Hemoglobinopathies - Clin Med

What does this refer to

• An 8-year-old African American boy presents with his mother to urgent care for severe pain in his hands and feet.

• He reports that he has had on and off pain for as long as he can remember, but this time the pain is unremitting and not responsive to pain medications at home.

• He had been playing outside in the snow when the pain started.

• His past medical history includes a blood disorder but his parents cannot remember what this was called, as it was diagnosed in a foreign hospital.

• On physical exam, he is noted to be pale and he has palpable splenomegaly.

• A peripheral blood smear shows sickled red blood cells.

• He is started on intravenous pain medications.

Sickle cell anemia

What does this refer to

• Hemolytic anemia

• Affects β–globin gene

• Genetic defect in synthesis of Hgb S

• “Sickled” shape —> hemolysis and vascular occlusion

• Includes

  • Sickle cell disease

  • Sickle beta thalassemia

  • Hgb SC disease

• Sickle cell trait

  • Usually asx

  • Doesn’t usually need tx

Sickle Cell

What does this refer to

• Autosomal recessive

• Genetic mutation

  • Chromosome 11

  • β-globin gene

• MC AA

• MC inherited blood disorder in US

• M = F

• Can be dx as early as 10 weeks of age

EpidemiologySickle Cell

What does this refer to

Sickle cell crisis may be referred to as acute painful episodes

What does this refer to

• Autosomal recessive

• Genetic mutation in HBB gene

• Genetically determined defect in synthesis of Hemoglobin S.

• Valine at 6th position on Beta globin chain, not glutamine

EtiologySickle Cell

What does this refer to

• Anemia

  • Shortness of breath

  • Fatigue

  • Delayed growth and development in children

• Repeated infections

• Periodic episodes of pain

• MC presenting sx is vaso-occlusive crisis

  • “Sickle Cell Crisis”

    • Cold temperatures, stress, alcohol, menses

Clinical historySickle Cell

What does this refer to

• Scleral icterus/jaundice

• Pallor

• Extremities/joints —> pain

  • Erythema and edema

  • Skeletal abnormalities

• Fundoscopic exam

  • Corkscrew shaped vessels

• Precordial systolic murmur and/or cardiomegaly

• Splenomegaly (childhood)

• Deficit in growth parameters

Physical examSickle Cell

What does this refer to

Aseptic Dactylitis (hand-foot syndrome) 

Physical exam sickle cell 

What does this refer to

• Distinguish between the anemias

• Hemoglobin C disease

• Legg-Calve-Perthes disease

• Ophthalmologic manifestations of leukemias

• Osteomyelitis

• PE

• RA

• Septic arthritis

Differential diagnosisSickle Cell

What does this refer to

WorkupSickle Cell

What does this refer to

look at this picture

What does this refer to

• Target cells, elongated cells, and characteristic sickle erythrocytes

WorkupPeripheral Blood Smear

What does this refer to

• RBCs with nuclear remnants (Howell-Jolly bodies) = asplenia

• Spherical or ovoid eccentrically located granules occasionally observed in the stroma of circulating erythrocytes that occur most frequently after splenectomy or in megaloblastic or severe hemolytic anemia

WorkupSickle Cell

What does this refer to

• Remnants of the RBC nucleus

• Normally removed by the spleen

• Seen in patients with splenectomy or who have functional asplenia (from sickle cell disease).

• Target cells (arrows) are another consequence of splenectomy.

Cell MorphologyHowell-Jolly bodies

What does this refer to

Clinical intervention Sickle cell

What does this refer to

TreatmentSickle Cell

What does this refer to

• Antimetabolites

  • Hydroxyurea

• Opioid analgesics for pain

• NSAIDS

  • Ketorolac (Toradol)

• TCA

  • Amitriptyline

• Vitamins

  • Folic acid

• Glutamine amino acid

Clinical pharmacotherapeuticsSickle Cell

What does this refer to

• Predictors of adverse outcome

  • Hand-foot syndrome (dactylitis) in infants younger than 1 year

  • Hb level of less than 7 g/dL

  • Leukocytosis in the absence of infection

PrognosisSickle Cell

What does this refer to

What does this refer to

• A 22-year-old Vietnamese female presents for a routine gyn exam. Her menstrual cycle is normal and there is no evidence of other bleeding. Guiac is negative. Her hemoglobin is at 11 (12-16), RBC is 5.8 (3.5-5.5), and an MCV of 70 (80-100) with a normal RDW of 10. WBC and platelets are normal. Hemoglobin electrophoresis shows an increase in amount of Hgb A2 and Hgb F

Alpha (⍺)-thalassemia

What does this refer to

• Decreased alpha globin chain production

• Sx – ↓ RBC

• Reduction in the amount of hemoglobin prevents enough oxygen from reaching the body's tissues

• Determined by 4 genes

  • 4 ⍺-genes and 2β-genes = 3 forms of Hgb (A, A2, and F)

⍺-Thalassemia

What does this refer to

• MC Southeast Asia followed by Mediterranean, Africa and Middle East

• Lowest among Caucasians

• ⍺-thalassemia is MC Asian Americans

• Congenital

• M = F

Epidemiology⍺-Thalassemia

What does this refer to

• Decrease in alpha (⍺) chain production

• Genetic

  • Deletions of HBA1 and HBA2 (we have 2 of each)

