Transcript Sickle-Cell Anemia

HEREDITARY/ACQUIRED
HEMOLYTIC ANEMIA
HEMOLYTIC ANEMIAS
Hemolytic anemias = reduced red-cell life
span
Classification of Hemolytic anemias
I. Red cell abnormality (Intracorpuscular factors)
A. Hereditary
1. Membrane defect (spherocytosis, elliptocytosis)
2. Metabolic defect (Glucoze-6-PhosphateDehydrogenaze (G6PD) deficiency, Pyruvate kinase (PK)
deficiency)
3. Hemoglobinopathies (unstable hemoglobins,
thalassemias, sickle cell anemia )
B. Acquired
1. Membrane abnormality-paroxysmal nocturnal
hemoglobinuria (PNH)
II. Extracorpuscular factors
A. Immune hemolytic anemias
1. Autoimmune hemolytic anemia
- caused by warm-reactive antibodies
- caused by cold-reactive antibodies
2. Transfusion of incompatible blood
B. Nonimmune hemolytic anemias
1. Chemicals
2. Bacterial infections, parasitic infections (malaria), venons
3. Hemolysis due to physical trauma
- hemolytic - uremic syndrome (HUS)
- thrombotic thrombocytopenic purpura (TTP)
- prosthetic heart valves
4. Hypersplenism
SOME TYPES OF HHA eg.
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SICKLE CELL DISEASE
THALASSEMIAS
G6PD DEFICIENCY
HEREDITARY SPHEROCYTOSIS
THALASSEMIAS
• MICROCYTIC, HYPOCHROMIC,
HEMOLYTIC ANEMIA
• MOST COMMON IN AFRICAN,
MEDITERRANEAN, MIDDLE EASTERN,
& SOUTHEAST ASIAN DESCENT
• MULTIPLE VARIANTS
THALASSEMIAS
• CHARACTERIZED BY DEFECTIVE
SYNTHESIS OF GLOBIN CHAINS,
UNABLE TO PRODUCE NORMAL
ADULT HEMOGLOBIN
• TRAIT THOUGHT TO BE PROTECTIVE
AGAINST MALARIA AS WELL
HEMOGLOBIN
• NORMAL ADULT RBC CONSISTS OF 3
FORMS OF Hb:
- HbA - 2 α and 2 β globin chains
- HbA2 – 2 α and 2 δ globin chains
- HbF - 2 α and 2 γ globin chains
• THALASSEMIAS α and β
THALASSEMIAS
• TYPES OF DZ CHARACTERIZED BY
DEFFERING EXTREMES OF ANEMIA
• DEPENDS ON AMOUNT OF
INEFFECTIVE ERYTHROPOIESIS AND
PREMATURE DESTRUCTION OF
CIRCULATING RBC’S
• HYPOXIA IN SEVERE CASES
G6PD DEFICIENCY
• MOST COMMON HUMAN ENZYME
DEFECT
• X-LINKED DISORDER
• AFFECTS 15% OF U.S. BLACK MALES
• DECREASE IN GLUTATHIONE LEVELS
G6PD DEFICIENCY
• HEINZ BODIES SEEN ON PERIPHERAL
BLOOD SMEAR
• NEONATAL JAUNDICE 1-4 DAYS AFTER
BIRTH IN SEVERE VARIANTS
• INCREASE INCIDENCE OF
PIDMENTED GALLSTONES AND
SPLENOMEGALY
G6PD DEFICIENCY
• ACUTE HEMOLYTIC CRISIS DUE TO:
- BACTERIAL/VIRAL INFECTION
- OXIDANT DRUGS (SULFAMETHOXAZOLE)
- METABOLIC ACIDOSIS (DKA)
- RENAL FAILURE
- INGESTION OF FAVA BEANS
G6PD DEFICIENCY
• DIAGNOSIS – QUANTITATIVE ASSAY
DETECTING LOW ENZYME
• TREATMENT – SUPPORTIVE AND
PREVENTATIVE
HEREDITARY SPHEROCYTOSIS
• RBS MEMBRANE DEFECT
• MOST COMMON HEREDITARY ANEMIA
FROM PTS OF NORTHERN EUROPEAN
DESCENT
• AUTOSOMAL DOMINANT
• MUTATIONS IN SPECTRIN AND
ANKYRIN (MEMBRANE PROTEINS)
HEREDITARY SPHEROCYTOSIS
• SPHEROCYTES – IN PERIPHERAL
BLOOD SMEAR
• SPHEROCYTES UNABLE TO PASS
THROUGH THE SPLEEN
• SEVERE CASES REQUIRE A
SPLENECTOMY
HEREDITARY SPHEROCYTOSIS
• NEONATAL JAUNDICE IN 1ST WEEK
OCCURS IN 30-50% OF HS PTS
• ANEMIA, SPLENOMEGALY, JAUNDICE,
AND TRANSFUSIONS NEEDED VARY
DEPENDING ON SEVERITY OF DZ
Hereditary microspherocytosis
1. Pathophysiology
- red cell membrane protein defects (spectrin
deficiency) resulting cytoskeleton instability
2. Familly history
3. Clinical features
- splenomegaly
4. Laboratory features
- hemolytic anemia
- blood smear-microspherocytes
- abnormal osmotic fragility test
- positive autohemolysis test
- prevention of increased autohemolysis by
including glucose in incubation medium
5. Treatment
- splenectomy
Sickle-Cell Anemia
Hemoglobin
Composed of:
1 Heme and 4 Globin Chains
4 Types of Globin Chains:
Alpha, Beta, Delta, Gamma
Sickle Cell Disease
• Cannot make Beta Chains
• Valine substituted for glutamate in
6th position of beta chain
