Drug-induced immune thrombocytopenia associated with use of tyrosine kinase inhibitor imatinib

AbstractSince their introduction in the late 1990s, tyrosine kinase Inhibitors (TKIs) have been widely used for the treatment of various cancers. The side effects of the TKI imatinib are well-documented in the literature and include fatigue, skin rash, myelosuppression, and derangement of liver enzymes. Rare side effects have been observed in the postmarketing surveillance and include cardiac tamponade and Steven Johnson Syndrome. In the present report, we present a rare case of imatinib-associated immune thrombocytopenia leading to severe intra-abdominal bleeding. A brief account of similar cases of TKI drug-induced immune thrombocytopenia (DIT) is also described

Cytoadherence in paediatric malaria: ABO blood group, CD36, and ICAM1 expression and severe Plasmodium falciparum infection

As a leading cause of childhood mortality worldwide, selection pressure by Plasmodium falciparum continues to shape the human genome. Severe disturbances within the microcirculation result from the adhesion of infected erythrocytes to host receptors on monocytes, platelets, and endothelium. In this prospective study, we compared expression of all major host cytoadhesion receptors among Ugandan children presenting with uncomplicated malaria (n = 1078) versus children with severe malaria (n = 855), including cerebral malaria (n = 174), severe anaemia (n = 522), and lactic acidosis (n = 154). We report a significant survival advantage attributed to blood group O and increased monocyte expression of CD36 and ICAM1 (CD54). The high case fatality rate syndromes of cerebral malaria and lactic acidosis were associated with high platelet CD36 expression and thrombocytopenia, and severe malaria anaemia was characterized by low ICAM1 expression. In a logistic regression model of disease severity, odds ratios for the mitigating effects of blood group O, CD36, and ICAM1 phenotypes were greater than that of sickle haemoglobin. Host genetic adaptations to Plasmodium falciparum suggest new potential malaria treatment strategies

Inter-Relationships of Cardinal Features and Outcomes of Symptomatic Pediatric Plasmodium falciparum Malaria in 1,933 Children in Kampala, Uganda

Malaria remains a challenging diagnosis with variable clinical presentation and a wide spectrum of disease severity. Using a structured case report form, we prospectively assessed 1,933 children at Mulago Hospital in Kampala, Uganda with acute Plasmodium falciparum malaria. Children with uncomplicated malaria significantly differed from those with severe disease for 17 features. Among 855 children with severe disease, the case-fatality rate increased as the number of severity features increased. Logistic regression identified five factors independently associated with death: cerebral malaria, hypoxia, severe thrombocytopenia, leukocytosis, and lactic acidosis. Cluster analysis identified two groups: one combining anemia, splenomegaly, and leukocytosis; and a second group centered on death, severe thrombocytopenia, and lactic acidosis, which included cerebral malaria, hypoxia, hypoglycemia, and hyper-parasitemia. Our report updates previous clinical descriptions of severe malaria, quantifies significant clinical and laboratory inter-relationships, and will assist clinicians treating malaria and those planning or assessing future research (NCT00707200) (www.clinicaltrials.gov)

Dysregulation of the haem-haemopexin axis is associated with severe malaria in a case-control study of Ugandan children.

BACKGROUND: Malaria is associated with haemolysis and the release of plasma haem. Plasma haem can cause endothelial injury and organ dysfunction, and is normally scavenged by haemopexin to limit toxicity. It was hypothesized that dysregulation of the haem-haemopexin pathway contributes to severe and fatal malaria infections. METHODS: Plasma levels of haemin (oxidized haem), haemopexin, haptoglobin, and haemoglobin were quantified in a case-control study of Ugandan children with Plasmodium falciparum malaria. Levels at presentation were compared in children with uncomplicated malaria (UM; n = 29), severe malarial anaemia (SMA; n = 27) or cerebral malaria (CM; n = 31), and evaluated for utility in predicting fatal (n = 19) vs non-fatal (n = 39) outcomes in severe disease. A causal role for haemopexin was assessed in a pre-clinical model of experimental cerebral malaria (ECM), following disruption of mouse haemopexin gene (hpx). Analysis was done using Kruskall Wallis tests, Mann-Whitney tests, log-rank tests for survival, and repeated measures ANOVA. RESULTS: In Ugandan children presenting with P. falciparum malaria, haemin levels were higher and haemopexin levels were lower in SMA and CM compared to children with UM (haemin, p \u3c 0.01; haemopexin, p \u3c 0.0001). Among all cases of severe malaria, elevated levels of haemin and cell-free haemoglobin at presentation were associated with subsequent mortality (p \u3c 0.05). Compared to ECM-resistant BALB/c mice, susceptible C57BL/6 mice had lower circulating levels of haemopexin (p \u3c 0.01), and targeted deletion of the haemopexin gene, hpx, resulted in increased mortality compared to their wild type littermates (p \u3c 0.05). CONCLUSIONS: These data indicate that plasma levels of haemin and haemopexin measured at presentation correlate with malaria severity and levels of haemin and cell-free haemoglobin predict outcome in paediatric severe malaria. Mechanistic studies in the ECM model support a causal role for the haem-haemopexin axis in ECM pathobiology

