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{{Hemolytic anemia}}
{{Hemolytic anemia}}
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{{CMG}}; {{shyam}}
 
==Overview==
==Overview==
[[Hemolytic anemia]] is [[anemia]] caused secondary to shortened survival of circulating red blood cells. The normal life span of RBCs is 110 to 120 days. RBC destruction before that time is defined as hemolytic anemia. As opposed to the normal senecence of RBC, the random hemolysis (premature RBC death) is increased in hemolytic anemia.
Laboratory evaluation begins with examination of the [[peripheral blood smear]]. Serum tests include [[LDH]], [[haptoglobin]], [[bilirubin]], and [[reticulocyte count]]. A combination of all of these tests can give insight into whether or note hemolytic anemia is present and, if present, the degree of [[hemolysis]]. The osmotic fragility test is less commonly used but can also be used to assess for predisposition to [[hemolysis]].
 
==Laboratory Findings==
===Peripheral blood smear===
* Fragments of the red blood cells ("[[schistocyte]]s") can be present.
* Some red blood cells may appear smaller and rounder than usual ([[spherocyte]]s).
* [[Reticulocytosis|Reticulocytes]] are present in elevated numbers. This may be overlooked if a special [[staining (biology)|stain]] is not used
* The reticulocytes response act as an important indicator for the severity of the hemolytic anemia. The different methods used to judge the correct response are, absolute reticulocyte count, corrected reticulocyte count, and reticulocyte production index.
===Reticulocyte count===
====Absolute reticulocyte count====
The normal values are:
* RBC count - 5 million/microLitre
* Reticulocyte count - 0.5 -1.5 %
* Absolute reticulocyte count - 25,000 to 75,000/microLitre
====Corrected reticulocyte count====
The corrected absolute reticulocyte count = absolute reticulocyte count / reticulocyte maturation time (in days).
====Reticulocyte production index====
* [[Reticulocyte]]s are newly-produced red blood cells. They are slightly larger than totally mature red blood cells, and have some residual ribosomal [[RNA]]. The presence of RNA allows a visible blue stain to bind or, in the case of fluorescent dye, result in a different brightness. This allows them to be detected and counted as a distinct population.
* The '''Reticulocyte production index''' (RPI, also called a ''corrected reticulocyte count'') is a calculated value used in the diagnosis of [[anemia]].
* This calculation is necessary because the raw [[reticulocyte count]] is misleading in anemic patients.  
* The problem arises because the reticulocyte count is not really a ''count'' but rather a ''percentage'': it reports the number of reticulocytes as a percentage of the number of red blood cells.
* In anemia, the patient's red blood cells are depleted, creating an erroneously elevated reticulocyte count.
* The idea of the RPI is to assess whether the [[bone marrow]] is producing an appropriate response to an anemic state.
* Reticulocyte production should increase in response to any loss of red blood cells.
* It should increase within 2-3 days of a major acute [[hemorrhage]], for instance, and reach its peak in 6-10 days.  
* If reticulocyte production is not raised in response to anemia, then the anemia may be due to an acute cause with insufficient time to compensate, or there is a defect with red blood cell production in the bone marrow.
* Marrow defects include nutritional deficiencies (i.e. iron, folate, or B12) or insufficient [[erythropoietin]], the stimulus for  red blood cell production.


* It corrects the reticulocyte response through two mechanism:
==Approach to diagnosis of hemolytic anemia==
* The degree of anemia (done by normalizing hematocrit of 45%)
* Reticulocyte maturation time (RMT)
* The Reticulocyte maturation time is 1.0 days for a hematocrit of 45 % to 2.5 days for a hematocrit of 15 %:
* Reticulocyte production index = Reticulocytes %  x  (HCT / 45)  x  (1 / RMT)
** Normal value of RPI is 1.
** RPI is said to be increased if it is more than 2
** Value low than 1 shows hypoproliferative responses
Reticulocyte Production Index is calculated as follows:


'''1.'''<math>Retic Index = Retic Count * {Hematocrit \over Normal Hematocrit}</math>
The most important initial diagnostic tests is the [[peripheral blood smear]]. This allows for direct visualization of the [[red blood cells]] and any other morphologic abnormalities. The results of the peripheral blood smear can frequently guide additional testing.<ref name="pmid26696800">{{cite journal| author=Packman CH| title=The Clinical Pictures of Autoimmune Hemolytic Anemia. | journal=Transfus Med Hemother | year= 2015 | volume= 42 | issue= 5 | pages= 317-24 | pmid=26696800 | doi=10.1159/000440656 | pmc=4678314 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26696800 }} </ref> The cost of a peripheral blood smear is low, and thus it is the test of choice for initial workup of hemolytic anemia. A peripheral blood smear is prepared by placing a small about of whole blood onto a glass slide, then using a second glass slide to smear the [[blood]] on the first slide. Stains are done to help visualize [[cells]].


A value of 45 is usually used as a normal hematocrit.  
===Peripheral blood smear===
*'''[[Schistocytes]]''': These are fragments of [[red blood cells]]. They are also known as helmet cells. Presence of [[schistocytes]] is not specific for [[hemolysis]] but is specific for a microangiopathic process, which can be associated with [[hemolysis]].
*'''[[Spherocyte|Spherocytes]]''': These are [[red blood cells]] that contain a high volume to surface area ratio. These cells have a relative lack of [[membrane]] and thus appear as spheres rather than the typical biconcave shape of normal [[red blood cells]]. They appear smaller and rounder than normal [[Red blood cell|red blood cells]].
*'''Bite cells''': These are also known as [[Heinz bodies]]. They are typically seen in patients with [[hemolysis]] from [[G6PD]] deficiency. Heinz bodies comprise denatured [[hemoglobin]].
*'''[[Target cell|Target cells]]''': These are also known as [[Codocyte|codocytes]]. They are not specific for [[hemolysis]], as they can be found in [[liver disease]], [[thalassemia]], [[hemoglobin E]], and [[hemoglobin C]]. [[Electrophoresis]] helps to differentiate between [[thalassemia]] and [[liver diseases]] (elevated [[liver enzymes]]), and other [[hemoglobinopathies]].
*'''[[Reticulocytes]]''': These are primitive or immature [[red blood cells]]. They contain residual [[ribosomes]] and [[RNA]]. The presence of RNA allows a visible blue stain to bind or, in the case of fluorescent dye, result in a different brightness. This is known as polychromasia.<ref name="pmid26696800">{{cite journal| author=Packman CH| title=The Clinical Pictures of Autoimmune Hemolytic Anemia. | journal=Transfus Med Hemother | year= 2015 | volume= 42 | issue= 5 | pages= 317-24 | pmid=26696800 | doi=10.1159/000440656 | pmc=4678314 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26696800  }} </ref> When [[reticulocytes]] are present in elevated numbers, this suggests an adequate [[bone marrow]] response to [[anemia]]. The [[reticulocytes]] response act as an important indicator for the severity of the hemolytic anemia. The normal [[reticulocyte count]] is 0.5-1.5%. In the case of [[hemolysis]], the [[reticulocyte]] count can increase to beyond 10%. The different methods used to assess the appropriate response are:
**Absolute reticulocyte count: This is measured in number of [[cells]] per [[microliter]]. The normal range for absolute reticulocyte count is 25,000 to 75,000 per microliter.
**Corrected reticulocyte count: This is calculated as absolute [[reticulocyte]] count divided by [[reticulocyte]] maturation time (in days).
**Reticulocyte production index: This is calculated as reticulocytes %  x  (hematocrit / 45)  x  (1 / reticulocyte maturation time). The reticulocyte index (RI) should be between 1.0 and 2.0 for a healthy patient.
***RI < 2 with [[anemia]] indicates decreased production of reticulocytes and therefore [[red blood cells]].
***RI > 2 with anemia indicates loss of red blood cells (destruction, [[bleeding]], etc) leading to increased compensatory production of reticulocytes to replace the lost red blood cells.


