1048 e1 1 Calculating Total Blood Volume (TBV) 1 TBV = 30 kg x 70 mL/kg = 2100 mL Example 2 Volume to transfuse = 2 Volume of pRBCs (mL) to transfuse = (Desired Hct − Current Hct) x TBV Hct of pRBCsa[.]
1048.e1 Calculating Total Blood Volume (TBV): Neonate: TBV = weight (kg) x 80 mL/kg Child/Adult: TBV = weight (kg) x 70 mL/kg Volume of pRBCs (mL) to transfuse = (Desired Hct − Current Hct) x TBV Hct of pRBCsa a The Hct of a pRBC unit depends on what anticoagulant or preservative solution was used: pRBCs preserved in CPD-A have a Hct of ~75% pRBCs preserved in additive solutions (e.g Adsol) have a Hct of ~55% Example: A 30 kg patient has a current Hct of 21% and you would like to increase the Hct to 30% Your blood bank has CPD-A units What volume of pRBCs should be transfused? TBV = 30 kg x 70 mL/kg = 2100 mL Volume to transfuse = (30 − 21%) x 2100 mL 75% A HbSf = Hcti Hctf = 252 mL pRBCs x HbSi HbSf = final percentage of HbS, after direct transfusion HbSi = initial percentage of HbS, before direct transfusion Hctf = final hematocrit (after transfusion) Hcti = initial hematocrit Example: The above 30 kg patient with Hct of 21% has a HbS of 93% After increasing the Hct to 30% what would the HbS be? 21% B 30% x 93% = 65% HbS • eFig 88.21 Transfusion formulas Details of how to perform an exchange transfusion vary depending on patient size, intravenous line access, available resources, and institutional biases; basics are outlined elsewhere If available, erythrocytapheresis (automated red cell exchange) is preferred by most over a manual exchange due to its speed, efficiency, and ease Modern machines require the patient weight, hematocrit (Hct), and estimated percent of sickle hemoglobin (HbS) in addition to the desired postexchange Hct and HbS An online calculator to estimate the volume of blood needed for red blood cell exchange in a patient with SCD is available at https://www.mdcalc.com/sickle-cell-rbc-exchange-volume (A) Formula to calculate the expected Hct after a red cell transfusion (B) Formula to calculate the expected percent of HbS after a direct red cell transfusion pRBC, Packed blood cells 1048.e2 Hematopoietic Stem Cell Transplantation, • eBOX 88.2 Gene Therapy, and Novel Therapies for Sickle Cell Disease (SCD) Hematopoietic Stem Cell Transplantation and Gene Therapy Hematopoietic stem cell transplantation is a curative option for SCD Once a procedure reserved for those with a history of overt stroke or other severe recurrent complications, children with less severe disease are increasingly receiving transplants Matched sibling transplants using a myeloablative-conditioning regimen have proven to be quite effective (85% event-free survival and a 94% overall survival with approximately 10% graft failure and 12%–20% significant graft-versus-host disease), and the indications for transplantation are liberalizing.139–144 Multiple SCD research transplant studies are evaluating lowerintensity and nonmyeloablative conditioning regimens, extending transplants to older patients, and using alternate donors (unrelated, cord blood, haploidentical).139–143,145 Gene therapy for SCD is actively being pursued and is discussed with gene therapy for thalassemia Novel Therapies The numerous pathophysiologic paths contributing to SCD are providing targets for novel therapeutics, too numerous to be reviewed here but discussed elsewhere12,146,147 (see Figs 88.17 to 88.20 for an overview).122 While work continues on inducing HbF, other promising agents are targeting P-selectin (crizanlizumab),148 metabolism (L-glutamine),46 and hemoglobin itself.149,150 eTABLE Distinguishing Laboratory Features of a- and b-Thalassemias 88.4 Diagnosisa BCB Prepb HbA2c HbF HbH Hb Barts in Newbornd Normal nl nl Nl a-Thalassemia nl nl nl or h b-Thalassemia nl or h nl or h Nl Table shows typical results; exceptions occur All forms of a- or b-thalassemia are pooled; specific results will vary b Brilliant cresyl blue or inclusion body prep Results vary by lab, but this can be done semiquantitatively and increases with the degree of a-thalassemia This can be negative when a one a-globin deletion is present (silent carrier) This assay is unreliable in the presence of other hemoglobins (e.g., HbS or HbE) This can be negative when a- and b-thalassemia are simultaneously present c HbA2 results vary depending on laboratory method d Hb Barts increases with the degree of a-thalassemia Hb, hemoglobin type; nl, normal; h, increased; 2, negative; 1, positive a Iron overload Marrow expansion and bone disease Extramedullary hemopoiesis and organomegaly α/β-Chain imbalance Ineffective erythropoiesis Organ damage (heart, liver, endocrine) Peripheral hemolysis and gallstones Anemia Hypercoagulability and vascular disease • eFig 88.22 Pathophysiology of patients with thalassemia syndromes (From Taher AT, Weatherall DJ, Cappellini MD Thalassaemia Lancet 