Important laboratory evidences of hemolysis
Low Hb (result from hemolysis of RBC).
- Increase retic count (BM compensation to hemolysis).
- Indirect hyperbilirubinemia (increase TSB mainly of indirect type).
- Increase plasma lactic dehydrogenase (LDH).
- Increase urine and fecal urobilinogen.
- In IVH occur Hburia, Hbnemia and Hemosideriuria.
- Blood film: to assess red cell morphology like: sickle cells, spherocytes, etc.
- Further investigation according to suspected causes of hemolysis like Hb electrophoresis, osmotic fragility test, coomb’s test and many other tests.
EVH
IVH
Pallor (from anemia).
- Jaundice (from hemolysis).
- Splenomegaly (main site of hemolysis).
- Pallor (from anemia).
- Jaundice (from hemolysis).
- Dark color urine.
Classification of hemolytic anemia
Inherited Hemolytic anemias
- Enzymo-pathies
e. g. G6PD deficiency and pyruvate kinase deficiency - Membrano-pathies
e. g. Hereditary elliptocytosis
spherocytosis
&
hereditary
3.Haemoglobino-pathies
Quantitative Hb-pathies: Thalassaemias Qualitative Hb-pathies: Hb S, C, D, E etc
II. Acquired Hemolytic anemias
- Immune
- Autoimmune: warm and cold types.
- Alloimmune: hemolytic transfusion reaction and hemolytic disease of newborn.
- Induced by drugs. - Non immune
- Infection as malaria, clostridia.
- Chemical / physical as burns, drowning.
- Mechanical hemolysis as MAHA (TTP, HUS, DIC).
- Acquired membrane defect as PNH, liver disease.
Main causes of IV hemolysis
- Incompatible blood transfusion, usually to ABO incompatibility.
- G6PD deficiency.
- RC fragmentation syndromes.
- Few types of warm and cold AIHA.
- Paroxysmal nocturnal hemoglobinurea (PNH).
- Some drug induce HA.
- Hemolytic anemia due to Unstable Hb.
What is G6PD deficiency
Definition: Sex-linked inherited disorder characterized usually by acute IVH following exposure to oxidant stress (like infections, drugs or fava beans) due to deficiency of RBC enzyme G6PD.
Variants of G6PD enzyme:
• About 52 variants with normal activity and about 400 variant with deficient activity mostly of Mediterranean type.
G6PD deficiency worldwide disease and quite frequent in Iraq especially in south area and in Iraq most variant is Mediterranean type.
Pathophysiology of hemolysis: Absence of G6PD enzyme with subsequent absent of reduce glutathione which essential for protection of RBC (membrane and Hb) from damage by oxidant effect which include free radicals formation from fava beans, drugs or infections.
Important triggering factors are: Acute hemolytic anemia G6PD D
Viral, bacterial infections.
– Acute illness as DKA.
– Drugs like antimalarial, sulphonamides, chlora, aspirin, and vitamin K analogous.
– Toxins as naphthalene.
– Fava bean (Favism).
3 main syndromes of presentation are: G6PD D
Acute hemolytic anemia triggered by drugs, infections or fava beans. Acute hemolytic attack characterize by sudden pallor, jaundice, red or dark color urine due to hemoglobinuria, fever and abdominal pain. Attack last usually 2-6 days followed by spontaneous recovery. Spontaneous anemia is rare but hemolytic crises are frequent precipitate by triggering factors. Important triggering factors ar
- Neonatal jaundice: G6PD deficiency is one of important hematological causes of NNJ.
- Chronic non spherocytic hemolytic anemia (CNSHA):
chronic lifelong EVH (anemia, splenomegaly and jaundice).
Favism
Syndrome of IVH after ingestion of fava bean (fresh, dried, frozen, and even pollens) or some time to other components like topical henna. Offending agents are DIVICINE and ISOURAMIL. Hemolysis is related to dose, body mass, and more in children.
