e4 136 Compernolle V, Chou ST, Tanael S, et al Red blood cell specifica tions for patients with hemoglobinopathies a systematic review and guideline Transfusion 2018;58(6) 1555 1566 137 Wayne AS, Kevy[.]
e4 136 Compernolle V, Chou ST, Tanael S, et al Red blood cell specifications for patients with hemoglobinopathies: a systematic review and guideline Transfusion 2018;58(6):1555-1566 137 Wayne AS, Kevy SV, Nathan DG Transfusion management of sickle cell disease Blood 1993;81:1109-1123 138 Gardner K, Hoppe C, Mijovic A, Thein SL How we treat delayed haemolytic transfusion reactions in patients with sickle cell disease Br J Haematol 2015;170(6):745-756 139 Tisdale JF, Eapen M, Saccardi R HCT for nonmalignant disorders Biol Blood Marrow Transplant 2013;19(suppl 1):S6-S9 140 King A, Shenoy S Evidence-based focused review of the status of hematopoietic stem cell transplantation as treatment of sickle cell disease and thalassemia Blood 2014;123:3089-3094; quiz 3210 141 Gluckman E Allogeneic transplantation strategies including haploidentical transplantation in sickle cell disease Hematology Am Soc Hematol Educ Program 2013;2013:370-376 142 Guilcher GMT, Truong TH, Saraf SL, Joseph JJ, Rondelli D, Hsieh MM Curative therapies: Allogeneic hematopoietic cell transplantation from matched related donors using myeloablative, reduced intensity, and nonmyeloablative conditioning in sickle cell disease Semin Hematol 2018;55(2):87-93 143 Walters, M Update of hematopoietic cell transplantation for sickle cell disease Curr Opin Hematol 2015;22(3):227-233 144 Hulbert ML, Shenoy S Hematopoietic stem cell transplantation for sickle cell disease: Progress and challenges Pediatr Blood Cancer 2018;65(9):e27263 145 Hsieh MM, Fitzhugh CD, Weitzel RP, et al Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype JAMA 2014;312:48-56 146 Telen MJ, Malik P, Vercellotti GM Therapeutic strategies for sickle cell disease: towards a multi-agent approach Nat Rev Drug Discov 2019;18(2):139-158 147 Zaidi AU, Heeney MM A scientific renaissance: novel drugs in sickle cell disease Pediatr Clin North Am 2018;65(3):445-464 148 Ataga KI, Kutlar A, Kanter J, et al Crizanlizumab for the prevention of pain crises in sickle cell disease N Engl J Med 2017;376(5): 429-439 149 Howard J, Hemmaway CJ, Telfer P, et al A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease Blood 2019;133(17):1865-1875 150 Vichinsky E, Hoppe CC, Ataga KI, et al A phase randomized trial of voxelotor in sickle cell disease N Engl J Med 2019; 381(6):509-519 151 Thein SL Molecular basis of b thalassemia and potential therapeutic targets Blood Cells Mol Dis 2018;70:54-65 152 Viprakasit V, Ekwattanakit S Clinical classification, screening and diagnosis for thalassemia Hematol Oncol Clin North Am 2018; 32(2):193-211 153 Rund D, Rachmilewitz E Beta-thalassemia N Engl J Med 2005;353:1135-1146 154 Piel FB, Weatherall DJ The alpha-thalassemias N Engl J Med 2014;371:1908-1916 155 Galanello R, Origa R Beta-thalassemia Orphanet J Rare Dis 2010;5:11 156 Musallam KM, Rivella S, Vichinsky E, Rachmilewitz EA Nontransfusion-dependent thalassemias Haematologica 2013;98:833844 157 Olivieri NF, Pakbaz Z, Vichinsky E HbE/beta-thalassemia: basis of marked clinical diversity Hematol Oncol Clin North Am 2010;24:1055-1070 158 Fucharoen S, Weatherall DJ The hemoglobin E thalassemias Cold Spring Harb Perspect Med 2012;2:a011734 159 Wood JC Estimating tissue iron burden: current status and future prospects Br J Haematol 2015;170(1):15-28 160 Kwiatkowski JL Oral iron chelators Pediatr Clin North Am 2008;55:461-482, x 161 Krittayaphong R, Viprakasit V, Saiviroonporn P, Wangworatrakul W, Wood JC Serum ferritin in the diagnosis of cardiac and liver iron overload in thalassaemia patients real-world practice: a multicentre study Br J Haematol 2018;182(2):301-305 162 Wood JC, Zhang P, Rienhoff H, et al Liver MRI is more precise than liver biopsy for assessing total body iron balance: a comparison of MRI relaxometry with simulated liver biopsy results Magn Reson Imaging 2015;33:761-767 163 St Pierre TG, Clark PR, Chua-anusorn W, et al Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance