EXTRAVASCULAR HEMOLYSIS

EXTRAVASCULAR HEMOLYSIS

PRELIMINARY

Hemolytic anemia is anemia caused by the hemolysis process, which is the premature breakdown of erythrocytes in blood vessels. In hemolytic anemia, the lifespan of erythrocytes is shorter (normal erythrocyte lifespan is 100-120 days).

Hemolytic anemia is anemia due to hemolysis, the abnormal breakdown of red blood cells (red blood cells), either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular).

Hemolysis is the increased destruction of erythrocytes and causes anemia when the bone marrow cannot compensate for the loss of erythrocytes. Hemolysis is the destruction or removal of red blood cells from the circulation before their normal lifespan of 120 days. While hemolysis can be a lifelong asymptomatic condition, it most often presents as anemia when erythrocytosis cannot keep up with the rate of destruction of red blood cells. Hemolysis may also manifest as jaundice, cholelithiasis, or isolated reticulocytosis.

Based on the cause is divided into intrinsic and extrinsic. Intrinsic causes are characterized by abnormalities in erythrocytes, including membrane, hemoglobin and enzyme abnormalities. Extrinsic causes are characterized by abnormal erythrocytes accompanied by an external process that causes hemolysis. In addition, there are those who divide hemolysis based on where the destruction occurs, namely intravascular and extravascular

Intravascular hemolysis is the destruction of circulating red blood cells by releasing their contents into the plasma. Mechanical trauma from damaged endothelium, complement fixation and activation on the cell surface, and infectious agents can cause direct membrane degradation and cell damage.

Perbandingan hemolisis intravaskular dengan ekstravaskular

Perbandingan hemolisis intravaskular dengan ekstravaskular

perberdaan mekanisme hemolysis intravaskuler dan ekstravaskuler

perberdaan mekanisme hemolysis intravaskuler dan ekstravaskuler

Extravascular hemolysis
Extravascular hemolysis is more common than intravascular hemolysis. Hemolysis occurs in macrophage cells of the reticuloendothelial system (RES), especially in the spleen, liver and bone marrow because these cells contain the enzyme heme oxygenase. Hemolysis occurs due to membrane damage (eg due to antigen-antibody reactions), precipitation of hemoglobin in the cytoplasm, and decreased flexibility of erythrocytes. Splenic capillaries with a relatively small diameter and a relatively hypoxic atmosphere will provide an opportunity for the destruction of erythrocytes, possibly through a fragmentation mechanism 2,3,10

PATHOGENESIS1,2
Hemolysis is the premature destruction of red blood cells. This can lead to anemia. Extravascular hemolysis occurs in macrophage cells of the reticuloendothelial system, especially the spleen, liver and bone marrow because these cells contain the enzyme heme oxygenase. Lysis occurs when erythrocytes are damaged in both the membrane, hemoglobin and flexibility. If erythrocytes are lysed by macrophages, they will break down into globin and heme. Globin is broken down into amino acids and used as a protein synthesis material while heme is broken down into iron and protoporphyrin.
The porphyrin ring is oxidized by microsomal heme oxygenase and produces biliverdin and iron (Fe3+). Iron is released into the plasma via iron channels and binds to apotransferrin or is stored in cells as ferritin. After that, ferritin is oxidized and degraded to hemosiderin.
Iron is transported again to be stored as reserves but protoporphyrin decomposes to CO and bilirubin. Biliverdin is reduced by biliverdin reductase to unconjugated bilirubin which is water soluble and released into the plasma bound to albumin and captured by hepatocytes. Bilirubin in the blood will bind to albumin to form indirect bilirubin, which is conjugated in the liver to become direct bilirubin which is excreted in the bile thereby increasing stercobilinogen in feces and urobilinogen in urine.

