Rituximab as a single agent in the management of adult patients with haemophilia A and inhibitors: marked reduction in inhibitor level and clinical improvement in bleeding but failure to eradicate the inhibitor.

Management of patients with severe haemophilia A who develop inhibitors is difficult and expensive. Standard treatment of this complication is immune tolerance induction (ITI) therapy, but is successful in only 60-80% of the patients. Failure of ITI results in a higher risk of morbidity and mortality. We used rituximab, an anti-CD20 antibody, in three patients with severe haemophilia A and inhibitors. Two patients with high-titre inhibitors had marked reduction in the inhibitor level; the third patient with low-titre inhibitor had a disappearance of the inhibitor. All patients improved clinically, with fewer bleeding episodes and a better quality of life. Inhibitor level increased with time in these patients, but the clinical benefit continued in two patients with high-titre inhibitors initially, after a follow-up of 48 and 22 months. One of the patients with concomitant human immunodeficiency virus (HIV) infection and a very low CD4 lymphocyte count developed severe truncal herpes zoster after the third weekly dose of rituximab. Caution is required in such patients, and we recommend avoiding rituximab use in HIV-infected patients with very low CD4 lymphocyte count. In conclusion, rituximab is useful in reducing the inhibitor level with clinical benefit in patients with severe haemophilia A and inhibitors, but it cannot eradicate the inhibitors for long periods with the currently used protocol of up to five doses.

Long-term audit of platelet consumption in a university hospital.

OBJECTIVES: To determine the long-term trend in platelet consumption in a university hospital. MATERIALS AND METHODS: The annual consumption of platelets concentrate (PC) was analyzed over 23 years (1985-2007) in King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia. RESULTS: The total 23 years consumption was 100,466 units of PC. Consumption went through 3 phases: the first, 1985-1994: the annual consumption increased from 1706 to 5912 which coincided with the increase in the number of patient admissions; the second, 1994-2003:featured a remarkable drop (48.9%) in annual consumption while patient admission remained stable. There was a concurrent decline in platelet consumption and all-cause mortality/patient. Third phase: 2003-2007, the consumption increased to reach 5642 units/year in 2007. The Department of Medicine consumed (52%), followed by Pediatrics (21%), and General Surgery (16%). CONCLUSION: This audit uncovered evidence of inappropriate platelet consumption that reached 48.9% in the period 1994 to 2003, which coincided with widely publicized HIV scare that dominated blood transfusion during that period. We also found evidence suggesting that reducing platelet transfusion could improve patient outcome.

Low dose danazol is effective in management of erythropoietin induced thrombosis.

Two patients (one male and one female) with end stage renal disease on chronic hemodialysis were treated with recombinant human erythropoietin (r-HuEPO). Both patients developed significant clotting in the vascular access and extracorporeal circuits. Coagulation studies indicated that both patients acquired high levels of tissue-type plasminogen activator inhibitor (PAI) with deficiency in tissue-type plasminogen activator (t-PA) and consequent impaired fibrinolysis. Their fibrinolytic activity was normalized with danazol therapy in doses as low as 2-4 mg/kg given orally once daily. We conclude that r-HuEPO-induced thrombosis is associated with impaired fibrinolysis due to acquired elevation of PAI which can be effectively prevented by small doses of danazol.

IgA antiphospholipid and adrenal insufficiency: is there a link?

We present two females with antiphospholipid antibody (APA) syndrome who came with adrenal insufficiency (Addison's disease), recurrent abortions and extensive deep vein thrombosis (DVT). Both cases were positive for lupus anticoagulant (LA), global antiphospholipid test (APA), and IgG, IgA, IgM APA antibodies. Seventeen other cases with documented lupus anticoagulant and various clinical associations were tested for APA IgG, IgA, IgM. Only two were positive for IgA as well as IgG and IgM APA. Thirty volunteer blood donors (24 males and 6 females, aged 19-35 years) were taken as a control group. One person was moderately positive for LA and showed low positivity for IgG APA. These data suggest that the presence of IgA APA may signify a severe disease. Further studies are needed to confirm this observation.

Baseline seroepidemiology of hepatitis B virus infection in two Saudi high-risk groups: patients on haemodialysis and patients with congenital bleeding disorders.