Sickle Cell Disease
• Affects people of African descent
• Affects 72,000 people in the US
• 2 million people are carriers
• Occurs once in every 375 African
American births
Sickle Cell Anemia
Sickle Cell anemia is an inherited red blood cell
disorder. Normal red blood cells are round like
doughnuts, and they move through small blood tubes
in the body to deliver oxygen.
Sickle red blood cells become hard, sticky and shaped
like sickles used to cut wheat. When these hard and
pointed red cells go through the small blood tube, they
clog the flow and break apart. This can cause pain,
damage and a low blood count, or anemia.
The origin of the disease is a small
change in the protein hemoglobin
The change in cell structure arises from a change in
the structure of hemoglobin.
A single change in an amino acid causes hemoglobin
to aggregate.
Hemoglobin is a carrier protein
O2
HbO2
CO2
deoxy Hb (CO2)
Lungs
Tissues
Hemoglobin changes structure for
efficient oxygen uptake and delivery
HbO2
deoxy Hb (CO2)
Strong binding state
R state
Weak binding state
T state
The small change in hemoglobin
structure leads to aggregation
a
b
Subunits
Normal hemoglobin (Hb A)
Sickle cell hemoglobin (Hb S)
Genetic Inheritance
Symptoms in Children
• Start to appear at 6 months
• Dactylitis (swelling of hands and feet)
• Heart Enlargement
• Growth Retardation
• Delayed Sexual Development
Dactylitis
Sickle Cell Crisis
• Severe pain caused by blocked blood
flow
• Triggered by Infection, Dehydration,
Fatigue, or Emotional Stress
• Can last up to 5 days
Splenic Sequestration
• Spleen tried to remove abnormal
cells
• Becomes enlarged and causes pain
• Autosplenectomy occurs
• Usually not seen in adults
Symptoms of Anemia
• Tiredness
• Headaches
• Dizziness
• Faintness
• Shortness of breath
Other Symptoms
• Chronic, low-level pain in joints and
bones
• Abdominal pain
• Retina Damage
• Gallstones
• Leg Ulcers (adults)
• Chest pain
Leg Ulcers
Blood Picture
• Sickle, Target and/or nRBCs
• Decreased Hemoglobin
• Increased retic count
• White cell count increased
• WBC shift to the left
Hgb Electrophoresis
• Amino acids in globin chains have
different charges
• Separates hemoglobin according to
charge
• 90% Hgb S, 10% Hgb F, small
fraction of Hgb A2
Prognosis
• No cure
• Life expectancy:
42 years men
48 years women
• 85% reach the age of 20
• 50% reach age 50
• Causes of death:
Infection, heart failure
Treatment
• Pain Medication
• Increase fluids
• Blood Transfusion
• Bone Marrow Transplant
Acquired Hemolytic
Anemia
Introduction
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Increased RBC Destruction –
Short RBC life span <120 days.
Normocytic normochromic, reticulocytosis
Anemia, Jaundice, marrow hyperplasia
Splenomegaly, bilirubin gall stones
Unconjugated “acholuric” (pale urine)
Common types - AIHA, MAHA
Types of acquired HA
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AutoImmune Haemolytic Anemias (+ve DAT)
Alloimmune haemolytic anemias
Drug-induced immune haemolytic anemias
Red cell fragmentation syndromes
Infections
Chemical & physical agents
Secondary Haemolytic anemias
Paroxysmal Nocturnal Haemoglobinuria (PNH)
Pathogenesis of Jaundice:
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Hb Globin-Iron-Haem Bilirubin 
Glucoronide–Conjugation  Bile  Gut
Stercobilinogen & Stercobilin (ex.in stool)
Urobilinogen & Urobilin (ex. In urine)
Ketabolism of Hb:
Classification :
• Auto Immune AIHA – Warm antibody type
– Cold antibody type
• Alloimmune
– Transfusion reactions
– Hemolytic disease of new born
• Non-Immune
– Microangiopathic hemolytic anemia
– Infections – Malaria, clostridia,
– Burns, Toxins, snake & spider bites.
