Hemolytic anemia is a
Features of Haemolysis
Red cell destruction overloads
pathways for Hb breakdown , causing a modest rise in unconjugated bilirubin in the blood and mild jaundice.
Features of Haemolysis(cont)
LDH Nucleated red cell precursors appear
Features of Haemolysis(cont)
Activation of the bone marrow
can result in a neutrophilia and immature granulocytes appearing in the blood to cause a leuco-erythroblastic blood film.
Features of Haemolysis(cont)
The appearances of the red cells
may give an indication of the likely cause of the haemolysis Spherocytes are small, dark red cells which suggest autoimmune haemolysis or hereditary spherocytosis.
Features of Haemolysis(cont)
haemoglobinopathy.
microangiopathic haemolysis.
Features of Haemolysis(cont)
The compensatory erythroid
hyperplasia may give rise to folate deficiency, when the blood findings will be complicated by the presence of megaloblastosis. Measurement of red cell folate is unreliable in the presence of haemolysis and serum folate will be elevated.
Intravascular haemolysis
Free haemoglobin is released into
the plasma. Decreased amount of haptoglobin. Methaemoglobin is produced. Methaemoglobin plus albumin>>>methaemalbumin.
Intravascular haemolysis(cont)
Methaemoglobin is degraded and any
free haem is bound to a second binding protein termed haemopexin. Free haemoglobin may appear in the urine. When fulminant, this gives rise to black urine, as in severe falciparum malaria infection. Haemosiderinuria, which is always indicative of intravascular haemolysis.
Extravascular haemolysis
Physiological red cell destruction in
Morphology
Most haemolytic anaemias
are either normocytic and normochromic or macrocytic and normochromic.
are produced healthy but are later destroyed by becoming trapped in the spleen, destroyed by infection, or destroyed from drugs that can affect red blood cells.These disorders are acquired . These are immune or non-immune mechanism.
(A)Due to intra-corpuscular
mechanisms: 1. Congenital 2. Acquired
Classification(cont.)
1. Congenital
>Membrane defects (Hereditary >Haemoglobin defects
spherocytosis, Hereditary elliptocytosis). (Haemoglobinopathies, Thalassemia)
2. Acquired
(Paroxysmal nocturnal haemoglobinuria)
Classification(cont.)
(B) Due to extra-corpuscular mechanism:
1. Congenital (None) 2. Acquired
Classification(cont.)
1. Congenital (None)
2. Acquired >Immune mechanisms
(Auto-immune acquired haemolytic anaemia/warm and cold antibody, Haemolytic disease of the newborn, Incompatibe blood transfusion, Drug induced haemolytic anaemia)
>Non-immune mechanisms
(Cardiac haemolytic anaemia, micro-angiopathic haemolytic anaemia, March haemoglobinuria)
>Miscellaneous
(Haemolytic anaemia due to direct action of drugs and chemicals, infection, burn, lead poisoning)
3. What is the aetiology? By the clinical features and the results of the special investigations.
complement, it will cause intravascular haemolysis, but if complement activation is weak, the haemolysis will be extravascular.
Types of auto-antibody
Warm antibodies bind best at 37 C and
account for 80% of cases. The majority are IgG .
can bind up to 37 C in some cases. They are usually IgM and bind complement. They account for the other 20% of cases.
Warm autoimmune HA
Approximately 1/100 000 population per annum; it occurs at all ages but is more common in middle age and in females.
Causes of W AIHA
Idiopathic: 50% cases. Lymphoid neoplasms: lymphoma, chronic
lymphocytic leukaemia, myeloma. Solid tumours: lung, colon, kidney, ovary, thymoma. Connective tissue disease: SLE, rheumatoid arthritis. Drugs: methyldopa, mefenamic acid, penicillin, quinidine. Miscellaneous: ulcerative colitis, HIV.
W AHIA (Cont)
Investigations
1.Evidence of haemolysis 2.Spherocytes on the blood film. 3.The diagnosis is confirmed by the direct Coombs or antiglobulin test.
