Ppt Presentation For Pac 5110

ANEMIAS II: HEMOLYTIC ANEMIAS

Clinical Medicine and Surgery I

Pamela Jaffey MD

OBJECTIVES

1. Identify general diagnostic findings of hemolytic anemia

2. Describe a classification system for hemolytic anemias:

a. Hereditary anemias ( defects within RBC )b. Acquired anemias ( external causes )

3. Sickle Cell Anemiaa. identify clinical complicationsb. identify diagnostic findingsc. describe treatment of sickle cell disease:

health care maintenance; painful crisis

OBJECTIVES

4. Thalassemias describe populations most affected beta thalassemia major: describe complications; diagnostic findings beta thalassemia minor ( trait ): describe clinical and diagnostic findingsdefine the 4 types of alpha thalassemia

5. Glucose-6-phosphate dehydrogenase ( G6PD ) deficiency

a. identify populations affected with diseaseb. identify causes of acute hemolytic crisesc. describe clinical presentation

OBJECTIVES

1. Autoimmune hemolytic anemiasa. identify major causes of " warm" and "cold"

autoimmune hemolytic anemias b. describe how the following tests can help

diagnose autoimmune hemolytic anemias:direct antiglobulin test ( direct Coomb’s test )cold agglutinin titer

c. describe clinical presentationd. describe emergency treatment for rapidly

developing/ and or severe autoimmune hemolytic anemia

2. Identify hemolytic anemias occurring due to mechanical shearing of RBCs

HEMOLYTIC ANEMIAS

Definition:

increased destruction of RBC outside the bone marrow resulting in shortened RBC lifespan; destruction may be within vessels ( intravascular ), within the spleen ( extravascular ), or both.

HEMOLYTIC ANEMIAS

I. GENERAL DIAGNOSTIC FINDINGSA. increased reticulocyte count

( % reticulocytes /total RBC )

absolute reticulocyte count is more accurate: allows correction for anemia -decreased RBC count in denominator falsely increases reticulocyte count ( for reference )absolute reticulocyte count = % reticulocytes x RBC/uLabsolute reticulocyte count > 100,000/uL = hemolytic anemia

HEMOLYTIC ANEMIAS

I. GENERAL DIAGNOSTIC FINDINGS

B.increased serum unconjugated bilirubin (hyperbilirubinemia )

product of breakdown of hemoglobin released by lysed RBC

heme is enzymatically converted in macrophages to bilirubin, which is then transported in plasma by albumin

unconjugated bilirubin has not been metabolized (conjugated to glucuronic acid ) in liver- to be discussed in liver function test lecture

HEMOLYTIC ANEMIAS

I. GENERAL DIAGNOSTIC FINDINGS

C. decreased serum haptoglobin

serum haptoglobin binds free hemoglobincomplex is rapidly cleared haptoglobin level decreases

HEMOLYTIC ANEMIAS

I. GENERAL DIAGNOSTIC FINDINGSD. increased lactate dehydrogenase: released upon

lysis of RBC

( is a cellular enzyme involved with anaerobic glucose metabolism which is contained in many cell types, and released upon cell necrosis )

both intravascular and extravascular hemolysis are associated with above findings- only intravascular hemolysis is associated with:

E. hemoglobinuria ( increased hemoglobin in urine )

F. hemoglobinemia ( increased free hemoglobin in blood )

HEMOLYTIC ANEMIAS

II. CLASSIFICATION OF HEMOLYTIC ANEMIAS

A. DEFECTS WITHIN RBC ( hereditary )1. synthesis of structurally abnormal hemoglobin

e.g. SICKLE CELL ANEMIA

2. decreased synthesis of globin chains ( structurally normal ) e.g. THALASSEMIAS

3. enzyme abnormalitiese.g. GLUCOSE-6-PHOSPHATE

DEHYDROGENASE DEFICIENCY

4. RBC membrane abnormalities ( for reference )e.g. hereditary spherocytosis

HEMOLYTIC ANEMIAS

II. CLASSIFICATION OF HEMOLYTIC ANEMIASB. EXTERNAL CAUSES OF HEMOLYTIC ANEMIAS

(acquired)1. Immune Mediated

a. autoimmune disease : e.g. systemic lupus erythematosus

b. infections ( e.g. Mycoplasma pneumoniae )c. drugsd. WBC malignancies ( e.g. chronic lymphocytic

leukemia )e. idiopathic ( cause unknown )