Combinations of Host Biomarkers Predict Mortality among Ugandan Children with Severe Malaria: A Retrospective Case-Control Study

Background: Severe malaria is a leading cause of childhood mortality in Africa. However, at presentation, it is difficult to predict which children with severe malaria are at greatest risk of death. Dysregulated host inflammatory responses and endothelial activation play central roles in severe malaria pathogenesis. We hypothesized that biomarkers of these processes would accurately predict outcome among children with severe malaria. Methodology/Findings: Plasma was obtained from children with uncomplicated malaria (n = 53), cerebral malaria (n = 44) and severe malarial anemia (n = 59) at time of presentation to hospital in Kampala, Uganda. Levels of angiopoietin-2, von Willebrand Factor (vWF), vWF propeptide, soluble P-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), soluble endoglin, soluble FMS-like tyrosine kinase-1 (Flt-1), soluble Tie-2, C-reactive protein, procalcitonin, 10 kDa interferon gamma-induced protein (IP-10), and soluble triggering receptor expressed on myeloid cells-1 (TREM-1) were determined by ELISA. Receiver operating characteristic (ROC) curve analysis was used to assess predictive accuracy of individual biomarkers. Six biomarkers (angiopoietin-2, soluble ICAM-1, soluble Flt-1, procalcitonin, IP-10, soluble TREM-1) discriminated well between children who survived severe malaria infection and those who subsequently died (area under ROC curve>0.7). Combinational approaches were applied in an attempt to improve accuracy. A biomarker score was developed based on dichotomization and summation of the six biomarkers, resulting in 95.7% (95% CI: 78.1-99.9) sensitivity and 88.8% (79.7-94.7) specificity for predicting death. Similar predictive accuracy was achieved with models comprised of 3 biomarkers. Classification tree analysis generated a 3-marker model with 100% sensitivity and 92.5% specificity (cross-validated misclassification rate: 15.4%, standard error 4.9%). Conclusions: We identified novel host biomarkers of pediatric severe and fatal malaria (soluble TREM-1 and soluble Flt-1) and generated simple biomarker combinations that accurately predicted death in an African pediatric population. While requiring validation in further studies, these results suggest the utility of combinatorial biomarker strategies as prognostic tests for severe malaria

Bleeding complications from the direct oral anticoagulants

Abstract Background Direct oral anticoagulants (DOACs) are now standard of care for the management of thromboembolic risk. A prevalent issue of concern is how to manage direct oral anticoagulant (DOAC)-associated bleeding for which there is no specific antidote available for clinical use. We conducted a retrospective case series to describe the Toronto, Canada multicenter experience with bleeding from dabigatran or rivaroxaban. Methods Retrospective chart review of DOAC bleeding necessitating referral to hematology and/or transfusion medicine services at five large University of Toronto affiliated academic hospitals from January 2011 to December 2013. Results Twenty-six patients with DOAC bleeding were reviewed; 42 % bleeds intracranial and 50 %, gastrointestinal. All patients had at least one risk factor associated with DOAC bleeding reported in previous studies. Inconsistent bleed management strategies were evident. Median length of hospital stay was 11 days (1–90). Five thromboembolic events occurred after transfusion based-hemostatic therapy and there were six deaths. Conclusions Management of DOAC bleeding is variable. Clinical trial data regarding DOAC reversal is needed to facilitate optimization and standardization of bleeding treatment algorithms