W AIHA (cont)
A positive test requires about 200 antibody
molecules to attach to each red cell; with a very avid complement-fixing antibody, haemolysis may occur at lower levels of antibody-binding. So the direct Coombs test can be negative in the presence of brisk haemolysis.
Management
Treatment of underlying cause. Removal of offending drugs. Prednisolone 1 mg/kg orally. A response is seen
in 70-80% of cases but may take up to 3 weeks. Once the haemoglobin has normalised and the reticulocytosis resolved, the corticosteroid dose can be reduced slowly over about 10 weeks. Transfusion support may be required for lifethreatening problems, such as the development of heart failure or rapid unabated falls in Hb.
Management(cont)
If the haemolysis fails to respond to
corticosteroids or can only be stabilised by large doses, then splenectomy should be considered. Good response in 50-60% of cases. or cyclophosphamide may be considered. This is least suitable for young patients, in whom long-term immunosuppression carries a risk of secondary neoplasms. The anti-CD20 (B cell) monoclonal antibody, rituximab, has shown some success in difficult cases.
Cold auto-immune HA
Usually IgM, which bind to the red cells at 4 C. It may cause
intravascular haemolysis if complement fixation occurs. acute or transient when the antibody is polyclonal.
C AHIA(cont)
Chronic cold agglutinin disease This affects elderly patients and may be associated with an underlying low-grade B cell lymphoma. It causes a low-grade intravascular haemolysis with cold, painful and often blue fingers, toes, ears or nose (so-called acrocyanosis). The blood film shows red cell agglutination and the MCV may be spuriously raised because the automated analysers count aggregates as single cells.
Management(C AHIA)
Treatment is directed at any underlying
lymphoma.
and blood transfusion may be considered, but the cross-match sample must be placed in a transport flask at a temperature of 37 C and blood administered via a blood-warmer.
1. disseminated carcinomatosis, 2. malignant or pregnancy-induced hypertension, 3. haemolytic uraemic syndrome, 4. thrombotic thrombocytopenic purpura 5. disseminated intravascular coagulation
NIHA(cont)
Infection:
1. Plasmodium falciparum (blackwater fever). 2. Clostridium perfringens septicaemia usually in the context of ascending cholangitis, may cause severe intravascular haemolysis with marked spherocytosis due to bacterial production of a lecithinase which destroys the red cell membrane.
NIHA(cont)
Chemicals or drugs
Dapsone and sulfasalazine cause haemolysis by oxidative denaturation of haemoglobin. Denatured haemoglobin forms Heinz bodies in the red cells, visible on supravital staining with brilliant cresyl blue. Arsenic gas, copper, chlorates, nitrites and nitrobenzene derivatives may all cause haemolysis.
expansion of haematopoietic stem cells deficient in GPI-anchor protein results in intravascular haemolysis and anaemia because of increased sensitivity of red cells to lysis by complement. Episodes of intravascular haemolysis result in haemoglobinuria, most noticeable in early morning urine which has a characteristic red-brown colour.
PNH (cont)
The disease is associated with an increased risk
of venous thrombosis in unusual sites such as the liver or abdomen. PNH is also associated with hypoplastic bone marrow failure, aplastic anaemia and myelodysplastic syndrome. Management is supportive with transfusion and treatment of thrombosis. Recently the anticomplement C5 monoclonal antibody ecluzimab was shown to be effective in reducing haemolysis.
concentration (MCHC), abnormal cell shape and reduced red cell survival due to extravascular haemolysis.
Hereditary spherocytosis
Usually autosomal dominant
inheritence. 25% of cases is new mutations. The incidence is approximately 1:5000 in developed countries. The most common abnormalities are deficiencies of beta spectrin or ankyrin.
Hereditary spherocytosis(cont)
Most cases are asymptomatic compensated
chronic haemolytic state. Pigment gallstones are present in up to 50% of patients and may cause symptomatic cholecystitis. Occasional cases are associated with more severe haemolysis; these may be due to coincidental polymorphisms in alpha spectrin or co-inheritance of a second defect involving a different protein.
