Immature reticulocytes and its relevance to thrombosis

University of Liverpool, Prescot Road, Liverpool, L7 8XP, UK, .
Annals of Hematology (Impact Factor: 2.63). 07/2008; 87(12):1025-6. DOI: 10.1007/s00277-008-0524-6
Source: PubMed
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    ABSTRACT: To review the pathophysiology of thrombosis in hemolytic disease, and the efficacy of thromboprophylaxis in dogs with immune-mediated hemolytic anemia (IMHA). Computerized searches of Pubmed, INDEX VETERINARIUS, and the journal database of the Veterinary Information Network, and a manual search of bibliographies of published manuscripts. Experimental data suggest that hemolysis leads to the induction of the potent procoagulant tissue factor on monocytes and endothelial cells and subsequent activation of coagulation. In addition, damaged red cells, activated platelets, and small cell-derived membrane vesicles called microparticles may contribute to coagulation by providing membrane surfaces containing exposed anionic phospholipids that serve as docking sites for prothrombinase (factor Va-factor Xa) and tenase (factor VIIIa-factor IXa) complexes of the coagulation cascade. Some microparticles also contain tissue factor, further fueling coagulation. Thromboprophylaxis for hemolytic disease in people primarily targets the coagulation cascade rather than platelets, as most thromboemboli are of venous rather than arterial origin. The use of unfractionated heparin is closely monitored to ensure therapeutic levels are reached. Thromboembolic disease is a major factor affecting survival in dogs with IMHA. It is likely that hemolysis contributes to the prothrombotic state. Thrombosis occurs in both veins and arteries, with pulmonary thromboembolism (a venous thrombus) occurring very commonly. Evidence suggests that tissue factor mediates the development of the prothrombotic state. Heparin, and the anti-platelet agents aspirin, and clopidogrel have been used for thromboprophylaxis in dogs with IMHA. However, a lack of validated therapeutic endpoints and controlled studies make it difficult to determine if survival is affected or if 1 drug is more effective than another. Prospective clinical trials comparing individually adjusted heparin or other anti-coagulant drugs to anti-platelet drugs are needed to make evidence-based recommendations for thromboprophylaxis in dogs with IMHA.
    01/2013; 23(1):3-13. DOI:10.1111/j.1476-4431.2012.00824.x
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    ABSTRACT: We recently reported results that erythropoiesis-stimulating agent (ESA)-related thrombotic toxicities in preclinical species were not solely dependent on a high hematocrit (HCT) but also associated with increased ESA dose level, dose frequency, and dosing duration. In this article, we conclude that sequelae of an increased magnitude of ESA-stimulated erythropoiesis potentially contributed to thrombosis in the highest ESA dose groups. The results were obtained from two investigative studies we conducted in Sprague-Dawley rats administered a low (no thrombotic toxicities) or high (with thrombotic toxicities) dose level of a hyperglycosylated analog of recombinant human erythropoietin (AMG 114), 3 times weekly for up to 9 days or for 1 month. Despite similarly increased HCT at both dose levels, animals in the high-dose group had an increased magnitude of erythropoiesis measured by spleen weights, splenic erythropoiesis, and circulating reticulocytes. Resulting prothrombotic risk factors identified predominantly or uniquely in the high-dose group were higher numbers of immature reticulocytes and nucleated red blood cells in circulation, severe functional iron deficiency, and increased intravascular destruction of iron-deficient reticulocyte/red blood cells. No thrombotic events were detected in rats dosed up to 9 days suggesting a sustained high HCT is a requisite cofactor for development of ESA-related thrombotic toxicities.
    Toxicologic Pathology 05/2013; 42(3). DOI:10.1177/0192623313486319 · 2.14 Impact Factor
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    ABSTRACT: The red cell distribution width (RDW) is a biomarker strongly associated with poor outcome in inflammatory and thrombotic diseases. Subarachnoid hemorrhage (SAH) is both an inflammatory and thrombotic state in which many biomarkers have been studied. In this exploratory pilot study, we sought to determine whether RDW predicts poor outcome in patients with SAH. Patients with moderate-to-severe SAH were prospectively enrolled in an observational study of biomarkers and outcome. CBC, ESR, high sensitivity CRP, D-dimer, and fibrinogen were obtained on post-bleed days (PBD) 1, 3, 5, 7, and 10. Poor outcome was defined as a modified Rankin score of 3-6 at 90-days. Of 40 patients, 5 (12.5 %) died and 19 (47.5 %) had a poor outcome. RDW (p = 0.046) when measured serially over the study period, was significantly higher among patients with poor outcome. Maximum RDW (OR 2.3 95 % CI 1.2-3.6; p = 0.014) and maximum WBC count (OR 1.29 95 % CI 1.04-1.60; p = 0.018) were associated with poor outcome. Stepwise addition of maximum ESR, CRP, D-dimer, and fibrinogen yielded a model with RDW (OR 2.54 95 % CI 1.21-5.35; p = 0.014) and fibrinogen (OR 1.01 95 % CI 1.002-1.01; p = 0.004) predicting outcome. With addition of age and Hunt and Hess grade, RDW, fibrinogen, and high-grade status remained significantly associated with poor outcome. Use of PBD1 RDW in lieu of maximum RDW, resulted in a similar model. An elevated RDW is associated with poor outcome in SAH patients. RDW may be a useful predictor of outcomes after SAH.
    Neurocritical Care 02/2015; 23(2). DOI:10.1007/s12028-015-0117-x · 2.44 Impact Factor

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