2. Mechanical traumaa. disseminated intravascular coagulationb. prosthetic heart valves

3. Parasitization of RBCe.g. Malaria

HEREDITARY HEMOLYTIC ANEMIAS

SICKLE CELL ANEMIAFORMS: ( autosomal recessive inheritance ) Homozygotes: sickle cell disease ( median life

expectancy 5th decade- forties )no normal, mature Hgb ( have Hgb S instead of normal Hgb A ): 1/400 African American births ( also seen in other groups; e.g. Caucasians )

Heterozygotes: sickle cell trait – in 8-10% African Americans ( normal lifespan )60% Hgb is normal ( Hgb A) and mature; 40% of Hgb is Hgb SThere is enough normal Hgb to prevent most complications which develop in homozygotes; complications which develop among heterozygotes will be discussed for reference


SICKLE CELL ANEMIAPATHOGENESIS ( for reference only )1. mutation at position 6 in beta globin chain of hemoglobin:

glutamic acid is replaced by valine on outer surface2. physiochemical properties of Hgb are altered:

Hgb aggregates upon deoxygenationRBC become sickled with rigid, abnormal membranes which are abnormally adhesive to endothelial cells

3. chronic hemolysis occurs in spleen and blood vessels4. repeated painful crises ( vasoocclusive episodes ) occur due

to occlusion of microvasculature in various tissues by abnormal sickle cells, because they stick to endothelial cells

5. heterozygotes mainly spared of problems because normal and abnormal hemoglobins don’t aggegate well together


COMPLICATIONS OF SICKLE CELL DISEASEChronic Hemolytic AnemiaMean RBC lifespan = 17 days ( normally 120 days )Hgb = 6-10 gm/dL; Reticulolyte count = 3- 15%

AGE AT PRESENTATION:1. may present in infancy2. 61% by 2 years3. 96% by 8 years

Most Common Presenting Symptoms:1. dactylitis ( acute pain in hands and/or feet )2. acute painful crisis ( to be discussed )3. splenic sequestration ( to be discussed )

SICKLE CELL DISEASE

PAINFUL CRISIS ( most frequent reason why homozygotes seek medical attn )

A. Precipitating events:deoxygenation; infection ( and fever ); dehydration; stress; menses; cold; alcohol consumption; often no identifyable cause widespread occlusion in microvasculature

B. Clinical presentationoften severe pain anywhere but most typically: back, chest, extremities abdomenother symptoms: fever, swelling, tenderness, increased respiratory rate, nausea and vomiting (may last a few hours – 2 weeks )

SICKLE CELL DISEASE

PAINFUL CRISIS ( most frequent reason why homozygotes seek medical attn )

C. Incidence of hospitalizations for pain per year: ( disease severity variable in different patients )1/3rd patients none ; 1/3rd: 2-6x; 1/3rd: > 6 x

D. Consequences necrosis in various tissues ( spleen; bones; lungs; kidneys; brain; skin etc.)

SICKLE CELL DISEASE:COMPLICATIONS

INFECTION

A. results from lack of protection from bacterial infection normally provided by spleen ( splenic macrophages engulf and clear bacteria; spleen is important in activation of alternative complement pathway )

1. in early childhood, spleen is enlarged and congested with abnormal RBC

2. infarction of spleen occurs by adolesence or early adulthood (from vasoocclusion by abnormal RBC: “autosplenectomy”)

SICKLE CELL DISEASE: COMPLICATIONS

INFECTION

NOTE: splenic infarction can develop at high altitude in patients with sickle cell trait; occurs more commonly in Caucasians rather than patients of African ancestry ( for reference )


INFECTION CONTINUED:B. infection is important cause of death in children:

(young children are treated prophylactically with penicillin )

C. patients have increased episodes of pneumonia, sepsis, meningitis ( infection of brain coverings ), osteomyelitis ( bone infection ) important organisms:patients especially vulnerable for infections by encapsulated bacteria:

Streptococcus pneumoniae; Hemophilus influenzae type bOther important bacteria causing infection:Salmonella and Staphylococcus aureus (osteomyelitis )


PULMONARY COMPLICATIONSboth acute and chronic problems occur: a leading cause of death

ACUTE CHEST SYNDROME: 30% patientsSymptoms: shortness of breath, chest pain, fever,

increased respiratory rate, leukocytosis, infiltrate on chest x-ray

Consequences: life-threateningextreme deoxygenation in blood ( hypoxemia) can result in widespread vaso-occlusion and failure of multiple organs”crash”

can be associated with infection due to Streptococcus pneumoniae, Hemophilus influenzae type b, Mycoplasma pneumoniae, and Chlamydia pneumoniae


