Category:Hematinics

A hematinic is a medicine that supports the production of normal blood cells, principally the erythrocytes, by supplying a nutrient or hormonal stimulus whose deficiency limits red-cell formation. The category covers three established nutrient deficiencies (iron, folate, vitamin B12) and the synthetic erythropoiesis-stimulating agents that replicate or augment the action of the endogenous hormone erythropoietin.

The recognition that pallor and weakness could be cured by iron is among the oldest pharmacological observations in Europe. Filings of iron suspended in wine were prescribed for chlorosis (a form of iron-deficiency anemia particularly common in young women of the era) in seventeenth- and eighteenth-century medicine. In 1832 the French physician Pierre Blaud of Beaucaire published a paper on a specific iron pill containing ferrous sulfate and potassium carbonate, given in escalating doses to chlorotic patients, that became known across Europe as Blaud's pills and is the recognisable ancestor of all subsequent oral iron preparations.^[1] Ferrous sulfate (325 mg, containing 65 mg of elemental iron) remains, two hundred years later, the standard first-line oral iron medicine; ferrous gluconate and ferrous fumarate, the polysaccharide iron complex, and the newer ferric maltol provide alternatives with somewhat different gastrointestinal tolerability profiles. The parenteral iron preparations, introduced in the mid-twentieth century with iron dextran (a high-molecular-weight medicine with a small but real risk of anaphylactoid reaction), have been progressively refined into ferric carboxymaltose, ferric derisomaltose, ferric gluconate, and iron sucrose, which can be administered intravenously without the anaphylaxis risk of iron dextran and in 500-to-1000 mg doses in a single infusion.

The treatment of pernicious anemia is the second great hematinic discovery. The disease was described by the Edinburgh physician Thomas Addison in 1855 and characterised by Anton Biermer in 1872 as a uniformly fatal "idiopathic" macrocytic anemia. In 1926 the Boston physicians George Whipple, George Minot, and William Murphy reported that feeding patients with pernicious anemia approximately a quarter pound of cooked liver each day produced sustained reticulocyte response and clinical recovery; they shared the 1934 Nobel Prize, the first awarded for a medical treatment of a previously fatal disease.^[2] The active substance was isolated, after twenty-two years of work, in 1948 by Karl Folkers at Merck and Lester Smith at Glaxo working independently from the same approach: a red cobalt-containing crystalline factor that they named vitamin B12 (cyanocobalamin). The British crystallographer Dorothy Hodgkin determined its three-dimensional structure in 1956, a work for which she received the Nobel Prize in Chemistry in 1964. Intramuscular cyanocobalamin replaced the daily liver diet within a year of its isolation; hydroxocobalamin, a longer-acting preparation, is now standard in most of the world. The recognition that the absorption of dietary B12 from the terminal ileum requires the gastric glycoprotein intrinsic factor, identified by William Castle in 1929, explained the clinical pattern (pernicious anemia is an autoimmune destruction of the gastric parietal cells producing intrinsic factor deficiency) and motivated the standard parenteral route of administration.

The third nutrient hematinic, folate, has a parallel story. The British physician Lucy Wills reported in 1931 from her work in Bombay that an extract of yeast (Marmite) cured the tropical macrocytic anemia of pregnancy in textile workers whose diet was otherwise inadequate.^[3] The yeast factor was identified in 1941 by Henry Mitchell at Texas as a substance present in spinach (whence the name folate, from the Latin folium for leaf); it was isolated chemically by Bob Stokstad and colleagues at Lederle in 1945. Folic acid (pteroylglutamic acid) is now the standard preventive supplement during the periconceptional period and the early weeks of pregnancy for the prevention of neural-tube defects; in 1998 the United States mandated the fortification of grain products with folic acid, an intervention that produced a measurable decline in the prevalence of anencephaly and spina bifida. Therapeutic folate is also used to treat established megaloblastic anemia where folate (rather than B12) is the deficient nutrient; an important clinical caveat is that empirical folate treatment of a megaloblastic anemia that is actually B12-deficient corrects the haematology but allows the underlying neurologic disease of B12 deficiency to progress, so B12 must be ruled out before folate is given.

The hormonal hematinics are a younger chapter. The discovery in 1977 by Eugene Goldwasser at Chicago of the human erythropoietin protein, and its cloning and expression by Amgen scientists in 1983-1985, led to the approval of recombinant human erythropoietin (epoetin alfa, epoetin) in 1989 for the anemia of chronic kidney disease. The medicine was extended to anemia in cancer chemotherapy, in HIV-associated anemia from zidovudine, and in selected preoperative anemia; the longer-acting analogue darbepoetin alfa followed in 2001. Aggressive correction of anemia in chronic kidney disease to haemoglobin concentrations near normal was found in the CHOIR and CREATE trials to increase cardiovascular events, and the contemporary target is a more modest 10-11 g/dL.^[4] The more recent class of HIF prolyl hydroxylase inhibitors (roxadustat, daprodustat, vadadustat), oral medicines that stabilise the transcription factor hypoxia-inducible factor and so increase endogenous erythropoietin production, was approved in the early 2020s in selected jurisdictions for anemia of chronic kidney disease.

By nutrient or hormone:

• Iron supplements:
  • Oral: ferrous sulfate, ferrous gluconate, ferrous fumarate, polysaccharide iron complex, ferric maltol, heme iron polypeptide
  • Parenteral: iron sucrose, ferric gluconate, ferric carboxymaltose, ferric derisomaltose, ferumoxytol; iron dextran (now rarely used because of anaphylaxis risk)
• Vitamin B12:
  • Cyanocobalamin (oral, sublingual, intramuscular)
  • Hydroxocobalamin (intramuscular, also used at high dose for cyanide poisoning)
  • Methylcobalamin (oral and sublingual, the methylated form preferred by some practitioners)
• Folate:
  • Folic acid (pteroylglutamic acid) (oral)
  • Levomefolate (the active 5-methyltetrahydrofolate)
  • Folinic acid (leucovorin), used to rescue from methotrexate toxicity and to potentiate fluorouracil, not for primary deficiency
• Erythropoiesis-stimulating agents:
  • Epoetin alfa, epoetin beta (the original recombinant erythropoietins)
  • Darbepoetin alfa (longer half-life through additional N-glycosylation)
  • Methoxy polyethylene glycol-epoetin beta (mircera, monthly dosing)
• HIF prolyl hydroxylase inhibitors (where approved):
  • Roxadustat, daprodustat, vadadustat, molidustat

The boundary of this category is "medicine that supports erythropoiesis by supplying a deficient nutrient or hormone." The thrombopoietin receptor agonists (romiplostim, eltrombopag, avatrombopag), used in immune thrombocytopenia and aplastic anemia, support platelet rather than erythrocyte production and are listed under haematologic growth factors rather than here. The granulocyte colony-stimulating factors (filgrastim, pegfilgrastim) are also haematopoietic growth factors but not hematinics. The medicines for thalassemia and sickle cell disease (hydroxyurea, the newer voxelotor and crizanlizumab and the gene therapies casgevy and lyfgenia) treat haemoglobinopathy through mechanisms other than nutrient replacement and are not hematinics. The medicines used to treat hemolytic anemia and aplastic anemia (immunosuppression, eculizumab for paroxysmal nocturnal hemoglobinuria) are listed under their primary mechanisms.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.