hemolytic anemia

Hemolytic anemia is anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs) either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular). It has numerous possible causes, ranging from relatively harmless to life-threatening. The general classification of hemolytic anemia is either acquired or inherited. Treatment depends on the cause and nature of the breakdown.

In a healthy person, a red blood cell survives 90 to 120 days in the circulation, so about 1% of human red blood cells break down each day. The spleen (part of the reticulo-endothelial system) is the main organ which removes old and damaged RBCs from the circulation. In healthy individuals, the breakdown and removal of RBCs from the circulation is matched by the production of new RBCs in the bone marrow.

In conditions where the rate of RBC breakdown is increased, the body initially compensates by producing more RBCs; however, breakdown of RBCs can exceed the rate that the body can make RBCs, and so anemia can develop. Bilirubin, a breakdown product of hemoglobin, can accumulate in the blood causing jaundice, and be excreted in the urine causing the urine to become a dark brown colour.

Symptoms

Signs of anemia (fatigue and, later, heart failure) are generally present as are those due to the release of free hemoglobin fragments. Jaundice may be present. Certain aspects of the medical history can suggest a cause for hemolysis, such as drugs, fava bean or other sensitivity, prosthetic heart valve, or another medical illness.

Normal RBC Lifecycle

Hemolytic anemia generally occurs as a modification of the RBC lifecycle. That is, instead of being collected at the end of its useful life and disposed of normally, the RBC disintegrates in a manner allowing free iron containing molecules to reach enter the blood. It is perhaps then helpful to understand the physiology of the RBC and things that can go wrong to cause it to "die" prematurely. With their complete lack of mitochondria, RBC's rely on glycolysis for the materials needed to reduce oxidative damage. Any limitations of glycolysis can result in more susceptibility to oxidative damage and a short or abnormal lifecycle. If the cell is unable to signal to the reticuloendothelial phagocytes by externalizing phosphatidylserine, it is likely to lyse through uncontrolled means^[1][2][3]. Dogs and cats differ slightly from humans in some details of their RBC composition and have altered susceptibility to damage, notably increased susceptbility to oxidative damage from onion or garlic.^{[4][5][6][7][8][9][10][11][12][13]}

Fate and Disposition of free Hemoglobin

The distinguishing feature of intravascular hemolysis is the release of RBC contents into the blood stream. The metabolism and elimination of these products, largely iron containing compounds capable of doing damage through Fenton reactions, is an important part of the condition. Several reference texts exist on the elimination pathways, for example.^[14][15] Free hemoglobin can bind to haptoglobin or it may oxidize and release the heme group which is able to bind to either albumin or hemopexin. The heme is ultimately converted to bilirubin and removed in stool and urine.^[14] Hemoglobin may be cleared directly by the kidneys resulting in fast clearance of free hemoglobin but causing the continued loss of hemosiderin loaded renal tubular cells for many days.

Additional effects of free hemoglobin seem to be due to specific reactions with NO^[16].

Tests

• Peripheral blood smear microscopy:
  • fragments of the red blood cells ("schistocytes") can be present
  • some red blood cells may appear smaller and rounder than usual (spherocytes)
  • Reticulocytes are present in elevated numbers. This may be overlooked if a special stain is not used.
• The level of unconjugated bilirubin in the blood is elevated. This may lead to jaundice.
• The level of lactate dehydrogenase (LDH) in the blood is elevated
• Haptoglobin levels are decreased
• If the direct Coombs test is positive, hemolysis is caused by an immune process.
• Hemosiderin in the urine indicates chronic intravascular hemolysis. There is also urobilinogen in the urine.

Clinical findings in hemolytic anaemias:

• increased serum bilirubin levels in blood, therefore jaundice
• pallor in mucous membrane and skin
• increased urobilinogen in urine
• Splenomegaly
• Pigmented gallstones may be found.

Classification of hemolytic anemias

Causes of hemolytic anemia can be either genetic or acquired. They may be classified according to the means of hemolysis, being either intrinsic in cases where the cause is related to the RBC itslef or extrinsic in cases where factors external to the RBC dominate.^[17] Intrinsic effects may include problems with RBC proteins or oxidative stress handling while external factors include immune attack and microvascular angiopathies ( RBC's are mechnically damaged in circulation).

Genetic

Main article: Congenital hemolytic anemia

Genetic causes can involve the RBC membrane, metabolism, or hemoglobin conditions.

Acquired

Main article: Acquired hemolytic anemia

Acquired hemolytic anemia can be divided into immune and non-immune mediated.

