Definition

1)     Hemoglobinopahty – genetic defect that results in an abnormal structure of one of the globin chains of the hemoglobin molecule

2)     Thalassemia – a genetic defect that results in production of an abnormally low quantity of a given hemoglobin chain or chains; the result is an imbalance in production of globin chains and the production of an inadequate number of red cells.

Pathophysiology of hemoglobinopathies

• severity depends on the position of substitution on the protein chain

Ø  substitution of valine or lysine for glutamate at position 6 of the b chain produces hemoglobins S and C respectively.

• abnormal globin structure can manifest itself in one or more of the following ways

1)     Increased O₂ affinity

Ø  the hemoglobin is easily taken up by from the alveoli, but is reluctant to give it up to the tissues.

Ø  The kidney, in response, cranks out some more erythropoietin which stimulates erythropoiesis and erythrocytosis results

2)     Decreased O₂affinity

Ø  reluctance in picking up O₂ from the alveoli

Ø  cyanosis – occurs when the level of deoxyhemoglobin exceeds 5 g/dL

3)     Methemoglobinemia

Ø  special class of low O₂ hemoglobin variants that are characterized by the presence of heme that contains iron in the ferric (Fe³⁺) oxidation state rather than in the normal Ferrous (Fe²⁺) state.

Ø  Designated Hb M

Ø  Cyanosis

Ø  Can also be caused by NADH-diaphorase deficiency

Ø  Brown blood

4)     Unstable hemoglobin (Heinz body anemia)

Ø  when the hemoglobin destabilizes, it forms erythrocyte inclusions called Heinz bodies

Ø  these inclusions attach to the internal aspect of the rbc membrane and reduce the deformability of the RBC.  Result = hemolytic anemia

Ø  autosomal dominant

5)     Sickling and crystallization

Ø  occur in HbS and HbC

Hemoglobin S and Sickle Cell Disease

Epidemiology and genetics

• Hb S gene found 1^o in pops of native tropical African origin
• Incidence in some African pops – high as 40%
• Incidence in African-Americans – 8%
• Also found in non-Indo-European aboriginal pops of India and in the Middle East
• Expression in heterozygotes (sickle cell trait) affords some protection against the consequences of Plasmodium falciparum infestation.

Pathophysiology

• Tactoids – the Hb S precipitates out of solution and forms these long microtubular arrays called tactoids
• The erythrocytes which contain the Hb S stretch around the tactoids to form the characteristic “sickle cells”
• Remember, only the deoxygenated form of Hb S makes tactoids
• Hb S results from the substitution of valine for glutamate at position 6 of the b chain
• Since Hb S is a b chain mutation, it doesn’t manifest itself until about 6 months of age (Remember the Hb F – a₂g₂)
• Several coexisting genetic abnormalities prevalent in African pops can actually ameliorate the course of the disease

1)     a-thalassemia carriers – have a lower MCHC than normal individuals.  This helps in decreasing the vaso-occlusive properties of sickled cells.

2)     Hereditary persistence of fetal hemoglobin – (HPFH) – sickling does not occur or is less prominent

3)     G-6-PD deficiency – controversial as an ameliorative cond.

Clinical Findings in Hb S (Sickle Cell Anemia)

• hemolytic anemia and a vaso-occlusive condition
• Effects of chronic hemolysis

1)     Anemia

2)     Jaundice

3)     Cholelithiasis

4)     Aplastic crisis – drop in marrow production as a result of common viral infections

5)     Hemolytic crisis

• Effects of vaso-occlusion

1)     Dactylitis – the hands and feet are swollen and painful; often presenting manifestation in 6 month old infant

2)     Autosplenectomy

3)     Priapism

4)     Renal papillary necrosis

5)     Infarctive (painful) crisis

6)     Sequestration crisis – sudden pooling of sickled erythrocytes in the RES and vascular compartment.

7)     Leg ulcers

Hemoglobin C

• also prevalent in the African-American population but with less frequency (2-3%) than the sickle cell gene
• DOES NOT FORM tactoids
• FORMS crystalloids – intracellular blunt ended crystals

Clinical Presentation

• decreased RBC survival time
• hemolysis is NOT as severe as in sickle cell disease
• vaso-occlusion are not generally noted
• good prognosis

Hb SC disease

• one inherits a Hb S gene from one parent and a Hb C gene from the other.
• Clinical severity – intermediate between that of sickle cell disease and Hb C disease
• Except — damage due to retinal vascular lesions is characteristically worse in SC disease than in sickle cell anemia
• Intracellular bodies are hybrids of the blunt-ended crystals of Hb C and sharp-pointes tactoids of Hb S.