Laboratory Diagnosis:
• RBC Breakdown:
– Hyperbilirubinemia
– Urobilinogen, stercobilinogen
– serum haptoglobins
• RBC Production:
– Reticulocytosis, *MCV
– Marrow hyperplasia*
• Damaged RBC
– Morphology, fragility, survival
Laboratory Diagnosis:
• Additional features of Intravascular
Hemolysis:
– Hb-naemia and Hb-nuria
– Haemosiderinuria
– Methaemoglobinemia
DRUG RELATED HA
• ALPHAMETHYLDOPA
• LEVODOPA
• PROCAINAMIDE
• SULFA DRUGS
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PENICILLIN
CEFTRIAXONE
CEFOTETAN
QUINIDINE
MICROANGIOPATHIC SYNDROMES
• THROMBOCYTOPENIC PURPURA
• HEMOLYTIC UREMIC SYNDROME
TTP & HUS - PATHOPHYS
• PLATELET AGGREGATION IN THE
MICROVASCULATURE CIRCULATION
VIA MEDIATION OF von WILLEBRAND’S
FACTOR LEADS TO
THROMBOCYTOPENIA AND
FRAGMENTATION OF RBC’S AS THEY
PASS THROUGH THESE OCCLUDED
ARTERIOLES AND CAPILLARIES
THROMBOCYTOPENIC PURPURA (TTP)
• PLATLET COUNTS < 20,000
• MORE COMMON IN WOMEN AGES 1060
• FEVER, NEUROLOGIC DEFICITS,
HEMORRAGE, AND RENAL
INSUFFICIENCY
• UNTREATED – 80-90% MORTALITY
TTP
• SCHISTOCYTES OR HELMET CELLS
SEEN OF PERIPHERAL SMEAR
• INCREASED BUN/Cr LEVELS
TTP
• PREGNANCY IS THE MOST COMMON
PRECIPITATING EVENT FOR TTP
• PREECLAMPSIA SIMILAR TO TTP;
DELIVERY TX FOR PREECLAMPSIA,
NOT CURE TTP
TTP – ER TREATMENT
• PREDNISONE 1-2mg/kg/day INITIALLY
• PLASMA EXCHANGE TRANSFUSION IS
FOUNDATION FOR TX (INFUSE FRESH
FROZEN PLASMA IF TRANSFUSION
UNAVAILABLE
• AVOID PLATELET TRANSFUSION
• NEVER USE ASPIRIN
TTP – ER TREATMENT
• PT MAY NEED SPLENECTOMY
• AZATHIOPRINE AND
CYCLOPHOSPHAMIDE FOR THOSE
WHO FAIL OR CANNOT TOLERATE
STEROIDS
HUS
• DZ OF EARLY CHILDHOOD
• PEAK INCIDENCE BETWEEN 6mo-4yr
• OFTEN FOLLOWS BACTERIAL/VIRAL
ILLNESS
• MORTALILY 5-15%, WORSE IN OLDER
CHILDREN & ADULTS
HUS
• CHARACTERIZED BY
-ACUTE RENAL FAILURE
-MICROANGIOPATHIC HA
-FEVER
-THROMBOCYTOPENIA (NOT AS
SEVERE AS TTP)
HUS
• THE MOST COMMON CAUSE OF
ACUTE RENAL FAILURE IN
CHILDHOOD
• E.Coli O157:H7 COMMON CAUSE
• MICROTHORMBI ARE CONFINED
MAINLY TO KIDENYS, WHERE TTP
MORE WIDESPREAD
HUS – ER TREATMENT
• MILD HUS < 24hr OF URINARY SX NEELS
ONLY FLUID/ELECTROLYTE CORRECTION
AND SUPPORT CARE
• STEROID THERAPY
• HEMODIAYLSIS IF ACUTE RENAL FAILURE
PRESENT
• ABX TX CONTROVERSIAL WHEN E.Coli
PRESNENT; DO NOT USE ANTIMOLITY
DRUG, INCREASE RISK OF DEVELOP HUS
HELLP SYNDROME
• HEMOLYSIS
• ELEVATED LIVER ENZYMES
• LOW PLATLET COUNTS
HELLP SYNDROME
• 1 IN 1OOO PREGNANCIES
• SEEN IN PRESENCE OF ECLAMPSIA,
PREECLAMPSIA, AND PLACENTAL
ABRUPTION
• MAY EXTEND UP TO 6 DAYS
POSTPARTUM
HELLP SYNDROME
• RUQ AND EPIGASTRIC PAIN – SEEN IN
90% OF PTS (POSSIBLE HEPATIC
RUPTURE)
• DX BASED ON LAB DATA
• DECREASED SERUM HAPTOGLOBIN
LEVEL MOST SENSITIVE
HELLP SYNDROME - TX
• PROMPT DELIVERY OF INFANT
• SUPPORTIVE CARE FOR SEIZURES
AND HTN CRISIS
• STEROIDS MAY HELP FETAL LUNGS,
BUT NO BENEFIT TO HELLP
SYNDROME
Warm
AIHA
• Idiopathic
• Secondary
Cold
• Idiopathic
• Secondary
– Autoimmune
lymphoma, drugs
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Spherocytes
IgG antibody, C3d
Direct Coombs - 37°
Anti c / anti e
– Infections
– Lymphoma
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RBC clumps
IgM antibody
Cold Ag. Titre 4°
DAT +ve compl*
Anti I / i
Warm
• Idiopathic
• Secondary
– SLE, Autoimmune
disorders.
