Intravascular hemolysis describes hemolysis that happens mainly inside the vasculature.[1] As a result, the contents of the red blood cell are released into the general circulation, leading to hemoglobinemia[2] and increasing the risk of ensuing hyperbilirubinemia.[3]

Mechanism

Intravascular hemolysis is the state when the red blood cell ruptures as a result of the complex of complement autoantibodies attached (fixed) on the surfaces of RBCs attack and rupture RBCs' membranes, or a parasite such as Babesia exits the cell that ruptures the RBC's membrane as it goes.[4]

Upon RBC's rupture, components of which are released and circulating in the blood plasma.[3]

These components comprise hemoglobin and others.[3] At this stage, the hemoglobin is called free hemoglobin.[3] Free hemoglobin (also called naked hemoglobin) is the un-bound hemoglobin that is not enclosed in the red blood cell. The naked hemoglobin is devoid of its anti-oxidant sentries that are normally available within the RBC.[5] Free hemoglobin is thus vulnerable to be oxidized.[5]

When the serum concentration of free hemoglobin is within the physiologic range of haptoglobin, the potential deleterious effects of free hemoglobin are prevented because haptoglobin will bind to "free hemoglobin" forming a complex of "free hemoglobin-haptoglobin" evidenced by reduced amount of haptoglobin.[6] However, during hyper-hemolytic conditions or with chronic hemolysis, haptoglobin is depleted so the remaining free hemoglobin readily distribute to tissues where it might be exposed to oxidative conditions,[2] thus some of the ferrous heme (FeII), the oxygen-binding component of hemoglobin, of the free hemoglobin are oxidized and becoming met-hemoglobin (ferric hemoglobin).[2] In such conditions, heme along with globin chains can be released from further oxidization of met-hemoglobin (ferric Hb).[2] In which, the free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades. At this time, hemopexin, another plasma glycoprotein come to bind with heme with its privilege of high heme affinity, forming a complex of heme-hemopexin, which is non-toxic, and travel together to a receptor on hepatocytes and macrophages within the spleen, liver and bone marrow.[7][2] (Note that the "free hemoglobin-haptoglobin" complex is taken up by hepatocytes and, to the lesser extent, macrophages.[2]) Thereafter, these complexes will undergo the metabolic mechanisms like extravascular hemolysis.[6]

Nevertheless, if the binding capacities of haptoglobin and hemopexin are saturated[note 1], the remaining "free hemoglobin" in the plasma will be oxidized to met-hemoglobin eventually, and then further disassociates into free heme and others.[3] At this stage, the "free heme" will bind to albumin, forming met-hemalbumin.[3][8] As to the remaining unbound (met)hemoglobin is filtered into the primary urine and re-absorbed via proximal tubules of the kidney.[3] In proximal tubules, the iron is extracted and stored as hemosiderin.[3] (Long-term hemoglobinuria is associated with substantial deposition of hemosiderin in proximal tubule (excessive accumulation of hemosiderin in proximal tubule), Fanconi syndrome (damaged renal re-absorption capability of small molecules which give rises to hyper-aminoaciduria, glycosuria, hyperphosphaturia, and bicarbonate and dehydration), and chronic kidney failure.[6])

In the end, if the plasma concentration of the "free met-hemoglobin" and/or "free hemoglobin" is still too high for proximal tubule to absorb back into the body, then hemoglobinuria occurs,[3] indicating an extensive intravascular hemolysis.[3] These remaining free hemoglobin entities also begin to consume nitric oxide, which is critical regulators of vascular homeostasis and basal and stress-mediated smooth muscle relaxation and vasomotor tone, endothelial adhesion molecule expression, and platelet activation and aggregation.[6] The reduction of nitric oxide deeply disturbs the body's mechanism to maintain the stability of the hemodynamics.[6] Additionally, free hemoglobin manifests direct cytotoxic, inflammatory, and pro-oxidant effects that in turn negatively impact endothelial function.[6] At the meantime, free heme exerts its multiple pro-inflammatory and pro-oxidant effects to the tissues it goes through.[6]

It is important to note that although hemosiderins are also included in the urine in the setting of intravascular hemolytic hemoglobinuria,[3] it will be detected only several days after the onset of the extensive intravascular hemolysis and will remain detectable several days after termination of intravascular hemolysis.[3] The phenomenon tells that the detection of hemosiderin in urine is indicative of either ongoing or recent intravascular hemolysis characterized by excessive hemoglobin and/or met-hemoglobin filtered through the renal glomerulus as well as the loss of hemosiderin-laden necrotic tubular cells.[3]

See also

Note

  1. ↑ Haptoglobin and hemopexin are not recyclable.[6]

References

  1. ↑ Stanley L Schrier. William C Mentzer; Jennifer S Tirnauer (eds.). "Diagnosis of hemolytic anemia in the adult". UpToDate. Archived from the original on 2017-12-26. Retrieved 2019-05-04.
  2. 1 2 3 4 5 6 "Intravascular hemolysis". eClinpath. Retrieved 2019-05-08.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 Muller, Andre; Jacobsen, Helene; Healy, Edel; McMickan, Sinead; Istace, Fréderique; Blaude, Marie-Noëlle; Howden, Peter; Fleig, Helmut; Schulte, Agnes (2006). "Hazard classification of chemicals inducing haemolytic anaemia: An EU regulatory perspective" (PDF). Regulatory Toxicology and Pharmacology. Elsevier BV. 45 (3): 229–241. doi:10.1016/j.yrtph.2006.04.004. hdl:10029/5596. ISSN 0273-2300. PMID 16793184. Archived from the original (PDF) on 2019-05-03. Retrieved 2019-05-04.
  4. ↑ "Bilirubin and hemolytic anemia". eClinpath. Retrieved 2019-05-08.
  5. 1 2 Schaer, D. J.; Buehler, P. W.; Alayash, A. I.; Belcher, J. D.; Vercellotti, G. M. (2012-12-20). "Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins". Blood. American Society of Hematology. 121 (8): 1276–1284. doi:10.1182/blood-2012-11-451229. ISSN 0006-4971. PMC 3578950. PMID 23264591.
  6. 1 2 3 4 5 6 7 8 Rother, Russell P.; Bell, Leonard; Hillmen, Peter; Gladwin, Mark T. (2005-04-06). "The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma Hemoglobin". JAMA. 293 (13): 1653–1662. doi:10.1001/jama.293.13.1653. ISSN 0098-7484. PMID 15811985. When the capacity of protective hemoglobin-scavenging mechanisms has been saturated, levels of cell-free hemoglobin increase in the plasma, resulting in the consumption of nitric oxide and clinical sequelae.
  7. ↑ Schaer, Dominik J.; Vinchi, Francesca; Ingoglia, Giada; Tolosano, Emanuela; Buehler, Paul W. (2014-10-28). "Haptoglobin, hemopexin, and related defense pathwaysâ€"basic science, clinical perspectives, and drug development". Frontiers in Physiology. Frontiers Media SA. 5: 415. doi:10.3389/fphys.2014.00415. ISSN 1664-042X. PMC 4211382. PMID 25389409.
  8. ↑ Kaushansky, Kenneth (2015). Williams hematology. New York: McGraw-Hill. ISBN 978-0-07-183300-4. OCLC 913870019.
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