Hemoglobin E

• very common b chain mutation among Southeast Asians
• this gene does not occur in ethnic Han Chinese or Japanese
• Heterozygous state – asymptomatic, but causes mircocytosis w/o anemia
• Homozygous state – more severe microcytosis and hypochromia, but little anemia
• Looks like thalassemia minor

Thalassemias

Genetics

• Chromosome 16 – contains the genes for the a-chain
• Chromosome 11 – contains the genes for the other important globin chains (g,g,b,d)
• Genes are linked on chromosome 11 (they are inherited as a group)

Biochemistry and pathophysiology

• remember the clinical problem in the thalassemias is the inability to maintain a balance between the rate of one type of globin chain with that of its mate.
• thalassemia named for that chain which is deficient or absent.

b thalassemia

• classic form but not most common
• “Cooley’s anemia”
• convenient to group the various b thalassemias into 2 groups, based on the amount of b globin chain production

1)     b^o thalassemia

Ø  no production of b chains

Ø  Individuals homozygous for this gene produce only Hb A₂, Hb F, and unstable a₄ tetramers

Ø  The a₄ tetramers destroy the RBCs while they are still in the marrow

2)     b⁺thalassemia

Ø  some, but not much production of b globin chains

Ø  homozygous individuals make subnormal amount of Hb A but still have the destructive effects of the a₄ tetramers on the RBCs and RBC precursors.

Ø  b⁺ (Negro) form is only mild form of homozygous b⁺thalassemia

• those heterozygous for any of the b thalassemia genes either are silent carriers or have minimal clinical effects

Ø  borderline anemia, disproportionate microcytosis (MCV ~ 60fL), high RBC count, increased Hb A₂

Ø  called thalassemia minor

• those that are homozygous for all of the b thalassemia genes have severe anemia

Ø  classical Cooley’s anemia

Ø  termed thalassemia major

• those homozygous for the b⁺ form have a relatively mild clinical anemia called thalassemia intermedia

Pathophysiology

• Microcytic anemia occurs because there is not enough globin to fill the red cells (like the lack of heme in iron deficiency causing micrcytosis)
• Increased Hb A₂ occurs in cases of strict b thalassemia and can be easily measured
• bd thalassemia causes the Hb A₂ NOT to be elevated (this is not a rare condition)
• Hb F survival is attempted in some cases
• In severe forms, the anemia is compounded by the hemolysis, ineffective erythropoiesis, and extramedullary hematopoiesis brought on by precipitation of the a₄ tetramers.
• In classic “Cooley’s anemia”, the ineffective erythropoiesis dominates the clinical picture by producing tremendous expansion of the marrow space
• The extramedullary hematopoiesis and hemolysis causes spleeomegaly , which produces hypersplenism, and more hemolysis
• The high turnover rate of the erythrocytes causes wastage of folic acid and may produce a complicating megaloblastic anemia.
• Hyperuricemia (gout) can also occur because of the high turnover rate.
• Treatment usually is the cause of death because of iron overload via numerous transfusions.

Ø  diabetes mellitus, hepatic cirrhosis, CHF, adrenal insufficiency, and failure to undergo puberty are complications of the excessive iron.

Ø  Treated with the iron chelating agent deferozamine

a thalassemia

• the most common of all hemoglobinopathies and thalassemias
• Remember, this will be present before birth
• Remember that you have two aa genes (one from mommy and one from daddy)

Ø  (a-/aa) is mildest form and (–/–) produces fatal intrauterine disease

Ø  (a-) gene is called the a thalassemia-2 gene

Ø  (–) gene is called the a thalassemia-1 gene

• (a-/aa) occurs in 20% of all African Americans

Ø  no symptoms, no abnormalities

Ø  may be an “anit-sickle cell” gene

• (a-/a-) or (–/aa)

Ø  usually not anemic but have microcytosis

• (–/a-)

Ø  Hemoglobin H disease – has significant production of b₄ chains/tetramer

Ø  Also will show some Hb Bart’s (d₄ tetramer)

Ø  Clinical: mild anemia to that which resembles b thalassemia major

• (–/–)

Ø  no production of a chains

Ø  Hb Bart’s, Hb H, Hb Portland

Ø  Most die in utero or within hours after birth

Ø  Autopsy: massive extramedullary hematopoiesis in virtually every parenchymatous organ of the body.

Ø  Severe anemia causes CHF and subsequent massive total body edema, termed “hydrops fetalis”

Tags: abnormal globin structure, anemia, Aplastic crisis, Autosplenectomy, Cholelithiasis, Cooley's anemia, Cyanosis, fetal hemoglobin, Heinz body anemia, Hemoglobin S, Hemoglobinopahty, Jaundice, Priapism, Sickle Cell Disease, Tactoids, thalassemia

This entry was posted on Friday, July 10th, 2009 at 5:00 am and is filed under Pathophysiology. You can follow any responses to this entry through the RSS 2.0 feed. Responses are currently closed, but you can trackback from your own site.