Pathobiology Clinical Features, And Management Of Sickle Cell Disease

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Chapter 14 Pathobiology Clinical Features, And Management Of Sickle Cell Disease

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Figure 14-2 SICKLE GENE AND MALARIA.

The five regions in which the sickle gene achieved high allelic frequency are superimposed on shading that identifies the Old World distribution of the sickle gene and of historical, endemic malaria.

(Adapted from Friedman MJ, Trager W: The biochemistry of resistance to malaria. Sci Am 244:154, 1981 and from Nagel RL, Steinberg MH: Genetics of the βS gene: Origins, epidemiology, and epistasis in sickle cell anemia. In Steinberg MH: Forget BG, Higgs DR, Nagel RL, eds: Disorders of hemoglobin: Genetics, pathophysiology, and clinical management, Cambridge, 2001, Cambridge University Press, p 711.)

Relationship of HbS Molecular Behaviors to Disease Features

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Figure 14-3 KINETICS OF HEMOGLOBIN S POLYMERIZATION, STUDIED BY NEAR-INSTANTANEOUS AND COMPLETE DEOXYGENATION.

A, Extreme dependence of delay time on hemoglobin concentration. B to D, Kinetic progress curves for polymer formation show that long delay times are highly variable (B), but very short delay times are highly reproducible (D). To the right is a representation of domains and corresponding red blood cell morphology postulated to result from these different scales of polymerization rate (see Fig. 14-1, B to E). E, Delay times for individual red blood cells are influenced by substituent hemoglobins. F, A double nucleation process is hypothesized to underlie polymer formation. G, Physiologically, the finite rate of deoxygenation effectively caps the polymerization rate and eliminates the relevance of delay times that are short relative to deoxygenation rate (<1 sec).

(A to E, Data from Eaton WA, Hofrichter J: Hemoglobin S gelation and sickle cell disease. Blood 70:1245, 1987; F adapted from Ferrone FA, Hofrichter J, Eaton WA: Kinetics of sickle hemoglobin polymerization II. A double nucleation mechanism. J Mol Biol 183:611, 1985; G, Data from Ferrone FA: Oxygen transits and transports. In Embury S, Hebbel RP, Mohandas N, Steinberg MH, eds: Sickle cell disease: basic principles and clinical practice, New York, 1994, Raven Press.)

Major Sickle RBC Membrane Defects

Membrane iron deposits →

Oxidative reactions targeted at membrane →

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Figure 14-5 MECHANISMS LEADING TO HEMOLYSIS IN SICKLE CELL DISEASE.

This integrated synthesis shows how the molecular behaviors of hemoglobin S (HbS) (top) cause development of multiple red blood cell (RBC) abnormalities (middle) that lead to the four mechanisms of accelerated RBC destruction (bottom).

(Modified with permission from The American Journal of Hematology from Hebbel RP: Reconstructing sickle cell disease: A data-based analysis of the “hyperhemolysis paradigm” for pulmonary hypertension from the perspective of evidence-based medicine. Am J Hematol 86:123-154, 2011.)

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Figure 14-8 Life expectancy in patients with sickle cell disease for patients with Hb SS disease (A), Hb SC disease (B), and with different levels of fetal hemoglobin (Hb F) (C).

(From Platt OS, Brambilla DJ, Rosse WF, et al: Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 330:1639, 1994.)

Table 14-1 Baseline Evaluations to Consider

  Tests
Blood tests CBC with differential
  Reticulocyte count
  Hemoglobin electrophoresis
  LDH
  Renal function tests
  Liver function tests
  Mineral panel
  Serum iron, ferritin, TIBC
  Hepatitis B sAg
  Hepatitis C antibody
  RBC alloantibody screen
  RBC typing
  D-dimer*
  C-reactive protein*
  Brain natriuretic peptide
Urine and kidney tests Urinalysis
  Renal ultrasonography
Radiology MRI or MRA brain (adults) or transcranial Doppler ultrasonography starting at age 2 years (children)
  Chest radiography§
  Hip or shoulder radiograph or MRI (or both)
  Bone density in teenagers and adults
Cardiology and pulmonary Echocardiogram
Neurocognitive Neurocognitive testing§

LDH, Lactate dehydrogenase; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; RBC, red blood cell; sAg, surface antigen; TIBC, total iron-binding capacity.

*Consider following as surrogate markers after initiation of disease-modifying intervention.

If hematuria with red blood cells in urine.

As clinically indicated.

§If the patient has poor school performance, an abnormal memory, or abnormal MRI findings.

