Prevalence of lipodystrophy in HIV-infected children in Tanzania on highly active antiretroviral therapy.

OBJECTIVE: Highly active antiretroviral therapy (HAART) has been associated with lipodystrophy (LD) in adults but data are more limited for children. The purpose of this study was to determine the prevalence of and risk factors for LD in Tanzanian children receiving HAART by clinical assessment and to compare the results with anthropometric data. DESIGN AND METHODS: A cross-sectional study was performed in a cohort of HIV-infected children aged 1-18 years receiving HAART in a single center in Moshi, Tanzania. Age, gender, past and current medication regimens and anthropometric measurements were recorded. A clinical scoring method was used to assess LD. Backward binary multivariate logistic regression was used to determine relationships between anthropometric measurements and the presence of clinical LD. RESULTS: Among 210 HIV-infected children, the prevalence of LD was 30% (95% confidence interval [CI]: 23.8-36.2) overall, 19% (95% CI: 13.7-24.3) for lipoatrophy only, 3.8% (95% CI: 1.2-6.4) for lipohypertrophy only and 7.1% (95% CI: 3.6-10.6) for the mixed type. Most cases were mild. Older age and use of stavudine increased the risk of LD. Overall, the study population was stunted but not underweight. In children with relatively lower weight-for-height (<1), only the mid-upper arm circumference was found to be associated with lipoatrophy, while nearly all anthropometric measurements were associated with lipoatrophy in the well-nourished (weight-for-height ≥1) children. CONCLUSIONS: Our findings demonstrate that LD is a significant problem among Tanzanian HIV-infected children receiving HAART. Anthropometric measurements predicted LD in well-nourished children but generally failed to do so in relatively wasted children. Our findings support current efforts to avoid stavudine use in children.

Severe dengue is associated with consumption of von Willebrand factor and its cleaving enzyme ADAMTS-13.

BACKGROUND: Thrombocytopenia, bleeding and plasma leakage are cardinal features of severe dengue. Endothelial cell activation with exocytosis of Weibel-Palade bodies (WPBs) may play an etiological role in this condition. METHODS AND PRINCIPAL FINDINGS: In a cohort of 73 Indonesian children with dengue hemorrhagic fever (DHF), of which 30 with dengue shock syndrome (DSS), we measured plasma levels of the WPB constituents von Willebrand factor antigen (VWF:Ag), VWF propeptide and osteoprotegerin (OPG), together with activity levels of the VWF-cleaving enzyme ADAMTS-13 and the amount of VWF in a platelet binding conformation (VWF activation factor). Compared with healthy controls (n = 17), children with DHF/DSS had significantly higher levels of VWF:Ag, VWF propeptide and OPG and decreased ADAMTS-13 activity. The VWF activation factor was also significantly higher in DHF/DSS and highest in children who died. There were significant differences in the kinetics of the various WPB constituents: VWF propeptide and OPG levels decreased toward discharge, while VWF:Ag levels were lower than expected at enrollment with plasma levels increasing toward discharge. Moreover, VWF propeptide levels correlated better with markers of disease severity (platelet count, liver enzymes, serum albumin and pleural effusion index) than corresponding VWF levels. Together, these findings suggest that there is consumption of VWF in DHF/DSS. In 4 out of 15 selected children with low ADAMTS-13 levels on admission, we found a remarkable reduction in the large and intermediate VWF multimers in the discharge blood samples, consistent with an acquired von Willebrand disease. CONCLUSION: These findings suggest that severe dengue is associated with exocytosis of WPBs with increased circulating levels of VWF:Ag, VWF propeptide and OPG. High circulating levels of VWF in its active conformation, together with low ADAMTS-13 activity levels, are likely to contribute to the thrombocytopenia and complications of dengue. During the convalescence phase, qualitative defects in VWF with loss of larger VWF multimers may develop.

Toll-like receptor 4 polymorphisms in dengue virus-infected children.