– CLL
– Lymphoma
– Drugs – Mdopa.
AIHA
Cold
• Idiopathic
• Secondary
– Infections
– Lymphoma
• PCH (anti-P)
Warm AIHA
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IgG, C3d, rarely other Ab.
Destruction in Spleen & RES
Loss of partial membrane – spherocytes
Clinical Features:
– Spleenomegaly
Autoimmune hemolytic anemia caused by
warm-reactive antibodies:
I. Primary
II. Secondary
1. acute
- viral infections
- drugs ( a-Methyldopa, Penicillin,
Quinine,Quinidine)
2. chronic
- rheumatoid arthritis, systemic lupus erythemat.
- lymphoproliferative disorders
(chronic lymphocytic leukemia, lymphomas,
WaldenstrÖm’s macroglobulinemia)
- miscellaneous (thyroid disease, malignancy )
Autoimmune hemolytic anemia
caused by cold-reactive antibodies:
I. Primary cold agglutinin disease
II. Secondary hemolysis:
- mycoplasma infections
- viral infections
- lymphoproliferative disorders
III. Paroxysmal cold hemoglobinuria
Alloimmune Haemolysis:
• Antibody from another person.
• Transfusion reactions
• Haemolytic disease of Newborn (HDN)
– RH-D, RH neg mother, + father, 2nd baby
Kleihauer test HbF,
– ABO – IgG in O mother, mild*, 1st babyagglutination & spherocytes, DAT neg/mild +
• Post transplantation induced.
Paroxysmal nocturnal hemoglobinuria
1. Pathogenesis
- an acquired clonal disease, arising from a somatic
mutation in a single abnormal stem cell
- glycosyl-phosphatidyl- inositol (GPI) anchor abnormality
- deficiency of the GPI anchored membrane proteins
(decay-accelerating factor =CD55 and a membrane
inhibitor of reactive lysis =CD59)
- red cells are more sensitive to the lytic effect of
complement
- intravascular hemolysis
2. Symptoms
- passage of dark brown urine in the morning
3. PNH –laboratory features:
- pancytopenia
- chronic urinary iron loss
- serum iron concentration decreased
- hemoglobinuria
- hemosiderinuria
- positive Ham’s test (acid hemolysis test)
- positive sugar-water test
- specific immunophenotype of erytrocytes (CD59,
CD55)
4. Treatment:
- washed RBC transfusion
- iron therapy
- allogenic bone marrow transplantation
Microangiopathy:
Spherocytes:
AIHA Cold ab type: Clumping.
Assesment of HA
Clinical features:
- pallor
- jaundice
- splenomegaly
Laboratory features:
1. Laboratory features
- normocytic/macrocytic, hyperchromic anemia
- reticulocytosis
- increased serum iron
- antiglobulin Coombs’ test is positive
2. Blood smear
- anisopoikilocytosis, spherocytes
- erythroblasts
- schistocytes
3. Bone marrow smear
- erythroid hyperplasia
Diagnosis of hemolytic syndrome:
1. Anemia
2. Reticulocytosis
3. Indirect hyperbilirubinemia
Autoimmune hemolytic anemia diagnosis
- positive Coombs’ test
Treatment:
- steroids
- splenectomy
- immunosupressive agents
- transfusion