See also Immune-mediated hemolytic anemia (outline)
Definitions
Hemolysis is the breakage of the red blood cells’ (RBC’s) membrane, causing the release of the hemologin and other internal components into the surrounding fluid. It is visually detected by showing a pink to red tinge in serum or plasma. There are a number of pathological conditions which can cause hemolysis.
Hemoglobin: is a tetrameric potein molecule composed of two identical alpha globin subunits (alpha 1 and 2) and two identical beta globin subunits (beta 1 and 2. In a hemaglobin tetramer, each alpah globin is associated with the beta globin to form two stable alpha/beta dimers, which in turn associated to form the tetramer. The subunits are noncovalently associated through Van der Waals forces, hydrogen bonds and salt bridges. A heme moleucle is incorporated into each of the alpha and beta globins. Heme is a large organic molecules coordinated around an iron atom. Heme that does not contain iron is called protoporphyrin IX (PIX) and is non-funcitonal (cannot bind a ligand). In the deoxygenated state, the four subunits form a tetrahedron. During ligand binding, the alpha1beta1 and alpha2beta2 interfaces remain relatively fixed while the alpa1beta2 and alpha2beta1 interfaces exhibit considerable movement. When the hemoglobin molecule is oxygenated, the intersubunit distances are increased relative to the deoxygenated distances and the moelcule assumes a relaxed state confirguation which is the predominant form of the molecule when a ligand is bound to the heme.
Hemophilia
Hemophila is due in over 80% of cases to a dificiency in factor VIII activity (hemophilia A), while in most of the remainder it is due to a deficiency in factor IX (hemophilia B). Global incidence of hemophilia is estimaited at between 200 to 400 thousand, with hemophilia A having an average incidence of about 2 per 10k people.
Treatment:
Disease severity is linked by the percentage of residual active factor produced by the patient, and the disease is treated via intravenous administration of the missing clotting factor. Before the introduction of clotting factor concentrates in the 1960s, the life expectancy was about 15-25 years. In the early 1980s, before the advent of screening tests of HIV in donated blood, large numbers of hemophiliacs contracted AIDS from clotting factors purified from human plasma. The introduction of recombinant clotting factors beginning in the ealry 1990s drastically reduced dependence on plasma derived products, and the 2017 global market value for such recombinant products stood at 8.5 billion. Treatment costs typically vary from 30k to several huundred thousand dollars annually. Clotting factor pdoucts are usually adminsitered therapeutically to control active bleeding or prophylactically to reduce frequency of future bleeding events. Administration for therapeutic purposes is tailed to individual circumstances while prophylactic adminsitration of unmodified (first generation) factors typically occurs three times weekly. Engineering to increase serum half life has relied on PEGylation, Fc fusion. (Gary Wash “Biopharmaceutical benchmarks 2018” Nature Biotechnology, 36(12), 2018)
Hemoglobinopathies/Hemoglobin Mutants:
Hemoglobinopathies, inherited disorders of hemoglobin structure and function, consist of structural hemoglobin variants and the thalassemias, inherited defects that reduce production in the synthesis of the alpha and beta globins of the human adult hemoglobin. (Hedrick, “Population genetics of malaria resistance in human” Heredity 2011, 107, 283-304).
Two alpah and two beta subunits compose the tetrameric protein backbone of adult hemoglobin, and the alpha and beta subunits are more up of 141 and 146 amino acids, respectively, each with three exons. The genes that conde for alpha dn beta globins, HBA (there are actually two genes, HBA1 and HBA2, with identical amino acid sequnces) adn HBB, are unlinked and are locatge don chromsomes 11 and 16, respectively. (Hedrick, “Population genetics of malaria resistance in human” Heredity 2011, 107, 283-304).
Hundreds of structural variatns of adult hemoglobin have been documented, but only three, all at the HBB locus, S, C and E, have reached substantial frequenceis in any popualtions. Two of these three, S and C, are different mutatns (with different phenotypes) at the same amino acid position 6 and although E is a structural variant at amino acid position 26, it also affects regulation in a manner similar to the thalassemias.
Sickle Cell Anemia:
The sickle-cell allele (symbolized as S) was one of the first human genetic variants that was associated with a specific molecular caused disease. The sickle-cell allele is widely known as a varaint that causes red blood cells to be deformed into a sickle shape when deoxygenated in AS heterozygotes, in which A incides the non-mutant form of the beta-globin gene, and also provides resistance to malaria in AS heterozygotes. In SS homozygotes, S casues the severe dsiease sicke-cell anemia. It is generally assumed that individuals with genotype SS had very low or zero fitness when, or if, there was no modern medical care. The greatest documented impact of S is that it protets agaisnt death or severe malarial disease in heterozygotes, and it apepars that S has less effect on the rate of infection. The S allele differs from the normal A allele at one nucleotide at codon position 6 in the beta globin molecule, which translate into a change form the amino acid glutamic acid to valine. The frequency of allele S is up to 0.2 in some parts of sub-Saharan Africa, Greece and India. There apepars to be five indpendent origins, or mutaitons, of the S allele form the A allele, based on theri existence in nearly non-overlapping geographical regions. (Hedrick, “Population genetics of malaria resistance in human” Heredity 2011, 107, 283-304).