Laboratory findings: of G6PD D
Management
- Blood picture normal between the hemolytic crises.
- Variable degree of anemia during the hemolytic episode with typical findings of IVH.
- Blood film during acute hemolysis showing normochromia, polychromasia, with nonspecific red cell morphology, sometimes showing bitten cell and blister cells.
- Reticulocytosis and Heinz body detection.
- Positive screening tests for enzyme activity.
- Specific assay for red cell G6PD (best to done 2 wks after the attack) to avoid high enzyme level in young red cells and reticulocytes.
- DNA analysis for G6PD gene in certain condition.
Management: Avoid precipitating factors.
Spontaneous recovery will happen and blood transfusion if required.
What is the most common HA in north Europe
Hereditary Spherocytosis
- Definition: Inherited disorder usually autosomal dominant disease resulting from an intrinsic defect involving red cell membrane proteins, making the RBC osmotically fragile and spherocytic in shape with variable degree of hemolysis in the spleen.
- Not common in Iraq, while consider is the common hereditary HA in North Europe.
- Pathophysiology: Defect in membrane proteins (Spectrin, Ankyrin and Band-3 proteins) making the lipid bilayer not supported by the skeleton proteins result in spherocytic shape of red cells which destructed in RES (mainly in the spleen).
Laboratory findings: of hereditary spherocytosis
- Variable anemia, increase MCHC.
- Peripheral blood showing spherocytosis or microspherocytes.
- Reticulocytosis.
- Right shift on Osmotic Fragility Test (OFT) which confirm the presence of spherocytic cells.
- Normal direct coomb’s test (exclude autoimmune hemolytic anemia).
- Membrane proteins or gene defect analysis (Diagnostic test).
Clinical features: of Hereditary Spherocytosis
- Majority present in first 10 years of life, with pallor, jaundice and splenomegaly.
- Anemia may present at any age and usually start at infancy or childhood.
- It one of hematological cause of NNJ.
- HA may aggravate by infections or during the pregnancy.
- Complications as gall stones, leg ulceration, growth retardation and iron overload.
Beta thalassemia
Types of beta thalassemia:
Important disorder because it is common and severe disorder.
- One of the most common inherited hematological disorders in Iraq, that gene frequency around 4-5% of population.
- Beta thalassemia more common in broad belt of Mediterranean region, part of North-West Africa, Middle East to South East Asia.
- βo mean absent of β globin chain, while β+ mean reduce in β globin chain.
Types of beta thalassemia:
- β Thalassemia major (βo βo) or (β+ β+) or (βo β+).
- β Thalassemia minor (βo β) or (β+ β).
- β Thalassemia intermedia of more complicated genetic background.
- β Thalassemia with other Hb variants (like Sickle, HbC, HbE, etc).
β- Thalassaemia major
Clinical features:
Homozygous or compound heterozygous inheritance of beta chain defect: (βo βo) or (β+ β+) or (βo β+).
Clinical features:
- First diagnosis between age of 6 m- 2 yrs and evidences start after the age of 3 months (time of Hb-switching).
- Presentation usually with pallor, jaundice, poor feeding, failure to thrive, abdominal swelling (due to HSM).
- Later the clinical picture depends on management approach, and run into two categories:
- Well transfused patients: showing early normal development and at puberty develop features of iron overload (liver, cardiac and endocrine).
- Inadequately transfused patients: early sever symptoms of disease with severe anemia, jaundice, HSM, bone changes particularly thalassemia face.
β- Thalassaemia major
Laboratory findings:
CBC: usually severe anemia, variable WBC and platelets counts.
MCV and MCH are both markedly reduced.
- Blood film: sever hypochromic microcytic anemia, NRBC, sever anisopoikilocytosis, target, tear drop cells and basophilic stippling.
- Reticulocytes: slight to moderately increase but not to degree of anemia (usually range 2-8%).
- Hb electrophoresis (key for diagnosis) HbF 10-90 %. HbA absent. HbA2 variable.
