IHO: Week 1 Flashcards
What are the plasma proteins found in blood plasma?
- Albumin (58%)
- Globulins (38%)
- Fibrinogen (4%)
What is the function of plasma proteins?
- Transport nutrients, metabolites, and hormones throughout the body
- Defend against infection
- Maintain integrity of circulation through clotting
- Maintain proper water distribution throughout body (oncotic pressure)
What is oncotic pressure and how is it calculated?
Oncotic pressure (pi)= form of osmotic pressure exerted by plasma proteins in blood vessels
Jv = Kf ([Pc-Pi] - o[pi c -pi i])
What are the effects of oncotic pressure at arteriolar and venous ends of blood vessels?
Arteriolar end hydrostatic pressure exceeds sum of tissue pressure (oncotic) which is largely related to albumin –> fluid leaves blood vessel
Venous end hydrostatic pressure is < tissue oncotic pressure causing fluid to enter the blood vessel
The _____ synthesizes and releases more than 90 percent of the _______ ________, including all albumins and fibrinogen, most globulins, and various prohormones.
liver
plasma proteins
What is the main function of albumin?
- Carrier of free fatty acids, calcium, zinc, steroid hormones, copper, and bilirubin
- Binds drugs which can decrease their effective concentration and lengthen lifetime in circulation
- Used to assess liver function
What is main function of globulins?
Globulins include antibodies and transport globulins.
- Antibodies attack foreing proteins and pathogens
- Transport globulins bind small ions, hormones, or compounds that might be lost at the kidneys/have low solubility
ex. transferrin (metalloprotein), apolipoprotein (ApoE/B, etc.)
What is main function of fibrinogen?
- Clotting; multiple fibrinogen molecules interact forming large insoluble strands of fibrin (basic framework for blood clots)
What are the two different ways anemia can be classified?
- RBC size (mean corpuscular volume -MCV): micro-, normo-, and macrocytic
- Hemoglobin concentration (mean corpuscular hemoglobin concentration - MCHC)
What is the normal range for MVC and what conditions represent microcytic and macrocytic MVC?
- Normal: 80-100 fls
> 100 fls (macro) - B12 def
<80 fls (micro) - Iron def
What is normal range for MCHC?
32-37 g/l (normochromic)
What is the journey of heme to conjugated bilirubin?
Senescent RBCs are phagocytosed by reticuloendothelial cells (macrophages typically) and heme is removed. The heme is then stripped of Fe and converted into biliverdin (green in color). The biliverdin is the converted to bilirubin (orange-yellow in color) and released into the bloodstream bound to albumin where it is transported to the liver for excretion in bile. It is in the liver that bilirubin is conjugated to UDP-glucuronate to be eliminated via urine or feces.
What conditions result when heme degradation goes array?
- Hemoglobinuria = large numbers of RBCs break down in bloodstream, urine may turn red or brown
- Hematuria = presence of intact RBCs in urine which occurs after kidney damage or damage to vessels along urinary tract
- Jaundice = bilirubin is not conjugated in the liver to UDP-glucuronate and diffuses into peripheral tissues if the bile ducts are obstructed
Methemoglobinuria can be congenital or acquired, what are the different etiologies for each condition?
- Congenital: deficiency in cytochrome b5 reductase; inherited hemoglobin M disease
o Single AA substitution in heme-binding pocket stabilizes ferric state (Fe3+) - Acquired: ingestion of oxidants such as nitrites, quinones, aniline, sulfonamides; benzocaine, lidocaine, or dapsone use
o Tx: reducing agents - ascorbic acid or methylene blue
What impact of 2,3-BPG, temperature, pH, and Co2 have on affinity of hemoglobin for oxygen?
Shift curve to right (O2 goes to tissue; decreased Hg-O2 affinity): increased H+, CO2, temp, [2,3-BPG]
Shift curve to left (O2 remains bound to Hbg): decrease H+, temp, CO2, [2,3-BPG]
What RBC membrane proteins give rise to the deformable nature of a RBC?
- Spectrin: heterodimer of alpha and beta subunits
- Actin: connects multiple spectrins to create a branched cytoskeleton
- Ankyrin: interacts with band 3 and spectrin
- Band 4.2: stabilizes ankyrin-spectrin connection
- Band 4.1: anchors spectrin skeleton to glycophorin C and actin complex
How is Heme Iron absorbed?
- Heme is released from ingested proteins by low pH proteolytic activity in the stomach
- Heme is thought to be absorbed across the duodenal brush border, but mechanisms are poorly understood;
• DMT1 mediates proton-dependent Fe2+ import
• HCP1 transports dietary heme iron - Heme oxygenase releases iron from heme; iron from heme and non-heme iron are now in pool of free iron
• Excess iron stored in ferritin
How is Non-heme Iron absorbed?
- Non-heme iron is usually present in the ferric form (Fe3+)
- The acidic pH of the stomach favors conversion of Fe3+ to Fe2+, which is more soluble
- Duodenal cytochrome b reductase (DCYTB) at duodenal brush border converts Fe3+ to Fe2+
- Divalent metal transporter 1 (DMT1) moves ferrous (Fe2+) iron into the enterocyte
How is iron exported from the enterocyte?