Differential diagnosis

• Ineffective hematopoiesis is sometimes misdiagnosed as hemolysis.
  • Clinically these conditions may share many features of hemolysis
  • Red cell breakdown occurs before a fully developed red cell is released into the circulation.
  • Examples: thalassemia, myelodysplastic syndrome
• Megaloblastic anemia due to deficiency in vitamin B12 or folic acid.

Therapy

Definitive therapy depends on the cause:

• Symptomatic treatment can be given by blood transfusion, if there is marked anemia.
• In severe immune-related hemolytic anemia, steroid therapy is sometimes necessary.
• Sometimes splenectomy can be helpful where extravascular hemolysis is predominant (ie most of the red blood cells are being removed by the spleen).

See also

• Red blood cell

References

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Further reading

Signalling in Normal RBC Collection

Failure to signal for normal removal is discussed in these papers:

• Bosman GJ, Lasonder E, Groenen-Döpp YA, Willekens FL, Werre JM, Novotný VM (August 2009). "Comparative proteomics of erythrocyte aging in vivo and in vitro". Journal of Proteomics. doi:10.1016/j.jprot.2009.07.010. PMID 19660581. 
• Kanno H (March 2008). "[Critical role of phosphatidylserine in hemolysis due to red blood cell enzyme/membrane defects]" (in Japanese). Nippon Rinsho 66 (3): 461–8. PMID 18330023. 
• Bratosin D, Mazurier J, Tissier JP, et al. (October 1997). "Molecular mechanisms of erythrophagocytosis. Characterization of the senescent erythrocytes that are phagocytized by macrophages". Comptes rendus de l'Académie des sciences. Série III, Sciences de la vie 320 (10): 811–8. PMID 9436535. 

Related Genetic Conditions

Some RBC related genes that effect hemolysis susceptibility:

• Kugler W, Lakomek M (March 2000). "Glucose-6-phosphate isomerase deficiency". Baillière's Best Practice & Research. Clinical Haematology 13 (1): 89–101. PMID 10916680. 
• Jacobasch G, Rapoport SM (April 1996). "Hemolytic anemias due to erythrocyte enzyme deficiencies". Molecular Aspects of Medicine 17 (2): 143–70. doi:10.1016/0098-2997(96)88345-2. PMID 8813716. 
• Pohl A, Blechschmidt E, Moser K (July 1984). "[Glucose-6-phosphate dehydrogenase deficiency and other erythrocyte enzyme abnormalities]" (in German). Wiener Klinische Wochenschrift 96 (14): 542–8. PMID 6089445. 
• Vives-Corrons JL, Rozman C, Kahn A, Carrera A, Triginer J (October 1975). "Glucose phosphate isomerase deficiency with hereditary hemolytic anemia in a Spanish family: clinical and familial studies". Humangenetik 29 (4): 291–7. doi:10.1007/BF00394191. PMID 240775. 
• Valentine WN (October 1975). "Metabolism of human erythrocytes. Studies in health and disease". Archives of Internal Medicine 135 (10): 1307–13. doi:10.1001/archinte.135.10.1307. PMID 1164111. http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=1164111. 
• Benöhr HC (January 1970). "[Hemolytic anemias caused by genetic disorders in human red cells]" (in German). Ärztliche Forschung 24 (1): 19–29. PMID 4398687. 

In Cats and Dogs

Some pets tend to be more susceptible to this than humans. The comparative situations helps illustrate some causes and effects of general interest to hemolysis.

In cats

• Hill AS, O'Neill S, Rogers QR, Christopher MM (March 2001). "Antioxidant prevention of Heinz body formation and oxidative injury in cats". American Journal of Veterinary Research 62 (3): 370–4. doi:10.2460/ajvr.2001.62.370. PMID 11277202. 
• Robertson JE, Christopher MM, Rogers QR (April 1998). "Heinz body formation in cats fed baby food containing onion powder". Journal of the American Veterinary Medical Association 212 (8): 1260–6. PMID 9569166. 

And in dog

• Tang X, Xia Z, Yu J (April 2008). "An experimental study of hemolysis induced by onion (Allium cepa) poisoning in dogs". Journal of Veterinary Pharmacology and Therapeutics 31 (2): 143–9. doi:10.1111/j.1365-2885.2007.00930.x. PMID 18307506. 
• Chang HS, Yamato O, Yamasaki M, Ko M, Maede Y (June 2005). "Growth inhibitory effect of alk(en)yl thiosulfates derived from onion and garlic in human immortalized and tumor cell lines". Cancer Letters 223 (1): 47–55. doi:10.1016/j.canlet.2004.10.008. PMID 15890236.