Hematopathology Flashcards
INTRODUCTION
The commonest and most useful approach to disorders of the hematopoietic system is based on whether they primarily affect red cells, white cells, or the coagulation system (platelets and clotting factors). This is an oversimplification, since in real life the production, function, and destruction of red cells, white cells, and components of the hematopoietic system are interlinked, with derangements primarily affecting one cell type or component often leading to alterations in others. Furthermore, the white cells are anatomically dispersed, in that, whether normal or malignant, they are able to “traffic” freely between bone marrow, blood and various solid tissues/organs.
All the cells of the hematopoietic system originally derive from the bone marrow, that central medullary cavity within bones.
We think of disorders of the cells of the hematopoietic system in terms of there being too few or too many. We use laboratory analyzers to count and attain other measurements of these cells in the blood, and we use normal ranges to decide if there are too many, too few, or abnormalities in the cells.
Red blood cell disorders
The main function of red blood cells (RBCs) is to carry oxygen around in the blood from the lungs to other organs/tissues and to carry carbon dioxide in the reverse direction. This is accomplished by binding of oxygen/carbon dioxide to hemoglobin, by far the commonest protein found within the red cell.
Anemia (too few RBCs) is more common and therefore more of a problem than polycythemia (too many RBCs, also referred to as erythrocytosis).
ANEMIA definition
Anemia is defined as a reduction in the oxygen-transporting capacity of blood, resulting from a decrease in the red cell mass to subnormal levels.
Practically speaking, we measure anemia by looking at the Hemoglobin concentration in the blood, as this reflects oxygen-transporting capacity.
Anemia can be classified based on the underlying mechanism causing it, or based on the morphological appearance of RBCs in the peripheral blood.
CLASSIFICATION OF ANEMIA, BASED ON UNDERLYING MECHANISM (PATHOPHYSIOLOGICAL CLASSIFICATION)
Anemia can stem from decreased red blood cell (RBC) production (where the bone marrow is at fault), or from blood loss or increased red cell destruction (where the problem arises outside the bone marrow, in the circulation).
In most cases when the cause for anemia is from outside the bone marrow (extramedullary), the decrease in tissue oxygen tension that accompanies anemia causes increased production of a growth factor erythropoietin by the kidney.
- This drives compensatory hyperplasia of erythroid precursors in the bone marrow, and, if severe, RBC production in secondary hematopoietic organs such as liver, spleen, and lymph nodes (extramedullary hematopoiesis).
- The accelerated production of RBCs leads to increased numbers of newly formed RBCs (reticulocytes) in the peripheral blood (reticulocytosis).
By contrast, anemia caused by decreased RBC production by the bone marrow is associated with subnormal reticulocyte counts (reticulocytopenia).
CLASSIFICATION OF ANEMIA BASED ON UNDERLYING MECHANISM - Blood loss
acute - i.e. trauma
chronic -i.e. gastrointestinal tract lesions, gynecologic disturbances
CLASSIFICATION OF ANEMIA BASED ON UNDERLYING MECHANISM - increased destruction (hemolytic anemias)
- Intrinsic (intracorpuscular) abnormalities
a. Hereditary
- membrane abnormalities, i.e. hereditary spherocytosis
- enzyme deficiencies, i.e. glucose-6-phosphate dehydrogenase deficiency
- disorders of hemoglobin synthesis.