'''2.'''The next step is to correct for the longer life span of prematurely released reticulocytes in the blood--a phenomenon of increased red blood cell production. This relies on a table:
==Laboratory Findings==
*Elevated '''total [[bilirubin]]''': Elevated [[bilirubin]], or [[hyperbilirubinemia]], is a hallmark of hemolytic anemia. Bilirubin is typically unconjugated (indirect).
*Elevated '''[[LDH]]''': This is an [[enzyme]] present in [[red blood cells]]. When [[hemolysis]] occurs, the [[intracellular]] contents of the cells are released, and [[LDH]] levels rise.
*Low '''[[haptoglobin]]''': Haptoglobin is produced in the [[liver]] and bind free [[hemoglobin]]. During hemolysis, [[haptoglobin]] decreases as it is consumed at a faster rate compared to the rate of production by the liver.
*Elevated '''[[reticulocyte count]]''': [[Reticulocytes]] are primitive [[red blood cells]] and are elevated in [[hemolysis]]. Please see above for detailed explanation of [[reticulocytosis]].
*'''[[Direct antiglobulin test]] (DAT) [[Coomb's test|(Coomb's test)]]'''<ref name="pmid26696800">{{cite journal| author=Packman CH| title=The Clinical Pictures of Autoimmune Hemolytic Anemia. | journal=Transfus Med Hemother | year= 2015 | volume= 42 | issue= 5 | pages= 317-24 | pmid=26696800 | doi=10.1159/000440656 | pmc=4678314 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26696800  }} </ref>: This measures the presence of [[antibodies]] on patient's [[red blood cells]]. This is an important diagnostic test to help differentiate immune-mediated [[hemolysis]] from non-immune-mediated hemolysis. A positive [[Coomb's test]] suggests immune-mediated hemolysis. The DAT can detect either [[IgG]] or [[complement]] protein C3 on the surface of [[red blood cells]]. Presence of IgG (or IgG plus C3) is characteristic of warm [[autoimmune]] hemolytic anemia, whereas presence of C3 is more characteristic of [[cold agglutinin disease]] or [[paroxysmal cold hemoglobinuria]].<ref name="pmid26696800">{{cite journal| author=Packman CH| title=The Clinical Pictures of Autoimmune Hemolytic Anemia. | journal=Transfus Med Hemother | year= 2015 | volume= 42 | issue= 5 | pages= 317-24 | pmid=26696800 | doi=10.1159/000440656 | pmc=4678314 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26696800  }} </ref>
*'''[[Indirect antiglobulin test|Indirect antiglobulin test (indirect Coombs' test)]]'''<ref name="pmid26696800">{{cite journal| author=Packman CH| title=The Clinical Pictures of Autoimmune Hemolytic Anemia. | journal=Transfus Med Hemother | year= 2015 | volume= 42 | issue= 5 | pages= 317-24 | pmid=26696800 | doi=10.1159/000440656 | pmc=4678314 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26696800  }} </ref>: This measures the presence of [[antibodies]] in a patient's [[serum]] but not coating their [[Red blood cell|red cells]]. This is another test that helps differentiate immune-mediated hemolysis from non-immune-mediated hemolysis. A positive indirect [[Coomb's test]] can suggest alloantibodies from prior [[Blood transfusion|transfusion]].
*'''Osmotic fragility test''': This test determines the fragility of [[red blood cells]] to hypotonic [[lysis]]. Patients with hereditary [[spherocytosis]] usually have red blood cells with high degrees of osmotic fragility.<ref name="pmid24466544">{{cite journal| author=Jung HL| title=A new paradigm in the diagnosis of hereditary hemolytic anemia. | journal=Blood Res | year= 2013 | volume= 48 | issue= 4 | pages= 237-9 | pmid=24466544 | doi=10.5045/br.2013.48.4.237 | pmc=3894378 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24466544  }} </ref>