Because background seroepidemiological data are required before nationwide vaccination against hepatitis B virus (HBV) is attempted, the rate of exposure to HBV was investigated in two high-risk Saudi groups: patients on haemodialysis and patients with congenital bleeding disorders. Although the HBsAg carrier rate was higher in patients with congenital bleeding disorders (11.1%) than in patients on haemodialysis (4.6%), the exposure rate to HBV was similar in both groups (38.8%-44.5%). Because of this high exposure rate it seems cost-effective, at least in the Saudi population or in countries which are endemic for HBV, to screen for HBV markers before vaccination against HBV is recommended.

Haemostatic variables in patients with unstable angina.

To assess the contribution of thrombus formation in the pathogenesis of unstable angina, we employed the recently developed assays of small fragments which reflect the degree of activation of various components of the haemostatic system. Such haemostatic measurements were undertaken in patients with unstable angina (n = 47) from the time of their admission to the coronary care unit (CCU) at 8-h intervals in the first 24 h and then daily for a total of 5 days. The results obtained were compared with healthy control values. Patients exhibited lower ATIII, prolongation of the APTT and TT, but not PT or the reptilase time, which is a consequence of heparinization. There was significant elevation of fibrinogen, factor VIII:C, von Willebrand factor:antigen and von Willebrand factor:ristocetin cofactor throughout the study period. There was also evidence of thrombin generation as indicated by the elevated levels of fibrinopeptide A (FPA) and thrombin-antithrombin complexes. The platelet release proteins, beta-thromboglobulin (BTG) and platelet factor 4 (PF4), were markedly elevated in the first 2 days and dropped gradually thereafter. The fibrinolytic inhibitor, plasminogen activator inhibitor (PAI), levels were elevated throughout. Proteins C and S, plasminogen and alpha 2-antiplasmin remained unchanged. It was concluded that in patients with unstable angina, there is significant activation of the clotting system and inhibition of fibrinolysis which confirms the existence of a tendency towards thrombus formation in patients with unstable angina.

Ceftazidime and amikacin as empiric treatment of febrile episodes in neutropenic patients in Saudi Arabia.

Sixty-four consecutive febrile episodes in 50 consecutive patients with malignancy and neutropenia were empirically treated with a combination of ceftazidime and amikacin. Of 52 analysable episodes, the response rate was 59.6% overall and 26.3% of episodes with microbiologically documented infections with septicaemia. Infection-related death occurred in 10 patients (19.2% of episodes). The response rates were similar in patients with acute leukaemia or other malignancies. Poor response is attributed to increased frequency of infections with Gram-positive and fungal organisms. A modified empiric regimen including cover for Gram-positive and fungal organisms is suggested in similar patient populations.

Significant elevation of protein C and protein S levels in thrombotic disorders by low dose danazol.

Six patients (three males and three females), mean age 35.2 years (range 31-43 years), with extensive venous thrombosis were studied. Initial laboratory data indicated that all patients had normal antithrombin III (ATIII), four patients had low protein C (PC), three patients had low protein S (PS) and two patients had low plasminogen. Four patients had high fibrinogen and all patients had reduced tissue-type plasminogen activator activity, elevated tissue plasminogen activator inhibitor and low fibrinolytic activity. All patients were treated with danazol, 5-7 mg/kg orally once daily. In all patients there was significant elevation of ATIII, PC, PS, and plasminogen, reduction in plasma fibrinogen and PAI and enhancement of fibrinolysis. During the 12-36 months period of follow-up, there were no symptoms or signs that suggested recurrence of thrombosis. Apart from weight gain of 5-10 kg and disturbed menstrual cycle in two women, no major side effects were seen. These data suggest that danazol is potentially useful therapy that may increase levels of natural anticoagulants in patients with thrombotic illnesses in which ATIII, PC and PS are low or normal. Further studies are needed to confirm these observations.

Effect of recombinant human erythropoietin (rHuEpo) on the hemostatic system in chronic hemodialysis patients.