Neurologic: ( 30% patients )

seizures; transient ischemic attack

( 11% ); cerebral infarction ( 54%- peaks in young children and adults > 29yrs; ); cerebral hemorrhage ( 34%- peaks in adults in twenties )


Renal: abnormal function of renal tubules (concentrating ability etc. )infarction of renal papilla results in hematuria (blood in urine )homozygotes may also have glomerular diseaseAND may develop chronic renal failure

NOTE: heterozytotes may also have: ( for reference )episodes of hematuria; impaired concentrating ability of renal tubules (less severe and presents later than in homozygotes); may have increased # of urinary tract infections


Priapism: prolonged, painful erection (may last long enough to require medical intervention)Incidence: 6 –42% males; peak ages: 5-13yrs and 21-29 yrs (may occur in pre-adolescent males)

Bone:1. significantly increased production of RBC in bone

marrow expands it and results in “ bossing of forehead”

2. infarction of bone secondary to vaso-occlusione.g. aseptic necrosis of femoral head; extreme pain may be associated with infarction

3. osteomyelitis ( infection of bone)


Leg Ulcers: ( also called “ stasis ulcers” )

1. major cause of disability- frequent, chronic, resistant to treatment

2. increased incidence in teenagers; at medial or lateral malleolus

3. caused by tissue necrosis associated with occlusion and stasis in skin microvasculature; may be associated with infection


Cardiac Complications:1. chronic anemia compensated by high

cardiac output resulting in enlargement of heart ( cardiomegaly ) and decreased cardiac reserve

2. heart at increased risk of going into failure with transfusions and fluid overload

3. myocardial infarction may occur4. “Cor pulmonale” ( right sided heart failure )

secondary to lung disease ( necrosis of lung tissue; pulmonary hypertension caused by chronic hypoxia )


Hepatobiliary System

bilirubin gallstones ( term for gallstones = cholelithiasis )


Splenic sequestration

occurs in young children; spleen is significantly enlarged and congested with red blood cells; shock can occur due to significantly decreased blood volume ( hypovolemia )

CASE

Splenomegaly secondary to acute sequestration crisis in a 20-month-old female with sickle cell disease:

An enlarged spleen was palpated on physical examination.

X-RAY SHOWING NORMAL SIZED SPLEEN IN AN ADULT

1. note the spleen outlined by the adjacent bowel

2. note how the spleen is on the left and does not cross the midline

SPLEEN IN YOUNG CHILD WITH SPLENIC SEQUESTRATION CRISIS

1. note the enormous spleen which crosses the midline extending into the right side of the patient

2. the spleen is enlarged due to extreme sequestration of abnormal sickled red blood cells within it


Retinopathy ( due to occlusion of retinal vessels: hemorrhage and eventual detachments ); visual loss can occur

Aplastic crisis:

temporary; caused by Parvovirus B19 (this virus causes aplastic crisis in patients with hereditary hemolytic anemias in general )


note: patients with sickle cell trait at higher risk of rhabdomyolysis ( muscle necrosis which may result in renal failure and death ) during:

1. prolonged physical conditions ( e.g. a military recruit undergoing a long march )

2. during exercise at high altitude

( for reference )

DIAGNOSIS OF SICKLE CELL ANEMIA

Note: only homozygotes have abnormal CBC and sickle cells on peripheral blood smear

1. sickle cells seen on peripheral blood smear2. Hgb = 6-10gm/dL; reticulocyte count = 3- 15% 3. MCV = normocytic ( 80-100fL ); may be macrocytic

due to reticulocytes4. hemoglobin electrophoresis: abnormal band seen

(called Hgb S ): both homozygotes and heterozygotes 5. solubility test ( homozygotes and heterozygotes )6. prenatal diagnosis: DNA analysis of fetal cells

( e.g. chorionic villus sampling )7. testing of all neonates occurs in most states in the

US currently

TREATMENT OF SICKLE CELL DISEASE

HEALTH CARE MAINTENANCE1. immunization of children against

Streptococcus pneumoniae; Hemophilus influenzae type B; hepatitis B virus, and influenza virus( immunization important for patients with splenectomy in general )

2. prophylactic penicillin for children 5yrs years and less for reference: 125 mg penicillin V orally 2X/day until 2-3 years, then 250 mg penicillin V orally 2X/day through 5 years