Blood 2005;105:855-861 164 Brittenham GM, Sheth S, Allen CJ, Farrell DE Noninvasive methods for quantitative assessment of transfusional iron overload in sickle cell disease Semin Hematol 2001;38(1 suppl 1):37-56 165 Kirk P, Roughton M, Porter JB, et al Cardiac T2* magnetic resonance for prediction of cardiac complications in thalassemia major Circulation 2009;120(20):1961-1968 166 Pepe A, Meloni A, Rossi G, et al Prediction of cardiac complications for thalassemia major in the widespread cardiac magnetic resonance era: a prospective multicentre study by a multi-parametric approach Eur Heart J Cardiovasc Imaging 2018;19(3):299-309 167 Vichinsky E, Levine L, Bhatia S, et al Standards of Care Guidelines for Thalassemia Oakland: Children’s Hospital & Research Center Oakland; 2012 168 Borgna-Pignatti C, Rugolotto S, De Stefano P, et al Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine Haematologica 2004;89(10): 1187-1193 Available at: http://thalassemia.com/documents/ SOCGuidelines2012.pdf 169 Cappellini MD, Cohen A, Porter J, et al., eds Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT) 3rd ed Nicosia, CY: Thalassaemia International Federation; 2014 170 Cooley’s Anemia Foundation Thalassemia Management Checklists Now Available for Download 2018 https://www.thalassemia.org/ thalassemia-management-checklists-now-available-download/ 171 Vichinsky E, Neumayr L, Trimble S, et al Transfusion complications in thalassemia patients: a report from the Centers for Disease Control and Prevention (CME) Transfusion 2014;54(4):972-981 172 Auger D, Pennell DJ Cardiac complications in thalassemia major Ann N Y Acad Sci 2016;1368(1):56-64 173 Pennell DJ, Udelson JE, Arai AE, et al Cardiovascular function and treatment in b-thalassemia major: a consensus statement from the American Heart Association Circulation 2013;128(3): 281-308 174 Olivieri NF, Nathan DG, MacMillan JH, et al Survival in medically treated patients with homozygous beta-thalassemia N Engl J Med 1994;331(9):574-578 175 Aydinok Y, Kattamis A, Cappellini MD, et al Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload Blood 2015;125(25):38683877 176 Taher AT, Origa R, Perrotta S, et al New film-coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower-risk MDS: Results of the randomized, phase II ECLIPSE study Am J Hematol 2017;92(5):420-428 177 Wood JC Impact of iron assessment by MRI Hematology Am Soc Hematol Educ Program 2011;2011:443-450 178 Patton N, Brown G, Leung M, et al Observational study of iron overload as assessed by magnetic resonance imaging (MRI) in an adult population of transfusion dependent patients with beta thalassaemia: significant association between low cardiac t2* , 10 ms and the occurrence of cardiac events Intern Med J 2010;40: 419-426 179 Vinjamur DS, Bauer DE, Orkin SH Recent progress in understanding and manipulating haemoglobin switching for the haemoglobinopathies Br J Haematol 2018;180(5):630-643 180 Porter JB, Wood J, Olivieri N, et al Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone J Cardiovasc Magn Reson 2013;15:38 e5 181 Machado RF, Farber HW Pulmonary hypertension associated with chronic hemolytic anemia and other blood disorders Clin Chest Med 2013;34:739-752 182 Morris CR, Kim HY, Klings ES, et al Dysregulated arginine metabolism and cardiopulmonary dysfunction in patients with thalassaemia Br J Haematol 2015;169:887-898 183 Porter J Beyond transfusion therapy: new therapies in thalassemia including drugs, alternate donor transplant, and gene therapy Hematology Am Soc Hematol Educ Program 2018;2018(1):361-370 184 Lavelle D, Engel JD, Saunthararajah Y Fetal hemoglobin induction by epigenetic drugs Semin Hematol 2018;55(2):60-67 185 Lettre G, Bauer DE Fetal haemoglobin in sickle-cell disease: from genetic epidemiology to new therapeutic strategies Lancet 2016;387(10037):2554-2564 186 Perrine SP, Pace BS, Faller DV Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies Hematol Oncol Clin North Am 2014;28:233-248 187 Lucarelli G, Andreani M, Angelucci E The cure of thalassemia by bone marrow transplantation Blood Rev 2002;16:81-85 