Hemostatic measurements were undertaken in eight chronic hemodialysis uremic patients on recombinant human erythropoietin (rHuEpo). Same measurements were repeated in another seven patients in whom anemia was corrected by the transfusion of red blood cells. The correction of the anemia by rHuEpo therapy was accompanied by 1. correction of the prolonged Simplate Bleeding Time (BT) to normal less than 10.0, minutes after 16 weeks of rHuEpo treatment; 2. significant increases in the levels of fibrinogen, clotting FVIII:C, vWF:antigen, vWF:ristocetin cofactor and platelet count; 3. enhanced aggregation responses to ADP, adrenaline, arachidonic acid, collagen and ristocetin. There was no significant fluctuation in other coagulation parameters PT, APTT, TT, reptilase time and antithrombin III and plasma fibrinogen. In patients who were treated with RBC transfusion and despite the correction of the anemia, the bleeding time shortened significantly but not corrected, mean BT before and after RBC transfusion was 17.1 +/- 1.4 and 11.6 +/- 1.9 minutes respectively. Besides there was significant elevation of vWF:Ricofactor levels but not FVIII:C, vWF:Ag or platelet count. Platelet aggregation responses to ADP remained unchanged. It is concluded that significant elevations of FVIII:related activities, plasma fibrinogen, improved platelet aggregability and correction of the BT are salient hemostatic changes that follow rHuEpo therapy in uremic patients.

Pregnancy outcome in women with antiphospholipid antibodies.

The association of antiphospholipid antibodies (APA) or lupus anticoagulant (LA) and recurrent fetal loss (RFL) is well established; however, the spectrum of pregnancy outcome in relation to various therapeutic approaches versus placebo is unknown. We studied 49 women with RFL, 14 with immune thrombocytopenia (ITP) 13 of whom without a history of RFL, and 32 controls (all in the first trimester of pregnancy) for the presence of APA. Tests for APA were positive in 15/49 women with RFL (30%), 6/14 ITP (43%) and 2/32 controls (6%). Treatment in the APA positive patients consisted of: no treatment for the 8 patients who had no history of RFL (Group A; all 34 previous pregnancies successful), aspirin alone (Group B, 5 patients; all 30 previous pregnancies unsuccessful), aspirin with prednisolone (Group C, 9 patients; 69/80 previous pregnancies unsuccessful), or aspirin, prednisolone and immunoglobulin G for resistant cases (Group D, 4 patients, previously in Group C). 10/11 (90.9%), 3/7 (43%), 7/13 (53.8%) and 4/7 (57.1%) pregnancies were successful in Group A, B, C and D, respectively. There was a total of 19/45 (42%) failures including 3 pregnancies in one patient who failed to respond to all forms of therapy. This open study with small subgroups of patients draws attention to a wide range of pregnancy outcome in women with APA and to the fact that APA may serve only as a marker for a wide range of pathological conditions with variable degrees of disease severity. More studies are, however, needed to explore the real mechanism of RFL in women with APA and RFL, especially those who are resistant to therapy.

Bilateral central retinal vein thrombosis in Behçet's disease.

Behçet's disease is a multisystem disorder affecting the skin, mucous membranes, eye, joints, central nervous system, and blood vessels. One of the known vascular complications of Behçet's disease is venous thrombosis or aneurysm formation. We report, herewith, a patient with Behçet's disease who developed radial artery aneurysm, deep venous thrombosis, and bilateral central retinal vein thrombosis. To our knowledge, this is the first report of bilateral central retinal vein thrombosis in association with Behçet's disease.

Intravenous iron sucrose complex in the treatment of iron deficiency anemia during pregnancy.

OBJECTIVE: To evaluate the safety and efficacy of intravenous iron sucrose complex (ISC) as compared with oral ferrous sulfate in the treatment of iron deficiency anemia during pregnancy. STUDY DESIGN: prospective, open, controlled study in which pregnant women with iron deficiency anemia were sequentially selected from the antenatal clinic and assigned either to ISC (study group) or to ferrous sulfate (control group). METHODS: Each study patient was given the total calculated amount of ICS (Hb deficit (g/l) x body weight (kg) x 0.3) in divided doses (200 mg (elemental iron) in 100 ml normal saline intravenously over 1 h daily) followed by 10 mg/kg to replenish iron stores. Each patient of the control group was given ferrous sulfate 300 mg (60 mg elemental iron) orally three times a day. All patients were monitored for adverse effects, clinical and laboratory response. RESULTS: There were 52 patients and 59 controls. ISC group achieved a significantly higher Hb level (128.5 +/- 6.6 g/l vs. 111.4 +/- 12.4 g/l in the control group P < or = 0.001) in a shorter period (6.9 +/- 1.8 weeks vs. 14.9 +/- 3.1 weeks in the control group, P < or = 0.001). ISC complex group showed no major side effects while 4 (6%) of the control group could not tolerate ferrous sulfate, 18 (30%) complained of disturbing gastrointestinal symptoms and 18 (30%) had poor compliance. CONCLUSION: We conclude that ISC is safe and effective in the treatment of iron deficiency anemia during pregnancy.