• Determined by 4 genes

  • 1/4 abnormal allele (silent carrier)

  • 2/4 abnormal alleles (minor trait)

  • 3/4 abnormal alleles (intermedia)

  • 4/4 abnormal alleles (hydrops fetalis) —> ⍺-thalassemia major = Hb Bart disease

    • Fetal demise (total body edema)

Etiology⍺-Thalassemia

What does this refer to

• Mild-moderate anemia

• Hepatosplenomegaly

• Jaundice

• Heart defects

• Increased bone marrow hematopoiesis

  • Frontal bossing

  • Maxilla overgrowth

• Abnormalities of the urinary system or genitalia

Physical exam ⍺-Thalassemia

What does this refer to

• Beta thalassemia

• Iron – folate deficiencies in pregnancy

• Autoimmune hemolytic anemia

• Non-immune hemolytic anemia

• Sideroblastic anemia

Differential diagnosis⍺-Thalassemia

What does this refer to

Workup⍺-Thalassemia

What does this refer to

Workup⍺-Thalassemia

What does this refer to

Workup⍺-Thalassemia

What does this refer to

• Mentzer Ratio = MCV/RBC (< 13)

• MCV - profoundly decreased

• TIBC - decreased

• Iron - increased

• Ferritin - increased

• Reticulocyte count - increased

• Transferrin saturation – increased

• Unexplained finding is that although there is a decrease in the Hgb concentration and MCV, there is a normal or slightly increased RBC count

How’s it diagnosed?thalassemia

What does this refer to

Results of diagnostics by type⍺-Thalassemia

What does this refer to

• Hydrops fetalis

• Hemoglobin - 4-10 g/dL

• MCV - 110-120 fL

• Peripheral blood smear - Severe anisopoikilocytosis, severe hypochromia, and nucleated red blood cells (RBCs)

Workup⍺-Thalassemia

What does this refer to

• Schistocytes

• Tear drop cells

• Increased reticulocytes

Hemolytic anemia⍺-Thalassemia

What does this refer to

• Consult/referral Hematology

• Episodic blood transfusions

• Vitamin C and folate supplements

• Iron chelating agents (deferoxamine) prevent iron overload

Clinical Management⍺-Thalassemia

What does this refer to

• Silent carriers have excellent prognosis

• Outcome deteriorates with HbH disease

• Hydrops fetalis is incompatible with life

Prognosis ⍺-Thalassemia

What does this refer to

• Microcytic Anemia

• Group of hereditary disorders characterized by a genetic deficiency (decreased production) in the synthesis of beta-globin chains

• Hb E variant

• Homozygous

• Heterozygous

β-Thalassemia

What does this refer to

• MC Mediterranean and African American populations

• Disease may not be detected until about 6 months after birth

• Β-thalassemia trait (minor) MC type

Epidemiology β-Thalassemia

What does this refer to

• Genetic

  • Β-thalassemia trait (minor) 1 abnml allele

  • B-thalassemia major (Cooley’s anemia) 2 abnml alleles

  • B-thalassemia intermedia mild homozygous form

Etiology of β-Thalassemia

What does this refer to

• Varies based on type/severity

• Β-thalassemia trait (minor) – asx

• B-thalassemia intermedia

  • Anemia

  • Hepatosplenomegaly

  • Bony disease

• B-thalassemia major

  • Ineffective erythropoiesis

  • Short RBC life span

Clinical history of β-Thalassemia

What does this refer to

• Delayed growth

• Severe, chronic anemia

• Hemolytic anemia

• Hepatosplenomegaly

• Bony abnormalities

  • Osteoporosis

  • Frontal bossing

  • Abnormal ribs

• Hypogonadism

Physical exam β-Thalassemia

What does this refer to

• Alpha thalassemia

• Anemia of chronic disease with renal failure

• Iron Deficiency Anemia

• Lead Nephropathy

• Sideroblastic Anemia

Differential Diagnosis β-Thalassemia

What does this refer to

Workup β-Thalassemia

What does this refer to

• Peripheral smear in beta-zero thalassemia minor

  • Microcytes (M)

  • Target cells (T)

  • Poikilocytes (P)

Workup for β-Thalassemia

What does this refer to

• Basophilic stippling

Work up β-Thalassemia

What does this refer to

• Consult/referral hematology

• Genetic counseling

• Beta thalassemia major requires tx

  • Long-term transfusion therapy

  • Iron chelation

  • Splenectomy

  • Allogeneic hematopoietic transplantation

  • Vitamin C and folate supplements

Clinical intervention for β-Thalassemia

What does this refer to

• Individuals with thalassemia minor (thalassemia trait) usually have mild, asymptomatic microcytic anemia and does not result in mortality or significant morbidity

• Thalassemia major prognosis depends on adherence to long term treatment

• The major causes of morbidity and mortality in beta thalassemia are anemia and iron overload

• The long-term increase in red-cell turnover causes hyperbilirubinemia and bilirubin-containing gallstones

• Onset osteoporosis usually by age 10

Prognosisβ-Thalassemia