HEALTH CARE MAINTENANCE3. hydroxyurea : ( increases production of fetal Hgb )

decreases painful crises and acute chest syndrome; may help prevent strokes; decreases mortality due to sickle cell disease ( note: newer findings indicate that drug has another helpful effect in addition to stimulating production of fetal Hgb )if hydroxyurea alone does not give good treatment response, add erythropoietin

4. assess and treat a febrile child immediately: physical exam; CBC ( look for “ left shift” ); urine culture; chest x-ray- hospitalization, blood culture and lumbar puncture ( to assess for meningitis ) may be needed


HEALTH CARE MAINTENANCE

5. education:

e.g. parents instructed how to detect early signs of infection and enlarging spleens in young children; genetic counseling

6. folate supplements: rapid turnover of RBC increases demand for folate

dose: 1mg oral folate/day


HEALTH CARE MAINTENANCE7. transcranial doppler ( TCD ) to assess blood

flow velocity in large intracranial vessels; can predict patients at risk for strokepatients with increased risk are given chronic exchange transfusions of packed red blood cells; is protective against strokefor reference: serial testing is needed, because normal flow velocity on a single test does not “assure continued low risk status”

8. retinal evaluation begun at school age ( due to ocular complications: e.g. early, proliferative sickle retinopathy)


CURATIVE THERAPY

a successful bone marrow

( or hematopoietic stem cell) transplant from a HLA-matched sibling; cord blood stem cells from a sibling are also used for transplantation

TREATMENT OF COMPLICATIONS

PAINFUL CRISIS:

“MOHA”: Morphine; Oxygen; Hydration; Antibiotics1. relieve severe pain rapidly and safely ( narcotics typically

needed; avoid respiratory depression )IV MORPHINE often given firstcan be given as patient controlled analgesia delivered via a pump:basal continuous rate of morphine with a bolus that can be delivered to the patient if the patient needs it, at a specified dose and interval )- for referencenote: morphine can also be given orally or as rectal suppositoryOther narcotic drugs:

a. hydromorphone hydrochloride ( Dilaudid ): can be given orally, by injection, or as a suppository

b. fentanyl citrate (Sublimaze): can be given as IV infusion or worn as a patch

TREATMENT OF COMPLICATIONS

Drugs with low risk for respiratory depression:a. ketorolac ( Toradol ) ( a potent non-steroidal anti-

inflammatory drug ) is especially good for bone painnote: is given by injection or orally over 5 days with H2 blocker because of severe GI side effects )

b. tramodol hydrochloride( Ultram): may be used for outpatient management of painful crisis: given orally; low risk for abuse or addiction

2. give OXYGEN3. HYDRATION with oral or IV fluid4. evaluate for infection and give ANTIBIOTIC if

present

TREATMENT OF COMPLICATIONS OF SICKLE CELL

DISEASE

Priapism: ( painful, prolonged erection: may persist for very long time )

1. IV hydration and pain medication: if persists 12 hrs

2. partial exchange transfusion ( to decrease abnormal Hgb): if persists

3. further medical intervention: if persists surgery ( urologist )

( treatment of priapism is for reference )

TREATMENT OF COMPLICATIONS OF SICKLE CELL

DISEASE Indications for Transfusion: ( for reference )1. Aplastic crisis: to increase oxygen carrying capacity of blood2. Splenic sequestration and hypovolemia: to expand blood

volume3. Before surgery ( to decrease perioperative complications )4. Acute chest syndrome: to protect from widespread

deoxygenation and vaso-occlusion resulting in multi-organ failure ( partial exchange transfusion is needed emergently- remove some of patient's blood and replace it with donor blood )

5. Stroke prevention in high risk patients ( chronic exchange transfusions given )

6. Avoid transfusing to Hgb much above 10gm/dL to avoid hyperviscosity and occlusive complications

THALASSEMIAS

PATIENTS AFFECTEDMediterranean ( Greece; Italy ), Southeast Asian, Asian Indian, African extraction

PATHOGENESIS OF THALASSEMIAS ( for reference only )

1. decreased synthesis of alpha or beta globin chains of hemoglobin

2. severity depends on extent of decreased chain production

3. beta thalassemias: decreased production of beta chainsalpha thalassemias: decreased production of alpha chains

PATHOGENESIS OF THALASSEMIA MAJOR

there is severe deficiency of globin chain production:a. globin chain produced is in excess and can’t find complementary chain precipitates; is toxic to RBC; causes RBC membrane defect and impairs DNA synthesisabnormal RBCs made in bone marrowb. vast majority of RBCs produced in bone marrow are “rejects”, and are destroyed in bone marrowonly few RBC released into circulationmany RBC released are hemolyzed in spleenc. profound anemia results; spleen enlarges ( (splenomegaly)