Differential viral recognition by cells bearing Toll-like receptor 4 (TLR4) polymorphisms Asp299Gly and Thr399Ile may influence susceptibility and severity of dengue virus infection. In central Java, Indonesia, we investigated 201 children with dengue hemorrhagic fever (DHF) and 179 healthy controls. Patients and controls were mostly ethnic Javanese. A nearly complete cosegregation of the two mutations was observed. The TLR4 299/399 genotype was found in five patients and four controls. Prevalence of the TLR4 299/399 genotype did not differ significantly between controls and DHF patients or between patients with different severities of DHF. Also, vascular leakage in patients with different TLR4 genotypes did not differ. Thus, the 299/399 TLR4 haplotype has only minor influence on susceptibility and severity of complicated dengue virus infection.

Increase of plasminogen activator inhibitor-1 and decrease of transforming growth factor-b1 in children with dengue haemorrhagic fever in Indonesia.

Mortality in children with severe dengue haemorrhagic fever (DHF) in Indonesia is high. The origin of the elevated plasminogen activator inhibitor-1 (PAI-1) levels in these children is unclear. We measured PAI-1, transforming growth factor-ß1 (TGF-ß1), platelet counts, plasma leakage and liver function in 71 children with DHF (3-15 years old) and in 30 healthy children. We found that PAI-1 concentrations in children with DHF were significantly higher on admission than on Day 2. Circulating TGF-ß1 concentrations on admission were significantly lower in DHF than in controls, but on Day 2 increased towards levels in controls. TGF-ß1 and PAI-1 concentrations were not correlated on either day. PAI-1 was correlated with platelet count and serum albumin on admission, and with degree of pleural effusion. Liver function tests were mildly elevated but not correlated with PAI-1. In conclusion, elevated PAI-1 concentrations in DHF were associated with platelet counts and plasma leakage.

Zinc and vitamin A supplementation fails to reduce sputum conversion time in severely malnourished pulmonary tuberculosis patients in Indonesia.

BACKGROUND: A previous study showed that combination of zinc and vitamin A reduced sputum conversion time in pulmonary tuberculosis (TB) patients. OBJECTIVE: We studied the efficacy of which single micronutrient contributed more to the sputum conversion time. METHODS: In a double-blind randomized community trial, newly sputum smear positive pulmonary TB patients were assigned randomly to receive zinc, vitamin A, zinc + vitamin A or placebo on top of TB treatment. Patients were asked to deliver their sputum on weekly basis to measure positivity of the bacteria. Nutritional status, chest x-ray, hemoglobin, C-reactive protein (CRP), retinol and zinc level were examined prior to, after 2 and 6 months of treatment. RESULTS: Initially, 300 patients were enrolled, and 255 finished the treatment. Most patients were severely malnourished (mean BMI 16.5 ± 2.2 Kg/m2). Patients in the zinc + vitamin A group showed earlier sputum conversion time (mean 1.9 weeks) compared with that in the other groups; however the difference was not significant. Also, no benefit could be demonstrated of any of the used supplementations on clinical, nutritional, chest x-ray, or laboratory findings. CONCLUSIONS: This study among severely malnourished TB patients, did not confirm that single or combined supplementation of zinc and vitamin A significantly reduced sputum conversion time or had other significant benefit.

Hanta virus infection during dengue virus infection outbreak in Indonesia.

AIM: To investigate which recent infection could have caused the present dengue-like symptoms, in adult patients clinically fulfilling the WHO criteria for dengue, in which serologically were not confirmed for dengue virus infections. METHODS: Prospective study. During an outbreak of dengue (between May 1995 and May 1996) 118 consecutive adults (>13 years) suspected by the WHO 1997 case definition of DF or DHF were investigated. Patients were examined for history of illness, physical and laboratory findings consisting of full blood counts, prothrombin time (PT), activated partial thromboplastin time (aPTT), liver function (bilirubin, ASAT, ALAT), renal function (creatinine), and serological assays included dengue, hantavirus, chikungunya, R. typhi, R. tsutsugamuchi, rubella virus, influenza A virus, and leptospira. RESULTS: In 58 of the total 118 patients, recent dengue virus infection was serologically confirmed. In 20 of the remaining 60 patients, we found serological evidence of another recent infection: hantavirus (5), chikungunya virus (2), R. typhi (5), R. tsutsugamuchi (2), rubella virus (3), influenza A virus (1), and leptospira (2). No evidence for recent infection with any of the mentioned agents was detected in the remaining 40 specimens. CONCLUSION: We conclude that based on clinical characteristics alone, it is not easy to diagnose dengue. Specific laboratory tests to differentiate dengue from other febrile illnesses are needed. Among these, in Indonesia hantavirus infection should be considered as well.