Patofisiologi hemolisis ekstravaskuler

Patofisiologi hemolisis ekstravaskuler

Metabolisme Hb

Metabolisme Hb

ETIOLOGI

ETIOLOGI

Causes of extravascular hemolysis:1,2,3

Erythrocyte membrane defects:
Hereditary spherocytosis
It is an autosomal dominant disorder (75%) with defects in erythrocyte cytoskeletal membrane proteins so that they are spheroidal in shape, not easily deformed and susceptible to sequestration and destruction in the spleen. Deficiency of structural proteins bound to the erythrocyte internal membrane. Erythrocytes that lack spectrin have an unstable membrane and are easily fragmented spontaneously.

Sferosit terlihat dengan bagian tengah lebih pucat dari sekitarnya

Sferosit terlihat dengan bagian tengah lebih pucat dari sekitarnya

Hemolysis 5
a. Autoimmune hemolytic anemia
Autoimmune Hemolytic Anemia (AIHA) occurs due to the presence of autoantibodies against erythrocytes causing hemolysis by macrophages in the RES. There are two types of autoimmune hemolytic anemia, namely the warm type and the cold type. The cause of AIHA is thought to be suppression of the immune system by a virus.

1. Warm Type
Approximately 70% of AIHA cases have the warm type, where autoantibodies react optimally at 37°C. Approximately 50% of AIHA patients with warm type are accompanied by other diseases. Erythrocytes are usually coated with immunoglobulin (IgG) alone or with complement, and are therefore taken up by reticuloendothelial macrophages that have receptors for the Fc IgG fragment. Part of the coated membrane is lost so the cell becomes progressively more spherical to maintain the same volume and is eventually destroyed prematurely, especially in the spleen.
2. Cold type
Antigen antibody reactions occur at cold temperatures (< 320 C). Causes include idiopathic, infectious. Antibodies, usually IgM, are highly efficient at fixing complement, and intra and extravascular hemolysis may occur. Treatment response is not good with corticosteroid administration.

Factors that affect the site of hemolysis is the duration of the disease, namely if acute then occurs intravascular while chronic then hemolysis occurs extravascular. In addition, the type of immunoglobulin also affects the place where hemolysis occurs. When mediated by IgG, extravascular hemolysis occurs, while IgM causes extravascular hemolysis.

b. Isoimmune Hemolytic Anemia
Isoimmune hemolysis is caused by Rhesus and ABO incompatibility. Rhesus positive has rh-antigen on its erythrocytes while rhesus negative does not. Antibody formation occurs after exposure to either transfusion or pregnancy. The rhesus blood group system is the strongest antigen when compared to other blood group systems. The antigen in rhesus positive is antigen D. Anti-D is an IgG type antibody, can cross the placenta and enter the fetal circulation. New hemolytic manifestations occur in the second pregnancy due to the presence of antibodies that cross the placenta.
Hemolysis caused by ABO incompatibility occurs in infants with blood type A, B or AB with mothers with blood type O. Hemolysis occurs directly in the first pregnancy because of the presence of anti-A and anti-B which crosses the placenta.

B cells produce IgG and/or IgM which can recognize their own erythrocyte epitope

B cells produce IgG and/or IgM which can recognize their own erythrocyte epitope

Strong complement repair antibodies result in the formation of a membrane attack complex, hole punching in the red blood cell causing the red blood cell to rupture in the circulation (intravascular hemolysis). Weak complement repair antibodies produce only the C3b opsonin, and attach to the erythrocyte membrane. Immunoglobulin binding or C3b-erythrocyte binding is destroyed by macrophages (which contain receptors for the C3b and Fc portion of immunoglobulins) as they cross organs such as the spleen (extravascular hemolysis).

hemoglobin abnormalities
Sickle cell
Hemoglobin S is abnormal hemoglobin caused by the substitution of the single nucleotide base valine in place of glutamic acid at the sixth position of the beta globin chain. These changes cause changes in the structure of the erythrocyte cell membrane which causes many complications of sickle cell disease.

