1047 e3 Membrane Phospholipid • eFig 88 18 Novelagentstargetinginflammationinsicklecelldisease(SCD) Multiplecelltypes,mole cules,andpathwayscontributetothechronicinflammatorystate[.]
1047.e3 d pi mbrane Phosp ho Me li • eFig 88.18 Novel agents targeting inflammation in sickle cell disease (SCD) Multiple cell types, mole- cules, and pathways contribute to the chronic inflammatory state in SCD In SCD, as in asthma, leukocyte membrane phospholipids are hydrolyzed into arachidonic acid (AA), which is metabolized via the 5-lipoxygenase (5-LPO) pathway, leading to formation of inflammatory leukotrienes Inhibition of this pathway by several agents currently used in asthma (mometasone, zileuton, and montelukast) is being investigated in SCD Activated leukocytes also produce various proinflammatory cytokines, including interleukin (IL)1b Canakinumab in a monoclonal antibody that targets IL-1b iNKT cells exhibit an activated phenotype and amplify the inflammatory response to hypoxia/reperfusion injury in SCD by producing IFN-Y NKTT120 is a humanized monoclonal antibody that specifically depletes iNKT cells Platelets contribute to inflammation Omega-3 fatty acids, in addition to favorably altering sRBC fatty acid membrane composition, have a myriad of antiinflammatory effects, and targets include leukocytes, platelets, and endothelial cells iNKT, Invariant natural killer T cells; iTCR, invariant T-cell receptor; PLA2, secretory phospholipase A2 (From Morrone K, Mitchell WB, Manwani D Novel sickle cell disease therapies: targeting pathways downstream of sickling Semin Hematol 2018;55[2)]:68–75.) 1047.e4 • eFig 88.19 Novel agents targeting inflammation and nitric oxide (NO) bioavailability Hemolysis in sickle cell disease and the resultant cell-free hemoglobin leads to NO scavenging Increased bioavailability of NO and its downstream target cyclic guanosine monophosphate (cGMP) lead to salutary effects in the endothelium, smooth muscles, leukocytes, platelets, and increased g-globulin Therapeutic agents enhancing NO bioavailability by various mechanisms are depicted in this image Of note, PDE9 has restricted tissue expression in the hematopoietic cells and brain as opposed to PDE5, which is more widely expressed, with the potential for reduced off-target effects Glutamine increases NADH within red cells, thus reducing effects of oxidative stress Dietary glutamine also serves as a precursor for the de novo production of arginine through the citrulline-arginine pathway, contributing to increased NO production GTP, Guanosine triphosphate; ICAM, intercellular adhesion molecule; NADH, nicotinamide adenine dinucleotide plus hydrogen; PDE, phosphodiesterase; RBC, red blood cell; sGC, soluble guanylate cyclase; VCAM, vascular cell adhesion protein (From Morrone K, Mitchell WB, Manwani D Novel sickle cell disease therapies: targeting pathways downstream of sickling Semin Hematol 2018;55[2]:68–75.) 1047.e5 • eFig 88.20 Therapeutic targets investigating chronic pain in sickle cell disease (SCD) Chronic pain in SCD is likely multifactorial and results from various mechanisms, such as mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, and central sensitization Nonopioid agents with established benefits in non-SCD chronic pain are being investigated Cannabinoids decrease chronic pain by their central effects as well as stabilization of mast cells and reduced neurogenic inflammation Memantine is an N-methyl-D-aspartate receptor antagonist and gabapentin binds to voltage-gated calcium channels in neurons (From Morrone K, Mitchell WB, Manwani D Novel sickle cell disease therapies: targeting pathways downstream of sickling Semin Hematol 2018;55[2]:68–75.) 