Hereditary spherocytosis(cont)
The clinical course may be complicated by crises: A haemolytic crisis ----this is rare, and usually associated with infection.
erythrovirus infection.Patients present with severe anaemia and a low reticulocyte count.
Hereditary spherocytosis(cont)
Investigations : Screening of the familly members.
Hereditary spherocytosis(cont)
Management : 1. Folic acid prophylaxis, 5 mg once weekly, should be given for life. 2. Splenectomy (indications include moderate to severe haemolysis with complications (anaemia and gallstones).
Meyerhof pathway generates ATP, and the hexose monophosphate shunt produces NADPH and glutathione to protect against oxidative stress.
What is G6PD?
It is an X-linked recessive inheritance. (males usually
affected and females are carriers)
Glycolytic Pathway
Know this diagram
Glucose
hexokinase
ATP ADP
Glucose-6-phosphate
isomerase
(2 Net ATP)
Drugs
ATP ADP
H2O2 Fe3+ + O2
MetHb reductase
Pyruvate
Fructose-6-phosphate
PFKinase
O2 + Fe2+
Fructose-1,6-bisphosphate
NAD+ NADH
NAD+
hydroxyetone hosphate
Glyceraldehyde3-phosphate
G-3-P Dehydrogenase
1,3-Bisphosphoglycerate
Ribose-5-phosphate
NADPH NADP+
GSH
GSH reductase
H2O2
H2 O
Catalase
O2
6-Phosphogluconate NADPH
GSSG
uh S es o ne P t
G6P Dehydrogenase
yceraldehydephosphate
ADP ATP
NAD+
NADH
Ribose-5-phosphate
NADPH NADP+
H2O2
GSH Peroxidase
Catalase NADPH
O2
6-Phosphogluconate NADPH
(Fe2+)
GSSG
H2 O
uh S es o ne P t
G6P Dehydrogenase
2 OH NADP+
yceraldehydephosphate
Glucose6-phosphate
Glucose
Hemolysis
Clinical features
Acute drug-induced haemolysis to
(e.g.) Analgesics: aspirin, phenacetin Antimalarials: primaquine, quinine, chloroquine, pyrimethamine Antibiotics: sulphonamides, nitrofurantoin, ciprofloxacin Miscellaneous: quinidine, probenecid, vitamin K, dapsone
feature of the B- enzyme Favism, i.e. acute haemolysis after ingestion of the broad bean Vicia faba
Laboratory features
Non-spherocytic intravascular haemolysis
during an attack The blood film will show:
Bite cells (red cells with a 'bite' of membrane missing) Blister cells (red cells with surface blistering of the membrane) Irregularly shaped small cells Polychromasia reflecting the reticulocytosis Denatured haemoglobin visible as Heinz
bodies within the red cell cytoplasm, if stained with a supravital stain such as methyl violet
cyclophosphamide (Cytoxan) Vitamin and mineral supplements (e.g. folic acid). Change in diet. If Hb levels , treatment may include blood transfusion or splenectomy (surgical removal of the spleen). If physical damage to RBC, then treat w/ blood transfusions or simple iron supplements. Iron - Taken during pregnancy and when iron levels are low. Erythropoietin (Procrit) - To increase RBC production in people w/ kidney problems.
Management
To stop any precipitant drugs
and treat any underlying infection.
Transfusion support.
Classifications
(A) Alpha thalassaemia--- Levels of Hb-A , Hb-F and Hb-A2 are equally depressed since they all have alpha chains. Causes microcytic and hypochromic anaemia. (B)Beta thalassaemia--- decrease production of beta chain leads to a reduction in the amount of Hb-A in red cell. Causes microcytic hypochromic anaemia. But Total Hb is maintained in part by the product of gama and delta chain. Thus increase Hb-F or Hb-A2 is usually found.
Beta thalassaemia
Beta 0 thalassaemia --Complete absence of
beta chain. Beta + thalassaemia --- Incomplete absence of beta chain. Clinically --- 1. Beta thalassaemia major (homozygous form of disease). 2.Beta thalassemia minor.
cells contain Hb-S. The sickling of the red blood cells in the circulating blood has two major pathological effects1. The distorted and rigid cells block small vessels , impairing flow and causing ischaemia and infarction. 2. Repeated sickle/unsickle cycles lead to loss of fragments of the cells and the cells become spherocytic and fragile.