Correlation of fundus lesions and hematologic findings in leukemic retinopathy.

This prospective study evaluated the relationship between the fundus findings in leukemic retinopathy and hematologic parameters. Seventy-four newly diagnosed consecutive patients with acute leukemia were included, 49 with acute myelocytic leukemia (AML), and 25 acute lymphocytic leukemia (ALL). Blood parameters were based on data obtained before starting any therapeutic modalities. Leukemic retinopathy was detected in 32 patients (43%). Patients with ALL and retinal hemorrhages had significantly lower hemoglobin and hematocrit levels than those without hemorrhages (p = 0.004 and 0.018 respectively). AML patients with white-centered hemorrhages had a significantly higher leukocyte count than those without (p = 0.0002). ALL patients with cotton-wool spots had significantly lower hemoglobin levels and hematocrit than patients without such lesions (p = 0.044 and 0.05 respectively). AML patients with cotton wool spots had significantly lower leukocyte and platelet counts than those without (p = 0.019 and 0.003 respectively). Our results suggest that anemia is related to the findings of retinal hemorrhage and cotton-wool spots in ALL patients, that high leukocyte count is associated with white centered hemorrhage in AML patients, and that thrombocytopenia is not associated with retinal hemorrhage in this group of patients.

An evaluation of a new gel system (ID-gel) for antibody screening and identification.

An evaluation of the new "ID-Gel System" (Diamed) for the detection of red cell antibody-antigen reactions was undertaken in the King Khalid University Hospital Blood Bank. Antibody screening was performed in 700 patient samples using both the conventional test tube (bovine albumin and LISS) techniques and the new ID-gel technique. The results obtained were as follows: a) 70 antibodies of various types were detected by the bovine albumin technique. b) 98 antibodies were spotted by LISS. c) The ID-gel system detected 122 antibodies (17.43%) which included all those detected by the other two techniques. It was concluded that the ID-gel system is a far more sensitive technique than the conventional Blood Bank immuno-haematological tests. In addition, the ID-system has the further advantage of standardization of the test, shorter incubation time, no washing procedure and reduces the technologist time, effort and perhaps number.

Coagulation inhibitors and fibrinolytic parameters in patients on peritoneal dialysis and haemodialysis.

Coagulation inhibitors and fibrinolytic parameters were studied in twelve patients on continuous ambulatory peritoneal dialysis (CAPD) and ten patients on haemodialysis (HD). Patients on CAPD exhibited higher levels of ATIII and proteins C and S than those on HD. No significant differences were noted in tPA and PAI levels. Both groups of patients showed higher levels of tPA than controls. Besides, patients on HD had significantly lower levels of ATIII and protein C than controls. PAI levels in both patient groups were similar to those of the controls, but tPA levels were higher in patients than in controls. These results indicate that HD is associated with marked diminution in the circulating levels of coagulation inhibitors. This is in contrast to CAPD patients who showed elevated levels of these inhibitors, despite their significant loss in the dialysate. The finding of enhanced fibrinolysis in both patient groups may be a natural protective mechanism against the development of a thrombotic tendency.

Toxoplasmosis in a group of glucose-6-phosphate dehydrogenase deficient patients.

OBJECTIVE: This was a retrospective study that aimed at evaluating the relative risk of Toxoplasma infection in patients with glucose-6-phosphate dehydrogenase deficiency as compared to a control group with no glucose-6-phosphate dehydrogenase deficiency. METHODS: Ninety-one blood donor volunteers had serology testing from Toxoplasma gondii and were screened for glucose-6-phosphate dehydrogenase deficiency by a qualitative method using fluorescent spot test. They were all males and their ages ranged from 17 to 52 years. RESULTS: Fifty-three persons (58%) were glucose-6-phosphate dehydrogenase deficient and 38 (42%) were glucose-6-phosphate dehydrogenase normal. In the glucose-6-phosphate dehydrogenase deficient group, 31 (58.5%) had positive titers for Toxoplasma; while in the glucose-6-phosphate dehydrogenase normal group 9 persons (24%) had positive titers for Toxoplasma. The relative risk of infection was 2.5 times more in the glucose-6-phosphate dehydrogenase deficient group, a statistically significant difference with a p value of 0.002. CONCLUSION: Glucose-6-phosphate dehydrogenase deficiency seems to increase the risk for Toxoplasma infection by 2.5 fold probably due to decreased killing effect, of phagocytic cells.