1047.e6 eTABLE Indications for Transfusion in Sickle Cell Disease 88.3 Duration Consensus Method Goala Stroke, acute Single Exchange HbS ,30% (for those with Hb S/C or other compound heterozygotes target a HbA of 70%) Stroke, ongoing care Chronic Either HbS ,30% (for those with Hb S/C or other compound heterozygotes, target a HbA of 70%) High-velocity TCD Chronic Either HbS ,30% ACS, initial episode Single (for severe or progressive ACS) Direct Exchange Hgb 10 ACS, recurrent 6–12 mo Either PHTN Chronic Either Multiorgan failure Single Exchange Major surgery Single Direct Acute anemia Single Direct Recurrent spleen sequestration Chronic Sepsis/meningitis Single Severe chronic pain 6–12 mo Congestive heart failure Chronic Silent infarct Chronic Pregnancy Direct Anemia/renal failure Chronic Leg ulcers 6–12 mo Severe growth delay Severe eye disease Priapism a Hgb 10 Goal of transfusion if a consensus has been reached ACS, Acute chest syndrome; Hb, hemoglobin; Hgb, hemoglobin concentration; PHTN, persistent hypertension; TCD, transcranial Doppler; 1, consensus reached; 2, consensus not reached 1048 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology varies with indication (see eTable 88.3) However, in most cases, the final Hb should never be higher than 11 g/dL because, whereas O2carrying capacity increases, O2 delivery may actually fall.137 Formulas helpful for planning routine and exchange transfusions are available (eFig 88.21) While simple transfusion can be considered for most clinical indications, one significant exception is acute stroke, for which an automated exchange to quickly bring down the HbS level while raising the Hgb is the standard of care.20 This requires either two largebore peripheral IV lines (which can be difficult in some patients) or a pheresis-compatible central line that can accommodate flow rates and pressures required during erythrocytapheresis Coordination and communication about the specific line to be placed should occur with the blood center or program operating the pheresis machine Children under 10 kg may not be able to tolerate automated erythrocytapheresis and may require a manual exchange transfusion Manual exchange, while effective, requires significant nursing time to complete but has the advantage of requiring only one large-bore peripheral IV line A brief summary table of recommendations for mode of transfusion is provided for reference (see eTable 88.3) 20,127,128 Transfusion Reactions and Hyperhemolysis lloimmunized patients with SCD are at increased risk of delayed A hemolytic transfusion reactions (DHTRs) that are potentially lifethreatening and can be difficult to diagnose One must maintain a high index of suspicion for DHTRs, as they are often mistaken for acute vasoocclusive pain episodes, presenting with similar symptoms of back pain and a drop in Hb attributable to hemolysis 10 to 14 days after transfusion Some cases of DHTR are associated with hyperhemolysis, whereby the Hb drops below pretransfusion levels due to destruction of both transfused and autologous red cells, thus, quickly becoming life-threatening This becomes critical, as transfusion may worsen the hemolysis and anemia Thus, it is critical to closely monitor for precipitous drops in hemoglobin and have a low threshold to evaluate for a transfusion reaction Treatment of DHTRs and hyperhemolysis is complex, should involve a transfusion medicine specialist when available, and generally involves a combination of immunosuppression (corticosteroids, IV immunoglobulin [IVIG], rituximab) and stimulation of endogenous red cell production with erythropoietin and IV iron Transfusion should be avoided whenever possible but may be required for life-threatening anemia and/or hemodynamic instability.138 Hematopoietic Stem Cell Transplantation, Gene Therapy, and Novel Therapies for Sickle Cell Disease Curative and novel therapies for SCD are increasingly being developed and clinical trials evaluated For a detailed discussion of these topics, see eBox 88.2 Thalassemia Molecular Description and Epidemiology The hallmark of thalassemia is an imbalance in the ratio of a- and b-chains, not necessarily a deficiency in chains In contrast to a single mutation being responsible for SCD and the mutant peptide directly leading to the pathophysiology, a textbook compendium of type mutations can lead to thalassemia, and it is the residual unpaired phenotypically normal globin chains that incite damage.3,151 Gene deletions account for the majority of a-thalassemias The severity in phenotype is dependent on whether one, two, three, or all four adult a-globin genes are missing.3 In contrast, the broad range of mutations that leads