Abdominal and bone/joint pain Breathlessness Delayed growth and puberty Fatigue and fever Jaundice (yellowed skin) Paleness Rapid heart rate Greater risk for infection Adolescents and adults can develop ulcers on their legs Chest pain Excessive thirst Poor eyesight, blindness when blood cant get to the back of eyes, they dont have a constant nourishment, causing people to not be able to see
* About 30% of Jamaican patients with Sickle Cell develop ulcers in comparison to 1% of Americans
Diseases and Conditions people with Sickle Cell are likely to develop:
Acute chest syndrome Aplastic crisis Dactylitis swelling of the hands and feet Painful crises: really painful episodes when blood cells are blocked from going to certain parts of the body pain can occur anywhere, but it is usually in the chest, arms, and legs An x-ray of a hand swollen from dactylitis Enlarged spleen sickle cells pool in the spleen, and in some cases there is no spleen in the body.
Black boy
White girl
People can live a relatively normal life with Sickle Cell if they have the proper treatment. The average life expectancy for males is 42. The average life expectancy for females is
48.
In 2003 the oldest patient to have Sickle cell was an 85 year old Jamaican woman.
Role of G6PD
Responsible for maintaining adequate levels of
NADPH inside cell.
G6PD Deficiency
Red cells deficient in G6PD are unable to
neutralize hydrogen peroxide - H2O2 converts to hydroxyl radicals and this can lead to oxidative damage/toxic injury.
also induce hemolytic anemia (Individuals with G6PD deficiency are particularly susceptible)
Required Tests
Blood tests are taken to measure levels of:
red cells, assess size and shape of red cells measure the Hb level determine the number of reticulocytes.
References
Ezra E. W. Cohen, M.D., Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL. 11 Jan 2004 <http://www.nlm.nih.gov/medlineplus/ency/article/000571.htm > <http://www.nlm.nih.gov/medlineplus/ency/article/000571.htm Updated by: Corey Culter, M.D. M.P.H., F.R.C.P.C., Department of Medical Oncology, Dana Farber Cancer INsitiute; Instructor of Medicine, Harvard University, Boston, MA. Review provided by VeriMed Healthcare Network. Source: MEDLINEplus Medical Information. 11 Jan 2004 http://www.hlm.nil.gov/medlineplus/ency/article/000528.htm Ramez A. Ethnasios. An Introduction to G6PD Deficiency. 7 Jan 2004 <http://www.rialto.com/g6pd/physiolo.htm> Ethnasios. <http://www.rialto.com/g6pd/physiolo.htm> Peggy Gulley, MD. Hemolytic Anemia Lecture. 9 Jan 2004 <http//:pathology.uthscsa.edu/MSII/Hemo.html> <http//:pathology.uthscsa.edu/MSII/Hemo.html> Rebecca Elstrom, M.D., Division of Hematology-Oncology, University of Pennsylvania Medical Center, Philadelphia, PA. Review provided by VeriMed Healthcare Network. . 11 Jan 2004 <http://www.umm.edu/blood/anehemol.htm> <http://www.umm.edu/blood/anehemol.htm> Patrick Yorba, MD, Staff Physician, Department of Emergency Medicine, University of Virginia Health Sciences Center. 11 Jan 2004 http://www.emedicinehealth.com/articles/4893-6.asp?pd=1/11/2004%2010:25:15%20PM Faculty of Harvard Medical School 1996-2003 Aetna InteliHealth Inc. 11 Jan 2004 < http://www.intelihealth.com/IH/ihtIH/WSIHW000/9339/21246.html> http://www.intelihealth.com/IH/ihtIH/WSIHW000/9339/21246.html> Images taken from http://health.allrefer.com/health/hemolytic-anemia-pictures-images.html> . 11 Jan 2004 http://health.allrefer.com/health/hemolytic-anemia-pictures-images.html>