188 Strocchio L, Locatelli F Hematopoietic stem cell transplantation in thalassemia Hematol Oncol Clin North Am 2018;32(2):317-328 e6 Abstract: Sickle cell disease and thalassemia are qualitative and quantitative disorders of hemoglobin, respectively In sickle cell disease, the polymerization of deoxyhemoglobin triggers downstream pathophysiology, including vasoocclusion, hemolysis, inflammation, altered endothelial adhesion, coagulation, and ischemia-reperfusion injuries Relevant clinical manifestations include pain, anemia, acute chest syndrome, sepsis, stroke, and pulmonary hypertension The thalassemias are a family of disorders that result in an imbalance of globin chains, leading to anemia Transfusion therapy, a key intervention for some types of thalassemia, can result in iron overload Untreated, iron overload leads to hepatic and cardiac failure, the latter of which is a common reason for intensive care unit admission Key words: Sickle cell disease, thalassemia, acute chest syndrome, iron overload, vasoocclusion, sepsis, stroke, chelation, aplastic crisis, pulmonary hypertension 89 Coagulation and Coagulopathy ROBERT I PARKER • Hemostasis dysfunction is a frequent component of critical illnesses and may comprise an intrinsic component of the illness (e.g., sepsis, trauma) or represent a byproduct or a comorbidity not directly related to the critical illness.1–3 While this may frequently lead to a bleeding diathesis, not all hemostatic alterations produce this end result Indeed, there is a spectrum of potential consequences ranging from none to minor to severe hemorrhage or development of a thrombotic disorder (Box 89.1) A brief review of the initiation and regulation of hemostasis as well as typical/ usual diagnostic studies to assess hemostasis provides information to adequately assess the severity and need for intervention in critically ill children (and adults) who present with abnormal hemostasis laboratory results or clinical abnormalities suggestive of altered hemostasis (Box 89.2) Overview of Hemostasis While the terms hemostasis and coagulation are frequently used interchangeably, they are not synonymous Coagulation is the process by which blood transforms from a liquid to a solid state and is defined by the process of clot formation However, hemostasis is more comprehensive and dynamic It includes all the processes involved in the arrest of bleeding and in maintaining liquid blood when clot formation is not desired.4 This latter feature requires the process of fibrinolysis to return blood to its flowing state following local clot formation While coagulation does not occur in flowing blood but rather on cell surfaces or in structures of the extracellular matrix (e.g., collagen), the tests used to measure coagulation use cell-free plasma However, 1052 • Traditionally, coagulation has been presented as a set of discrete “intrinsic,” “extrinsic,” and “common” pathways, but this view fails to include the many interactions between pathways, any of the natural inhibitors of clot formation, involvement of inflammatory mediators, platelets, endothelial cells, adhesive glycoproteins, or thrombolytic factors in the process of hemostasis Generalized bleeding in critically ill children and infants is often caused by trauma or sepsis-related disseminated intravascular coagulation (DIC) The combination of a prolonged prothrombin time, hypofibrinogenemia, thrombocytopenia, and evidence of microangiopathic hemolysis on peripheral blood • • PEARLS smear in the appropriate clinical setting is sufficient to suspect the diagnosis of DIC Children with severe trauma frequently present with massive bleeding and acidosis secondary to hypoperfusion Platelets not only produce a physical barrier at the site of vascular injury, they also serve to focus the clotting process at the point of bleeding by delivering vasoconstrictors and clotting factors to the bleeding site and by providing a surface on which clot development occurs Additionally, in concert with endothelial cells, they moderate both coagulation and host immune response hemostasis involves platelets and