CONGENITAL ABNORMALITIES OF THE RED CELL MEMBRANE

CONGENITAL ABNORMALITIES OF THE RED CELL MEMBRANE:
• There are 4 types of inherited red cell membrane abnormalities:
1. Hereditary spherocytosis
2. Hereditary elliptocytosis
3. Hereditary pyropoikilocytosis
4. Hereditary stomatocytosis
• Each syndrome may represent a group of disorders with differing structural defects
Hereditary Spherocytosis
Introduction:
• Inherited as autosomal dominant disease
• Intrinsically abnormal red cells are destroyed in an otherwise normal spleen
• It’s incidence is approximately 1:4500
• In 20% of patients the absence of the hematologic abnormalities in family members suggests occurrence of spontaneous mutation
• The disorder is sometimes clinically apparent in early infancy
• But often escapes detection until adult life
Etiology & Pathophysiology:
• The molecular abnormality in hereditary spherocytosis invloves the proteins of the cytoskeleton
• Nearly all patients have a significant deficiency of spectrin correlating with the severity of anemia & decreased membrane lipid content
• Some (perhaps most) patients have a decreas and/or a structural abnormality of ankyrin, the protein that links spectrin to protein 3
• The cells are emerged as normocyte from the B.M, but get spherocyte by microcirculation compression
• Their spheroidal contour and rigid structure impede their passage through the spleen
• There, they are exposed to an environment where their metabolic rate cannot be sustained
• Their membrane is more permeable to sodium, which activates cationic pump & K+ loss then dehydration
• The first injury they imposed by the spleen is a further loss of surface membrane
• This “conditioning” produces a subpopulation of hyperspheroidal & more osmotically fragile red cells in the peripheral blood
• These are subsequently engulfed by the spleen macrophages
Clinical Manifestations:
• The major clinical features of hereditary spherocytosis are:
1. Anemia: mild to moderate in severity, but can be compensated hemolysis
2. Splenomegaly: is a consistant feature
3. Jaundice: formerly was designed as “congenital hemolytic jaundice
• The clinical complications can be:
1. Hypoplastic or aplastic crisis (self-limited) precipitated by viral infections
2. Acute megaloblastic changes due to folate deficiency particularly in pregnancy
3. Increased hemolytic rate may occur during infection
4. Gallstones development in 50% of patients
5. Recurrent lower leg ulcer & dermatitis, rapidly heal after splenectomy
Laboratory Findings:
• Hematological findings:
- Mild anemia & Hb values in adults >10 g/dl, infants & children levels (8-11 g/dl)
- The MCV is normal or mildly reduced (77-87fl)
- The MCHC is increased (350-380g/L), basically it is the only disease in which the MCHC is elivated
- The reticulocyte counts (5-20%) & more increased after aplastic crisis recovery
• The peripheral blood picture:
- demonstrates numerous microspherocytes. they appear small & lack central pallor
- anisocytosis occur as a mixture of microspherocytes & polychromatic macrocytes
- there are little poikilocytes other than spherocytes
• B.M:
-Displays normoblastic hyperplasia causing skeletal abnormalities on X-ray
- It can be hypoplastic on aplastic crisis .
• Special hematological tests:
- spheroidicity may be assessed quantitatively in terms of osmotic fragility
- because spherocytes have a decreased surface area to volume ratio
- they lyse more readily when exposed to solutions of low salt concentration
- they will not influence the O.F.T unless they constitute >1-2% of red cell population
• A prominent increase in the osmotic fragility following sterile incubation of whole blood for 24hr at 375 C is also a characteristic for H.S
• Autohemolysis test is an extension for O.F.T which measure the amount of spontaneous hemolysis occuring after 48hr of sterile incubation
• In H.S about 10-50% of red cells are lysed (the normal is <4%)
• In this situation it is corrected by addition of glucose to prior incubation
• Biochemistry:
• Other lab findings common to hemolytic processes support the diagnosis of H.S
- A slight to moderate rise in unconjugated bilirubin
- Elevated fecal urobilinogen
- Decreased haptoglobin levels may occur
- Absence of intravascular hemolytic indicators (3 indicators?)

