Zuccotti GV. Prevalence of undiagnosed celiac disease in the parents of preterm and/or small for gestational age infants. Am J Gastroenterol 2007;102(1):168–73. [8] Tata LJ, Card TR, Logan RF, Hubbard RB, Smith CJ, West J. Fertility and pregnancy-related events in women with celiac disease: a population-based cohort study. Gastroenterology 2005;128(4):849–55.

Plasma Homocysteine and Hematological Factors in Patients with Venous Thromboembolic Diseases in Kuwait

Background: Venous thromboembolic disease (VTE) is a common cause of morbidity in Kuwait, but the risk factors have not been studied. Hyperhomocysteinemia has been suggested as one of the risk factors. We postulate that hyperhomocysteinemia acts synergistically with hematological variables to increase VTE risk. This study evaluates the roles of hyperhomocysteinemia and hematological variables in patients with VTE. Methods: We measured fasting plasma total homocysteine (tHcy), activated protein C resistance, protein C (PC), protein S (PS) and antithrombin (AT) in 201 patients with VTE and 166 healthy controls. We also measured factor VIII, factor II, lupus anticoagulant, anticardiolipin, serum vitamin B12, folate, creatinine, lipid profile, glucose, full blood count and red cell folate. The glomerular filtration rate (GFR) was calculated from creatinine. Results: When patients on warfarin were excluded, 13.1% of patients (18 out of 137) had a deficiency in PC, 16.8% (23 out of 137) had a deficiency in PS, and when patients on heparin were excluded, 8.3% of patients (14 out of 168) had low AT. Spearman’s rank correlation analysis showed that tHcy had significant correlations with age, creatinine and PS, and significant inverse correlations with GFR, high-density lipoprotein cholesterol and serum folate. Partial correlation analysis after correcting for age and sex showed that tHcy retained a significant correlation with creatinine, GFR and serum folate. Binary logistic regression analyses of the determinants of hyperhomocysteinemia included age, creatinine, GFR and serum folate. Multivariate logistic regression analysis showed significant association of tHcy with VTE (OR = 5.6; p < 0.0001) in the presence of known risk factors for VTE. Conclusion: We conclude that elevated tHcy is a significant risk factor for the development of VTE, and therefore, it should be included in the workup for patients at risk of VTE, but the determinants of tHcy should be kept in mind.

Determinants and associations of homocysteine and prothrombotic risk factors in Kuwaiti patients with cerebrovascular accident.

Objective: The objective ofthis study was to evaluate the determinants and associations of some prothrombotic risk factors in patients with cerebrovascular accidents (CVAs). Subjects and Methods:In this case-control study, plasma total homocysteine (tHcy), lupus anticoagulant, protein C, protein S, activated protein C resistance (APC-R) and antithrombin were measured in 102 patients (60 males and 42 females) and 167 controls (87 males, 80 females). Serum vitamin B12, folate, red cell folate, creatinine, lipid profile and glucose were also determined. Glomerular filtration rate (GFR) was calculated. Results:13 (22%) of the 60 male patients, and 16 (39%) of the 42 female patients had hyperhomocysteinemia. Median (interquartile range) tHcy was higher in male patients [11.22 µmol/l (9.60–15.40)] than female patients [10.05 µmol/l (8.72–17.54)]. On binary logistic regression analysis, the significant (p < 0.05) determinants of tHcy were urea, creatinine and GFR. Comparing patients with control subjects showed that tHcy, age, fasting glucose, urea, serum creatinine, white blood cell count, protein S, APC-R and factor VIII were significantly higher, while protein C, factor II, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were significantly lower in patients. Lupus anticoagulant was not associated with tHcy and not detected in patients and controls. Low concentrations of vitamins B12 and folate were not associated with tHcy. Logistic regression analysis showed a significant association of tHcy with CVA (OR = 9.55; p = 0.047) in males in the presence of other traditional CVA risk factors but tHcy is not independently associated with CVA in females. Conclusion:Hyperhomocysteinemia is common in Kuwaiti patients with CVA and tHcy probably interacts with prothrombotic factors (protein C, APC-R and factor VIII) to increase CVA risk. The main determinants, age and GFR markers, should be kept in mind when determining the risk associated with tHcy.