L1: Hematopoiesis Flashcards
In blood w/ and w/o anti-coagulation after centrifugation, where do clotting factors reside?
W/o anticoagulant: In the clot, which contains cells and coagulation factors
W/ anticoagulant: In plasma
In the adult peripheral blood, what are the WBCs? Which are most and least numerous?
Neutrophils > Lymphocytes > Monocytes > Eosinophiols > Basophils
“Never Let Monkeys Eat Bananas”
Do RBCs have a nucleus?
No
Do WBCs have a nucleus?
Yes
Do platelets have a nucleus?
No
What is the average blood volume in adult men and women?
Adult men: 5 to 6 liters
Adult women: 4 to 5 liters
Myeloid development
Bone marrow
Includes production of neutrophils, eosinophils, basophils, monocytes, erythrocytes, platelets
Lymphoid development
Primary sites: Bone marrow (B lymphs) and thymus (T lymphs)
Secondary sites: Spleen, lymph nodes, gut-associated tissue (where B and T cells become competent and proliferate in response to antigen)
Describe site of hematopoiesis by age
In fetus, liver produces hematopoetic cells. Bone marrow begins to produce blood cells in second trimester and is the major organ producing blood at birth. The liver stops producing hematopoietic cells shortly after birth.
Why do newborns have a “pot belly” appearance?
They have a slightly enlarged liver due to residual hematopoiesis
What are the functions of bone marrow?
Constitutive hematopoiesis: provides a continuous and adequate supply of blood and immune cells throughout life (“steady state”)
Induced hematopoiesis: Response abnormal conditions (e.g. increased production of neutrophils in response to bacterial infections)
Apoptosis: programmed cell death of old, damaged cells, or cells no longer needed
What are the components of bone marrow?
Hematopoietic cells
Support (stromal) cells and extracellular matrix: adipocytes endothelial cells, macrophages and lymphocytes, reticular adventitial cells (fibroblasts), collagen, proteoglycans, fibronectin, etc.
Bone-producing cells: ostebolasts and osteoclasts
Blood vessels: arteries, veins, and a network of sinuses
Where do blood cells develop in the bone marrow?
They develop in cords, suspended b/w trabeculae (“scaffold” of bone)
What separates the network of blood sinuses from the blood cells?
A lining of endothelial cells, which forms a “barrier” b/w them
What cells make platelets?
Megakaryocytes
What is a hematopoietic microenvironment?
Environment that is specific for every type of cell that develops in the bone marrow
Each niche has specialized support cells to nurture and protect a particular type of cell
What are cell location, trafficking and growth in hematopoietic microenvironments regulated by?
Cytokine and chemokine secretion (produced by stromal cells)
Receptors and adhesion molecules on cells
How are mature blood cells released?
As blood cells mature, they change their receptors and adhesion molecules and move closer to the edge.
They migrate through the endothelial cells into the vascular sinus, then into the peripheral blood.
How are platelets released?
Megakaryocytes (located next to the sinus) protrude proplatelet processes through endothelial cells and release platelets directly into the sinus
When are blood cells normally released into the sinus?
When they are almost fully mature
What is blood cell release controlled by?
Adhesion molecules and cytokines
What does red marrow consist of?
90% hematopoietic cells
What does yellow marrow consist of?
Adipocytes and some blood cells
In infants, what do bones consist of?
90 - 100% red marrow in all bones
What is involution?
Process by which with age (beginning at 5 - 7 years), fat begins to replace some of the red marrow
At about 20 years of age, where is red marrow located?
Only located in axial skeleton, a little bit in skull, pelvis (flat bones), and proximal ends of long bones
Why is bone marrow collected from the iliac crest?
Bc the pelvic area still contains red marrow, which is hematopoietic tissue
What is medullary hematopoiesis?
Blood cell growth in bone marrow cavity
What is extramedullary hematopoiesis?
Blood cell growth outside the bone marrow cavity, commonly in the spleen and liver
Occurs in abnormal conditions in adults
How is the body’s response to increase in demand for cells regulated?
Regulated by growth factors
How does the body respond to increase in demand for cells?
Increase in proportion of hematopoietic cells to fat in bone marrow (increased cellularity)
Early release of cells from bone marrow (will see immature cells in peripheral blood smears)
Extramedullary hematopoiesis - blood cells will develop in spleen and liver (see hepatosplenomegaly on physical exam)
Why do bone deformities sometimes occur in children when the proportion of hemtatpoietic cells to fat in bone marrow is increased?
Fat can be totally replaced by hematopoietic tissue to the point that bones can actually expand and cause bone deformities
Such as in untreated thalassemia major
What are the hematopoietic cell compartments in bone marrow?
<0.1% hematopoietic stem cells (HSCs): a low, fixed # of HSCs remain in the bone marrow throughout life; are capable of self-renewal
About 3% progenitor cells (PCs): committed to certain blood cell types (lineages); not capable of self-renewal
> 95% maturing cells: morphologically identifiable cells that are committed to be a certain lineage
Describe basic blood differentiation from HSC
HSC → common myeloid progenitor (CMP) and common lymphoid progenitor (CLP)
CMP →megakaryocyte (→ platelet), erythrocyte, neutrophil, eosinophil, basophil, monocyte (→macrophage)
CLP → T lymph, B lymph (→plasma cell), NK cell
How does a limited # number of HSCs provide blood and immune cells over a lifetime?
