Chapter 12 - Hematopoietic and Lymphoid Systems
Red Cell Disorders
Pathology of Anemia:
Causes
o Blood loss hemorrhage
o Increased red cell destruction hemolysis
o Decreased red cell production
Morphology
o Microcytic iron deficiency, thalassemia
o Macrocytic folate or vitamin B12 deficiency
o Normocytic, but with abnormal shaped hereditary spherocytosis, sickle cell
disease
Clinical manifestations
o Acute: shortness of breath, organ failure, shock
o Chronic
Pallor, fatigue, lassitude
With hemolysis: jaundice and gallstones
With ineffective erythropoiesis: iron overload, heart and endocrine
failure
If severe and congenital: growth retardation, bone deformities due to
reactive marrow hyperplasia
Anemia of Blood loss: Hemorrhage
The effects of acute bleeding are mainly due to the loss of intravascular volume, which if
massive can lead to cardiovascular collapse, shock and death. With chronic blood loss, iron
stores are gradually depleted.
Hemolytic Anemia
Hemolytic anemias are a diverse group of disorders that have as a common feature
accelerated red cell destruction (hemolysis).
Extravascular hemolysis is caused by defects that increase destruction of red cells by
phagocytes, particularly in the spleen. Specific findings:
Hyperbilirubinemia and jaundice degradation of hemoglobin
Splenomegaly work hyperplasia
Bilirubin rich gall stones and increased risk of cholelithiasis
Intravascular hemolysis is characterized by injuries so severe that red cell literally burst
within circulation.
Hemoglobinemia, hemoglobinuria and hemosiderinuria
Loss of iron
Hereditary Spherocytosis autosomal dominant
This disorder stems from inherited (intrinsic) defects in the red cell membrane that lead to
the formation of spherocytes, nondeformable cells that are highly vulnerable to
sequestration and destruction in the spleen.
, Hereditary spherocytosis is caused by inherited defects in the membrane skeleton, a
network of proteins that stabilizes the lipid bilayer of red cells. The common feature of the
pathogenic mutations is that they weaken vertical interactions between the membrane
skeleton and intrinsic red cell membrane proteins. The critical role of the spleen in
hereditary spherocytosis is illustrated by the beneficial effect of splenectomy: although red
cell defect and spherocytes persist, the anemia is corrected.
The characteristic features are anemia, splenomegaly and jaundice. There is no specific
treatment. Splenectomy improves the anemia by removing the major site of red cell
destruction.
Sickle Cell Anemia autosomal recessive
Hemoglobinopathies are a group of hereditary disorders caused by inherited mutations that
lead to structural abnormalities in hemoglobin.
Sickle cell anemia is caused by a single amino acid substitution in beta-globin that results in a
tendency for deoxygenated HbS to self-associate into polymers. The sickling of red cells has
two major pathologic consequences: chronic moderately severe hemolytic anemia,
produced by red cell membrane damage, and vascular obstruction, which results in ischemic
tissue damage and pain crises.
Thalassemia autosomal codominant
Thalassemia’s are inherited disorders caused by mutations in globin genes that decrease the
synthesis of alfa- or beta-globin.
Defective synthesis of beta-globin in beta-thalassemia contributes to anemia through two
mechanisms:
1. Inadequate HbA formation, resulting in small (microcytic), poorly hemoglobinized
(hypochromic) red cells
2. By allowing accumulation of unpaired alfa-globin chains, which form toxic
precipitates that severely damage the membranes of red cells and erythroid
precursors.
Alfa-thalassemia is caused mainly by deletions involving one or more of the alfa-globin
genes. The severity of the disease is proportional to the number of genes that are deleted.
The trait version of both diseases is typically asymptomatic. Beta-thalassemia major manifest
postnatally as HbF synthesis diminishes. Blood transfusions improve the anemia and reduce
skeletal deformities.
Glucose-6-phosphate dehydrogenase deficiency x-linked
G6PD deficiency is associated with transient episodes of intravascular hemolysis caused by
exposure to an environmental factor (infectious agents or drugs) that produces oxidant
stress.
Paroxysmal Nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic anemia that stems from acquired
mutations in PIGA, a gene required for the synthesis of phosphatidylinositol glycan (PIG),
which serves as a membrane anchor for many proteins. The most frequent complication of
PNH is thrombosis, which often occurs within abdominal vessels such as the portal vein and
the hepatic vein.