Differential Diagnosis:
• H.S must be distinguished from the spherocytic hemolytic anemias associated with red cell antibodies
• The family history is helpful
• Immune spherocytosis is readily established by a positive DCT
• Considerable number of spherocytes are seen associated with cirrhosis or chronic infection
• Few spherocytes in the course of the widevariety of hemolytic disorders, particularly G6PD defic.
Treatment & Prognosis:
• Splenectomy reliably corrects the anemia despite persistence of red cell defect
• The operative risk is low
• Red cell survival then is normal or nearly so
• Rarely relapses may occur, attributable to postoperative growth of splenic autotransplants or to hyperplasia of secondary spleens that were overlooked at operation
• Because of the potential for gallstones & for episodes of B.M hypoplasia or hemolytic crisis, the patient should be splenectomized, even with mild anemia
• Pediatric splenectomy postponded up to 4 years age
• Polyvalent pneumococcal vaccination is done prior to splenectomy
• Folic acid therapy corrects hemolysis-induced deficiency of the vitamin & increases Hb level
•
2. Hereditary Elliptocytosis & H. Pyropoikilocytosis
Introduction:
• Red cells of oval shape are normally found in birds,reptiles, camels & llamas
• They occur in appreciable no. in humans only in H. elliptocytosis
• A disorder that transmitted as an autosomal dominent affecting 1/4000 to 5000 of the population
• The frequency that is similar to H.S
Etiology:
• It is also referred to as H. ovalocytosis
• In most cases, a structural abnormality of spectrin leads to impaired assembly
• Others often have a deficiency of erythrocyte membrane protein 4.1
• It is important in stabilizing the interaction of spectrin to actin in the cytoskeleton
• Homozygotes with total absence of this protein have more marked hemolysis
Pathophysiology:
• The factors determining the elliptical shape are unknown
• B.M normoblasts &circulating reticulocytes are normal in shape
• Red cells assume the elliptical shape as they age
• Red cells in H.E appear to utilize more ATP than normal cells
• Also increases the rate of Na+ efflux (a flowing out of the cell)
• Associated by bipolar concentration of hemoglobin (as shown by e. microscopy)
• Also polarization of the cholestrol in the membrane
• Neither biochemical nor the structural lesion of the patient correlates with the degree of hemolysis
• The hemolytic mechanism is known to involve membrane loss, decreased red cell deformability
& shortened red cell survival due to spleen
Clinical Manifestations:
• Most affected people have no clinical manifestations
• When present, hemolysis usually mild & accompanied by anemia, jaundice & splenomegaly
Lab Findings:
• CBC:
- The red cells are normocytic normochromic
- Hb values is greator than 12 g/dl
- The retics count is less than 4%
- The blood picture reveals 25% elliptocytes &oval erythrocytes, more commonly>75%
- patients with hemolysis frequently have microovalocytes, bizzare-shapped red cells & red cell fragment & increases with splenectomy
• B.M:
• Displays normoblastic erythropoiesis
• Erythroid hyperplasia correlates with degree of compensation for hemolysis
• Special Hematological Tests:
• Osmotic fragility & autohemolysis tests are usually normal.
• Biochemistry:
• Increased S. unconjugated bilirubin & fecal urobilinogen and decreased S. haptoglobin levels can be observed when hemolysis is present
Treatment:
• In most cases no treatment is necessary
• People with moderately severe hemolytic disease may benefit from splenectomy
• Which ameliorates anemia & restores a normal reticulocyte count, but elliptocytes on the peripheral film persists
• Other forms of poikilocytes may increase because they are not removed by spleen.





Hereditary Pyropoikilocytosis (HPP)
Definition & Genetics:
• Is an extreme rare hemolytic disorder
• Characterized by extreme anisocytosis & poikilocytosis with budding red cells, fragments, spherocytes, elliptocytes & other bizarre-shaped cells
• Inheritance is autosomal recessive & the disorder characteristically occurs in black children
Pathophysiology:
• The red cell membrane structural abnormality is related to a spectrin dimer-dimer association defect
• It is thought to be related to H.E, since both have been reported in the same family
• The extreme instability of the red cell membrane leads to both extreme morphologic abnormality & thermal instability
• The mechanism of hemolysis is related to membrane loss & rigidity
• HPP red cells also characterized by elevated calcium content with it’s increased inflow & reduced outflow
• This
Clinical Manifestations:
• Presents in infancy or early childhood with severe, often transfusion-dependant hemolytic anemia
• Jaundice
• Splenomegaly
• Gallbladder disease may occur
Lab Findings:
• CBC:
• The most striking feature is microcytosis
• The MCV is often bet 25-55fl
• Hb is decreased in proportion to the degree of hemolysis
• Retics counts are elevated, but the RPI depends on the ability of the patient’s B.M response to anemia
• The peripheral blood film:
• Anisopoikilocytosis with microspherocytes, fragmented cells, elliptocytes & other bizzare forms
• Polychromasia ia also present
• Special Hematological Tests:
• Susspected HPP red cells are tested for thermal sensitivity
• Noormal red cells fragment at < 495C & in HPP >45-465C
• Also increase in O.F, especially after incubation as well as markedly elevated autohemolysis test results
• Following splenectomy, hemolysis is reduced but not always corrected
• Abnormal red cell morphology is also remains.
•
Hereditary Stomatocytosis (Hydrocytosis) & Xeroctosis (Desiccytosis:

• Stomatocytes are red cells having a slit-like central zone of pallor on dried smears
• It a H.A inherited in an autosomal dominant pattern
• A number of entities are involved & two major red cells defect described
• The 1st, increased their permeability to to sodium & potassium, compensated for by an increased active transport of cations
• 2nd, increase in surface area & lipid content
• The red cells are swollen due to excess ions & water with decreased MCHC (overhydrated stomatocytes)
• In other patients red cells are shrunken with decreased ion & water and increased MCHC (dehydrated stomatocytes “desiccytosis”)
• They apear as target cells
• In both cases red cells appear as cup or bowl-shaped in wet preparation
• O.F decreases in overhydrated cells & increases in underhydrated stomatocytes
• Autohemolysis test increased correctable by glucose
• Clinically, most patient have splenomegaly & mild anemia
• Splenectomy donot correct the hemolysis
& it is similar to H.S
















Sickle Cell Anemia
Lab Findings:
• Leukocytosis is common (10-30X10 9/L)
• Differential leukocyte count shows neutrophilia
• Left shift may occur in infections, hence (leukoerythroblastic blood picture)
• Thrombocytosis is also common (440X10 9/L) due to fibrotic spleenthat fail to pool 1/3 of blood platelets as does normal spleen
Special Hematologic Tests:
• All patients have Hb S should have a positive solubility screening tests
• Hemoglobin electrophoresis is performed to confirm the presence of Hb S, where Hb F may be increased
• Osmotic fragility decreases owing to the target & sickle cells
• ESR is low despite anemia
• The half-life of Hb S containing red cells 10-20dy
B.M aspiration:
• Reveals erythroid hyperplasia with M:E ratio 1:1 (normal?)
Chemistry:
• LDH, unconjugated bilirubin & urobilinogen are all increased
• S haptoglobin is decreased.

H.W
• Write about sickle cell trait
• Unstable hemoglobinopathy
• Other structural hemoglobinopathies
• Acquired hemolytic anemias