— structurally abnormal globin synthesis (hemoglobinopathies), i.e. sickle cell anemia
— deficient globin synthesis, i.e. thalassemia syndromes
b. Acquired
- membrane defect: paroxysmal nocturnal hemoglobinuria
- Extrinsic (extracorpuscular) abnormalities
a. Antibody-mediated
- alloantibodies, i.e. transfusion reactions
- autoantibodies, i.e. idiopathic autoimmune disease (primary), drug-associated
b. Mechanical trauma to red cells
- microangiopathic hemolytic anemia, i.e. disseminated intravascular coagulation (DIC)
- defective cardiac valves
- infections, i.e. malaria
CLASSIFICATION OF ANEMIA BASED ON UNDERLYING MECHANISM - disturbed erythroid proliferation (diminished erythropoiesis)
Disturbed proliferation and differentiation of stem cells: aplastic anemia, pure red cell aplasia
Disturbed proliferation and maturation of erythroblasts
- defective DNA synthesis: deficiency or impaired use of Vitamin B12 and folic acid (megaloblastic anemia)
- anemia of renal failure (erythropoietin deficiency)
- anemia of chronic
- anemia of endocrine disorders
- defective hemoglobin synthesis: deficient heme synthesis (i.e. iron deficiency), deficient globin synthesis (i.e. thalassemias)
Marrow replacement, i.e. by primary hematopoietic neoplasms such as acute leukemia
Marrow infiltration (myelophthisic anemia), i.e. metastatic neoplasms, granulomatous disease
CLASSIFICATION OF ANEMIA, BASED ON MORPHOLOGY
In anemia, the size, colour, and shape of the RBCs often point to particular causes. These features are judged by microscopic examination of stained peripheral blood smears and also expressed quantitatively using RBC indices (measured or automatically calculated by clinical laboratory instruments), such as Mean cell volume (MCV), Mean cell hemoglobin (MCH), Mean cell hemoglobin concentration (MCHC).
By morphology, anemic RBCs can be:
1. Normochromic, Normocytic = normal pink colour, normal size
2. Hypochromic, Microcytic = too pale (low MCH), too small (low MCV)
3. Macrocytic = too big (high MCV)
4. Abnormally shaped e.g. sickled cells.
Depending on the differential diagnosis arrived at from the two above approaches, other blood tests may be performed to further evaluate and determine the type of anemia. When anemia is accompanied by thrombocytopenia (low platelets) and/or granulocytopenia (low neutrophils), it is much more likely to be due to reduced marrow production, and a bone marrow examination is usually needed for diagnosis.
CLINICAL PRESENTATION OF ANEMIA
The clinical consequences of anemia are determined by its severity, rapidity of onset, and underlying pathogenic mechanism.
In most cases, the onset of anemia is gradual, allowing the O2-carrying deficit to be physiologically compensated for by increases in cardiac output, respiratory rate, and RBC 2,3- diphosphoglycerate (DPG), a glycolytic pathway intermediate that enhances the release of O2 from hemoglobin. These changes temper the effects of mild to moderate anemia in otherwise healthy persons. Slow onset of pallor, fatigue, and lassitude results.
Anemia caused by the premature destruction of red cells (hemolytic anemia) is associated with jaundice (confirmed by hyperbilirubinemia), and pigment gallstones (if hemolysis is chronic), related to increased turnover of hemoglobin.
Anemia that stems from ineffective hematopoiesis (the premature death of marrow erythroid progenitors) e.g. thalassemia, is associated with an inappropriate increase in iron absorption from the gut, that can lead to iron overload (secondary hemochromatosis) with consequent damage to endocrine organs and the heart.
Anemia of Blood Loss: Hemorrhage
- Acute bleeding
Anemia of blood loss can be due to acute bleeding (hemorrhage) or slow chronic blood loss. 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. If blood loss is ≥20% of blood volume, the immediate threat is hypovolemic shock rather than anemia. If the patient survives, hemodilution begins and maximizes in 2 to 3 days, when the full extent of RBC loss is seen. This anemia is normocytic and normochromic. Recovery occurs via a compensatory rise in erythropoietin levels, stimulating increased bone marrow RBC production and reticulocytosis.
- Chronic blood loss
With chronic blood loss, iron stores are gradually depleted when blood loss is occurring to outside the body e.g. mucosal bleeding. Iron is essential for hemoglobin synthesis and erythropoiesis, and its deficiency leads to chronic anemia of underproduction i.e. iron deficiency anemia.
