Describe the sites of hematopoiesis in various age groups
Embryo = fetal yolk sac
Fetus = bones, liver, spleen
Child = long and short bones
Adult = all bones, but bone marrow biopsy only performed the iliac crest of the pelvis and sternum)
How is hematopoiesis regulated?
Development potential is only realized in the presence of colony-stimulating factors. Most CSF’s produced in bone marrow. Interleukins produced by macrophages and T lymphocytes stimulate as well as erythropoietin (kidney).
Describe the pathways of differentiation of pluripotent hematopoietic stem cells.
All cell lineages originate from a developmentally pluripotent stem cell. This common precursor gives rise to developmentally restricted stem cells: erythromyeloid stem cells and lymphoid stem cells.
The descendants of these intermediated stem cells are mature T and B lymphocytes, erythrocytes, neutrophils, monocytes, eosinophils, basophils, and megakaryocytes.
Compare serum and plasma and explain which one you would collect for various blood tests.
Serum = defibrinated plasma (contains all proteins except fibrinogen, prothrombin, coag factors)
Plasma = typically used for the study of clotting disturbances
Explain the molecular structure of hemoglobin.
Heme = oxygen binding part (must have iron), has four pyrrole rings held together by iron in the ferrous form. On degradation, iron and globin are reutilized, while pyrrole gives rise to bilirubin.
Hemoglobin consists of four heme groups and four globins. Globin has four polypeptide chains (alpha, beta, gamma, and delta).
Describe the major events in the life of erythrocytes.
Live in circulation for 120 days.
- nucleated RBC precursors, stimulated by erythropoietin, form erythroctes in the bone marrow.
- normal synthesis of hemoglobin occurs only in the presence of nutrients, iron, b12, and folic acid
- mature RBCs released into circulation
- old and defective RBCs are degraded in the spleen
- iron and globin reutilized stat, bilirubin released in bile
Explain the significance of various erythrocytic parameters such as MCV, MCH, and MCHC, and describe how they are measured.
MCV = mean volume of each RBC, calculated by HCT/RBC count, Nl 83-99 fL
lo = < 80 microcytic anemia
hi = >100 macrocytic anemia
MCH = denotes content of hemoglobin per each RBC, HGB conc. divided by RBC count, Nl 28-32 pg/cell
MCHC = concentration of hemoglobin in red blood cells, HGB/HCT, Nl 32-36 g/dL
What are the normal values for a white blood cell count?
Compare neutrophils and lymphocytes
Neutrophils - short-lived and survive no more than 4 days in peripheral circulation. Bone marrow contains three times more WBC precursors than erythroid precursors
Lymphocytes - long-lived
What is the function of platelets
Essential clotting factors. Derived from megakaryocytes, have no nuclei. 8-10 days in circulation.
What is anemia?
= the reduction of hemoglobin in RBCs below normal
females = < 11.5 g/dL
males = <13 g/dL
Provide an etiologic and a morphologic classification of anemias
- decreased hematopoiesis
- abnormal hematopoiesis
- increased loss or destruction of RBC
Which anemias are caused by decreased hematopoiesis?
aplastic anemia (bone marrow failure)
myelophthisic anemia secondary to BM replacement with TUMOR cells
- multiple myeloma
- folic acid
- multiple myeloma
- folic acid
Which anemias are caused by abnormal hematopoiesis?
sickle cell anemia
Structural protein defects
Which anemias are caused by increased loss or destruction of RBCs?
Immune hemolytic anemia
List typical examples of normocytic, microcytic, and macrocytic anemia.
massive blood loss
chronic liver disease
B12/folic acid deficiency
List typical examples of anemias that present with abnormal red blood cell shapes.
Explain the pathogenesis and pathology of aplastic anemia.
aplastic anemia = pancytopenia (generalized bone marrow failure)
Two forms: idiopathic, secondary (drugs, radiation, virus)
BM is depleted of hematopoietic cells, and consists of fibroblasts, fat cells, scattered lymphocytes
Clinical features: uncontrollable infections, bleeding tendency *most patients dies of overhwelming infection
List the causes of iron deficiency anemia.
iron deficiency = most common form of anemia
more prevalent among women
depletion of body iron (chronic blood loss)
Can be caused by
1. increased iron loss
2. inadequate iron intake/absorption
3. increased iron requirements (growth, PG)
Note: the bone marro shows normal hematopoiesis but contain reduced number of hemosiderin laden macrophages
anisocytosis = variation in size
poikilocytosis = variation in shape
What are the critical events in the metabolism of iron in the human body
1. Uptake of heme or ferrous iron occurs in the intestine.
2. Iron transported on transferrin to the liver or bone marrow.
3. Transferrin binds to RBC precursors in the BM and delivers iron for incorporation into hemoglobin.
4. RBC in the circulation contain 60-80% of body iron.
5. Old RBCs are destroyed in the spleen.
6. The iron is bound to transferrin for recirculation.
7. 20-30% of iron is stored in the form of hemosiderin in the spleen, liver, BM. *esp stroma, can see with Prussian blue
8. Remaining iron is in the respiratory ezymes of somatic cells.
Iron is lost by desquamation of skin and intestinal cells.