Red Cell Disorders
Pathology of Anemia:
Causes
o Blood loss hemorrhage
o Increased red cell destruction hemolysis
o Decreased red cell production
Morphology
o Microcytic iron deficiency, thalassemia
o Macrocytic folate or vitamin B12 deficiency
o Normocytic, but with abnormal shaped hereditary spherocytosis, sickle cell
disease
Clinical manifestations
o Acute: shortness of breath, organ failure, shock
o Chronic
Pallor, fatigue, lassitude
With hemolysis: jaundice and gallstones
With ineffective erythropoiesis: iron overload, heart and endocrine
failure
If severe and congenital: growth retardation, bone deformities due to
reactive marrow hyperplasia
Anemia of Blood loss: Hemorrhage
The effects of acute bleeding are mainly due to the loss of intravascular volume, which if
massive can lead to cardiovascular collapse, shock and death. With chronic blood loss, iron
stores are gradually depleted.
Hemolytic Anemia
Hemolytic anemias are a diverse group of disorders that have as a common feature
accelerated red cell destruction (hemolysis).
Extravascular hemolysis is caused by defects that increase destruction of red cells by
phagocytes, particularly in the spleen. Specific findings:
Hyperbilirubinemia and jaundice degradation of hemoglobin
Splenomegaly work hyperplasia
Bilirubin rich gall stones and increased risk of cholelithiasis
Intravascular hemolysis is characterized by injuries so severe that red cell literally burst
within circulation.
Hemoglobinemia, hemoglobinuria and hemosiderinuria
Loss of iron
Hereditary Spherocytosis autosomal dominant
This disorder stems from inherited (intrinsic) defects in the red cell membrane that lead to
the formation of spherocytes, nondeformable cells that are highly vulnerable to
sequestration and destruction in the spleen.
, Hereditary spherocytosis is caused by inherited defects in the membrane skeleton, a
network of proteins that stabilizes the lipid bilayer of red cells. The common feature of the
pathogenic mutations is that they weaken vertical interactions between the membrane
skeleton and intrinsic red cell membrane proteins. The critical role of the spleen in
hereditary spherocytosis is illustrated by the beneficial effect of splenectomy: although red
cell defect and spherocytes persist, the anemia is corrected.
The characteristic features are anemia, splenomegaly and jaundice. There is no specific
treatment. Splenectomy improves the anemia by removing the major site of red cell
destruction.
Sickle Cell Anemia autosomal recessive
Hemoglobinopathies are a group of hereditary disorders caused by inherited mutations that
lead to structural abnormalities in hemoglobin.
Sickle cell anemia is caused by a single amino acid substitution in beta-globin that results in a
tendency for deoxygenated HbS to self-associate into polymers. The sickling of red cells has
two major pathologic consequences: chronic moderately severe hemolytic anemia,
produced by red cell membrane damage, and vascular obstruction, which results in ischemic
tissue damage and pain crises.
Thalassemia autosomal codominant
Thalassemia’s are inherited disorders caused by mutations in globin genes that decrease the
synthesis of alfa- or beta-globin.
Defective synthesis of beta-globin in beta-thalassemia contributes to anemia through two
mechanisms:
1. Inadequate HbA formation, resulting in small (microcytic), poorly hemoglobinized
(hypochromic) red cells
2. By allowing accumulation of unpaired alfa-globin chains, which form toxic
precipitates that severely damage the membranes of red cells and erythroid
precursors.
Alfa-thalassemia is caused mainly by deletions involving one or more of the alfa-globin
genes. The severity of the disease is proportional to the number of genes that are deleted.
The trait version of both diseases is typically asymptomatic. Beta-thalassemia major manifest
postnatally as HbF synthesis diminishes. Blood transfusions improve the anemia and reduce
skeletal deformities.
Glucose-6-phosphate dehydrogenase deficiency x-linked
G6PD deficiency is associated with transient episodes of intravascular hemolysis caused by
exposure to an environmental factor (infectious agents or drugs) that produces oxidant
stress.
Paroxysmal Nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic anemia that stems from acquired
mutations in PIGA, a gene required for the synthesis of phosphatidylinositol glycan (PIG),
which serves as a membrane anchor for many proteins. The most frequent complication of
PNH is thrombosis, which often occurs within abdominal vessels such as the portal vein and
the hepatic vein.
