- Craig Davison, EM Consultant, Edinburgh
Tweet: Who gives a schistocyte?
Can be nonspecific and mimic sepsis. Important to have it in the back of your mind especially if there’s something else in the history which increases risk Hb/RBC abnormalities, heart valves, new drugs, tropical diseases.
Fatigue, tachycardia, pallor and shortness of breath suggest anaemia.
The association of new onset jaundice, dark coloured urine, fever, abdominal pain, back pain should raise alarm bells and implies more severe intravascular haemolysis.
Examination might reveal hepatosplenomegaly in extravascular haemolysis. Lymphadenopathy may suggest a lymphoproliferative cause. Petechiae or bruising may reflect underlying thrombocytopenia or microangiopathic haemolytic anaemia (MAHA).
This podcast focussed on how we could take forward and understand the investigations of suspected haemolytic anaemia in the ED.
Are they haemolysing?
Haemoglobin value at diagnosis was the most important predictor of outcome, correlating with risk of death and the requirement of multiple medical therapies
Generally, RBC destruction rate is much higher in intravascular haemolysis. RBC destruction in extravascular haemolysis is 10-fold less.
Bilirubin: The lab will sometimes withhold the result if they think the same has undergone in vitro haemolysis. You can call and chat to the lab to find out the underlying result and point of care gas machines will often still give you a reading.
85% of circulating bilirubin derives from Hb breakdown in the Reticuloendothelial system. Other sources include ineffective red cell production in the bone marrow. As such it is more of a marker of extra rather than intravascular haemolysis, although it goes up in both. Obviously unconjugated bilirubin is cleared by the liver, so levels can go up due to impaired hepatic clearance.
Reticulocytes: are non nucleated precursors of RBSs. They have a high MCV and usually represent about 1% of peripheral RBCs. Marker of marrow activity and usually increased in haemolysis, but also other physiological and pathological conditions.
The compensatory reticulocytosis may be inadequate or absent in the presence of concomitant marrow involvement, iron and vitamin deficiency, infections, or autoimmune reaction against bone marrow-precursors.
In Autoimmune Haemolytic Anaemia 39% of children and 20% of adults, don’t see a rise in reticulocytes. This is bad and represents a high transfusion need and poorer outcomes.
Haptoglobin is a glycoprotein, made in the liver. Scavenges for free serum circulating haemoglobin which is not good for kidneys. In haemolysis obviously free haemoglobin binds with haptoglobin and the whole complex is degraded so haptoglobin is used up. In theory a marker of intravascular haemolysis it also decreases in conditions associated with extravascular haemolysis conditions as in reality some RBS escape the liver or spleen and are destroyed in the circulation.
We also see a decrease in haptoglobin with liver impairment and malnutrition. Levels go up with inflammatory disorders, in smokers and also in nephrotic syndrome.
Lactate Dehydrogenase is an enzyme that catalyzes the conversion of lactate into pyruvic acid, located in cytoplasm and distributed in various organs (e.g., heart, muscle, liver, and brain). LDH is raised where there is increased cellular turnover. 5 isoenzymes are present. In particular, LDH-1 and LDH-2 isoenzymes are expressed in RBC.
Slightly raised in extravascular but 4-5x upper limit of normal in intravascular haemolysis. In AIHA appears to correlate with clinical severity.
Quite non specific though as is present throughout the body. Any condition with cell necrosis and increased cell turnover could cause increased LDH: myocardial infarction, heart failure, hepatitis of all aetiologies, extreme muscular effort, and solid and hematologic tumors
Schistocytes are Fragmented RBCs caused by underlying microangiopathic haemolytic anaemia (MAHA).
Schistocytes derive from a mechanical fragmentation of RBC due to an obstacle within the vessels, such as fibrin clots, mechanical artificial heart valve, or any other intravascular devices. In healthy individuals, normal schistocyte count is below 0.5%.
MAHA is caused by a group of similar conditions for instance: DIC, TTP, HUS, HELLP
A count superior to 1% is typical of thrombotic thrombocytopenic purpura (TTP) with a common range of 310%, whereas a value between 0.5% and 1% is suggestive of disseminated intravascular coagulation (DIC).
When warm autoantibodies attach to red blood cell surface antigens, these IgG-coated red blood cells are partially ingested by the macrophages of the spleen, leaving microspherocytes, the characteristic cells of AIHA. These spherocytes, which have decreased deformability compared with normal red blood cells, are trapped in the splenic sinusoids and removed from circulation.
The direct antiglobulin test (DAT), also known as the direct Coombs’ test, demonstrates the presence of antibodies or complement on the surface of red blood cells and is the hallmark of autoimmune haemolysis. The patient’s red blood cells are mixed with rabbit or mouse antibodies against human IgG or C3. Agglutination of the patient’s antibody- or complement-coated red blood cells by anti-IgG or anti-C3 serum constitutes a positive test. Red blood cell agglutination with anti-IgG serum reflects warm AIHA, while a positive anti-C3 DAT occurs in cold AIHA.
Subdivided into warm or cold agglutination. Can be chronic or acute and severe depending on the subtype.
Managed with Haematology and mainly revolves around immunosuppression and supportive care.
Although most cases of autoimmune haemolysis are idiopathic, other potential causes should always be sought. Lymphoproliferative disorders (e.g. chronic lymphocytic leukemia, non-Hodgkin’s lymphoma) may produce warm or cold auto-antibodies.
Prescribed drugs can induce production of both types of antibodies.
Warm AIHA also is associated with autoimmune diseases (e.g. SLE)
Cold AIHA may occur following infections, particularly infectious mononucleosis and Mycoplasma pneumoniae infection.
Human immunodeficiency virus infection can induce both warm and cold AIHA.
W. Barcellini and B. Fattizzo, Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia, Disease Markers, vol. 2015, Article ID 635670, 7 pages, 2015. doi:10.1155/2015/635670 (Open Access)
Dhaliwal G, Cornett PA, Tierney LM., Jr Hemolytic anemia. Am Fam Physician. 2004;69:2599606. (Open Access)
– UCSF Internal Medicine Chief Resident Blog
– EM Docs
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