Antibodies against human platelet alloantigens and human leucocyte antigen class 1 in Saudi Arabian multiparous women and multi-transfused patients

Objectives:

To determine the frequency of alloimmunization against human platelet antigens (HPAs) and human leucocyte antigen class 1 (HLA1) in multiparous women and multi-transfused patients.

Methods:

This prospective study was conducted between January and August 2013, on 50 multiparous women with no history of previous blood transfusion recruited from the Obstetrics and Gynecology Clinic, and 50 patients, who received multiple platelet transfusions, recruited from the Hematology/Oncology Ward, King Khalid University Hospital, Riyadh, Saudi Arabia.

Results:

The frequency of alloimmunization among multiparous pregnant women was 76%, as follows: 16% against HLA1 only, 8% against HPAs only, 52% against both HPAs and HLA1 antigens. In multi-transfused patients, the rate of alloimmunization was 42% as follows: 2% against HLA1 only, 22% against HPAs only, 18% against both HPAs and HLA1 antigens. The frequency of alloimmunization increases with the number of pregnancies, but not with the number of platelet transfusions.

Conclusion:

Alloimmunization against HPAs and HLA1 is very common among Saudi multiparous women and multi-transfused patients, which encourages the search for the extent of the possible complications in the fetus and newborn and in multitransfused patients and how to prevent their occurrence.Alloimmunization against human platelet antigens (HPAs) and human leucocyte antigens class 1 (HLA1) results in the development of platelet reactive antibodies, which occur mostly in multi-transfused patients,1 and as a result of pregnancy.2 Detection of these antibodies and recognizing their specificities will help in safeguarding effective transfusion therapy as well as the prediction of the severity of thrombocytopenia, feto-maternal allo-immune thrombocytopenia (FMAIT), and its management. Another problem associated with these antibodies is passive alloimmune thrombocytopenia in recipients of blood collected from female blood donors immunized as a result of previous pregnancies.3 The detection of these antibodies in such recipients may also falsely indicate the production of platelet specific antibodies.4 In hemato-oncology patients receiving multiple transfusions, the production of these antiplatelet antibodies will result in shortening the survival of donated platelets and render the patient refractory to platelet transfusions.5,6 Information on these areas is lacking in our population and, in view of the genetic variations that exist within and between ethnic groups and the current practice of random selection and transfusion of platelet products, it is of interest to find out the extent of alloimmunization to these antigens. Therefore, the main aim of this study is to determine the frequency of antibodies to HPAs and HLA1 in multiparous women and multi-transfused patients from Saudi Arabia.     

Stress dose of hydrocortisone is not beneficial in patients with classic congenital adrenal hyperplasia undergoing short-term, high-intensity exercise

Classic congenital adrenal hyperplasia (CAH) is associated with impaired function of the adrenal cortex and medulla leading to decreased production of cortisol and epinephrine. As a result, the normal exercise-induced rise in blood glucose is markedly blunted in such individuals. We examined whether an extra dose of hydrocortisone, similar to that given during other forms of physical stress such as intercurrent illness, would normalize blood glucose levels during exercise in patients with CAH. We studied hormonal, metabolic, and cardiorespiratory parameters in response to a standardized high-intensity exercise protocol in nine adolescent patients with classic CAH. Patients were assigned to receive either an additional morning dose of hydrocortisone or placebo, in addition to their usual glucocorticoid and mineralocorticoid replacement in a randomized, double-blind, crossover design 1 h before exercising. Although plasma cortisol levels approximately doubled after administration of the additional hydrocortisone dose compared with the usual single dose, fasting and exercise-induced blood glucose levels did not differ. In addition, no differences were observed in the serum concentrations of the glucose-modulating hormones epinephrine, insulin, glucagon, and GH and of the metabolic parameters lactate and free fatty acids. Although maximal heart rate was slightly higher after stress dosing (193 +/- 3 vs. 191 +/- 3 beats/min, mean +/- sem, P < 0.05), this did not affect exercise performance or perceived exertion. We conclude that patients with classic CAH do not benefit from additional hydrocortisone during short-term, high-intensity exercise. Although this has not been tested with long-term exercise, a high degree of caution should be used when considering the frequent use of additional hydrocortisone administration with exercise, given the adverse side effects of glucocorticoid excess.     

