Introduction and Hematopoiesis (Test 1)

immunology

-involves a combination of basic, applied, and clinical sciences

-reveals diseases caused by unwanted or exacerbated immune responses

thymus and bone marrow

What are the primary lymphatic tissues?

thymus

where are T cells produced?

bone marrow

Where are B cells produced?

1) Innate immune system

2) Adaptive immune system

What are the 2 arms of the immune systems?

innate immune system

-rapid response (hours)

-non-specific response to foreign molecules (bacteria/pathogens)

-response fixed (non adaptive)

-no immunological memory

adaptive immune system

-delayed response (days)

-highly specific response to antigen

-response adaptive (changes over time)

-immunological memory

B and T cells

What are the 2 major cell types in adaptive immunity?

-basophils, neutrophils, eosinophils

-dendritic cells

-macrophages

-natural killer cells

-complement proteins

-mast cells

-granulocytes

What are the cell types found in innate immunity?

1) neutrophils

2) eosinophils

3) basophils

What are the 3 types of granulocytes?

early reactions of innate immunity and later responses of adaptive immunity

How is defense against pathogens mediated?

immunological memory

refers to the ability of the immune system to respond more rapidly and effectively to a pathogen that has been encountered previously to a pathogen that has been encountered previously

2

How many exposures are required to have immune memory?

1st exposure

A vaccine is an example of a _____st exposure.

hematopoiesis

formation of blood cells in bone marrow

bone marrow

All immune cells are derived from where?

Myeloid and Lymphoid

What are the pathways that involve differentiation, proliferation, and maturation of cells?

cytokines/growth factors

drive the cloning-expansion of cell lineages

EPO (erythroid progenitor cells)

How do we increase production of red blood cells?

G-CSF (granulocyte progenitor)

If you want a patient's neutrophils levels to increase what do you give the patient?

1. Autocrine

2. Paracrine

3. Endocrine

What are the 3 modes of cytokine-mediated cell-to-cell communication?

autocrine

same cell communication

paracrine

cell to cell communication to neighboring cells

endocrine

cell to cell communication to distant cells

neutrophil

nucleus with 2-4 lobes connected by thin filaments; cytoplasmic granules stain a light pink or reddish purple; 10-12 micro-meter in diameter

basophil

nucleus with 2 indistinct lobes; cytoplasmic granules stain blue-purple; 10-12 micro meters in diameter

epsinophil

nucleus often bilobed; cytoplasmic granules stain orange-red or bright-red; 11-14 micro meters in diameter

plasma and formed elements

What are the two main components of blood?

monocytes

leave the blood and enter tissue macrophages

erythrocytes

-most abundant cell type-transport of oxygen via hemoglobin

-RBC

-renewable resources with a limited lifespan of about 120 days, and have an intracellular content of about 95% hemoglobin

nucleus

What is ejected from the orthochromatophilic erythroblast before entering the blood?

NO they lose all of them and their intracellular machineries during their maturation process

Do RBCs have their organelles, nucli, ribosomes, or mitochondria when they become mature erthrocytes?

antigen

described surface glycoproteins on RBCs

antigen A

What antigen is found on A blood types?

Antigen B

What antigen is found on B blood types?

Antigens A and B

What antigen(s) is/are found on the surfaces of the RBCs of type AB blood?

none

What antigen is found on the surface of the RBCs of type O blood?

Anti-B

What antibody is present for A blood type?

Anti-A

What antibody is present for B blood type?

none

What antibody is present in AB blood type?

Anti-A and Anti-B

What antibody is present in O blood type?

O+

What is the most common blood type?

AB-

What is the least common blood type?

O-

universal donor

AB+

universal recipient

the cloudy plasma is from foods with saturated fats and a patient who has increased cholesterol

Why is the plasma sample of patient 1 could and the other one clear?

erythropoietin (EPO)

is a glycoprotein hormone that regulates the daily production of 200 billion new red blood cells in the human body

EPO binding to erythroid progenitor cells

What promotes EPO survival, proliferation, and differentiation to mature erythrocytes?

hypoxia

EPO production is __________ inducible and is made in the interstitial cells in the adult kidney in response to anemia, ischemic stress or high altitude.

endocrine function

What type of function does EPO have in bone marrow?

insufficient production of EPO in the kidneys and increased hepcidin levels with block intestinal iron absorption/recycling

In patients with chronic kidney disease anemia is common because it is caused by low erythropoietic activity which is consistent with what?

erythropoietin stimulating agents (ESA)

-significantly raises Hb levels

-reduces the need for blood transfusions

-improves hematocrit levels

Epogen, Procrit (epoetin alpha, rhEPO)

-stimulates erythropoiesis

-approved for anemias due to CDK, zidovudine in HIV patients, chemo

Retacrit (epoetin alfa-epbx)

-biosimilar

-approved for anemias due to CDK, zidovudine in HIV patients, chemo

Aranesp (darbepoetin alfa)

-biosimilar with longer half life

-approved for anemias due to CDK, zidovudine in HIV patients, chemo

Mircera (methoxy-PEG-epoetin-beta)

-PEGylated so much longer half life

-approved for anemia associated with chronic kidney disease (CKD) in adult patients

ESA's indications

-anemia associated with HIV infection

-anemia associated with chemo

-anemia associated with renal failure

-anemia associated with CKD

-anemia associated with iron deficiency

12-16 g/dL

What is the normal hemoglobin levels for women?