Hemolytic Anemias - causes and methods of classification
The multiple causes of hemolytic anemia all have in common accelerated red cell destruction (hemolysis). By definition, red cell life span is shortened to less than the normal 120 days. Regardless of cause, low tissue O2 levels trigger increased erythropoietin from the kidney, which in turn stimulates erythroid hyperplasia in the bone marrow and increased release of reticulocytes into the blood - hallmarks of all hemolytic anemias. In severe hemolytic anemias, the erythropoietic drive may be so pronounced that extramedullary hematopoiesis appears in the liver, spleen, and lymph nodes.
There are several ways to organize hemolytic anemias. One approach groups them according to pathogenesis - whether the RBC defect is intrinsic to the RBCs (intracorpuscular) or extrinsic to them (extracorpuscular).
A second, more clinical approach classifies hemolytic anemias according to whether hemolysis is primarily occurring extravascular or intravascular. Most hemolytic anemias result from extravascular hemolysis.
Hemolytic Anemias - Extravascular hemolysis
Extravascular hemolysis is caused by defects that increase the destruction of either partly damaged or antibody-coated RBCs by phagocytosis in the spleen. Extreme alterations of shape are necessary for red cells to navigate the sluggish blood flow through splenic sinusoids and any reduction in red cell deformability makes this passage difficult; abnormal RBCs become recognized and phagocytosed by resident splenic macrophages.
Findings that are relatively specific for extravascular hemolysis (as compared to intravascular) include:
- hyperbilirubinemia & jaundice, from degradation of hemoglobin in macrophages,
- enlarged spleen (splenomegaly) due to “work hyperplasia” of phagocytes in the spleen,
- formation of bilirubin-rich gallstones (pigment stones) and increased risk of cholelithiasis
Hemolytic Anemias - Intravascular hemolysis
Intravascular hemolysis is characterized by such severe injuries that RBCs literally burst within the circulation. It may be due to mechanical forces (e.g., turbulence over a defective heart valve), biochemical or physical agents that severely damage the red cell membrane (e.g., complement fixation, bacterial toxins, intracellular parasites like malaria, or heat.)
Findings that distinguish intravascular hemolysis from extravascular hemolysis include:
- hemoglobinemia, hemoglobinuria, and hemosiderinuria (hemoglobin released into the circulation is small enough to filter into the urinary space, is partly processed into hemosiderin, then lost in the urine),
- loss of iron may lead to iron deficiency if hemolysis is persistent
- decreased serum levels of haptoglobin, a plasma protein that binds free hemoglobin before it is removed from the circulation.
SOME MORE COMMON CAUSES OF HEMOLYTIC ANEMIA
Hereditary Spherocytosis
Sickle Cell Anemia
Thalassemia
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
Immune Hemolytic Anemias
Hereditary Spherocytosis
Autosomal dominant, caused by mutations affecting RBC membrane skeleton, leading to loss of membrane and eventual conversion of red cells to spherocytes, which are phagocytosed and removed in the spleen. Clinically presents as anemia with splenomegaly.
Sickle Cell Anemia
Autosomal recessive, abnormal hemoglobin resulting from a β-globin mutation that causes deoxygenated hemoglobin to self-associate into long polymers that distort the red cell, producing a sickle shape. Blockage of vessels by sickled cells causes pain crises and tissue infarction, particularly of the marrow and spleen. RBC damage caused by repeated bouts of sickling results in moderate to severe hemolytic anemia. Patients are at high risk for bacterial infections and strokes.
Thalassemia
Autosomal codominant disorders caused by mutations/deletions in α- or β-globin that reduce hemoglobin synthesis, resulting in microcytic, hypochromic anemia. A relative excess of the unpaired globin chains results in formation of aggregates that damage red cell precursors to further impair erythropoiesis, and also result in some degree of extravascular hemolysis.
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
X-linked disorder caused by mutations that destabilize G6PD, affecting the hexose monophosphate shunt (glutathione) metabolic pathway. G6PD deficiency makes red cells susceptible to oxidant damage.
Immune Hemolytic Anemias
Caused by antibodies against either normal red cell constituents or antigens modified by haptens (e.g. drugs). Antibody binding results in either red cell opsonization and extravascular hemolysis or (uncommonly) complement fixation and intravascular hemolysis.