Laboratory diagnosis of pulmonary tuberculosis in TB and HIV endemic settings and the contribution of real time PCR for M. tuberculosis in bronchoalveolar lavage fluid.

BACKGROUND: Tuberculosis (TB) in Africa is increasing because of the human immunodeficiency virus (HIV) epidemic, and in HIV/AIDS patients it presents atypically. Pulmonary tuberculosis (PTB) in Africa is mainly diagnosed clinically, by chest radiograph or by sputum smear for acid fast bacilli (AFB). METHODS: We evaluated in 120 HIV-infected patients with chest infection the diagnostic accuracy of AFB smear of sputum and bronchoalveolar lavage (BAL) fluid, sputum Mycobacterium tuberculosis (MTB) culture, real-time PCR and MycoDot serological test, using MTB culture of BAL fluid as gold standard. We correlated PCR cycle threshold values (C(T)) to the culture results. Retrospectively, we evaluated the development of active TB in patients with positive PCR but negative culture. RESULTS: Culture of BAL fluid identified 28 patients with PTB. Fifty-six patients could not produce adequate sputum. Sputum AFB smear and the serological test had sensitivities of 66.7% and 0%, respectively. PCR with C(T) 40 was positive in 73 patients, 27 of whom were also TB culture positive (96.4% sensitivity and 52.3% specificity of PCR). PCR with C(T) 32 had sensitivity of 85.7% and specificity of 90.9% to diagnose PTB in BAL. No patients with positive PCR but negative culture developed active TB during 18 months follow-up. CONCLUSION: In these HIV-infected patients, AFB smear and serology had very low sensitivities. PCR of BAL with C(T) value 32 had improved specificity to diagnose active PTB. A prospective follow-up study is warranted in TB/HIV endemic settings, applying real time PCR to both sputum and BAL.

M. tuberculosis genotypic diversity and drug susceptibility pattern in HIV-infected and non-HIV-infected patients in northern Tanzania.

BACKGROUND: Tuberculosis (TB) is a major health problem and HIV is the major cause of the increase in TB. Sub-Saharan Africa is endemic for both TB and HIV infection. Determination of the prevalence of M. tuberculosis strains and their drug susceptibility is important for TB control.TB positive culture, BAL fluid or sputum samples from 130 patients were collected and genotyped. The spoligotypes were correlated with anti-tuberculous drug susceptibility in HIV-infected and non-HIV patients from Tanzania. RESULTS: One-third of patients were TB/HIV co-infected. Forty-seven spoligotypes were identified. Fourteen isolates (10.8%) had new and unique spoligotypes while 116 isolates (89.2%) belonged to 33 known spoligotypes. The major spoligotypes contained nine clusters: CAS1-Kili 30.0%, LAM11- ZWE 14.6%, ND 9.2%, EAI 6.2%, Beijing 5.4%, T-undefined 4.6%, CAS1-Delhi 3.8%, T1 3.8% and LAM9 3.8%. Twelve (10.8%) of the 111 phenotypically tested strains were resistant to anti-TB drugs. Eight (7.2%) were monoresistant strains: 7 to isoniazid (INH) and one to streptomycin. Four strains (3.5%) were resistant to multiple drugs: one (0.9%) was resistant to INH and streptomycin and the other three (2.7%) were MDR strains: one was resistant to INH, rifampicin and ethambutol and two were resistant to all four anti-TB drugs. Mutation in the katG gene codon 315 and the rpoB hotspot region showed a low and high sensitivity, respectively, as predictor of phenotypic drug resistance. CONCLUSION: CAS1-Kili and LAM11-ZWE were the most common families. Strains of the Beijing family and CAS1-Kili were not or least often associated with resistance, respectively. HIV status was not associated with spoligotypes, resistance or previous TB treatment.

The toll-like receptor 4 Asp299Gly variant and tuberculosis susceptibility in HIV-infected patients in Tanzania.