Figure 6. Sickle cell

Figure 6. Sickle cell

CLINICAL MANIFESTATIONCLINICAL MANIFESTATION

Clinical manifestations of hemolysis in general are the presence of jaundice, splenomegaly. In extravascular hemolysis, urine color is dark yellow due to urobilinogenuria. Anemia may also occur. If extravascular hemolysis is suspected, diagnostic tests for a specific hemolytic state based on the etiology are performed.

SUPPORTING INSPECTION1,2,3
• Routine blood
Low Hb levels with normochromic normocytic erythrocyte index can be hypochromic microcytic. The leukocyte and platelet counts were normal.
• Reticulocytosis
• Peripheral Blood smear
Peripheral blood smear examination can show morphology of erythrocytes suggesting an etiology. The most common cell types are:
– Spherocytes are found in hereditary spherocytosis, autoimmune hemolysis, hemoglobinopathies
– Eliptosis / ovalocytes in hereditary elliptocytosis
– Fragmentation (schistocytes) i.e. sharp-pointed triangular poikilocytes in microangiopathic hemolytic states
– Poikilocytosis in hemoglobinopathies

Figure 8a. Schistocytes Figure 8b. Elliptosis / ovalocyte

Figure 8a. Schistocytes Figure 8b. Elliptosis / ovalocyte

• Bilirubinemia, blood haptoglobin slightly decreased/normal
• Urobilinogenuria

Picture . Metabolism results from intravascular and extravascular hemolysis.

Picture . Metabolism results from intravascular and extravascular hemolysis.

CONCLUSION
Hemolysis is the increased destruction of erythrocytes and causes anemia when the bone marrow cannot compensate for the loss of erythrocytes. Hemolysis is based on the site of destruction, namely intravascular and extravascular.
Extravascular hemolysis is more common than intravascular hemolysis. Hemolysis occurs in macrophage cells of the reticuloendothelial system (RES), especially in the spleen, liver and bone marrow.
Causes of extravascular hemolysis:1,2,3
• Erythrocyte membrane defects:
Hereditary spherocytosis
• Hemolysis 5
a. Autoimmune hemolytic anemia
b.Isoimmunity.
• hemoglobin abnormalities
Sickle cell
Clinical manifestations of hemolysis in general are the presence of jaundice, splenomegaly. In extravascular hemolysis, urine color is dark yellow due to urobilinogenuria.

REFERENCES

  1. Arceci R, Hann I, Smith O. Pediatric hematology 3rdWiley .Blackwell publishing. 2016.p126,523
  2. Extravascular hemolysis (online), (http://ahdc.vet.cornell.edu/clinpath/modules/chem/extravasc.hem.htm)
  3. Bernadette F, Rodak, George A, Fritsma, Kathryn D. Clinical principles and applications. Elsevier Health Sciences. 2017.p 321
  4. Kenneth D. Clinical laboratory medicine. Lippincott Williams & Wilkins. 2016.p1633
  5. Maria C L. Oliveira, Benigna M. Oliveira, Murao,Zilma M V, Letícia T. Gresta, Marcos B. Viana. Clinical course of autoimmune hemolytic anemia:an observational study. J Pediatr . 2016;82(1):58-62
  6. Dhaliwal G. Hemolytic Anemia.San Francisco Veterans Affairs Medical Center/University of California–San Francisco School of Medicine, San Francisco, California Am Fam Physician.2014 Jun 1;69(11):2599-2607.
  1. Shoenfield, Y, et al (2018). Diagnostic Criteria in Autoimmune Disease. Humana Press.
  2. Bakta. Anemia Hemolitik. 2016. Available at Http//www.scribd. com
  3. Sudoyo. Anemia Hemolitik.2016. Available at Http//www.scribd. com
  1. Aljedai A. Immune Haemolytic Anaemias. 2015. Available at http/www.emedicine.com

By :

dr.Haryanty Huntoyungo,SpA, DR.dr.Nadirah Rasyid Ridha.Mkes,SpA (K), Prof.DR.dr. Dasril Daud, SpA(K)

 

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