PATHOGENESIS OF THALASSEMIA MAJOR

beta thalassemias more severe than alpha thalassemias:

excess of alpha globin chains made with beta thalassemias is more toxic to the RBC than the excess of beta globin chains made with alpha thalassemias

BETA THALASSEMIAS

BETA THALASSEMIA MAJOR ( homozygotes )

Presentation:

1. 4-12 months (after fetal hemoglobin disappears)

2. pallor; irritability; growth retardation; jaundice and scleral icterus due to hyperbilirubinemia; abdominal swelling due to hepatosplenomegaly ( hepatosplenomegaly due to RBC destruction and attempts at production of RBCs in these organs )

BETA THALASSEMIA MAJOR

Complications:1. bony abnormalities ( initially of skull and

face )significant expansion of bone marrow occurs due to extreme attempts to produce RBCcortex thinnednew bone formed on external aspect of skull

a. “crew haircut” or “hair on end” appearance of skull on x-ray due to perpendicular radiations of new bone formation on the outer table

b. large maxilla with malocclusion: " chipmunk facies"

c. thinning of cortex of other bones predisposes to fractures


Complications:2. bilirubin gallstones ( due to hyperbilirubinemia: increased

serum unconjugated bilirubin: 2-4mg/dL )3. profound anemiaheart failure; death in early childhood if

untreatedtreated by regular blood transfusions4. IRON OVERLOAD – secondary hemochromatosis

a. causes: regular transfusions with packed red blood cells (big source of iron ) and increased absorption of iron from GI tract

b. consequences: iron accumulates in various organs and is toxic

i. chronic liver failure with fibrosis ( cirrhosis )ii. endocrine organ involvement results in hormonal

insufficiencyiii. cardiac disease ( cardiomyopathy )

results in heart failure; arrhythmias


Diagnostic Findings:

1. CBC: Hgb 3-4gm/dL; severe hypochromia ( decreased MCH) and severe microcytosis (decreased MCV)

2. peripheral blood smear: target cells (RBCs have a “bull’s eye” appearance )

3. prenatal diagnosis: DNA study of fetal cells


Treatment: ( for reference )1. regular packed RBC transfusions to

maintain Hgb level at 9-10gm/dL 2. iron chelation therapy with deferoxamine

(iron binding agent which rids body of iron)- to prevent iron overload

3. splenectomy when transfusion requirements very excessive( so RBC no longer destroyed in spleen)immunizations and prophylactic penicillin needed as with sickle cell disease


Treatment: ( for reference )4. frequent monitoring of cardiac function5. folic acid supplementation because of increased

RBC production in bone marrow6. treat endocrine deficiencies resulting from iron

overload7. good screening; genetic counseling; prenatal

diagnosis8. bone marrow or stem cell transplantation donated

by HLA-matched relative: only chance for cure ( 90% cure when performed on younger child with minimal liver pathology and receiving adequate iron chelation therapy with deferoxamine )

9. stem cell transplantation: harvesting progenitor blood cells in peripheral blood


Prognosis:

1. survival significantly shortened, but at least into 3rd decade if transfusion therapy performed with iron chelation

2. bone marrow or stem cell transplant only chance for cure ( see above )

BETA THALASSEMIAS

BETA THALASSEMIA MINOR ( TRAIT ): heterozygotes1. asymptomatic or symptoms of mild anemia: may

be discovered on routine exam in older children or adults

2. during pregnancy, anemia often more severe and transfusions may be necessaryimportant to distinguish from iron deficiency anemia: iron can worsen anemiaHOWEVER: if a patient with thalassemia minor develops iron deficiency anemia, “ they should not be denied iron”: www.uptodate.com- Treatment of beta thalassemia retrieved on 10/13/09

BETA THALASSEMIAS

BETA THALASSEMIA MINOR ( TRAIT ): heterozygotes3. diagnostic findings

a. mild anemia ( Hgb rarely < 10gm/dL) b. striking microcytosis ( MCV < 75fL: as low as 55fL ) and

hypochromia ( decreased MCH )c. abnormal pattern on hemoglobin electrophoresis

( increased Hgb A2; is not always present )d. iron studies: total iron binding capacity normal

iron and ferritin normal or may be increased ( due to mild iron absorption from GI tract )

e. peripheral blood smear: target cellsf. normal or increased RDW; normal reticulocyte count

4. iron therapy won't help ( may worsen anemia )

