Objective 6 - Diseases

What is are Sickle Cell Diseases (Hgb S)?

• most common form of hemoglobinopathy

• SCD - describes a group of genetic disorders

  • production of abnormal HbS

• involves 1 amino acid switch at 6th position on Beta Chain

  • glutamic acid → valine

What are features of Sickle Cell Disease?

• Autosplenectomy - loss of splenic function

• Acute Chest Syndrome - pulmonary infarction from sickling in lung

• Vaso Occlusion - severe pain / inflammation from cells trapped in microvessels

• Bacterial infections

• Leg Ulcers

• Avascular necrosis - impaired blood to head of femur/humerus

What are lab findings of Sickle Cell Disease?

• diagnosed after about 6 months

• ↑ WBC and bilirubin

• MCV/MCHC : normocytic/normochromic anemia

• ↑ retic

  • except in aplastic crisis (low)

• BM: erythroid hyperplasia

• positive hemoglobin solubility test

What can be seen on a blood smear in someone with sickle cell disease?

• Sickle cells

• Target cells

• HJ bodies

• Basophilic stipplings

• nRBCs

• spherocytes

What percentages will indicate Sickle Cell anemia (HbSS disease), the most common homozygous form of sickle cell disease?

• HbS: > 80%

• HbA: none

• HbF: 1-20%

• A2: 2-20%

What Hgb Electrophoresis pattern indicates sickle cell disease?

• migrate electrophoretically to the same position as HbD and HbG at alkaline pH (cellulose acetate)

• acid pH differentiates

What clinical clues can point to Sickle Cell Disease?

• recurrent severe pain

• acute chest syndrome

• anemia

• autosplenectomy

• frequent infection

• sickle cells

What results indicate Sickle Cell Trait (HbAS)?

• 40% Hgb S

• 60% Hgb A

• typically asymptomatic

  • sickling and crisis can occur when pts are hypoxic

• PB: normal, few target cells

• positive Hgb solubility test

• ↑ reticulocytes (5-20)

• sideroblastic granules / HJ bodies possible

• possible shift to left

  • ↑ immature WBC and PLTs

• BM - erythroid hyperplasia

  • not during crisis

What lab findings indicate Hgb C Trait (AC)?

• pt has 1 normal B globin gene and 1 HbC gene

• Labs

  • 30-40% Hgb C

  • 60-70% Hgb A

• target cells on PB

• mild hypochromia

What is Hemoglobin CC disease?

• a₂B₂^6Glu-Lys

• Change from glutamic acid → lysine

  • Hgb C polymerizes under low oxygen tension

• has short thick crystals within RBCs “bar of gold”

• less hemolysis

What lab findings indicate Hemoglobin CC disease?

• normocytic / normochromic

• target cells, microspherocytes, schistocytes

• RBC indices: normal

• mod inc in retics

• nRBCs may be present

• negative hgb solubility test

What electrophoresis results indicate Hgb CC disease?

• Hgb C = 95%

• HbA = none

• HbF = < 7

• HbA2 = negligible

• needs acidic pH to be separated

What is hemoglobin SC disease?

• a₂B^6Glu-ValB^6Glu-Lys

• at position 6, glutamic acid is replaced by valine (Hgb S) on one chain and is replaced by lysine (Hgb C) on other globin chain

• less severe than Hgb S but more severe than Hgb C

• patient produces BOTH HbS and HbC

  • HbS from one parent

  • HbC from other parent

What clinical findings indicate Hemoglobin SC disease?

• presents in teenage years

• vaso occlusive crisis is less frequent than in Hgb SS

• HbS from 1 parent and HbC from other

• moderate hemolytic anemia

• splenomegaly

• resp. tract infections with S. pneumonia

• med lifespan

  • women: 60 yrs

  • men: 68 yrs

What lab results indicate Hemoglobin SC disease?

• normocytic / normochromic

• normal RBC indices

• Hgb: 11-13 g/dL

• retic: 3-5%

• positive hgb solubility test

What on a peripheral blood smear indicate Hemoglobin SC disease?