endothelial cells (ECs) along with various plasma proteins that promote and inhibit clot formation Consequently, the traditional clotting tests most commonly used in clinical medicine (i.e., prothrombin time [PT] and/or International Normalized Ratio [INR], activated partial thromboplastin time [aPTT, also PTT], thrombin time [TT]) assess only one aspect of hemostasis The process of hemostasis can be thought of as consisting of three separate though highly interdependent and interconnected steps: (1) primary hemostasis (i.e., the adhesion of platelets to ECs with secondary platelet activation and platelet plug formation; Fig 89.1); (2) coagulation (the sequential activation of procoagulant clotting factors; Fig 89.2); and (3) fibrinolysis (the dissolution of formed clots by activation of fibrinolytic proteases from their zymogen to active form; Figs 89.3 and 89.4) In critical illness, the normal regulation (i.e., “balance”) of hemostasis is disrupted, resulting in either hemorrhage (e.g., disseminated intravascular coagulation [DIC]) or pathologic thrombosis (e.g., deep venous thrombosis [DVT], pulmonary embolism; Fig 89.5) Traditionally, coagulation has been presented as a set of discrete pathways—intrinsic, extrinsic, and common—that progress in an orderly nonoverlapping sequence.4 This depiction, while useful when explaining the various tests to assess clot formation (i.e., PT/INR, aPTT, TT), fails to represent the many interactions between pathways or include any of the natural inhibitors of clot formation or the involvement of inflammatory mediators, platelets, ECs, adhesive glycoproteins, or thrombolytic factors in the process of hemostasis CHAPTER 89 Coagulation and Coagulopathy 1053 • BOX 89.1 Disorders of Hemostasis in Critical Illness Platelet recruitment Hemorrhage Abnormalities in fibrin generation • Consumption of clotting factors • Decreased synthesis of clotting factors Abnormalities in primary hemostasis • Thrombocytopenia Endothelial cell dysfunction • Local inhibition of clot formation (e.g., generation of heparan sulfate cleaved from cell membranes) • Increase in fibrinolysis (decreased PAI-1, increased tPA) Increase in fibrinolysis • Decrease in fibrinolytic inhibitors (e.g., TAFI, PAI-1) Thrombosis Endothelial cell dysfunction • Decrease in generation of natural anticoagulant activated protein C with resultant continued activation of clot formation Decrease in fibrinolysis in conjunction with ongoing thrombin generation • Decrease in ATIII protein C or protein S synthesis In vivo platelet activation Decreased cleavage (degradation) of vWF (i.e., decreased ADAMTS13) with resultant increase in platelet adhesion to ECs and collagen matrix ADAMTS13, A disintegrin and metalloprotease with thrombospondin motifs 1, type 13; ATIII, antithrombin-III; ECs, endothelial cells; PAI-1, plasminogen activator inhibitor type-1; TAFI, thrombin activatable fibrinolysis inhibitor; tPA, tissue plasminogen activator; vWF, von Willebrand factor • BOX 89.2 Hemostasis Primary Hemostasis n Vascular Phase • Vasoconstriction in response to vascular injury • Platelet activation and adhesion to endothelial cells and subendothelial matrix (e.g., collagen) • Local platelet activation results in release of peptides that further stimulate vasoconstriction and activation of additional platelets (e.g., serotonin, ADP, thromboxane A2) Secondary Hemostasis n Clot Formation • Sequential activation of soluble zymogen clotting factors resulting in production of a fibrin clot and platelet scaffold on cell surfaces (e.g., platelets, endothelial cells) and subendothelial matrix (e.g., collagen) • Clot retraction mediated by platelets in the scaffold results in strengthening of local clot Fibrinolysis n Reestablishment of Blood Flow • Activation of endogenous fibrinolytic enzymes (e.g., conversion of plasmin n plasminogen by thrombin or tPA) ADP, Adenosine diphosphate; tPA, tissue plasminogen activator Historically, the intrinsic pathway, beginning with the activation of factor XII (FXII) to activated FXII in contact with some biological or foreign surface, was believed to be physiologically