2018;391[10116]:155–167) 1048.e3 “Flip-flop” PS Erythroblast PS H bodies PS Inclusion bodies Immune removal Adhesion Va β Mutations chromosomes 11, 16 Autologous IgG + complement PS α ↓ GSH ↑ ROS Hemichromes PS Plasma Prothromb complex Thrombin PS Activation Xa Hemolysis Ineffective erythropoiesis PS Excess globin chains Fe+++ Hypercoagulability Spectrin-band abnormalities Prot S/C Denaturation Degradation Mechanical removal Thrombotic manifestations Hb Mature RBC Apoptosis ↑ Fragmentation ↑ Rigidity ↓ Deformability Fe+++ (NTBI) RBC transfusions • eFig 88.23 Overview of the pathophysiology of thalassemia Oxidation of a-, b-, or g-hemoglobin sub- units leads to the formation of hemichromes, whose rate of formation determines the rate of hemolysis Because a-chains dissociate into monomers more readily than b- or g-chains, they form hemichromes at a faster rate, which explains why b-thalassemia is clinically much more severe than a-thalassemia Precipitates of unpaired b-chains form single large inclusions known as Heinz bodies This process occurs at a later stage of maturation than does the formation of smaller multiple inclusions because of the precipitation of unpaired a-chains Hemichromes bind to or modify various components of the mature red cell membrane, such as protein band 3, protein 4.1, ankyrin, and spectrin After precipitation of hemichromes, heme disintegrates and toxic non–transferrin-bound iron species are released The resulting free iron catalyzes the formation of reactive oxygen species Iron-dependent oxidation of membrane proteins and formation of red cell “senescence” antigens such as phosphatidylserine cause thalassemic red cells to be rigid and deformed and to aggregate, resulting in premature cell removal Phosphatidylserine is also involved in the activation of the coagulation system Fe111, ferric ion; GSH, glutathione; Prot, protein; NTBI, non–transferrin-bound iron; Prothromb., prothrombin; PS, phosphotidyl serine; RBC, red blood cell; ROS, reactive oxygen species (Courtesy D Rund.) ↓ GSH ↑ ROS Platelets 1048.e4 A • eFig 88.24 Facial B and skull bone changes associated with thalassemia (A) Child with b-thalassemia with maxillary hyperplasia due to increased marrow activity (B) Radiograph from the same patient demonstrating increased marrow activity in the skull (From Zitelli BJ, Davis HW Hematology and oncology In: Zitelli BJ, Davis HW, eds Atlas of Pediatric Physical Diagnosis 5th ed Philadelphia: Elsevier; 2007.) CHAPTER 88 Hemoglobinopathies 1049 as the thalassemic facies (eFig 88.24) and thinning of the cortex of long bones, which, along with endocrine abnormalities (see the following section), lead to increased fractures Expansion of erythroid precursors leads to the release of GDF15 and erythroferrone leads to low levels of hepcidin, which results in inappropriately increased intestinal absorption of iron and high levels of nontransferrin-bound iron even in the nontransfused patient This and therapeutic transfusions lead to iron deposition, resulting in liver, cardiac, and endocrine dysfunction Forms and Variations a-Thalassemia Typical laboratory findings are summarized in eFig 88.25 Although a-thalassemia leads to a tremendous burden on health worldwide and is well reviewed elsewhere, it is not a major cause of ICU admissions in the United States Thus, the focus of this chapter is on complications seen in b-thalassemia major.154 b-Thalassemia In contrast to a-thalassemia, the plethora of b-gene mutations leads to a continuous spectrum of disease b0-thalassemia denotes nonexpressing alleles, whereas b1-thalassemia is used for genes that express a reduced amount of normal protein Most mutations not eliminate ε- or g-gene expression; thus, it is unusual for clinical complications to occur until several months of life, when infants become dependent on adult b-globin chains.3,151,153,155 Nomenclature is based on this continuum of phenotypic severity rather than genotype b-Thalassemia trait, also referred to as thalassemia minor, is benign and of note only for primary care (e.g., avoiding automatically prescribing iron for the microcytosis) and genetic counseling The term thalassemia major (also known as Cooley anemia) is reserved for transfusion-dependent phenotypes, whereas those with clinical sequelae but who are not dependent on transfusions for survival are referred to as having thalassemia intermedia or transfusion independent The latter require the most thoughtful clinical decisionmaking, as there is increasing awareness of the high morbidity in many of these patients, many of whom may benefit from transfusion.3,155,156 Assessment of Iron Overload Direct tissue measurement of iron is essential Though ubiquitously available and inexpensive, serum ferritin is a poor indicator of iron stores; it is elevated with inflammation and does not correlate well with tissue iron