Toll-like receptor 4 (TLR4) plays an important role in the pattern recognition of Mycobacterium tuberculosis, and polymorphisms in the TLR4 gene influence the function of the receptor. We therefore investigated in a cohort of HIV-infected Tanzanian patients whether the Asp299Gly TLR4 polymorphism is associated with the development of active tuberculosis. We found a greater risk of developing active tuberculosis as well as a reduction in CD4 T-cell counts in patients with the Asp299Gly TLR4 polymorphism.

Cytokines related to nutritional status in patients with untreated pulmonary tuberculosis in Indonesia.

Although several studies have dealt with the patterns of cytokine production in tuberculosis, little is known about the association between nutrient deficiencies and cytokines in tuberculosis. The objective of this study was to assess the concentration of cytokines related to nutritional status during tuberculosis. In 41 untreated tuberculosis patients and matched healthy controls in an urban hospital in Indonesia, we measured: height and weight, parameters of iron, vitamin A and zinc; and cytokines concentrations in the circulation and production in whole blood cultures. Plasma interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were significantly higher in patients than in controls. Patients with cavities (n=26) had higher concentrations of IL-6 than patients without cavities (n=15). Body mass index <18.5 kg/m2 was associated with high concentrations of tumor necrosis factor-alpha (TNF-alpha) and IL-6. Anaemia was associated with high concentrations of IL-6 and IL-1ra. Zinc deficiency was associated with high LPS-stimulated production of TNF-alpha and IL-1ra. Marginal plasma retinol concentrations were associated with high concentrations of IL-6 after LPS stimulation. In conclusion, low concentrations of micronutrients in tuberculosis were associated with increased cytokine production. An intervention study would allow causality to be examined.

Serum and BAL macrophage migration inhibitory factor levels in HIV infected Tanzanians with pulmonary tuberculosis or other lung diseases.

Macrophage migration inhibitory factor (MIF) activates macrophages, promotes delayed-type hypersensitivity reaction, and regulates Th1/Th2 balance in inflammatory response. Serum MIF concentration is high in patients with pulmonary tuberculosis (PTB). Higher MIF levels are associated with high mortality. No study has addressed MIF levels and its role in PTB/HIV-co infection. We determined serum and BAL MIF levels in Tanzanian HIV-infected patients with and without PTB, and correlated the levels with 1-month outcome. We compared with serum MIF levels of HIV seronegative patients with PTB and of healthy controls. All HIV-infected patients irrespective of PTB infection had significantly higher serum MIF levels than HIV-seronegative patients with PTB, and than healthy controls. In HIV seropositive patients low serum MIF levels were associated with high 1-month mortality. In conclusion, HIV infection was associated with elevated serum MIF levels regardless of PTB. Low serum MIF levels were associated with high mortality.

Capacity of health-care facilities to deliver HIV treatment and care services, Northern Tanzania, 2004.

Few data exist on the current capacity of Tanzanian health-care facilities to deliver antiretroviral therapy (ART). We evaluated this capacity among Northern Zone facilities in 2004 using a questionnaire that addressed human resources, clinical facilities and services, and laboratory capacity. Of 19 facilities surveyed, nine (47%) had staff trained to manage ART and three (16%) prescribed ART. Two (11%) offered CD4 counts, five (26%) offered liver function tests, 16 (84%) offered chest radiography, and 18 (95%) offered acid-fast sputum staining. Of 12 (67%) facilities offering outpatient HIV/AIDS services, 12 (100%) provided co-trimoxazole to outpatients and six (50%) provided isoniazid (INH). All 19 (100%) facilities offered rapid HIV tests and full blood pictures. Overall in 2004, facilities needed strengthening to increase staff training in ART management and to implement INH for treatment of latent tuberculosis. Laboratory facilities for ART monitoring were inadequate, and outpatient ART was limited.

Cytokine patterns during dengue shock syndrome.