'''Hematocrit (%)......Retic
===Specific findings for intravascular hemolysis===
*Elevated urine [[hemosiderin]]
*Elevated urine [[hemoglobin]]
*Microangiopathic blood smear


'''So,''' in a person whose reticulocyte count is 5%, hemoglobin 7.5 g/dL, hematocrit 25%, the RPI would be:
===Specific findings for extravascular hemolysis===
 
*Spherocytic red cell morphology
''5 x [corrected retic count]/[maturation correction] = 5 x (25/45) /2'' = '''1.4'''
*Negative urine [[hemosiderin]]
 
*Negative urine hemoglobin
*The reticulocyte index (RI) should be between 1.0 and 2.0 for a healthy individual.
*RI < 2 with anemia indicates decreased production of reticulocytes and therefore red blood cells.{{ref|Adamson}}
*RI > 2 with anemia indicates loss of red blood cells (destruction, bleeding, etc) leading to increased compensatory production of reticulocytes to replace the lost red blood cells.{{
 
===Other lab tests===
* Elevated [[lactate dehydrogenase]] (LDH)
* Elevated [[haptoglobin]]
* The direct [[Coombs test]] is positive if hemolysis is caused by an immune process
===Liver function test===
* The level of unconjugated [[bilirubin]] in the blood is elevated. This may lead to [[jaundice]].
===Urinalysis===
* Hemosiderin in the urine indicates chronic intravascular hemolysis.
* There is also [[urobilinogen]] in the urine.


(Images shown below are courtesy of Melih Aktan MD, Istanbul Medical Faculty - Turkey, and Hospital Universitario La Fe Servicio Hematologia)
(Images shown below are courtesy of Melih Aktan MD, Istanbul Medical Faculty - Turkey, and Hospital Universitario La Fe Servicio Hematologia)
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==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
[[Category:Hematology]]
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Latest revision as of 14:23, 31 October 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]

Overview

Laboratory evaluation begins with examination of the peripheral blood smear. Serum tests include LDH, haptoglobin, bilirubin, and reticulocyte count. A combination of all of these tests can give insight into whether or note hemolytic anemia is present and, if present, the degree of hemolysis. The osmotic fragility test is less commonly used but can also be used to assess for predisposition to hemolysis.

Approach to diagnosis of hemolytic anemia

The most important initial diagnostic tests is the peripheral blood smear. This allows for direct visualization of the red blood cells and any other morphologic abnormalities. The results of the peripheral blood smear can frequently guide additional testing.[1] The cost of a peripheral blood smear is low, and thus it is the test of choice for initial workup of hemolytic anemia. A peripheral blood smear is prepared by placing a small about of whole blood onto a glass slide, then using a second glass slide to smear the blood on the first slide. Stains are done to help visualize cells.

Peripheral blood smear

Laboratory Findings

Specific findings for intravascular hemolysis

Specific findings for extravascular hemolysis

  • Spherocytic red cell morphology
  • Negative urine hemosiderin
  • Negative urine hemoglobin

(Images shown below are courtesy of Melih Aktan MD, Istanbul Medical Faculty - Turkey, and Hospital Universitario La Fe Servicio Hematologia)

References

  1. 1.0 1.1 1.2 1.3 1.4 Packman CH (2015). "The Clinical Pictures of Autoimmune Hemolytic Anemia". Transfus Med Hemother. 42 (5): 317–24. doi:10.1159/000440656. PMC 4678314. PMID 26696800.
  2. Jung HL (2013). "A new paradigm in the diagnosis of hereditary hemolytic anemia". Blood Res. 48 (4): 237–9. doi:10.5045/br.2013.48.4.237. PMC 3894378. PMID 24466544.

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