to b-thalassemia results in a continuum of clinical phenotypes.3 As with SCT, the thalassemia trait is thought to provide increased fitness in malaria zones The coexistence of a- and b-thalassemia in the same geographic regions leads to compound heterozygotes being common, resulting in a huge spectrum of disease and complicating diagnostics Laboratory and Diagnostics Although the sine qua non of diagnostics is a microcytic anemia with the demonstration of an a- to b-globin chain imbalance, this is not practical for routine testing Thus, most clinical laboratories rely on a variation of a thalassemia screen The screen helps distinguish thalassemia from iron deficiency and a- from b-thalassemia Due to the wide range of defects and frequent mixed a- and b-thalassemia patients, it is impossible to state absolutes for diagnostic interpretation Thus, there should be a low threshold to consult with a hematologist.152 Components of the screen include (1) a CBC in which emphasis is placed on the MCV, which is decreased in proportion to Hb production, the RBC to assess the degree of compensation for the decreased cell size, the Hb, and the smear; (2) a Hb electrophoresis or high-pressure liquid chromatography (HPLC) to quantitate normal (including HbF and A2) and variant Hb; (3) an inclusion body or Brilliant Cresyl Blue preparation to semiquantitatively assess excess b-like chains and distinguish a- and b-thalassemia; and a (4) zinc-protoporphyrin or similar screen to exclude iron deficiency a-Thalassemia results in excess b-like chains that form tetramers (b4: HbH, g4: Hb Barts) that precipitate in proportion to the number of missing a-genes, resulting in a positive inclusion body prep (eTable 88.4) The diagnosis of b-thalassemia is less direct Excess a-chains are less stable and degrade; thus, no a-tetramers are detectable on electrophoresis or HPLC Therefore, a microcytic anemia with negative inclusion body preparation in the face of adequate iron is suggestive of b-thalassemia Frequently, b-thalassemia results in upregulation of HbA2 and/or HbF; thus, the presence of either is suggestive of the diagnosis DNA testing is increasingly available and cost-effective However, it remains problematic, as no single assay or panel detects all abnormalities, and the turnaround time is high With the increasing application of high-throughput genome sequencing to clinical medicine, it will not be long before comprehensive sequencebased assays will be available Pathophysiology The pathophysiology of thalassemia results from having unpaired globin chains that lead to ineffective erythropoiesis and hemolysis, the degree of which depends on the specific form of thalassemia and the patient’s genetic background (eFigs 88.22 and 88.23).3,153 The presence of free unpaired globin chains increases reactive oxygen species A decrease in glutathione and antioxidant stores results in oxidative damage to the fragile red cell membrane and Fas-mediated apoptosis The result is a cadre of processes contributing to the heterogeneity of disease presentation Phosphatidyl serine moves to the outer leaf of the red cell membrane, enhancing macrophage-mediated destruction in the spleen and marrow and acting as a substrate for factors V and VIII binding, enhancing the generation of thrombin, which, together with decreased protein C and S levels and increased platelet activation and adhesion, leads to increased thrombosis In an attempt to compensate for the hemolysis and ineffective erythropoiesis, medullary and extramedullary erythropoiesis lead to skeletal abnormalities, such ... g-globulin Therapeutic agents enhancing NO bioavailability by various mechanisms are depicted in this image Of note, PDE9 has restricted tissue expression in the hematopoietic cells and brain as... widely expressed, with the potential for reduced off-target effects Glutamine increases NADH within red cells, thus reducing effects of oxidative stress Dietary glutamine also serves as a precursor... automated exchange to quickly bring down the HbS level while raising the Hgb is the standard of care.20 This requires either two largebore peripheral IV lines (which can be difficult in some patients)