13.5-17.5 g/dL

What is the normal hemoglobin levels for men?

less than 13 g/dL

What do hemoglobin levels have to be for a man to have an anemia diagnosis?

less than 12 g/dL

What do hemoglobin levels have to be for a woman to have an anemia diagnosis?

ESAs and adjuvant iron supplemenatation (folate and vit B12 as well)

What is the current standard of care in patients with anemia in CKD?

less than 10 g/dL

When hemoglobin is ______________ in patients with anemia in CKD they should receive partial treatment.

cardiovascular reactions and stroke

What is the adverse event for ESA?

increases the risk of CV events

When you use ESAs to target a hemoglobin level of greater than 11 g/dL it increases the risk of what?

lowest

The ____________ ESA dose is recommended to reduce the need for transfusions.

Mircera (Methoxy polyethylene glycol-epoetin beta)

-continuous erythropoietin receptor beta

-134 hr half life which extends dosing schedules

-once a month dosing (subq)

PEG

means long lasting

Peginesatide (Omontys)

-is a synthetic peptide-based ESA which was FDA approved in March 2012 for the treatment of anemia in patients with CKD

-recall was made in 2013 due to new reports of severe hypersensitivity reactions, including anaphylaxis, which can be life-threatening or fatal

Jesducroq (daprodustat)

-works just as well as ESA (erythropoiesis-stimulating agents)

-first in class oral hypoxia inducible factor proyl hydroxylase inhibitor for a once a day treatment of anemia due to CKD in adults who have been receiving dialysis for at least 4 months

-is a hypoxia inducible factor (HIF alpha) prolyl hydroxylase 2 (PHD2) inhibitor

strong CYP2C8 inhibitors (gemfibrozil)

What is the contraindication with Jesduvroq (daprodustat)?

HIFs

transcriptional factors that function as master regulators of oxygen hemostasis

neutrophils

-Largest subpopulation of WBC (65-60 % of total WBC count)

-14 days to mature from stem cells in bone marrow

-Phagocytes

phagocytes

capture and digest bacteria

neutropenia

(decrease neutrophil count), result of chemotherapy, severe infection and sepsis

therapeutic growth factor

How is neutropenia treated?

maturity

Neutrophils are classified depending on what?

chemo agents target rapidly proliferating cells which include normal hematopoietic cells (bone marrow)

How does chemo induce neutropenia?

cytotoxic

What type of drugs may lead to neutropenia?

if neutrophils go too low then you may have to lower or stop the treatment

What does dose-limiting adverse event mean with chemo?

1st cycle

When is neutropenia most common onset in the chemotherapy cycle?

ANC

absolute neutrophil count that measures neutrophils both band and segmented

segmented neutrophils

mature neutrophils

Band Neutrophil

immature neutrophil

total WBC% multiplied by total neutrophils

How do you calculate the ANC?

2000-8000 cells/micro L

What is the normal ANC range for adults?

grade 1

ANC 1500-2000

grade 2

ANC 1000-1499

grade 3

ANC 500-999

grade 4

-ANC less than 500

-most severe

G-CSF drugs

-neupogen

-neulasta

-zarxio

-endogenous growth factors

Neupogen (filgrastim)

-stimulates neutrophil, proliferation, differentiation, and migration

-A human recombinant granulocyte colony-stimulating factor (G-CSF)

-approved for Cancer patients receiving myelosuppressive chemotherapy or bone marrow transplant; patients with myeloid leukemia; patients with severe neutropenia

Neulasta (pegfilgrastim)

-stimulates neutrophil, proliferation, differentiation, and migration with a longer half life

-A covalently linked analog of recombinant G-CSF (filgrastim) and monomethoxypolyethylene glycol (PEG); longer half life!

-approved for neutropenia in AIDS, post-chemo, or bone-marrow transplantation; severe neutropenia

Zarxio (filgrastim-sndz)

-first biosimilar approved in US

-approved for neutropenia in AIDS, post-chemo, or bone-marrow transplantation; severe neutropenia

recombinant G-CFS

-acts to accelerate neutrophil proliferation and function while decreasing the incidence and severity of neutropenia

-selectively targets neutrophil precursor cells

biologic effects of G-CSF

-Stimulates proliferation (replication) of neutrophil precursors

-Enhances differentiation and maturation of neutrophil precursors

-Activation and enhancement of mature neutrophils

Neulasta (Onpro)

colony stimulating factor used to manage myelosuppresion

chemo-induced neutropenia (CIN)

is a major dose-limiting toxicity of systemic cancer chemotherapy-Increases risk of infection, prompts dose delays/reductions, impacts effectiveness and impairs quality of life

febrile neutropenia (FN)

-Oncologic emergency

-Fever of 101 ºF or greater + neutropenia

-Often requires hospitalization and broad-spectrum antibiotic use

-Associated with substantial morbidity, mortality, and cost

1st

Recent data in different tumor types have shown that the greatest risk for CIN is in the _____ cycle.