• few sickle cells

• target cells

• intraerythrocytic crystalline structures (SC crystals)

What electrophoresis results would indicate Hemoglobin SC disease?

• near equal amounts Hgb S and C

• No HbA

• small HbF

What is used to treat Hemoglobin SC disease?

• same as for Hgb SS

What is used to treat Hgb CC and AC disease?

• none

What is characteristic of BOTH Beta and alpha thalessemia?

• ↓ hgb function

• microcytic , hypochromic anemia

What is Beta Thalassemia?

• adult Hgb

• inherited genetic mutations

• divided by gene symbols B0 or B+

What is B0 Beta Thalassemia?

• set of genetic mutations that result in complete absence of B chains

What is B+ Beta Thalassemia?

• set of genetic mutations that result in reduced amounts of B globin

What are the different B thalassemias - caused by genetic mutations?

• major -severe

• intermedia

• minor - least severe (trait)

What are the different a thalassemias - caused by gene deletions?

• Hgb Barts

• Hgb H

• Hgb Constant Spring

What percentages indicate B thalassemia major?

• Hgb F: 70-90%

• HbA2

• NO HbA

What is associated with B thalassemia major?

• severe hemolytic anemia

• Hgb < 7.0 g/dl

• micro / hypo

• rigid RBC → destroyed by spleen

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What are features of B thalassemia major?

• homozygous

• transfusion dependent

• BOTH parents have B thalassemia

• Dx: between 6 m and 2 yrs of age

  • failure to thrive, pallor, infections, splenomegaly

• four a globin chains, no B chains (B0B0)

What happens in B thalassemia major in non transfused / inadequately transfused infants?

• severe chronic anemia → strong stimulus for erythropoiesis

• causes: marked expansion of the marrow space

• characteristic skeletal changes of skull, long bones, hand bones

• stunted growth and prominent facial bones

What is on a peripheral blood smear for B thalassemia major?

• target cells, teardrop cells, elliptocytes

• basophilic stipplings (RNA)

• H-J bodies (DNA)

• Pappenheimer bodies (iron)

• Heinz bodies (hgb)

• polychromasia

• nRBCs

What lab results indicate B Thalassemia Major?

• ineffective erythropoiesis

• ↑ retics and LDH

• ↓ haptoglobin

• Hgb < 7.0 g/dL

• micro/hypo anemia

• severe hemolytic anemia

What is used to treat B Thalassemia Major?

• hematopoietic stem cell transplant - only cure

• 10-15 mL/kg of RBCs transfusion every 2-5 weeks

• iron chelation

• hydroxyurea

• desferrioxamine

What are characteristics of B Thalassemia Intermedia?

• malfunctioning hepcidin → increased iron absorption

  • iron overload

• present with symptoms > 2 yrs old

• pt may need occasional transfusion of RBC

• lead to severe infections , gall stones

What lab findings indicate B thalassemia intermedia?

• Hgb 7-10 g/dL

• varying degrees of anemia

• ↑ bilirubin

• jaundice, splenomegaly

• physical, bony characteristics

What are characteristics of B thalassemia Minor?

• B-thal trait

  • silent carriers

• one beta gene is mutated and one is normal (B0B)

• asymptomatic anemia

• stress can trigger:

  • infections/ trauma

What percentages indicate B thalassemia Minor?

• Hgb A: 92-95%

• Hgb A2: 3.5 to 7%

• Hgb F: 1 to 5%

What lab findings indicate B Thalassemia Minor?

• Hgb: 10-13 g/dL

• RBC norm / ↑

  • minimal ineffective erythropoiesis

• mild micro / hypo

  • MCV < 75 fl

  • MCHC < 32%

• target cells elliptocytes, basophilic stipplings

What is a-thalassemia?

• involves adult / fetal hgb

• extent of decreased production of a chain depends on mutation, number of globin genes affected, and which gene is affected

• a2 globin gene produces 75% of a chains in normal RBCs

• normal: aa/aa

What is a⁰ Thalassemia?

• deletion of BOTH a globin genes on chrom 16

• no a chains are produced

• 21 known mutations

• affects 4% of pop of SE Asia

What is a+ Thalassemia?