BETA THALASSEMIAS

BETA THALASSEMIA INTERMEDIA ( for reference )

Some clinical manifestations of thalassemia major presenting later in life due to chronic hypoxia and iron overload ( heart failure, pulmonary hypertension ); patients are less transfusion dependent

Note: hydroxyurea, which is used in the treatment of sickle cell disease to stimulate fetal Hgb synthesis is helpful in some patients with beta thalassemia intermedia

THALASSEMIAS

ALPHA THALASSEMIAS 1. alpha thalassemia minima: MCV may be slightly low;

patients asymptomatic; Hgb electrophoresis normal; important for genetic counseling

2. alpha thalassemia minor: (similar to, but may be milder than beta thalassemia trait: MCV 60 – 75fL )MCV often low; hypochromia; target cells; normal Hgb electrophoresis ( no increase in Hgb A2 )

3. Hbg H disease: chronic hemolytic anemia presenting at birth;neonatal jaundice ( severity like beta thalassemia intermedia )

4. Hgb Barts: usually death in utero or at birth

HEMOGLOBINOPATHIES

NOTE: patients can have a combination of sickle cell anemia and thalassemia (beta or alpha):

e.g. sickle cell trait/ beta thalassemia minor

Other anemias with hemoglobin mutations and abnormal structure exist: e.g. Hgb C; Hgb SC; Hgb D; Hgb G

In general:

hemoglobinopathies are hemolytic anemias in which the Hgb is abnormal in structure or amount

GLUCOSE-6-PHOSPHATE DEHYDROGENASE

DEFICIENCY (G6PD deficiency) Pathogenesis:deficiency of the G6PD enzyme increases

susceptibility of RBC to oxidative damage by certain agents such as antimalarial drugs (e.g. Primaquine); sulfonamides; nitrofurantoin; fava beans; infections ( ex. viral hepatitis; pneumonia; Salmonella; Ecoli; beta-hemolytic Streptococci; Rickettsia ); diabetic ketoacidosis


DEFICIENCY (G6PD deficiency)

Incidence: x-linked recessive inheritance

typically affects males; female carriers are rarely affected

different disease variants; most common variants of disease:

1. G6PD A-: 10-11% African Americans; moderate enzyme deficiency

2. G6PD Mediterranean: Middle East; more severe enzyme deficiency


DEFICIENCY (G6PD deficiency) Clinical Presentation: patient has intermittent

acute hemolytic episodes and is healthy with normal CBC in between episodes

1. self-limited acute hemolytic crisis occuring within hours – a few days of exposure to oxidant stressor; is self- limited because only old RBC are lysed: when only “younger RBC” remain, episode is over

2. symptoms: sudden onset of jaundice, pallor and dark urine (due to hemoglobinuria) with or without abdominal and back pain


DEFICIENCY (G6PD deficiency) Clinical Presentation: patient has intermittent

acute hemolytic episodes3. abrupt fall in Hgb by 3- 4gm/dL; increased

unconjugated bilirubinreticulocytosis is present upon recovery (within 5 days after onset )

4. Favism:occurs in young children in Italy or Greece ( with more severe form of G6PD deficiency ); presentation hours after consumption of fava beans results in a fatal anemia if children are not transfused )



Diagnosis:1. Assay can assess enzyme function

2. Peripheral blood smear during hemolytic crisis: “bite cells”- oxidized denatured Hgb “puddles” to 1 side of the RBC, leaving a clear zone adjacent to the RBC membrane on the opposite side which looks like a “bite” in an “oreo cookie”



Treatment: ( for reference )

1. avoidance of drugs precipitating hemolytic crises

2. during hemolytic crisis:a. transfuse if anemia is sufficiently severe

b. withdraw precipitating agent

HEREDITARY SPHEROCYTOSIS

Pathophysiology:

1. structural defect in RBC membrane results in spheroidal shape and lack of deformability of RBC

2. hemolysis in spleen results from lack of deformability (RBC cannot get back into sinuses and general circulation, so are phagocytosed by macrophages in the spleen)


NOTE ON ADDITIONAL SIGNIFICANCE OF SPHEROIDAL SHAPE OF RBCs:

spheroidal shape is associated with a increased concentration of Hgb per RBC area, therefore, the mean cell hemoglobin concentration (MCHC) is increased


Incidence: highest in people of Northern European extraction: 1/5000

Clinical Presentation and Course:1. major clinical features: anemia,

splenomegaly, and jaundice2. variation in severity: from asymptomatic

to presentation at birthTreatment:Splenectomy

ACQUIRED HEMOLYTIC ANEMIAS

AUTOIMMUNE HEMOLYTIC ANEMIAS

Pathogenesis:

Autoantibodies directed against RBCs are bound to RBCs and increase clearance of RBCs in spleen by macrophages:

antibody binds to receptors on splenic macrophages and causes macrophages to phagocytize the RBCs

activation of complement by autoantibody may also occur


Classification:

I. “Warm” Autoimmune Hemolytic Anemiaautoantibodies preferentially reacting at body temperature

A. primary ( no known cause )- many cases have no known cause


Classification:I. “Warm” Autoimmune Hemolytic Anemia

B. Secondary (known causes)1. malignancies of white blood cells ( e.g. chronic

lymphocytic leukemia )2. autoimmune disease ( e.g. SLE)3. drugs: many

a. penicillin; cephalosporins ( antibiotics )especially after very large intravenous dose; sulfonamides

b. alpha-methyl dopa ( anti-hypertensive drug used in pregnancy )1% patients on alpha methyl dopa have clinically significant disease

c. various other drugs: e.g. NSAIDs; quinine/quinidine4. viral infections ( usually in children )


Classification:

II. “Cold” Autoimmune Hemolytic Anemiaautoantibodies preferentially react at cold temperatures (4-18oC)

A. chronic: typically cause is unknown; WBC malignancies ( e.g. lymphoma ) may be a known cause )acrocyanosis: dark, purple-grey discoloration of fingertips, toes, nose, and ears due to RBC agglutination at cold temperature


Classification:II. “Cold” Autoimmune Hemolytic Anemia

autoantibodies preferentially react at cold temperatures (4-18oC)

A. acute: post-infectious1. Mycoplasma pneumoniae ( primary

atypical pneumonia ); Epstein Barr Virus

2. abrupt onset occurring during recovery; self limited; typically clinical findings of cold autoimmune hemolytic anemia not present


Diagnostic Findings:1. POSITIVE DIRECT ANTIGLOBULIN TEST

( direct Coomb’s test ):detection of autoantibodies on patient’s RBC

1. CBC:a. mild –severe decrease in Hgbb. increased reticulocyte count

2. cold agglutinin titer increased in cold autoimmune hemolytic anemia: e.g. acute, post-infectious autoimmune hemolytic anemias ( with Mycoplasma pneumonia )


Presentation of Autoimmune Hemolytic Anemias:1. slight jaundice and scleral icterus; pallor2. may have shortness of breath or dyspnea on

exertion3. splenomegaly ( enlarged spleen ) in many patients

( secondary to increased hemolysis in spleen ): occurs especially after several months of anemia

4. presentation can vary in mode of onset and severity:

a. gradual; patients relatively asymptomaticb. rapid development with severe anemia and severe

symptoms e.g. high-output heart failure


Treatment: (of symptomatic, unstable disease )

1. Immunosuppressive therapy

a. corticosteroids (prednisone): first line therapy

b. cytotoxic drug therapy:cyclophosphamide: azathioprine

(if dependence on high dose of prednisone or bad side effects from steroid)

2. splenectomy: removes primary site of RBC destruction

3. If a drug is causing hemolysis, terminate drug


Treatment: (of symptomatic, unstable disease )

for rapidly developing and/or severe anemia:

4. transfusion with packed RBC is needed

Hgb <7gm/dL (or higher in patient with preexisting cardiac disease):

Patient can develop high output cardiac failure and pulmonary edema, MI, and/or cardiac arrythymias due to severe hypoxemia

patient may also need oxygen therapy


Treatment:

5. cold agglutinin disease: prevention - patients should avoid cold and dress warmly even in summer

PARASITIZATION OF RBC

malarial parasites: Plasmodium falciparum, vivax, malariae, or ovale

pathogenesis: cycles ( for reference only )

parasite is engulfed by RBC after binding RBC receptortakes over RBC metabolic machineryingests Hgbbursts out of RBCcycle repeats again

MECHANICAL CAUSES: SHEARING STRESS ON RBC

Macrovascular: prosthetic heart valves ( 10% artificial aortic prostheses) turbulent blood flow through narrow openings occurs, causing RBC shearing (e.g. seen with paravalvular leaks)

anemia can be severe: 5-7gm/dL; diagnostic findings of intravascular hemolysis are present ( increased reticulocyte count; decreased haptoglobin; hemoglobinemia, and hemoglobinuria ); schistocytes ( fragmented RBCs ) are present