Critical intestinal ischaemia in a patient with patent mesenteric vasculature

We present a case of a 62-year-old man with known coeliac disease who was admitted for investigation of abdominal pain and weight loss. He underwent multiple biochemical, haematological, radiological and endoscopic investigations (which were all normal) and also had a normal laparoscopy. Abdominal computerized tomography angiography, however, suggested significant mesenteric stenosis. Mesenteric angiography confirmed superior mesenteric artery stenosis and reproduced the patient's abdominal pain when the catheter crossed the lesion. Balloon angioplasty successfully dilated the stenosis, and since then the patient has gained 19 kg in weight (returning his body mass index from 17 to 23) and has been symptom free. Symptomatic single vessel mesenteric ischaemia (other than coeliac artery stenosis in median arcuate syndrome) is not previously well described. The symptom reproduction on catheterization highlights how useful angiography can be in diagnosis of disease significance. Symptom resolution after angioplasty demonstrated clearly how even single vessel disease can cause significant compromise to the mesenteric circulation.     

Formative research for an mHealth program to improve the HIV care continuum in South Africa

ABSTRACT

In South Africa, high attrition rates throughout the care continuum present major barriers to controlling the HIV epidemic. Mobile health (mHealth) interventions may provide innovative opportunities for efficient healthcare delivery and improving retention in care. In this formative research, we interviewed 11 patients and 28 healthcare providers in North West Province, South Africa, to identify perceived benefits, concerns and suggestions for a future mHealth program to deliver HIV Viral Load and CD4 Count test results directly to patients via mobile phone. Thematic analysis found that reduced workload for providers, reduced wait times for patients, potential expanded uses and patient empowerment were the main perceived benefits of an mHealth program. Perceived concerns included privacy, disseminating distressing results through text messages and patients’ inability to interpret results. Participants felt that an mHealth program should complement face-to-face interactions and educational information to interpret results is needed. Providers identified logistical considerations and suggested protocols be developed. An mHealth program to deliver HIV test results directly to patients could mitigate multiple barriers to care but needs to be tested for efficacy. Concerns identified by patients and providers must be addressed in designing the program to successfully integrate with health facility workflow and ensure its sustainability.     

Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension

We have found in chronically hypoxic rats that acute intravenous administration of the Rho kinase inhibitor Y-27632 nearly normalizes the pulmonary hypertension (PH) but has no pulmonary vascular selectivity. In this study, we tested if oral or inhaled Y-27632 would be an effective and selective pulmonary vasodilator in hypoxic PH. Although acute oral Y-27632 caused a marked and sustained decrease in mean pulmonary arterial pressure (MPAP), it also decreased mean systemic arterial pressure (MSAP). In contrast, 5 minutes of inhaled Y-27632 decreased MPAP without reducing MSAP. The hypotensive effect of inhaled Y-27632 on hypoxic PH was greater than that of inhaled nitric oxide, and the effect lasted for at least 5 hours. Inhaled fasudil, another Rho kinase inhibitor, caused selective MPAP reductions in monocrotaline-induced PH and in spontaneous PH in fawn-hooded rats, as well as in chronically hypoxic rats. These results suggested that inhaled Y-27632 was more effective than inhaled nitric oxide as a selective pulmonary vasodilator in hypoxic PH, and that Rho kinase-mediated vasoconstriction was also involved in the other models of PH. Inhaled Rho kinase inhibitors might be useful for acute vasodilator testing in patients with PH, and future work should evaluate their efficacy in the long-term treatment of PH.     