OBJECTIVE: To investigate the patterns of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, interferon-gamma (IFN-gamma) and interleukin-1 receptor antagonist (IL-1Ra) during the course of dengue shock syndrome. DESIGN: Prospective clinical study. SETTING: Pediatric Intensive Care Unit, Dr. Kariadi Hospital, the university hospital of Diponegoro University, Semarang, Indonesia. PATIENTS: Fifty children with dengue shock syndrome. MEASUREMENTS: The plasma concentration and the ex vivo production, with and without lipopolysaccharide (LPS), of TNF-alpha, IL-1beta and IL-1Ra were measured in duplicate by nonequilibrium radioimmunoassay (RIA); IFN-gamma and IL-6 were measured by ELISA. RESULTS: During the acute phase, the plasma concentrations and the ex vivo production without LPS of IL-1Ra were considerably elevated and returned to normal on recovery. However, the ex vivo LPS-stimulated production of the proinflammatory cytokines TNF-alpha and IL-1beta were considerably depressed. Also, these concentrations returned towards normal on recovery. In non-survivors, the plasma concentrations of IL-6 and IL-1Ra were significantly higher than in survivors (p = 0.00001 and p = 0.0005, respectively). In addition, the ex vivo production of IL-1Ra in non-survivors was significantly higher than in survivors, both without LPS stimulation (p = 0.0008) and with LPS (p < 0.004). IL-1Ra was significantly associated with mortality (p = 0.007). CONCLUSION: Since IL-1Ra was significantly associated with mortality, this measurement may be used as an index of disease severity in dengue shock syndrome.

Persistence of Salmonellae in blood and bone marrow: randomized controlled trial comparing ciprofloxacin and chloramphenicol treatments against enteric fever.

We performed a randomized controlled trial involving 55 adult patients with enteric fever to compare ciprofloxacin and chloramphenicol. Blood and bone marrow cultures and cytokine profiles during therapy were done to compare the clinical and bacteriological efficacies of these drugs. All patients were randomly assigned to receive chloramphenicol (500 mg four times a day orally) for 14 days or ciprofloxacin (500 mg twice a day orally) for 7 days. In each treatment group, patients were subsequently randomized to have blood and bone marrow cultured after either 3 or 5 days of treatment. Twenty-seven patients received chloramphenicol, and 28 received ciprofloxacin. The two groups were similar in terms of baseline characteristics. No significant differences in clinical cure and time to defervescence were found. All strains isolated were susceptible to both antibiotics. Although ciprofloxacin was more effective in the elimination of Salmonella enterica serovars Typhi and Paratyphi A from bone marrow than chloramphenicol, there was still an impressive persistence of Salmonella in the bone marrow culture (67%). In the ciprofloxacin-treated patients the suppressed cytokine production capacity showed a trend to normalize earlier than in patients treated with chloramphenicol.

Respiratory symptoms and dust exposure among male workers in small-scale wood industries in Tanzania.

Few studies have assessed respiratory symptoms and dust exposure levels in small-scale wood industry workers in Africa. We interviewed 546 workers exposed to wood dust and 565 control subjects using a respiratory health questionnaire. Inhalable dust measurements were collected for 106 workers. The dust exposure was high, and job title-based geometric mean exposure levels ranged from 2.9 to 22.8 mg/m3. Prevalence of respiratory symptoms in the previous 12 months was significantly higher in the exposed group compared with the nonexposed office workers. Allergy and sensitivity symptoms were reported regularly in the exposed group with Odds ratios and 95% confidence intervals (CIs) varying from 2.4 (95% CI = 1.8-3.1) for low- and 2.7 (1.8-4.0) for high-exposure groups compared with controls. We conclude that working in the small-scale wood industry in Tanzania is associated with an increased prevalence of respiratory symptoms.

Impaired fibrinolysis in the pathogenesis of dengue hemorrhagic fever.

The mechanisms contributing to bleeding complications in dengue hemorrhagic fever were studied by investigating the pattern of activation of the coagulation and fibrinolytic systems in 50 children with severe dengue hemorrhagic fever. Thirteen patients (26%) died, and activation of coagulation was most pronounced in the deceased group. Fibrinolysis was also activated, but this activation was relatively weak compared with that of coagulation as a result of persistently high plasminogen activator inhibitor levels. Plasminogen activator inhibitor also prevented a switch from the procoagulant to the profibrinolytic state in lethal dengue hemorrhagic fever, which was further enhanced by an acquired protein C deficiency. The present study is the first to demonstrate such a mechanism in a viral infection. This imbalance between coagulation and fibrinolysis may be used as a prognostic marker, but it may also be a target for future therapeutic intervention.

A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status.

