1051CHAPTER 88 Hemoglobinopathies pulmonary hypertension, as do the direct effects of iron overload and high output state on the vascular endothelium and myocar dium stiffness and function In addition[.]
CHAPTER 88 Hemoglobinopathies pulmonary hypertension, as the direct effects of iron overload and high output state on the vascular endothelium and myocardium stiffness and function In addition, platelet and red cell– derived microparticles can cause vasoconstriction in the pulmonary vasculature, which is worsened with splenectomy As in SCD, screening by transthoracic echo is suggested, with concerns raised for a TR jet of over 2.5 m/s and a need for diagnostic catheterization if over m/s.167,169,181,182 Treatment should address the multiple pathways contributing to each individual’s pulmonary hypertension.167,169,181 Maintaining the Hgb over 9.5 g/dL helps suppress ineffective erythropoiesis and the resultant hemolysis and NO destruction and helps decrease cell debris If evidence of cardiac dysfunction from iron overload chelation is critical, oxygenation should be maintained, applying continuous airway pressure and keeping saturations over 95%, and anticoagulation should be considered To address abnormalities in NO metabolism, inhaled nitrite, NO, and sildenafil should be considered, and there are some data for the use of bosentan and epoprostenol.167,169,181 Endocrine Iron deposition in endocrine organs can lead to polyendocrine dysfunction of the pancreas, pituitary, adrenal, thyroid, and hypothyroid glands This should be monitored for in the ICU setting Hematopoietic Stem Cell Transplantation, Gene Therapy, and Novel Therapies for Thalassemia New therapies for thalassemia are being introduced into clinical trials at an amazing pace For a detailed discussion of these topics, see eBox 88.4 1051 Key References Bender MA, Douthitt Seibel G Sickle Cell Disease: Critical Elements of Care 5th ed Seattle: Seattle Children’s Hospital; 2012 Children’s Hospital & Research Center Oakland Standards of Care Guidelines for Thalassemia 2012 Available at: http://thalassemia com/documents/SOCGuidelines2012.pdf Cappellini MD, Cohen A, Porter J, Taher A, Viprakasit V, eds Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT) 3rd ed Thalassaemia International Federation TIF publication No 20 Available at: https://www.resonancehealth.com/images/ files/clinician-information/patient-management-guidelines/TIF%20 Guidelines%20for%20the%20Management%20of%20Transfusion %20Dependent%20Thalassaemia.pdf Kassim AA, Galadanci NA, Pruthi S, DeBaun MR How I treat acute strokes and long-term management in sickle cell disease Blood 2015;125:3401-3410 Kato GJ, Piel FB, Reid CD, Gaston MH, et al Sickle cell disease Nat Rev Dis Primers 2018;4:18010 Moerdler S, Manwani D New insights into the pathophysiology and development of novel therapies for sickle cell disease Hematology Am Soc Hematol Educ Program 2018;2018(1):493-506 Rees DC, Robinson S, Howard J How I manage red cell transfusions in patients with sickle cell disease Br J Haematol 2018;180(4):607-617 Taher AT, Weatherall DJ, Cappellini MD Thalassaemia Lancet 2018;391(10116):155-167 Vichinsky EP, Neumayr LD, Earles AN, et al Causes and outcomes of the acute chest syndrome in sickle cell disease National Acute Chest Syndrome Study Group N Engl J Med 2000;342:1855-1865 Yawn BP, Buchanan GR, Afenyi-Annan AN, et al Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members JAMA 2014;312:1033-1048 The full reference list for this chapter is available at ExpertConsult.com 1051.e1 Hematopoietic Stem Cell • eBOX 88.4 Transplantation, Gene Therapy, and Novel Therapies for Thalassemia Novel Therapies Interventions for specific complications have been described earlier, in comprehensive guidelines,3,167,169 and in eFig 88.28 Although transfusions are the mainstay of therapy for severe thalassemia, guidelines for when to initiate transfusions and what Hb to target vary with the individual’s presentation and among centers Increasingly, new agents are being evaluated to target specific steps in thalassemia pathophysiology.3,183 Ineffective erythropoiesis is being targeted by Jak2 inhibitors, and decreasing GDF11 signaling with activin inhibitors to decrease erythroid hyperproliferation, and increase differentiation, respectively Minihepcidins and TMPRSS inhibitors are being developed to increase hepcidin activity, thereby reducing inappropriate iron uptake Induction of HbF remains the holy grail of b-thalassemia and sickle cell disease therapy After decades of limited success, elucidating the multiple pathways involved in globin gene regulation is facilitating the development of multiple genetic and pharmacologic approaches to inducing HbF The rapidly evolving field of HbF inducers is reviewed elsewhere.179,184–186 Cures: Hematopoietic Stem Cell Transplantation and Gene Therapy Currently, hematopoietic stem cell transplantation (HSCT) is the most available cure for thalassemic patients, though an increasing number have been cured by gene therapy For HSCT, long transfusion histories and marrow expansion increase the chance of graft failure, necessitating an aggressive myeloablative conditioning regimen that in turn can lead to high treatment-related toxicity, especially if significant end-organ damage is present Thus, success depends on having an adequate donor and the degree of end-organ damage Not surprisingly, the risk of complications increases with age Organ damage is assessed with the Lucarelli staging system, which factors in the degree of hepatomegaly, the degree of portal fibrosis, and the quality of chelation.183,187 With improved pretransplant care and increased myeloablation and immunosuppression, even the highest risk groups have done well with matched-sibling donors Results vary depending on context, but 90% event-free survival, 95% overall survival, and 7% rejection rates can be achieved.183,188 Sotatercept Luspatercept TMPRSS inhibitors ä ROS ä GDF11 Iron overload å Differentiation Minihepcidins Ineffective erythropoiesis α/β-Chain imbalance å Hepcidin Erythroferrone ä Proliferation Gene therapy Gene editing JAK2 inhibitors • eFig 88.28 Novel ä EPO Anemia targets and therapies for patients with b-thalassemia EPO, Erythropoietin; ROS, reactive oxygen species (From Taher AT, Weatherall DJ, Cappellini MD Thalassaemia Lancet 2018 Jan 13;391[10116]:155–167.) 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