the most important in the initiation of clot formation because deficiencies of FVIII (hemophilia A) or FIX (hemophilia B) produced a severe bleeding diathesis However, we now understand that the activation of FX to FXa through the action of the FVIIa/ tissue factor (TF) complex plays a more central role in this process (see Fig 89.2) The elements of the clotting cascade act in concert, hence the use of the term tenase to describe the action of FVIIa/TF ADP, 5HT, Ca++, etc Collagen TF vWF • Fig 89.1 Initial phase of hemostasis composed of platelets adhering to injured endothelial cells, and subendothelial matrix (including collagen and von Willebrand factor [vWF]) Activated platelets secrete substances—e.g., adenosine diphosphate (ADP) and serotonin—that enhance subsequent activation of regional circulating platelets with consequent recruitment to adhesion and aggregating, thereby increasing the formation of a platelet plug Additionally, platelets secrete vasoactive substances, causing vasoconstriction limiting local blood flow Ca11, Calcium ion; 5HT, serotonin; TF, tissue factor complex, along with the FIXa/FVIIIa complex on the activation of FX to FXa, and the use of the term prothrombinase to describe the FXa/FVa complex, which cleaves prothrombin (FII) to form thrombin (FIIa) Various positive feedback loops involving thrombin enhance clot formation, and several points of crosstalk exist between the two arms of the clotting cascade, among which is FVIIa being able to enhance the activation of FIX to FIXa and FXI to FXIa, further highlighting the central role of FVIIa and TF in vivo (see Fig 89.2).5 Activation of coagulation initiated by FVIIa/TF results in clotting on biological surfaces (e.g., platelets, ECs, the subendothelial matrix) and biological polymers (catheters, grafts, stents, etc.) Role of Platelets and von Willebrand Factor in Hemostasis Platelets not only participate in clot formation through the formation of a platelet plug but also provide an important surface on which clot formation may occur, bring additional procoagulant proteins to areas of injury (e.g., FVIII and von Willebrand factor [vWF]), and provide specific proteins that regulate the clotting response (FVIII, inhibitors of fibrinolysis, etc.) required to limit clot formation to the area of tissue injury and bleeding (Fig 89.6).6 Under resting unstimulated conditions, platelets not adhere to the vascular endothelium, but upon stimulation or when the endothelium is mechanically disrupted (e.g., cut) or activated by inflammation, platelets will become activated and express on their surface vWF mobilized from internal pools and bound from plasma-derived vWF This binding of vWF to the platelet allows for the efficient binding of platelets to activated ECs and to the subendothelial matrix.7 Once adherent, activated platelets secrete various molecules that further enhance platelet adherence and aggregation, vascular contraction, clot formation, and wound healing Platelet adhesion to ECs or to subendothelial matrix can be enhanced or diminished by the amount and structure of vWF Deficiency or inhibition of the metalloproteinase ADAMTS13 will result an increase in circulating unusually large molecular weight multimers of vWF (UL-vWF) with consequent enhanced platelet adhesion, which is associated with an increased risk of unwanted thrombus formation.8 Conversely, a decrease in the total amount of vWF in circulation or bound to platelets—or in vivo degradation of vWF, as is seen with certain subtypes of von ... directly related to the critical illness.1–3 While this may frequently lead to a bleeding diathesis, not all hemostatic alterations produce this end result Indeed, there is a spectrum of potential... Perrine SP, Pace BS, Faller DV Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies Hematol Oncol Clin North Am 2014;28:233-248 187 Lucarelli G, Andreani M, Angelucci E The cure... in the arrest of bleeding and in maintaining liquid blood when clot formation is not desired.4 This latter feature requires the process of fibrinolysis to return blood to its flowing state following