BACKGROUND: The results of cross-sectional studies indicate that micronutrient deficiencies are common in patients with tuberculosis. No published data exist on the effect of vitamin A and zinc supplementation on antituberculosis treatment. OBJECTIVE: Our goal was to investigate whether vitamin A and zinc supplementation increases the efficacy of antituberculosis treatment with respect to clinical response and nutritional status. DESIGN: In this double-blind, placebo-controlled trial, patients with newly diagnosed tuberculosis were divided into 2 groups. One group (n = 40) received 1500 retinol equivalents (5000 IU) vitamin A (as retinyl acetate) and 15 mg Zn (as zinc sulfate) daily for 6 mo (micronutrient group). The second group (n = 40) received a placebo. Both groups received the same antituberculosis treatment recommended by the World Health Organization. Clinical examinations, assessments of micronutrient status, and anthropometric measurements were carried out before and after 2 and 6 mo of antituberculosis treatment. RESULTS: At baseline, 64% of patients had a body mass index (in kg/m(2)) < 18.5, 32% had plasma retinol concentrations < 0.70 micromol/L, and 30% had plasma zinc concentrations < 10.7 micromol/L. After antituberculosis treatment, plasma zinc concentrations were not significantly different between groups. Plasma retinol concentrations were significantly higher in the micronutrient group than in the placebo group after 6 mo (P < 0.05). Sputum conversion (P < 0.05) and resolution of X-ray lesion area (P < 0.01) occurred earlier in the micronutrient group. CONCLUSION: Vitamin A and zinc supplementation improves the effect of tuberculosis medication after 2 mo of antituberculosis treatment and results in earlier sputum smear conversion.

Changes in the plasma lipid profile as a potential predictor of clinical outcome in dengue hemorrhagic fever.

In 50 consecutive children admitted to the intensive care unit with the clinical diagnosis of dengue hemorrhagic fever (DHF)/dengue shock syndrome (grade III or IV), 20 patients with mild DHF (grade I or II), and 20 healthy control patients, the plasma lipid profile was measured. Levels of total plasma cholesterol, high-density lipoprotein, and low-density lipoprotein were significantly decreased in patients with the severest cases, compared with patients with mild DHF and healthy controls. Changes in the plasma lipid profile differentiate between patients with different stages of DHF disease severity and could be used as a potential predictor for clinical outcome.

Evaluation of a simple and rapid dipstick assay for the diagnosis of typhoid fever in Indonesia.

To support the clinical diagnosis of typhoid fever in Indonesia, where most hospitals and health centres have no facilities for culture, a rapid dipstick assay for the detection of Salmonella typhi-specific IgM antibodies was evaluated on serum samples from 127 patients clinically suspected of having typhoid fever. In a single blood sample collected on admission to hospital, the sensitivity of the dipstick assay was 69.8% when compared with bone marrow culture and 86.5% when compared with blood culture. The specificity as calculated for the group of patients with suspected typhoid fever but a negative culture result was calculated to be 88.9%. Of 80 patients with febrile illnesses other than typhoid fever, reactivity was observed in only three patients with dengue haemorrhagic fever. The assay uses stabilised components that can be stored outside the refrigerator, does not require special equipment, and may be of use in remote health facilities that have no culture facilities.

The role of cytokines in activation of coagulation and fibrinolysis in dengue shock syndrome.

In a prospective clinical study of 50 patients with Dengue Shock Syndrome (DSS), we investigated the association of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), and IL-6 with activation markers of coagulation (F1+2 and TATc) and fibrinolysis (t-PA, PAPc, and D-dimer). We found that TNF-alpha, IL-1beta and Il-1Ra, but not IL-6, concentrations were elevated in the circulation during the early stage of infection and at discharge from hospital. TNF-alpha was significantly associated with D-dimer, an activation marker of fibrinolysis (p < 0.003), but not with activation markers of coagulation. IL-1beta was significantly associated with t-PA (p < 0.03). IL-1Ra was significantly associated with F1+2, TATc (p < 0.04 and p < 0.02, respectively), whereas IL-6 was significantly associated with both, activation markers of coagulation (F1+2; p < 0.03) and fibrinolysis (PAPc; p = 0.002). Our data are in line with studies in bacterial sepsis. In severe dengue virus infection the same cytokines are involved in the onset and regulation of hemostasis.