Unusual presentation of vitamin B12 deficiency.

Cobalamin (vitamin B12) deficiency could be masked by lack of hematological abnormalities or by concomitant conditions associated with microcytosis such as iron deficiency and thalassemia traits. We examined blood and bone marrow morphology, serum ferritin and vitamin B12 levels and fasting gastric pH in nine patients who were suspected to have vitamin B12 deficiency with unusual manifestations. Two patients had neurological symptoms without any hematological abnormalities, two had thalassemia traits, and five had achlorhydria with severe iron and B12 deficiencies. Serum B12 was low in all cases, bone marrow was diagnostic in seven cases and peripheral blood showed hypersegmentation of neutrophils only in five cases. We conclude that vitamin B12 deficiency could be masked by lack of hematological changes or by concomitant causes of microcytosis and that serum vitamin B12 levels as well as other ancillary tests should be considered in all suspected cases.

Hypocalcemia due to hypoparathyroidism in beta-thalassemia major patients.

BACKGROUND: This is a retrospective analysis of case records of AA(2)-thalassemia major patients who developed hypoparathyroidism (HPT). The objective of this study was to assess the prevalence of hypocalcemia and hypoparathyroidism in AA(2)-thalassemia major patients being followed at King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia. PATIENTS AND METHODS: Diagnosis was based on low serum calcium (S/Ca), high serum phosphate (Po4), normal serum magnesium and alkaline phosphatase, and low serum parathyroid hormone levels. Other parameters analyzed included age, sex, serum ferritin levels, age of onset of HPT, any symptoms of hypocalcemia, and presence of other complications in these patients. RESULTS: Out of 40 patients, eight (20%) were diagnosed to have HPT. The mean age at diagnosis was 13.6 years (range 11-16 years), mean serum calcium was 1.88 mmol/L (range 1.58-2.04), mean serum ferritin was 7490 AA(1/4)g/L (range 2000-23,064) and mean serum phosphate was 1.88 mmol/L (range 1.50-2.73). Serum parathyroid hormone (PTH) levels were low in most of the patients. Only two patients (25%) had mild symptoms of hypocalcemia. Growth retardation was present in all patients, while four patients had liver dysfunction, two had diabetes mellitus and two had cardiac dysfunction. CONCLUSION: HPT due to iron overload may develop in a significant number of thalassemia major patients, especially when chelation therapy is not optimal, therefore, all thalassemics should be carefully watched for this complication from early in their second decade.

Pernicious anemia in Saudi Arabs.

Over a five-year period extending from January 1986 to December 1990, seven cases of pernicious anemia in Saudi patients were diagnosed at King Khalid University Hospital in Riyadh. There were five males and two females. The age range was 45 to 73 with a mean age of 61 years. The presenting symptoms, laboratory features and the disease pattern were similar to those described in northern European patients with the possible exception of male predominance in our patients. One patient demonstrated an interesting phenomenon of masking the macrocytosis of pernicious anemia by concurrent beta thalassemia minor. No association with any other autoimmune diseases was detected in any of our patients.

Hereditary bleeding disorders in Riyadh, Saudi Arabia.

The result of an eight-year retrospective analysis of patients with hereditary bleeding disorders (HBD) at King Khalid University Hospital, Riyadh, is presented. One hundred and sixty-eight patients referred for investigation for suspected bleeding disorders had bleeding symptoms which fulfilled the criteria for HBD and were categorized as follows: 1) coagulation factor deficiencies: 41 patients had hemophilia A, while 16 had hemophila B; two patients each had factors XI and XII deficiency; four patients each had factors V and VIII deficiency and one patient had factor VII deficiency. There were two patients with dysfibrinogenemias and one with afibrinogenemia. 2) Von Willerbrand's disease was the second most common cause of HBD-25 patients were encountered in 15 different families. 3) Qualitative platelet disorders consisted of Glanzmann's thrombasthenia, with 18 patients, Bernard-Soulier disease, with five patients, and other qualitative platelet disorders, with 33 patients. 4) In 14 patients who presented with a history of bleeding, the only abnormality noted was prolongation of the bleeding time and normal coagulation and platelet function, and no definitive diagnoses could be established. The distribution of hereditary bleeding disorders obtained in this study resembles what has already been established in Western countries, with the exception of an increase of platelet disorders, mostly due to the increased rate of consanguinity in the community.