Whole blood transfusion improves vascular integrity and increases survival in artemether-treated experimental cerebral malaria

Abstract

Pathological features observed in both human and experimental cerebral malaria (ECM) are endothelial dysfunction and changes in blood components. Blood transfusion has been routinely used in patients with severe malarial anemia and can also benefit comatose and acidotic malaria patients. In present study Plasmodium berghei-infected mice were transfused intraperitoneally with 200 µL of whole blood along with 20 mg/kg of artemether. ECM mice showed severe thrombocytopenia and decreases in hematocrit. Artemether treatment markedly aggravated anemia within 24 hours. Whole blood administration significantly prevented further drop in hematocrit and partially restored the platelet count. Increased levels of plasma angiopoietin-2 (Ang-2) remained high 24 hours after artemether treatment but returned to normal levels 24 hours after blood transfusion, indicating reversal to quiescence. Ang-1 was depleted in ECM mice and levels were not restored by any treatment. Blood transfusion prevented the aggravation of the breakdown of blood brain barrier after artemether treatment and decreased spleen congestion without affecting splenic lymphocyte populations. Critically, blood transfusion resulted in markedly improved survival of mice with ECM (75.9% compared to 50.9% receiving artemether only). These findings indicate that whole blood transfusion can be an effective adjuvant therapy for cerebral malaria.

Intravenous whole blood transfusion results in faster recovery of vascular integrity and increased survival in experimental cerebral malaria

“…Therefore, in the present study we performed whole blood transfusion as adjunctive therapy to artemether in mice with late-stage ECM by means of intravenous injection of heparinized blood using a technique of right jugular vein injection. The results show that the outcome in terms of survival, which reached 90%, was markedly improved compared to intraperitoneal transfusion as previously described [15], and recovery of hematological and vascular parameters was also more prominent.…”

“…PbA-infected C57BL/6 mice with ECM, using intraperitoneal route for blood administration, resulting in 76% survival (compared to 51% survival in ECM mice receiving artemether only) [15]. The present study demonstrates that a single intrajugular transfusion of whole blood along with artemether resulted in a 90% survival of mice with ECM.…”

“…Endothelial protein markers such as angiopoietins have been found to play a critical physiological role in maintenance of vascular integrity. It has been previously shown that the levels of the endothelial cell quiescence promoter ANG-1 are depleted, whereas the levels of endothelial cell activation/inflammation promoter ANG-2 are elevated, in mice with ECM [15]. It is noteworthy that blood transfusion given intraperitoneally had no effect on restoring ANG-1 levels, but when given intravenously a timid but significant increase in ANG-1 levels was observed after 6 hours, and a more robust increase was seen at 24 hours.…”

“…In a first set of experiments, on day 6 post inoculation, hypothermic mice (31-36 °C) [25] were randomly allocated in three equal groups to define the effect of treatments on survival rate: i) artemether only; ii) artemether plus 200 μL of blood and; iii) artemether plus 200 μL of plasma. The amount of blood and plasma to be transfused was previously defined [15] (200 μL, approximately equivalent to 10 mL/kg) and were obtained from healthy C57BL/6 mice. Artemether 20mg/ml (Dafra Pharma GmbH, Basel, Switzerland) was injected intraperitoneally at 20 mg/kg [25].…”

“…Recently, a multicenter study in Africa showed that children hospitalized with severe P. falciparum malaria, particularly those with impaired consciousness or severe acidosis, benefited from whole blood transfusion, exhibiting increased survival [13,14]. Accordingly, whole blood transfusion, when administered intraperitoneally to mice with late-stage ECM also receiving artemether, resulted in increased survival and had beneficiary effects in terms of restoring hematocrit and markers of vascular health [15]. These findings with whole blood transfusion in ECM follow prior evidence indicating that interventions that restore vascular function are beneficial as adjunctive therapy in ECM [16][17][18][19].…”