MECHANICAL CAUSES: SHEARING STRESS ON RBC

Microvascular: “microangiopathic hemolytic anemia”

diseases with widespread formation of thrombi ( clots ) in microcirculation; red blood cells are torn as they pass through clots

fragments = schistocytes

1. disseminated intravascular coagulation (DIC )

2. thrombotic thrombocytopenic purpura – hemolytic uremic syndrome ( TTP – HUS )

CONCLUSION

DIC and TTP-HUS to be discussed in lecture on thrombotic complications

SUMMARY: CLASSIFICATION OF ANEMIAS BY MCV: pages 18-20

TABLE 1: USE OF IRON STUDIES TO DIFFERENTIATE BETWEEN:

Iron Deficiency Anemia; Anemia of Chronic Disease; Thalassemia Minor Page18

MCV<80 fL

Iron DeficiencyChronic Disease

ThalassemiasSideroblastic

AnemiasLead

intoxication

MCV80–100 fL

Reticulocyte>100 k/L

Reticulocyte<100 k/L

Megaloblastic

HereditaryVit B12 deficiencyFolate deficiency

Non-megaloblastic

Schistocytes

Autoimmunehemolytic anemia

Malaria

DICTTP-HUSProsthetic

heart valves

Acquired WBCPLT

Normal

Acute blood lossEarly iron defic

Chronic DzChronic renal

failure

Sickle cell anemia

G6PD deficspherocytosis

WBC &/or PLTLow

InfectionMedications

Aplasticanemia

LeukemiaHypersplenism

HypothyroidismLiver Dz

AlcoholismAplastic anemia

Classification of Anemias by MCV

MCV>100 fL

NoYes

IRON STUDIESnml or serum iron & ferritinNormal TIBC

serum iron & ferritin TIBC

find source of bleeding

serum ironnml or ferritin, TIBC

thalassemia minor

HgbA2 onelectrophoresis

Molecular studies

beta thalassemia

alpha thalassemia

striking MCV, mild Hgb

iron deficiency + RDW

chronic diseaseMCV 70 – 80fL

bone marrow Bx

ringed sideroblasts

sideroblastic anemia

serum lead level lead intoxication

basophilic stippling

peripheral blood smear

Work-up of Microcytic Anemias

Work-up of Normocytic AnemiasAbsolute Retic Count <100,000/L

IRON STUDIESSERUM FERRITIN 1st

then Serum iron, TIBC

BONE MARROW BIOPSY

RENAL FUNCTION TESTS

normal or ferritin TIBC

Find bleeding source

early iron deficiency

chronic disease

HYPOCELLULARVERY FATTY

HYPERCELLULARREPLACEMENT

APLASTIC ANEMIA LEUKEMIA

UA

CHRONIC RENAL FAILUREACUTE BLOOD LOSS

SERUM HAPTOGLOBIN 25 mg/dL serum LDH, total bilirubin, indirect bilirubin

HEMOLYTIC ANEMIAS

Hemoglobin electrophoresis Direct antiglobulin (Coomb’s) test

HbSother hemoglobinopathies

HbC, HbSC, HbD etc.sickle cell anemia

NEG POS

Peripheral blood smear autoimmunehemolytic anemia

POS

NEG

platelets

nml

G-6-P-D deficiency

spherocytosis

heterozygotes homozygotes

Nml CBC

NEG POS

Sickle RBC PT, PTT, D-dimers

nml

Prosthetic heart valve

DIC

TTP - HUS

schistocytes

Work-up of Normocytic AnemiasAbsolute Retic Count >100,000/L

MCV80-100 fL

megaloblastic+

microcytic

earlymegaloblastic

Bone marrowBiopsy

aplastic anemia

>110 – 115 fL

megaloblasticanemia

Serum vitaminB12level

Serum folatelevel

< 200 pg/mL

< 2 ng/mL

Vitamin B12

deficiency

anti-intrinsic Factor Abparietal cell Ab

pernicious anemia

Schilling test

Folate deficiency

alcoholabuse

100 – 110 fL

LFT TFT

Liver disease

hypothyroidism

retic count

hemolytic anemias

NEG

POS

Work-up of Macrocytic Anemias

TABLE 2: USE OF IRON STUDIES TO DIFFERENTIATE BETWEEN:Iron Deficiency Anemia - Anemia of Chronic Disease - Thalassemia Minor

SERUM IRON FERRITIN TIBCIron

DeficiencyAnemia

Anemia ofChronic Dz NL or

ThalassemiaMinor NL or NL or NL

Ppt Presentation For Pac 5110

Health & Medicine

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