Explain the pathogenesis of megaloblastic anemia
B12 or folic acid = 2 essential cofactors for DNA synthesis
RBCs do not mature, but transform to megaloblasts.
BM hypercellular, many megaloblasts
Clinical: destruction of posterior and lateral columns in the SC result in loss of vibration, proprioception, DTR
Compare anemia caused by vitamin B12 with anemia caused by folic acid deficiency.
- binds to IF in the terminal ileum
- treated with IV
- abosrbed in the duodenum and jejunum
- treated with oral
Compare hemolytic anemia caused by intracorpuscular defects with anemia caused by extracorpuscular factors.
Common to all the conditions = anemia, compensatory erythroid hyperplasia of the BM, hyperbilirubinemia, jaundice
When does jaundice appear?
When bilirubin in serum exceend 2-3 mg/dL
Explain the pathogenesis of sickle cell anemia.
formation of abn hemoglobin S d/t genetic defect in the beta chain (subs. of valine for glutamine)
- <40% HbS asymptomatic
- 40-80% HbS mild/moderate
- >80% HbS typical disease
* symptoms only occur in homozygotes
Pathogenenisis of Sickle Cell
Hbs >> polymerization at low O2 tension
Symptoms noticed at 1-2 years of age b/c fetal hgb replaced by HbA.
Sickling crisis: anoxic situations, avoid mountain climbing, strenuous exercise, pregnancy, respiratory disease, fever
Sickle Cell Pathology
Multiple infarcts in various organs
Spleen: repeated infarcts, becomes fibrotic and shrinks
Sickle Cell Clinical Features
- retarded IQ and neurologic deficits
- cardiopulmonary insufficiency
- recurrent infections
Explain the pathogenesis of thalassemia
In contrast to sickle cell, defect is quantitative, not qualitative.
HbA has four chains: 2 alpha, 2 beta
2 genes >> beta chains
4 genes >> alpha chains
** Note: b/c there are only 2 beta genes, these anemias are MORE SEVERE. Beta is more common, and thalasessemia minor.
Compare thalassemia minor and thalassemia major.
Thalassemia minor = 1 deletion, mild anemia (trait)
*note: looks like iron deficiency!!
Thalassemia major = hemolysis accompanied by splenomegaly, hemosiderosis, hepatomegaly, BM compensatory hyperplasia
Why are RBCs round in hereditary spherocytosis?
There are mutations in the genes encoding that proteins that make up the membrane skeleton.
What is immune hemolytic anemia?
Recall: four blood groups = A, B, AB, O
Autoimmune hemolytic anemias develop as a consequence of an immune reaction to RBC autoantigens or neoantigens formed between the body's own proteins and hapten.
Explain the pathogenesis of immune hemolytic anemia.
1. Autoantigens present on RBCs are normally not recognized as foreign by the body. In some persons the body produces antibodies to its own antigens on RBCs. This occurs for no obvious reasons.
2. Alloantigens are foreign antigens. For example, blood group B RBCs are recognized as foreign by group A persons.
3. Neoantigens are from from the body's own protein's linked to a non-immunologic hapten. IgG, immunoglobulin G.
Compare primary and secondary polycythemia.
Primary = clonal proliferation of hematopoietic stem cells and increased total RBC mass (neoplastic)
Secondary = increased RBC volume as a result of erythroid bone marrow hyperplasia caused by erythropoietin
What is leukopenia, and what are its causes?
leukopenia = reduction in the WBC count
Can be caused by:
What is leukocytosis, and what are its causes?
leukocytosis = increased WBCs (>10,000)
reactive luekocytosis (splenomegaly in response to bacterial infection)
What are the possible causes of lymph node enlargement?
- common in children with URI
- with EBV
- early stages of AIDs
- most common presenting symptom of lymphoma
What is the difference between lymphoma and leukemia?
Lymphoma = lymphoid cell malignant disease prodominantly involving the lymph nodes
Leukemia = increased number of malignant WBC in the peripheral blood due to WBC precursors in the BM
What causes lymphomas and leukemias?
Most causes are unknown.
viruses = HTLV-1, EBV
oncogenes = translocation (Burkitts), philadelphia chromosome (CML), hybrid BCR, ABL
What are the common features of all leukemias?