HSCs are capable of self-renewal through asymmetric division
When it divides, it produces one cell that differentiates and one cell that retains stem cell properties
What does the pluripotency of HSCs mean?
It can differentiate into all blood cell types
One HSC can repopulate all the blood and immune cells in the body
Describe myelopoiesis
Bone marrow:
Myeloblast → promyelocyte → myelocytes → metamyelocyte
Peripheral blood:
→ band → segmented neutrophil
In myelopoiesis, what distinguishes a band from a metamyelocyte?
The nucleus shape (semi-circle shape in a band)
Describe lymphopoiesis
Bone marrow:
Lymphoblast → prolymphocyte
Peripheral blood:
→ Lymphocyte
Describe monopoiesis
Bone marrow: Monoblast → promonocyte
Peripheral blood:
→ Monocyte
Describe megakaryopoiesis
Bone marrow: Megakaryoblast → promegakaryocyte → megakaryocyte
Peripheral blood:
→ platelets
Describe erythropoesis
Bone marrow: Immature RBC precursor cells → nucleated RBCs or NRBCs
Peripheral blood:
→ reticulocyte → erythrocyte
The nucleus is extruded as cell is being released through the endothelial cells into the peripheral blood
What are the neutrophil pools?
50% MNP (storage) and 50% CNP (functional)
MNP = marginal neutrophil pool; neturophils localized to capillary walls mainly in lung, spleen, liver
CNP = circulating neutrophil pool
What is the life span of neutrophils in peripheral blood?
They circulate for about 10 - 14 hours before they go into tissues
What are the first responders microorganisms?
Neutrophils
How can the body rapidly increase circulating neutrophils?
Mobilize them from MNP to CNP
Provides rapid increase in WBCs to fight off infection
Steroids can also increase neutrophils due to MNP → CNP
Why are neutrophils the first blood cells to decrease w/ chemotherapy?
Bc they have the shortest lifespan in circulation
What is the life span of red blood cells in peripheral blood?
120 days
100% of RBCs are circulating
Why is HbA1c level used to monitor diabetes mellitus?
It reflects the glycation of hemoglobin (addition of glucose) as the RBC ages
What is the life span of platelets in peripheral blood?
7 - 10 days
30% of platelets are stored in spleen and 70% are circulating/functional
What does aspirin do to platelets?
Irreversibly binds to cyclooxygenase in the plateley and inhibits its activation for the remainder of its life span
After aspirin is discontinued, it takes about a week for new platelets to replace the inhibited platelets to restore platelet activity
What does deficiency of vitamin B12 or folate result in?
Impaired DNA synthesis in the nucleus → ineffective hematopoiesis (apoptosis of hematopoietic cells) → megaloblastic anemia
Bone marrow:
Nuclear-cytoplasmic asynchrony (nucleus matures slower than the cytoplasm) and large, abnormal RBC precursors
Peripheral blood:
Pancytopenia (decreased WBCs, RBCs, and PLTs), oval macrocytes, hypersegmented neutrophils
Where are growth factors/cytokines produced?
Most produced in the bone marrow microenvironment
Exception is erythropoietin (EPO) which is secreted by the kidney via endocrine signaling
What do growth factors/cytokines do?
Bind to growth factor receptors on hematopoietic cells
What is erythropoietin (EPO) released by and in response to what?
By kidney (peritubular cells) in response to hypoxia caused by anemia, repiratory disorders, high altitude
What does release of EPO cause?
It binds to receptor on RBC progenitors in bone marrow and triggers them to increase or speed up production of RBCs
It causes increased RBCs in circulation and some immature RBCs are released (reticulocytes, NRBCs)
What prevents more erythropoietin production by peritubular cells of kidney?
Negative feedback by increased RBCs in circulation and release of immature RBCs
What is used to treat anemia in pts with chronic kidney disease?
Exogenous EPO
What are the colony stimulating factors? What are their functions?
G-CSF (granulocyte colony-stimulating factor): stimulates differentiation and maturation of neutrophils; mobilizes HSCs into the peripheral blood
GM-CSF (granulocyte-macrophage colony-stimulating factor): stimulates differentiatoin and maturation of neutrophils and monocytes; mobilizes HSCs into the peripheral blood
What is exogenous G-CSF used for?
To increase the WBC count in cancer pt w/ leukopenia (low WBC count) by mobilizing WBCs from the BM to PB
Also given to donors to mobilize their HSCs and progenitor cells into the PB. After mobilization, these cells are collected by venous access and leukapheresis, and are used for treatment in patients w/ various hematologic conditions. This eliminates the need for bone marrow aspiration.
What is the preferred site of bone marrow collection?
Posterior iliac crest (location w/ hematopoietic marrow)
Describe aspirate method for bone marrow collection. What is it used for?
Suctioned w/ syringe; contains marrow particles and sinusoidal blood
Used to identify abnormal morphology of hematopoietic cells
Describe biopsy method for bone marrow collection. What is it used for?
“Core” of bone marrow obtained using a biopsy needle
Important to observe bone marrow architecture and cells in fixed location; helpful for diagnosis of benign and malignant conditions
