Disease sickle cell

Sickle cell syndromes are hereditary disorders characterized by the presence of sickle hemoglobin (HbS) in red blood cells (RBCs). 

The most common abnormal hemoglobin in the United States is hemoglobin S (HbS). Two genes for HbS result in sickle cell disease (SCD) or sickle cell anemia, which occurs in 0.3% of African Americans. One gene for HbS results in sickle cell trait, which occurs in 8% of African Americans. Hemoglobin C, another abnormality, occurs in 2% to 3% of African Americans. 

Clinical manifestations of SCD are attributable to impaired circulation, RBC destruction, and stasis of blood flow. These problems are attributable to disturbances in RBC polymerization and to membrane damage. Polymerization allows deoxygenated hemoglobin to exist as a semisolid gel that protrudes into the cell membrane, distorting RBCs into sickle shapes. Sickle-shaped RBCs increase blood viscosity and encourage sludging in the capillaries and small vessels. Such obstructive events lead to local tissue hypoxia and accentuate the pathologic process. 

Additional contributing factors include functional asplenia (and increased risk of bacterial infection), deficient opsonization, and coagulation abnormalities. 

SCD involves many organ systems. Clinical manifestations depend on the genotype (Table 34-1). 

Amino acids are the building blocks of proteins. Each amino acid has both amino (—NH2) and caiboxy (—COOH) functional groups, in addition to a side group that may be polar or nonpolar. Valine (Val), histidine (His), leucine (Leu), threonine (Thr), proline (Pro), and glutamic acid (Glu) are 6 of the 20 amino acids [M4 Section 10.6] that make up human proteins. The characteristic side group of each amino acid is shaded to identify it  

Proteins form when amino acids are joined together with peptide bonds, also known as amide linkages, in which the caiboxy group on one amino acid connects to the amino group of the next. The carboxy group of the second amino acid connects to the amino group of another, and so on. A water molecule is eliminated with the formation of each peptide bond. What remains of each amino add after the formation of peptide bonds (and the corresponding loss of water molecules) is referred to as an amino acid residue, or simply a residue. (Peptide bonds are shown in blue.) 

The primary structure of a protein refers to the sequence of amino acids that make up the protein chain. 

Secondary stmcture refers to the shape the protein chain adopts as the result of hydrogen bonding between nearby residues. One of the possible secondary stmctures is a helix. 

Tertiary stmcture refers to the folding of the protein into a characteristic shape, which is stabilized by attractive forces between more distant residues. 

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Embury, S.H. The clinical pathophysiology of sickle-cell disease. Annu. Rev. Med. 37 361-376, 1986. 

In nephrogenic diabetes insipidus the kidney s ability to respond to AVP is impaired by different causes, such as drugs (e.g. lithium), chronic disorders (e.g. sickle cell disease, kidney failure) or inherited genetic disorders (X-linked or autosomal NDI). This type of diabetes insipidus can not be treated by exogenous administration of AVP or AVP analogues. Instead, diuretics (hydrochlorothiazide combined or not with amiloride) and NSAI (indomethacin) are administrated to ameliorate polyuria. 

Influenza vaccine. Influenza vaccine is recommended annually for children age > 6 months with certain risk factors (including but not limited to asthma, cardiac disease, sickle cell disease, HIV, diabetes see MMWR. 2001 50(RR-4) 1-44), and can be administered to all others wishing to obtain immunity. Children aged <12 years should receive vaccine in a dosage appropriate for their age (0.25 mL if age 6-35 months or 0.5 mL if age >3 years). Children aged <8 years who are receiving influenza vaccine for the first time should receive two doses separated by at least 4 weeks. 

Kumpati, J. (1987). Liposome-loaded phenylalanine or tryptophan as sickling inhibitor A possible therapy for sickle cell disease, Biochem. Med. Metabol. Biol., 38, 170-181. 

Bunn HF Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997 337 762. 