- BM is infiltrated with malignant cells
- Peripheral blood contains increased immature cells
- Chromosomal and genetic changes specific for each disease
- Complications: anemia, recurrent infections, uncontrollable bleeding
**INFECTION = most common cause of death in all forms of leukemia
What distinguishes acute from chronic leukemia and lymphocytic from myelogenous leukemia?
List the most important features of acute lymphoblastic leukemia and correlate the pathologic findings with the clinical features of this disease.
massive BM infiltration with immature lymphoid cells (blasts = T and B precursors)
most common form of leukemia in children, and most common malignant disease in children <5yrs
rapid course, marked recurrent infections, generalized weakness, bleeding into the skin and internal organs
- remission can be induced, 2/3 are CURED
List the most important features of acute myelogenous leukemia.
Clonal proliferation of myeloblasts in the bone marrow. Must find 20% in the BM biopsy!
- Most common form of acute leukemia in adults.
- Treatment: high dose radiation and chemo.
List the most important features of chronic myelogenous leukemia.
Malignant disease of pluripotent stem cells capable of differentiating into neutrophilic leukocytes.
- Mostly affects ADULTS
- SLOW onset; anemia, SM, thrombosis
- Tx: radiation + chemo = 70% 3 yr survival
3 phases of CML
chronic phase: marked leukocytosis, increased eosinophils and basophils. BM <10 % blasts
accelerated phase: BM >10% blasts, >20% basophils in peripheral blood.
blast crisis: BM >20% blasts
90% of patients have the Philadelphia chromosome with BCR-ABL gene arrangement . . . for which leukemia???
Do you have worse or better prognosis when you have the Philadelphia chromosome?
List the most important features of chronic lymphocytic leukemia.
Malignant disease of lymphoid cells.
- Disease of OLDER age (>50)
- SLOW course
- Sx = lymphadenopathy and peripheral leukocytosis
- Tx: cells do not grow rapidly, therefore NO CHEMO
- can TRANSFORM into more aggressive form
How do you diagnose CLL?
CLL cells look NORMAL on a smear!! Suspect if lymphocytes >5000 (Nl = <4000). BM Biopsy confirms diagnosis.
How are non-Hodgkin’s lymphomas classified?
- T-cell and NK cell
True or False:
All lymphomas are malignant
True or False:
Most lymphomas have a B-cell phenotype
Extranodal sites for lymphomas are . . .
can be outside of the lymph nodes, like eyes, brain, skin.
Most common is the GI system!
Uses antibodies to analyze tissues for tumor cells.
Can help determine B and T cell and zones of the lymph node (cortical, mantle, germinal center)
What method is used to determine maturation and phenotype of lymphocytes?
List the most common symptoms and clinical findings of non-Hodgkin’s lymphomas.
- painless lymphadenopathy
- systemic constitutional symptoms
- extranodal spread
What are systemic constitutional symptoms?
- weight loss
What is the most common form of lymphoma in the UNited states?
The follicular structure of lymph nodes is preserved.
- SLOW growing
- Sx: long term lymphadenopathy, mild constitutional sx
- Tx: does not response well to chemo
What is the most common aggressive form of NHL?
Diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma
Lymphocyte tissue is infiltrated with large lymphoid cells that have irregular outlines and prominent nucleoli.
- commonly spread into parenchyma of major organs
- Tx: CHEMO!!!! 75% remission
True or False:
Burkitt's lymphoma can be cured
Responds to CHEMO
Highly malignant, with small B cells that divide rapidly
- cells prone to apoptosis, "starry sky"
- originates in BM or lymph nodes
- endemic in children with EBV
- common in subsaharan Africa
How does Burkitt's lymphoma present outside of endemic areas?
What does in mean that Hodgkin’s lymphoma is BIMODAL?
It peaks at 25 yrs and also at 55 yrs.
What is a Reed Sternberg cell?
Binucleated and multinucleated.
Classical Hodgkin's Lymphoma Divisions
- Lymphocyte-rich classical
- Nodular sclerosis
Nodular lymphocyte predominant HL
Clinical features of HL
- lymph node enlargement
- neck nodes
- central nodes
- High rate of CURE with CHEMO!
- neck nodes
- central nodes
Involvement of single node or group of nodes
Involvement of 2 or more sites of same side of diaphragm
Disease on both sides of diaphragm; may include spleen or localized extranodal disease
Widespread extralymphatic involvement (liver, bone marrow, lung, skin)
What is multiple myeloma?
Malignant disease of plasma cells
With what disease do you find Bence Jones proteins in the urine?
What is the most common cause of death in multiple myeloma?
Which disease process do you find "punched out" lesions in radiographs of the skull, ribs, and vertebrae?
Begins with single malignant plasma cell.
- secrete all the same form of Ig! = monoclonal "spike" on electrophoresis
- Old age
- punched out holes in blood forming bones
- anemia, leukopenia, thrombocytopenia
- CHEMO is INEFFECTIVE