Pathobiology Clinical Features, And Management Of Sickle Cell Disease

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

Robert P. Hebbel, Yogen Saunthararajah, Elliott P. Vichinsky

Figure 14-1 SICKLE RED BLOOD CELL (RBC) MORPHOLOGIES.

A, Blood smear from the first patient report on sickle cell disease. B to E, Blood smears prepared under differing conditions from the same sickle cell anemia patient. B, Antecubital venous blood was fixed immediately at a pO₂ of approximately 40 mm Hg to document RBC shapes in vivo. Several RBC morphologies are evident, including two granular (raisinlike) cells, five somewhat elongated cells, and two highly elongated and curved cells. C, The mixed venous blood (B) was then fully oxygenated. Most cells have resumed normal shape, but one irreversibly sickled cell is present. D, The oxygenated cells (C) were then partially deoxygenated and assumed classical holly-leaf forms typical of rapid deoxygenation. E, The already partially deoxygenated mixed venous cells (B) were then fully deoxygenated (pO₂ = 0 mm Hg) and display the more elongated shape having fewer spikes that is assumed by slowly deoxygenated sickle RBC.

(B to E from Obata K, Mattiello J, Asakura K, et al: Exposure of blood from patients with sickle cell disease to air changes the morphological, oxygen-binding, and sickling properties of sickled erythrocytes. Am J Hematol 81:26, 2006. A from Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch Intern Med 5:517, 1910.)

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 β^S 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

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 →

Band 3 clumping → Ig attraction → erythrophagocytosis

Oxidative reactions targeted at membrane →

Figure 14-4 MARKED HETEROGENEITY IN SICKLE RED BLOOD CELL (RBC) HYDRATION.

Compared with normal RBCs (A) studied by discontinuous density-gradient centrifugation, RBCs from a sickle subject with four α genes (D) include cells of unusually low density (usually reticulocytes) and abnormally high density (dehydrated cells). Sickle subjects with three and two α genes are shown in C and B, respectively.

(From Embury SH, Clark MR, Monroy G, Mohandas N: Concurrent sickle cell anemia and a-thalassemia. J Clin Invest 73:116, 1984.)

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.)

Figure 14-6 THE CENTRALITY OF ENDOTHELIAL DYSFUNCTION IN SICKLE CELL DISEASE.

Sickle hemoglobin (HbS) polymerization provides the system input, ischemia–reperfusion provides the incessant driving force, and the resulting systemic inflammation is the executor of the HbS affect on vascular biology, which is realized by the disparate consequences of endothelial dysfunction. NO, nitric oxide; RBC, red blood cell.

(Modified 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, 2011.)

Figure 14-7 SICKLE CELL DISEASE AND HEMOGLOBIN SC PERIPHERAL BLOOD SMEARS.

The peripheral smear in sickle cell disease (A) shows sickle cells that are mostly irreversibly sickled and sometimes referred to as “cigar forms.” Higher power detail (B) shows a sickle cell (upper left), red blood cell containing a Howell-Jolly body (middle right), and polychromatophilic cell (lower center). These indicate sickle cell anemia and splenic dysfunction but marrow response with reticulocytosis, respectively. A peripheral smear of a patient with Hgb SC (C) shows no sickled cell, but there are target forms (D) and occasional cells (E) with hemoglobin condensed at each pole of the cell.

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.)

Figure 14-9 WHERE THERAPEUTICS INTERVENE IN THE PATHOPHYSIOLOGICAL CASCADE.

Hb, Hemoglobin; RBC, red blood cell.

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

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) = (Hct_d − Hct_i) × TBV × Hct_rpB

Manual partial-exchange transfusion:* Hb Sf = 1 − (PRBCV × Hct_rp)(TBV × Hct_i) + (PRBCV × Hct_rp) × Hb S_iC

Automated exchange transfusion: Exchange volume (mL) = (Hct_d − Hct_i) × TBVHct_rp − (Hct_i + Hct_d)2D

RBC volume (mL) = Hct_i × TBV

Hct_d, desired hematocrit; Hct_i, initial hematocrit; Hct_rp, hematocrit of replacement cells (usually 0.75); Hb S_i, initial Hb S; Hb S_f, 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).

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

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.

Figure 14-10 PARVOVIRUS.

Bone marrow aspirate in a patient with sickle cell disease and aplastic crisis (A). Note the absence of red blood cell precursors except for the single, large degenerating pronormoblast (lower center). Such pronormoblasts contain large nuclear inclusions (B) as a result of replication of parvovirus B19. The same can be seen in the tissue sections of a bone core biopsy (C and D). The parvovirus can now be recognized immunohistochemically with an immunostain (E).

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

* 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.

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.)