Intravascular hemolysis

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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]

Contents

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]

Related Research Articles

Hemolysis Rupturing of red blood cells and release of their contents

Hemolysis or haemolysis, also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid. Hemolysis may occur in vivo or in vitro.

Hemoglobinopathy Medical condition

Hemoglobinopathy is the medical term for a group of inherited blood disorders and diseases that primarily affect red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits.

Haptoglobin

Haptoglobin is the protein that in humans is encoded by the HP gene. In blood plasma, haptoglobin binds with high affinity to free hemoglobin released from erythrocytes, and thereby inhibits its deleterious oxidative activity. Compared to Hp, hemopexin binds to free heme. The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system.

<span class="mw-page-title-main">Hereditary spherocytosis</span> Medical condition

Hereditary spherocytosis (HS) is a congenital hemolytic disorder, wherein a genetic mutation coding for a structural membrane protein phenotype leads to a spherical shaping of erythrocytic cellular morphology. As erythrocytes are sphere-shaped (spherocytosis), rather than the normal biconcave disk-shaped, their morphology interferes with these cells' abilities to be flexible during circulation throughout the entirety of the body - arteries, arterioles, capillaries, venules, veins, and organs. This difference in shape also makes the red blood cells more prone to rupture under osmotic and/or mechanical stress. Cells with these dysfunctional proteins are degraded in the spleen, which leads to a shortage of erythrocytes resulting in hemolytic anemia.

Paroxysmal nocturnal hemoglobinuria Medical condition

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occurs due to deficiency of the red blood cell surface protein DAF, which normally inhibits such immune reactions. Since the complement cascade attacks the red blood cells within the blood vessels of the circulatory system, the red blood cell destruction (hemolysis) is considered an intravascular hemolytic anemia. Other key features of the disease, such as the high incidence of venous blood clot formation, are incompletely understood.

Hemolytic anemia Medical condition

Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels or elsewhere in the human body (extravascular). This most commonly occurs within the spleen, but also can occur in the reticuloendothelial system or mechanically. Hemolytic anemia accounts for 5% of all existing anemias. It has numerous possible consequences, ranging from general symptoms to life-threatening systemic effects. The general classification of hemolytic anemia is either intrinsic or extrinsic. Treatment depends on the type and cause of the hemolytic anemia.

Hemoglobinuria Abnormally increased hemoglobin in urine

Hemoglobinuria is a condition in which the oxygen transport protein hemoglobin is found in abnormally high concentrations in the urine. The condition is caused by excessive intravascular hemolysis, in which large numbers of red blood cells (RBCs) are destroyed, thereby releasing free hemoglobin into the plasma. Excess hemoglobin is filtered by the kidneys, which excrete it into the urine, giving urine a purple color. Hemoglobinuria can lead to acute tubular necrosis which is an uncommon cause of a death of uni-traumatic patients recovering in the ICU.

Hemopexin

Hemopexin, also known as beta-1B-glycoprotein, is a glycoprotein that in humans is encoded by the HPX gene and belongs to the hemopexin family of proteins. Hemopexin is the plasma protein with the highest binding affinity for heme.

Autoimmune hemolytic anemia (AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in the circulation. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs. AIHA is a relatively rare condition, with an incidence of 5-10 cases per 1 million persons per year in the warm-antibody type and 0.45 to 1.9 cases per 1 million persons per year in the cold antibody type. Autoimmune hemolysis might be a precursor of later onset systemic lupus erythematosus.

Paroxysmal cold hemoglobinuria (PCH) is an autoimmune hemolytic anemia featured by complement-mediated intravascular hemolysis after cold exposure. It can present as an acute non-recurrent postinfectious event in children, or chronic relapsing episodes in adults with hematological malignancies or tertiary syphilis. Described by Julius Donath (1870–1950) and Karl Landsteiner (1868–1943) in 1904, PCH is one of the first clinical entities recognized as an autoimmune disorder.

The Schumm test(shoom) is a blood test that uses spectroscopy to determine significant levels of methemalbumin in the blood. A positive result could indicate intravascular hemolysis. The Schumm test was named for Otto Schumm, a German chemist who lived in the early 20th century.

Hemosiderinuria is the presence of hemosiderin in urine. It is often the result of chronic intravascular hemolysis, in which hemoglobin is released from red blood cells into the bloodstream in excess of the binding capacity of haptoglobin. The function of haptoglobin is to bind to circulating hemoglobin, thereby reducing renal excretion of hemoglobin and preventing injury to kidney tubules. The excess hemoglobin that is not bound to haptoglobin is filtered by the kidneys and reabsorbed in the proximal convoluted tubule, where the iron portion is removed and stored in ferritin or hemosiderin. The tubule cells of the proximal tubule become damaged, slough off with the hemosiderin and are excreted into the urine, producing a "brownish" color. It is usually seen three to four days after the onset of hemolytic conditions.

Hemoglobinemia Abnormally increased hemoglobin in blood plasma

Hemoglobinemia is a medical condition in which there is an excess of hemoglobin in the blood plasma. This is an effect of intravascular hemolysis, in which hemoglobin separates from red blood cells, a form of anemia.

Hematologic diseases are disorders which primarily affect the blood & blood-forming organs. Hematologic diseases include rare genetic disorders, anemia, HIV, sickle cell disease & complications from chemotherapy or transfusions.

Normocytic anemia is a type of anemia and is a common issue that occurs for men and women typically over 85 years old. Its prevalence increases with age, reaching 44 percent in men older than 85 years. The most common type of normocytic anemia is anemia of chronic disease.

Alpha-1-microglobulin is a microglobulin, a small globular protein. It is found in all vertebrates, including humans, and is distributed in blood plasma and extravascular tissues of all organs. It is synthesized in most cells of the body, but mainly in the liver from a gene that codes for the alpha-1-microglobulin/bikunin precursor.

Urine test strip

A urine test strip or dipstick is a basic diagnostic tool used to determine pathological changes in a patient's urine in standard urinalysis.

Sickle cell nephropathy is a type of nephropathy associated with sickle cell disease which causes kidney complications as a result of sickling of red blood cells in the small blood vessels. The hypertonic and relatively hypoxic environment of the renal medulla, coupled with the slow blood flow in the vasa recta, favors sickling of red blood cells, with resultant local infarction. Functional tubule defects in patients with sickle cell disease are likely the result of partial ischemic injury to the renal tubules.

Mechanical hemolytic anemia is a form of hemolytic anemia due to mechanically induced damage to red blood cells. Red blood cells, while flexible, may in some circumstances succumb to physical shear and compression. This may result in hemoglobinuria. The damage is induced through repetitive mechanical motions such as prolonged marching and marathon running. Mechanical damage can also be induced through the chronic condition microangiopathic hemolytic anemia or due to prosthetic heart valves.

Hemolytic jaundice, also known as prehepatic jaundice, is a type of jaundice arising from hemolysis or excessive destruction of red blood cells, when the byproduct bilirubin is not excreted by the hepatic cells quickly enough. Unless the patient is concurrently affected by hepatic dysfunctions or is experiencing hepatocellular damage, the liver does not contribute to this type of jaundice.

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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