Characterization of primitive hematopoietic cells from patients with dyskeratosis congenita

Dyskeratosis congenita (DC) is an inherited bone marrow (BM) failure syndrome associated with mutations in telomerase genes and the acquisition of shortened telomeres in blood cells. To investigate the basis of the compromised hematopoiesis seen in DC, we analyzed cells from granulocyte colony-stimulating factor mobilized peripheral blood (mPB) collections from 5 members of a family with autosomal dominant DC with a hTERC mutation. Premobilization BM samples were hypocellular, and percentages of CD34⁺ cells in marrow and mPB collections were significantly below values for age-matched controls in 4 DC subjects. Directly clonogenic cells, although present at normal frequencies within the CD34⁺ subset, were therefore absolutely decreased. In contrast, even the frequency of long-term culture-initiating cells within the CD34⁺ DC mPB cells was decreased, and the telomere lengths of these cells were also markedly reduced. Nevertheless, the different lineages of mature cells were produced in normal numbers in vitro. These results suggest that marrow failure in DC is caused by a reduction in the ability of hematopoietic stem cells to sustain their numbers due to telomere impairment rather than a qualitative defect in their commitment to specific lineages or in the ability of their lineage-restricted progeny to execute normal differentiation programs.     

Identification of a fibrin-independent platelet contractile mechanism regulating primary hemostasis and thrombus growth

A fundamental property of platelets is their ability to transmit cytoskeletal contractile forces to extracellular matrices. While the importance of the platelet contractile mechanism in regulating fibrin clot retraction is well established, its role in regulating the primary hemostatic response, independent of blood coagulation, remains ill defined. Real-time analysis of platelet adhesion and aggregation on a collagen substrate revealed a prominent contractile phase during thrombus development, associated with a 30% to 40% reduction in thrombus volume. Thrombus contraction developed independent of thrombin and fibrin and resulted in the tight packing of aggregated platelets. Inhibition of the platelet contractile mechanism, with the myosin IIA inhibitor blebbistatin or through Rho kinase antagonism, markedly inhibited thrombus contraction, preventing the tight packing of aggregated platelets and undermining thrombus stability in vitro. Using a new intravital hemostatic model, we demonstrate that the platelet contractile mechanism is critical for maintaining the integrity of the primary hemostatic plug, independent of thrombin and fibrin generation. These studies demonstrate an important role for the platelet contractile mechanism in regulating primary hemostasis and thrombus growth. Furthermore, they provide new insight into the underlying bleeding diathesis associated with platelet contractility defects.     

Very late antigen-4 in CD18-independent neutrophil emigration during acute bacterial pneumonia in mice

This study tested the hypothesis that very late antigen (VLA)-4 mediates CD18-independent neutrophil emigration into the airspaces induced by either Streptococcus pneumoniae, a stimulus that induces primarily CD18-independent neutrophil emigration, or Escherichia coli, toward which only 20-30% of the total number of neutrophils emigrate through CD18-independent pathways. In wild-type (WT) mice, VLA-4 expression was less on neutrophils that emigrated into the airspaces than on circulating neutrophils. Vascular cell adhesion molecule-1 (VCAM-1) mRNA, the major endothelial cell ligand for VLA-4, increased more in E. coli than in S. pneumoniae pneumonia. VCAM-1 protein expression was not detected in capillaries, the major site of neutrophil emigration. Neutrophil emigration during E. coli or S. pneumoniae pneumonia was similar in mice given antibodies against both CD18 and VLA-4 compared with mice given the anti-CD18 antibody and a control antibody. However, in hematopoietically reconstituted mice with both WT and CD18-deficient neutrophils in their blood, the migration of CD18-deficient neutrophils in response to S. pneumoniae was slightly but significantly less in animals pretreated with the anti-VLA-4 antibody than in those receiving a control antibody. These data suggest that VLA-4 plays a small role in CD18-independent neutrophil emigration, but the majority of CD18-independent neutrophil emigration induced by bacteria in the lungs occurs through VLA-4-independent mechanisms.