Management
بيتا ثلاسيميا ميجور
• Prevention:
- Population screening for carrier detection and choice of marriage.
- Antenatal screening and choice of termination of pregnancy.
- BM transplant.
- Symptomatic treatment with blood transfusion in associated with iron chelation agents to reduce risk of iron overload.
- Life long folic acid supplementation.
- Splenectomy in indicated cases.
β- Thalassaemia minor
Heterozygous inheritance of genetic defect ……… (β β+) or (β βo).
- Clinically usually asymptomatic and may discovered by chance.
- Mild anemia and splenomegaly are rare. During stressful condition especially in pregnancy the patients may become symptomatic because of aggravation of mild anemia.
- It is important challenge to differentiate β- Thalassaemia minor from iron deficiency anemia.
β- Thalassaemia minor
Laboratory findings:
Mild anemia.
- MCH and MCV are reduced (more reduction to the degree of anemia in compare with iron deficiency anemia).
- RBC count usually high (normal or low RBC count in IDA).
- Reticulocyte count is slightly increased (usually low in IDA).
- Blood film showing hypochromia, microcytic red cells with mild anisopoikilocytosis including few target cells.
- Increase in Hb A2 4-6%, consider key for diagnosis: (normal range of Hb A2 is 1.8-3.5%).
Management: No need for specific management, except in periods of stress like pregnancy.
Four types of alpha thalassemia according to genetic defects are
One gene deletion
(α α/ α-)
α + thalassemia trait (silent carrier)
Two gene deletion
(α -/ α-) or (α α/ –)
α o thalassemia trait (carrier α thalassemia)
Three gene deletion
(α -/ –)
Hemoglobin-H disease
Four gene deletion
(- -/ –)
hydrops fetalis syndrome (Hb Bart’s)
Types of sickle cell disorders:
- Sickle cell anemia (HbSS): Homozygous inheritance to sickle cell gene defect.
- Sickle cell trait (HbSA): Heterozygous inheritance to sickle cell gene defect.
- Sickle cell with other globin chain disorders like β-thalassemia, α thalassaemia, Hb C.
Sickle cell disease (HbSS)
Pathophysiology
- Hemoglobin S (beta chain variant) result from substitution of the Glutamic acid position 6 of the beta chain by Valine.
- This changes result in conformational changes of RBC with deoxygenation and polymerization of HbS make the RBC sickle in shape and unable to pass through ECs.
- Red cells with deoxygenation become sickle in shape initially of reversible event until the membrane damage occur become irreversible leading to EVH in the macrophage of RES.
- Factors triggering the sickling process may include; increase HbS, decrease HbA, decrease HbF, deoxygenation, dehydration, acidosis, infection, fever, pregnancy and anesthesia.
Geographic distribution of sickle cell & Clinical features:
More in black, West Africa, area of high malaria prevalence. In Iraq in more in south, especially in Basra.
extremely variable including:
Chronic HA
Splenomegaly
Sickle cell crisis
Other features: Infections especially by pneumococci, meningococci and H- influenza, retinopathy, gall stones, liver abscess, leg ulceration, and decrease in growth and development.
Chronic HA: of sickle cell
features will not be apparent until the age of 3-6 months (time of Hb switching), and is characterized by variable degree of anemia, jaundice and splenomegaly, extenuated by episodes of sickle cell crisis.
Sickle cell crisis is any new syndrome developing rapidly in a patient with sickle cell disease, include:
(1) Vaso occlusive crises at any site like painful bone crisis, acute abdomen, acute brain syndrome, acute chest syndrome and priapism.
(2) Acute sequestration crisis; sudden trapping of the blood in the spleen, characterize by severe sudden anemia and huge tender spleen.
(3) Aplastic crisis; sudden anemia, low reticulocyte count and reduce level of jaundice. Usually follows parvo viral B19 infection.
(4) Hemolytic crisis; sudden drop in Hb level, increase in reticulocyte count and bilirubin level.
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