Manning JM et aJ Normal and abnormal protein subunit interactions in hemoglobins.] Biol Chem 1998 273 19359-Mario N, Baudin B, Giboudeau J Qualitative and quantitative analysis of hemoglobin variants by capillary isoelectric focusing. J Chromatogr B Biomed Sci Appl 1998 706 123-Reed W, Vichinsky EP New considerations in the treatment of sickle cell disease. Annu Rev Med 1998 49 46l. 

The classic example is sickle cell disease, which is caused by mutation of a single base out of the 3x10 in the genome, a T-to-A DNA substitution, which in... 

Point mutations Protein folding Transcriptional control Frameshiftand nonsense mutations RNA processing Sickle cell disease P-Thalassemia P-Thalassemia P-Thalassemia... 

Sickle cell disease again provides an excellent example of how recombinant DNA technology can be applied to the smdy of human disease. The substitution of T for A in the template strand of DNA in the P-globin gene changes the sequence in the region that corresponds to the sixth codon from... 

If the genetic lesion is understood and a specific probe is available, prenatal diagnosis is possible. DNA from cells collected from as little as 10 mL of amniotic fluid (or by chorionic villus biopsy) can be analyzed by Southern blot transfer. A fetus with the restriction pattern AA in Figure 40-10 does not have sickle cell disease, nor is it a carrier. A fetus with the SS pattern will develop the disease. Probes are now available for this type of analysis of many genetic diseases. 

Rosse WF et al New Views of Sickle Cell Disease Pathophysiology and Treatment. The American Society of Hematology. www.asheducationbook.org... 

Ischemic stroke has numerous causes. Cerebral infarction may result from large artery atherosclerosis, cardiac embolism, small artery lipohyalinosis, cryptogenic embolism, or, more rarely, from other diverse conditions such as arterial dissection, infective endocarditis, and sickle cell disease. Arterial occlusion is the cause of at least 80% of acute cerebral infarctions. " ... 

Systemic lupus erythematosus, Sjogren s syndrome, multiple myeloma, obstructive uropathy, cirrhosis, and sickle cell disease... 

Cocaine and intravenous drug use Low socioeconomic status Increased hematocrit Sickle cell disease... 

Onset of action is slow at around 30 minutes, which limits spontaneity. In addition, patients and partners may complain of a cold, lifeless, discolored penis that has a hinge-like feel. Painful ejaculation or inability to ejaculate are additional adverse effects. VEDs are contraindicated in persons with sickle cell disease and should be used with caution in patients on oral anticoagulants or who have bleeding disorders due to the increased possibility of priapism. 

Dunlop RJ, Bennet CL. Pain management for sickle cell disease. Cochrane Database Syst Rev 2006 2 CD003350. 

Hick JL, Nelson SC, Hick K, et al. Emergency management of sickle cell disease complications Review and practice guidelines. Minn Med 2006 89 42 44. 

Explain the underlying causes of sickle cell disease and their relationship to patient signs and symptoms. 

Identify the typical characteristics of sickle cell disease as well as symptoms that indicate complicated disease. 

Identify the desired therapeutic outcomes for patients with sickle cell disease. 

Describe the components of a monitoring plan to assess effectiveness and adverse effects of pharmacotherapy for sickle cell disease. 

O Sickle cell disease is an inherited disorder caused by a defect in the gene for hemoglobin. Patients may have one defective gene (sickle cell trait) or two defective genes (sickle cell disease). 

Sickle cell disease involves multiple organ systems. 

Chronic transfusion therapy programs have been shown to be beneficial in decreasing the occurrence of stroke in children with sickle cell disease. 

FIGURE 65-1. Sickle gene inheritance scheme for both parents with sickle cell trait (SCT). A, normal hemoglobin S, sickle hemoglobin. Possibilities with each pregnancy 25% normal (AA) 50% SCT (AS) 25% sickle cell anemia (SS). (From Chan CYJ, Moore R. Sickle cell disease. In DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy A Pathophysiologic Approach. 6th ed. New York McGraw-Hill 2005 1856.)... 

TABLE 65-1. Clinical Features of Sickle Cell Trait and Sickle Cell Disease... 

TABLE 65-2. Acute Complications of Sickle Cell Disease (SCD)... 

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