Acute Lung Injury during Antithymocyte Globulin Therapy for Aplastic Anemia

The case of a 33-year-old man with aplastic anemia who experienced recurrent episodes of hypoxemia and pulmonary infiltrates during infusions of antithymocyte globulin (ATG) is described. With the use of high-dose corticosteroids, the patient’s original episodes resolved, and were subsequently prevented before additional administrations of ATG. Rare reports of an association between ATG and acute lung injury are found in the literature, but this is the first report of successful steroid-supported re-exposure. Although the mechanism of ATG-related acute lung injury remains uncertain, it may be parallel to the mechanism of transfusion-related acute lung injury because the pathogenesis of the latter relies, in part, on antileukocyte antibodies. ATG-related toxicity should be included in the differential diagnosis of new, infusion-associated pulmonary infiltrates, and corticosteroids may be a useful therapeutic consideration in the management

Acute Lung Injury during Antithymocyte Globulin Therapy for Aplastic Anemia

The case of a 33-year-old man with aplastic anemia who experienced recurrent episodes of hypoxemia and pulmonary infiltrates during infusions of antithymocyte globulin (ATG) is described. With the use of high-dose corticosteroids, the patient’s original episodes resolved, and were subsequently prevented before additional administrations of ATG. Rare reports of an association between ATG and acute lung injury are found in the literature, but this is the first report of successful steroid-supported re-exposure. Although the mechanism of ATG-related acute lung injury remains uncertain, it may be parallel to the mechanism of transfusion-related acute lung injury because the pathogenesis of the latter relies, in part, on antileukocyte antibodies. ATG-related toxicity should be included in the differential diagnosis of new, infusion-associated pulmonary infiltrates, and corticosteroids may be a useful therapeutic consideration in the management.Peer Reviewe

The effect of blood storage age on treatment of lactic acidosis by transfusion in children with severe malarial anaemia: a pilot, randomized, controlled trial

<p>Abstract</p> <p>Background</p> <p>Severe malarial anaemia requiring blood transfusion is a life-threatening condition affecting millions of children in sub-Saharan Africa. Up to 40% of children with severe malarial anaemia have associated lactic acidosis. Lactic acidosis in these children is strongly associated with fatal outcomes and is corrected by blood transfusion. However, it is not known whether the storage age of blood for transfusion affects resolution of lactic acidosis. The objective of this pilot study was to evaluate the effect of blood storage age on resolution of lactic acidosis in children with severe malarial anaemia and demonstrate feasibility of conducting a large trial.</p> <p>Methods</p> <p>Children aged six to 59 months admitted to Acute Care Unit of Mulago Hospital (Kampala, Uganda) with severe malarial anaemia (haemoglobin ≤ 5 g/dL) and lactic acidosis (blood lactate ≥5 mmol/L), were randomly assigned to receive either blood of short storage age (one to 10 days) or long storage age (21–35 days) by gravity infusion. Seventy-four patients were enrolled and randomized to two equal-sized study arms. Physiological measurements, including blood lactate, oxygen saturation, haemoglobin, and vital signs, were taken at baseline, during and after transfusion. The primary outcome variable was the proportion of children whose lactic acidosis resolved by four hours after transfusion.</p> <p>Results</p> <p>Thirty-four of 37 (92%) of the children in the short storage treatment arm compared to 30/37 (81%) in the long storage arm achieved a blood lactate <5 mmol/L by four hours post transfusion (p value = 0.308). The mean time to lactic acidosis resolution was 2.65 hours (95% CI; 2.25–3.05) in the short storage arm, compared to 3.35 hours (95% CI; 2.60–4.10) in the long storage arm (p value = 0.264).</p> <p>Conclusion</p> <p>Pilot data suggest that among children with severe malarial anaemia and lactic acidosis transfused with packed red blood cells, the storage age of blood does not affect resolution of lactic acidosis. The results support a larger and well-powered study which is under way.</p> <p>Trial registration</p> <p>clinicaltrials.gov NCT01580111</p

Transfusion-related Acute Lung Injury in the Perioperative Patient

Transfusion-related acute lung injury is a leading cause of death associated with the use of blood products. Transfusion-related acute lung injury is a diagnosis of exclusion which can be difficult to identify during surgery amid the various physiologic and pathophysiologic changes associated with the perioperative period. As anesthesiologists supervise delivery of a large portion of inpatient prescribed blood products, and since the incidence of transfusion-related acute lung injury in the perioperative patient is higher than in nonsurgical patients, anesthesiologists need to consider transfusion-related acute lung injury in the perioperative setting, identify at-risk patients, recognize early signs of transfusion-related acute lung injury, and have established strategies for its prevention and treatment