Sickle cell anemia is a blood condition seen most commonly in people of African ancestry. It is inherited form both parents. If you inherit the sickle cell gene form only one of your parents, you will have a sickle cell trait but not the symptoms of sickle cell anemia. It is caused by an abnormal type of hemoglobin called hemologin S. Hemologlobin is a protein inside red blood cells that carries oxygen. The Hemoglobin S changes the shape of red blood cells so that they become shaped like crescents or sickles. These fragile, sicke-shaped cells deliver less oxygen to the body’s tissue and can also get stuck more easily in small blood vessels, as well as break into pieces that can interrupt healthy blood flow. The sickle gene has a genetic advantage in that it protects heterozygous carries from succumbing to Plasmodium falciparum malaria infection. Symptoms include painful episodes which cause pain in the bones of the back, the long bones and the chest. Treatment of SCD typically begins with early intervention involving newborn screen and prophylactic penicillin. One of the key components in the management of patients with SCD is transfusion, usually packed red blood cell therpy. As is noted by Staurt, however, sickle cell disease “is a systemic disease of monumental complexity” (Lancet, 364, 2004, p. 1357, last ¶).
The high motality and widespread impact of matlaria have resulted in this disease being the strongest evolutionary selective force in recent human history, and genes that confer resistance to malaria provide some of the best known case studies of strong positive selection in modern humans. (Hedrick, “Population genetics of malaria resistance in human” Heredity 2011, 107, 283-304). See also evolution
Sickle cell disease (SCD), a group of inherited blood disorders characterized by abnormal hemoglobin, reduces life expectancy by >20 years. SCD primarily affects persons whose ancestors came from Africa, where malaria is endemic, because the carrier state (sickle cell trait, inheritance of a sickle cell gene from only one parent) confers a selective advantage by protecting against the harmful effects of malaria. Thus, >90% of the estimated 100,000 persons in the United States with SCD are non-Hispanic Black or African American (Black), and an estimated 3%–9% are Hispanic or Latino (Hispanic). In persons with SCD, red blood cells become rigid and deform into a crescent or sickle shape. Sickled cells die early and often become lodged in small blood vessels, compromising blood flow, which can lead to serious health problems. SCD-associated complications include anemia; acute and chronic pain; infections; pneumonia and acute chest syndrome; stroke; and kidney, liver, and heart disease. Despite their extensive health care needs, many persons with SCD have difficulty accessing appropriate care and report feeling stigmatized and having their symptoms dismissed when they do seek care. SCD comprises four main genotypes; among these, the hemoglobin SS and hemoglobin Sβ0-thalassemia genotypes are the more severe forms and are collectively referred to as sickle cell anemia (SCA). SCA accounts for an estimated 75% of SCD cases in the United States. See CDC
Given that SCA is a common cause of childhood stroke, children and adolescents aged 2–16 years with SCA be screened annually with transcranial Doppler (TCD) ultrasound to identify high cerebral blood velocity, an indicator of elevated stroke risk. Chronic blood transfusion therapy, the recommended intervention, substantially reduces stroke occurrence in children and adolescents identified as being at risk. Children and adolescents aged ≥9 months with SCA (including asymptomatic children) should also be offered treatment with hydroxyurea, a medication shown to be efficacious in preventing or reducing severe pain episodes, acute chest syndrome, and other SCA-associated complications and increasing patient survival. See CDC
Beta-Thalassemia: is a genetic blood disorder where the body produces less than normal hemoglobin, the protein in red blood cells that carries oxygen. This can lead to anemia and various helth problems.
–Reblozyl (luspatercept-aamt – Bristol Myers Squibb): is an erythroid maturation agent indicated for teh treatment of anemia in (i) adult patients with transfusion dependent and non-transfusion dependent eta thalassemia who rquire regular red blood cell transfusions, (ii) adult patients with very low to intermediate risk MS who have ring sideroblasts and require red blood cell transfusions as well as (iii) adult patients without previous erythropoiesis stimulating agent use with very low to intermedaite risk MDS who may require regular red blood cell transfusions. US reveneus increased 80% in 2024.