Monoclonal antibody against tissue factor shortens tissue plasminogen activator lysis time and prevents reocclusion in a rabbit model of carotid artery thrombosis.

BACKGROUND: Tissue factor (TF)-dependent activation of the coagulation is important in the pathophysiology of intravascular thrombus formation. We tested the effects of a monoclonal antibody against TF (AP-1) on lysis time induced by tissue-type plasminogen activator (TPA) and on reocclusion rate in a rabbit model of carotid artery thrombosis. METHODS AND RESULTS: Intravascular thrombosis was obtained by placing an external constrictor around carotid arteries with endothelial injury. Carotid blood flow velocity ws measured continuously with a Doppler flow probe. Thirty minutes after thrombus formation, the rabbits received either AP-1 (0.15 mg/kg IV, n=8) or placebo (n=8). All rabbits also received TPA (80 microg/kg bolus plus 8 microg x kg(-1) x min(-1) infusion for up to 90 minutes or until reperfusion was achieved) and heparin (200 U/kg IV as a bolus). At reperfusion, TPA was discontinued, and the rabbits were followed for an additional 90 minutes. AP-1 shortened lysis time from 44+/-8 minutes (mean+/-SEM) in control rabbits to 26+/-7 minutes in AP-1 rabbits (P<.01). Reocclusion occurred in all control rabbits in 10+/-3 minutes, whereas it occurred in only two of eight AP-1 treated rabbits in 72 and 55 minutes (P<.01). No changes in prothrombin time and ex vivo platelet aggregation in response to various agonists were observed after AP-1 administration, indicating the absence of systemic effects by this antibody. CONCLUSIONS: TF exposure and activation of the extrinsic coagulation pathway play an important role in prolonging lysis time and mediating reocclusion after thrombolysis in this model. AP-1, a monoclonal antibody against TF, might be suitable as adjunctive therapy to TPA.

Iron nutritional status of adolescent girls from rural area and urban slum.

Iron nutritional status of adolescent girls belonging to an urban slum and rural areas was assessed by measuring serum ferritin levels. Overall anemia was observed in 25% of the girls irrespective of their urban rural residence. A higher percentage of rural girls (37.5%) especially below the age of 12 years showed evidence of anemia. Thereafter, the prevalence was similar in both urban and rural girls who had not attained menarche. With increasing age, urban girls who had attained menarche showed an increase in the prevalence of anemia. The prevalence of iron deficiency (serum ferritin < 12 micrograms/dl) showed a progressive increase from 60% at < 12 to 28% at > 14 yrs especially in the girls not attained menarche in the girls not attained menarche in the rural area. Overall iron deficiency was of much higher order in the rural girls irrespective of the menarcheal status. Distribution of iron/folate tablets to cover girl population may go a long way to correct the anemia and iron deficiency in the vulnerable groups.

A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries.

Tissue factor (TF) is a transmembrane protein that binds factor VII/VIIa, thus activating the extrinsic blood coagulation pathway. Since this pathway appears to be involved in the formation of intravascular thrombi, the anti-rabbit TF monoclonal antibody, AP-1, was produced and tested as an antithrombotic agent in a rabbit model of recurrent intravascular thrombosis. In this model, a plastic constrictor is positioned around the injured rabbit carotid arteries, and flow is monitored with a Doppler flow probe. This produces cyclic flow variation (CFV) in the carotid artery, which is caused by recurrent formation and dislodgment of thrombi at the site of the stenosis. After monitoring CFV pattern for 30 minutes, AP-1 was infused intravenously into nine rabbits at doses of 0.05 to 1.5 mg/kg body weight, and a control monoclonal antibody that does not react with rabbit TF was infused into four additional rabbits. In all rabbits receiving AP-1, CFV was abolished, and a steady normal blood flow was restored, indicating that thrombus formation had been blocked by AP-1. By contrast, in all rabbits that received the control monoclonal antibody, CFV continued unaltered. There was no change in the partial thromboplastin time and ex vivo platelet aggregation to several different agonists after infusion of AP-1, indicating an absence of systemic effects on the coagulation process. We conclude that activation of the extrinsic coagulation pathway has a key role in triggering intravascular thrombosis and that an anti-TF monoclonal antibody is an effective antithrombotic agent that could have therapeutic potential for humans.

Hyperferritinemia in pregnancy induced hypertension and eclampsia.

A study of serum iron and ferritin levels in Indian women with pregnancy induced hypertension (PIH) (mild/severe) and eclampsia compared with controls of similar gestational ages, revealed that mean serum iron was elevated slightly in PIH and significantly in eclampsia as compared to controls. Mean ferritin levels were significantly elevated both in PIH and eclampsia as compared to controls indicating that ferritin measurement in PIH and eclampsia would not reflect iron nutritional status. Lack of significant changes in liver enzymes and in hemoconcentration in PIH and eclampsia indicate that liver damage and altered hemodynamics only play a partial role in causing hyperferritinemia. Possible role of placental ferritin, being released as a result of placental damage in these conditions seems to be an area needing further research.

Iron nutritional status of preschool children.

Low hemoglobin and low MCHC levels were indicative of high incidence of iron deficiency in preschool children. The extent of iron deficiency as assessed by serum ferritin and free erythrocyte protoporphyrin showed a different trend. While FEP levels were highly suggestive of extensive iron deficiency (in 40-45% of children below the age of 5 years), low serum ferritin was seen in only 16-20% of children. The discrepant finding of high serum ferritin, and high erythrocyte protoporphyrin despite low MCHC in the present study, possibly reflects iron deficiency status along with chronic infection resulting in hyperferritinemia and hyperprotoporphyrinemia. It may be also due to associated folate deficiency resulting in non utilization of iron leading to the elevated levels of protoporphyrin.

Plasma ferritin in the assessment of iron status of Indian infants.

In order to assess the iron nutritional status of infants, plasma ferritin levels were measured in the infants and children at different time intervals till two years of age from two different socio economic groups. While ferritin levels at 3-4 months age were significantly higher in upper income group infants, levels were almost similar in the subsequent infancy between the two income groups. A close correlation was seen between ferritin levels of mothers and infants at 1-3 months of age (p less than 0.001). Prenatal iron supplements (oral or parenteral) resulted in higher ferritin levels at 4-6 months age as compared to placebo group. While the infants born to mothers receiving parenteral iron did not show any evidence of iron deficiency (serum ferritin levels less than 12 ng/ml), 23.5 and 25.0% of infants in oral iron and placebo group had evidence of iron deficiency between 6-12 months. Thus it would appear that improving the iron status of mothers during pregnancy will have significant impact on the iron status of breast fed infants till 6 months.