content, especially in chelated patients, and in most situations should be used for tracking trends and when to image.3,159,160 MRI-based assessment of iron overload is based on relaxation times correlating with iron content and is now widely accepted The use of serial ferritins should be reserved for when MRI or other imaging modalities are not accessible.159,161,162 Techniques and hardware are evolving rapidly, and standards and practices vary greatly and influence interpretations, making it essential to discuss options with local radiologists.159 Ferriscan and SQUID are used at limited locations and are limited to the assessment of hepatic iron.163,164 In contrast, T2* imaging is increasingly available and allows simultaneous assessment of hepatic, pancreatic, and cardiac iron and, potentially, other target organs.159 A lower T2* correlates with higher degrees of myocardial iron overload T2* is increasingly combined with additional cardiac imaging to help improve the prediction of pending arrhythmias and heart failure and allowing for intervention (see Cardiac Complications below).165,166 Spectrum of Disease Although a summary of clinical problems and management is presented here, the reader is referred to several reviews.3,155,167,168 For more detailed guidelines of care, the reader is referred to Oakland Children’s Hospital,167,168 the Thalassemia International Foundation,169 and Cooley’s Anemia Foundation checklists.170 Natural History Anemia Although there is much debate as to the optimal Hgb that should be targeted, one must factor in the acuteness of the anemia, the degree of cardiovascular compromise, and the patient’s baseline Hgb in the ICU Over time, the threshold to transfuse has been lowering Currently, a baseline Hgb of under g/dL is often the threshold for initiating chronic transfusions, though a higher threshold is used if growth, skeletal malformations, or extramedullary erythropoiesis becomes problematic.167–169 The goal should be to maintain an Hgb of 9.5 to 10.5 g/dL pretransfusion (11–12 g/dL if cardiac disease is present) but no higher than 14 g/dL posttransfusion As with SCD, profound anemia or cardiac compromise may require a slow transfusion, diuretics, or even an exchange transfusion to avoid congestive heart failure Blood products should be leukoreduced to minimize alloimmunization, febrile nonhemolytic transfusion reactions, and CMV transmission, but there is no need for irradiation unless a transplant is planned As with SCD, blood should be matched for ABO, Rh (Cc, D, Ee), and Kell.171 Family and related donor transfusion should be avoided if a hematopoietic stem cell transplant is to be considered, as alloimmunization to donor antigens increases graft rejection Natural history is highly variable depending on the genotype, modifying genetic factors, and, critically, if and what interventions (e.g., transfusion and chelation) are available.3,153,155 If not diagnosed by newborn screening or from a known familial risk, children can present with anemia, growth delays, bony abnormalities, iron overload (even if untransfused), and, most common for the intensivist, congestive heart failure, the latter often occurring with little warning Chronic or frequent transfusions increase iron overload, the risk of alloimmunization, and infectious risk171 (also described in Chapter 91) Because of inappropriately low hepcidin levels, the ability of the body to absorb iron is unopposed, leaving blood loss and sloughing of endothelial and skin cells as the only mechanism to decrease iron in the face of iron overload This is estimated to lead to a loss of mg/day in an adult, which pales in comparison to the HbE/b0-Thalassemia Of the numerous Hb variants, this compound heterozygous state is worth special mention The HbE mutation is common throughout Southeast Asia, which results in a ribonucleic acid–splicing abnormality and a destabilizing amino acid substitution, leading to a thalassemic allele When combined with another b-thalassemic allele, the phenotype is extraordinarily variable, with some thriving and a subset being transfusion dependent.3,157,158 Management is similar to that for other thalassemias and guided by clinical presentation, not genotype Transfusion-Related Complications ... vary by lab, but this can be done semiquantitatively and increases with the degree of a-thalassemia This can be negative when a one a-globin deletion is present (silent carrier) This assay is unreliable... Diagnosis 5th ed Philadelphia: Elsevier; 2007.) CHAPTER 88 Hemoglobinopathies 1049 as the thalassemic facies (eFig 88.24) and thinning of the cortex of long bones, which, along with endocrine abnormalities... the face of iron overload This is estimated to lead to a loss of mg/day in an adult, which pales in comparison to the HbE/b0-Thalassemia Of the numerous Hb variants, this compound heterozygous