Table 14-2 Disease-Modifying Treatments to Consider

Robust clinical data Penicillin prophylaxis
  Streptococcus pneumoniae vaccination
  Hydroxyurea
  Chronic exchange transfusion
  Iron chelation for chronic iron overload*
Limited clinical data Folate supplementation
  Haemophilus influenzae vaccination
  Influenza vaccination
  Erythropoietin
  Phlebotomy
Experimental Hb F reactivation with decitabine, histone deacetylase inhibitors, or imids
  Erythropoietin for chronic relative reticulocytopenia
  Nutritional supplements and antioxidants (e.g., glutamine, zinc, multivitamins)
  N-acetylcysteine

Hb F, Fetal hemoglobin.

*Best data from thalassemia patient experience.

Risks minimal (however, can mask vitamin B12 deficiency). Therefore, it is generally done.

Table 14-3 Clinical Effects of Hydroxyurea Therapy

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Adapted from data in Charache S, Barton FB, Moore RD, et al: Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive “switching” agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 75:300, 1996.

Table 14-4 Transfusion Formulas

Dilutional effects of transfusion on Hb S: PRBC volume (PRBCV) (mL) = (Hctd − Hcti) × TBV × HctrpB
Manual partial-exchange transfusion:* Hb Sf = 1 − (PRBCV × Hctrp)(TBV × Hcti) + (PRBCV × Hctrp) × Hb SiC
Automated exchange transfusion: Exchange volume (mL) = (Hctd − Hcti) × TBVHctrp − (Hcti + Hctd)2D
RBC volume (mL) = Hcti × TBV

Hctd, desired hematocrit; Hcti, initial hematocrit; Hctrp, hematocrit of replacement cells (usually 0.75); Hb Si, initial Hb S; Hb Sf, final Hb S; PRBC, packed red blood cells; TBV, estimated total blood volume in milliliters (children, 80 mL/kg; adults, 65 mL/kg; nomograms are available).

*In these formulas, Hct and Hb S are fractions (e.g., 40% = 0.4).

From Nieburg and Stockman, with permission. Copyright 1977, American Medical Association and Linderkamp et al, with permission. Copyright 1977, Springer-Verlag.

Table 14-5 Recommended Dose and Interval of Analgesics Necessary to Obtain Adequate Pain Control in Patients With Sickle Cell Disease

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IM, Intramuscular; MAOI, monoamine oxidase inhibitor; MS, morphine sulphate; PO, oral.

Adapted from Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 332:1317, 1995.

Table 14-6 Bacteria and Viruses That Most Frequently Cause Serious Infection in Patients With Sickle Cell Disease

Microorganism Type of Infection Comments
Streptococcus pneumoniae Septicemia Common despite prophylactic penicillin and pneumococcal vaccine
  Meningitis Less frequent than in years past
  Pneumonia Rarely documented except in infants and young children
  Septic arthritis Uncommon
Haemophilus influenzae type b Septicemia  
Meningitis    
Pneumonia Much less common in recent years because of immunization with conjugate vaccine  
Salmonella species Osteomyelitis  
Septicemia Most common cause of bone and joint infection  
Escherichia coli and other gram-negative enteric pathogens Septicemia  
Urinary tract infection    
Osteomyelitis Focus sometimes inapparent  
Staphylococcus aureus Osteomyelitis Uncommon
Mycoplasma pneumoniae Pneumonia Pleural effusions; multilobe involvement
Chlamydia pneumoniae Pneumonia  
Parvovirus B19 Bone marrow suppression (aplastic crisis) High fever common; rash and other organ involvement infrequent
Hepatitis viruses (A, B, and C) Hepatitis Marked hyperbilirubinemia

Data from Buchanan GR, Glader BE: Benign course of extreme hyperbilirubinemia in sickle cell anemia: Analysis of six cases. J Pediatr 91:21, 1977.

Table 14-7 Organ-Related Infection in Sickle Cell Disease

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* Against Streptococcus pneumoniae and Haemophilus influenzae type b.

Data from Buchanan GR, Glader BE: Benign course of extreme hyperbilirubinemia in sickle cell anemia: Analysis of six cases. J Pediatr 91:21, 1977.

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Figure 14-11 COMPARISON OF STROKE RECURRENCE OVER 62 MONTHS IN A TRANSFUSED GROUP AND IN UNTRANSFUSED HISTORICAL CONTROL GROUPS.

(Adapted with permission from Pegelow CH, Adams RJ, McKie V, et al: Risk of recurrent stroke in patients with sickle cell disease treated with erythrocyte transfusions. J Pediatr 126:896, 1995.)