• deletion or non deletional mutation in one of two a globin genes on chrom 16

  • other one is intact and functional

• decreased a chain production

• 50-80% carriers in

  • Saudi Arabia, India, SE Asia, Africa

What is the a1 (silent carrier) clinical syndrome of a-thalassemia?

• 1 a gene deleted

• asymptomatic, incidental discovery

• borderline low MCV possible

What is the a2 (a-thalasemia minor, trait) clinical syndrome of a-thalassemia?

• 2 a genes deleted

• asymptomatic, incidental discovery

• mild micro / hypo

• ↑ RBCs

• target cells

What is the a3 (Hgb H disease B4) clinical syndrome of a-thalassemia?

• 3 a genes deleted, excess of B chains

• unstable hgb, heinz bodies, rigid RBCs destroyed in spleen

• mod micro/hypo

• 30% HbH, rest is HbA

What is the a4 (Hgb Barts y4) clinical syndrome of a-thalassemia?

• all 4 genes deleted

• no normal chains produced

• 80% hgb Barts - can not carry O2

• incompatible with life

  • die in utero or just after both

What is Alpha Silent Carrier (a+ thalassemia trait)?

• defect in one of the four a-globin genes

• presence of a very small amount (up to 2%) of hemoglobin Barts at birth

• not anemic, normal blood smear

• slightly low MCV - clue to the carrier state

What is the correlation between Women and Alpha Silent Carrier (a+ thalassemia)?

• not at risk of hemoglobin Barts hydrops fetalis

• may have children with hemoglobin H disease

What is a thalassemia minor (trait)?

• defects of two of four a-globin genes

  • cis (—/aa) - both delete on one chromosome

  • trans (a-/a-) one delete on each chrome

• at birth

  • 5-15% hemoglobin Barts - disappear with development

• parents are asymptomatic with mild microcytic, hypochromic anemia

  • MCV: 70-75 fl

How is a thalassemia minor identified?

• incidentally or by screening programs in regions with high prevalence

What is associated with Hemoglobin H disease?

• deletion of 3 out of 4 a genes (only 1 functional

• Denoted: B4 (tetramers)

• splenomegaly

• BM erythroid hyperplasia

• main finding: Hgb H inclusions (brilliant cresyl blue stain) B tetramers

What lab findings indicate hemoglobin H disease?

• mild/mod anemia

• hgb 7-10 g/dL

• 5-40% HbH

  • rest is HbA

  • small amount HbA2 and Hb Barts

• hypochromia microcytosis

• target cells

What is Hgb Bart associated with?

• (—/—) homozygous a⁰ that result in absence of all a chain production

• 4 gamma chains present

• death in utero or shortly after birth - edema, pallor

What is Hydrops fetalis

• life threatening condition of fluid build up in several body compartments

• in Hgb Barts - cardiac failure and edema are associated

What lab findings indicate Hgb Barts?

• marker: micro/hypo

• Hgb 3-8 g/dL, nRBCs

• tear drop cells, target cells

• BM: erythroid hyperplasia

What pregnancy symptoms indicate Hgb Barts?

• preeclampsia common

• complications

• hemorrhage postpartum

What percentages are associated with Hgb Barts disease?

• predominant Hgb: Hgb Bart (y₄)

• followed byL

  • Hgb Portland (z₂y₂)

  • Hgb H (B₄)

What is Constant Spring?

• HbCS

• point mutation in the a₂ globin gene

  • results in additional bases added to end of mRNA during transcription

• elongated mRNA is unstable

• abnormal a chains join B chains

• difficult to see in electrophoresis

  • alkaline pH

What is homozygous Constant Spring?

• thalassemia minor

• HbCS 5-8%

• microcytosis

What is heterozygous Constant Spring?

• asymptomatic

• HbCS 1%

What is Thalassemia with HgbS “Sickle like” B-thalassemia.

• 50-80% HgbS

• 20-50% HgbA

• ↑ HgbF

  • opposite of sickle cell trait

  • indicates decreased severity of sickling process

• microcytosis