- Ferroportin is the only putative iron exporter identified to date.
- Ferroportin takes ferrous iron from the enterocyte and transports it to the portal plasma
- Hephestin (cerulopasmin in non-enterocytes) at the BL membrane of enterocytes converts Fe2+ to Fe3+
- Fe3+ then transported via transferrin in the portal bloodstream
Iron can also be removed through the sloughing of enterocytes from the body
What are some promoters and inhibitors of iron absorption?
- Promoters: Ascorbic acid, Citric Acid, Some spices, B-carotene, Alcohol
- Inhibitors: Phytic acid, Polyphenols, Tannins, Calcium
How is iron homeostasis maintained?
Hepcidin is a key regulator of iron homeostasis.
- Hepcidin is produced in response to inflammation (AOCD, IL6) and results in increased iron stores
- Hepcidin binds to ferroportin and triggers internalization/degradation of lysosomes which decreases Fe release from macrophages, enterocytes, and hepatocytes
- Net result: increased intracellular [Fe], decreased bioavailability of Fe
What happens in hepcidin deficiency and excess hepcidin?
Since hepcidin regulates iron stores in the body a hepcidin deficiency would result in iron overload and an excess of hepcidin is implicated in AOCD
Ultimately, hepcidin prevents the release of iron from cells.
What increases and decreases transcription of Hepcidin through the HAMP gene?
INcreases: inflammation, plasmatic iron increasing, genetic abnormalities (IRIDA syndrome)
Decreases: hypoxemia, anemia, iron def, erythropoietin, genetic abnormalities (hereditary hemochromatosis)
How is ferritin and transferrin synthesis mediated?
Both depend on iron levels:
Low iron: ferritin has IRP bound to 5’UTR halting transcription of its mRNA; transferrin has IRPs bound at 3’UTR which stabilizes the mRNA allowing transcription to occur
High iron: IRPs leave ferritin mRNA allowing transcription to occur; IRPS leave transferrin mRNA which causes it to be degraded
What are the iron findings for AOCD and Iron Deficiency?
Serum Iron Serum Ferritin Transferrin Iron Sat % Total Iron Binding Capacity (TIBC) Transferrin
AOCD:
- Serum Iron: decreased
- Serum Ferritin: increased
- Transferrin Iron Sat %: decreased
- Total Iron Binding Capacity (TIBC): decreased
- Transferrin: decreased
Iron Deficiency:
- Serum Iron: decreased
- Serum Ferritin: decreased
- Transferrin Iron Sat %: decreased
- Total Iron Binding Capacity (TIBC): increased
- Transferrin: increased
What are the symptoms and pathophysiology of Acute Intermittent Porphyria?
Symptoms:
- GI (95%): pain, vomiting, constipation, tender abdomen (not rigid)
- Hyponatremia in severe attack
- Neuropathy (2/3): motor, sensory, psychiatric
- CV (70%): increased BP, tachycardia
- Photosensitivity NOT present
Pathophys: gene mutation in PBG deaminase (autosomal dominant; chrom. 11) resulting in accumulation of PBG and ALA
How is Vitamin B6 deficiency related to Isoniazid use?
Patients that are being treated for TB with isoniazid can acquire vitamin B6 deficiency since isoniazid (INH) competitively inhibits reactions that utilize Vitamin B6 for functioning; need to receive vitamin B6 supplementation while on this medication
What is the defective enzyme, clinical presentation, precipitating factors, and associated diseases of Porphyria Cutanea Tarda?
How is it treated?
Deficient enzyme: URO-D (uroporphyrinogen decarboxylase)
- Presentation: bullous dermatosis, scarring, hypertrichosis, hyperpigmentation
- Precipitating factors: increased iron stores (due to down regulation of hepcidin), Hepatitis C, HFE hemochromatosis, alcohol, estrogens
- Associated diseases: HFE hemochromatosis, African iron overload
- Tx: phlebotomy (500 ml/week until remission); iron chelation if phlebotomy not possible
What happens when the innate immune system is activated?
Invading organism enters body and mast cells are the first to react either directly (mast cells themselves), by activating the complement system, or through antibody activation. Neutrophils act as the first line of defense and sacrifice themselves by phagocytosing the invading organism and cutting up antigen which is then presented to macrophages. Macrophages engulf the pieces of antigen and secrete different cytokines which results in different local effects (fever, interferons, etc.). Macrophages then present the antigen to myeloid dendritic cells (mDCs) which bind the epitopes of the antigens through their TLRs. This binding activates a signal cascade within the mDC to express MHC II on the surface of the mDC. This expression causes the mDC to seek the lymph node, change shape to become stellate, and express more MHC II receptors.
What happens in the adaptive immunity response?
Once the mDC is in the lymph node the adaptive immune system begins. The mDC binds CD4 helper cells (To) throgh TCRs. Once bound the mDC secretes IL-12 to act on To causing it to mature and differentiate into: Th1, Th2, Th17, or T reg T cells depending on cytokine secretion. Once the certain type of T cell matures IL-2 is secreted to act upon itself (autocrine signaling) to produce more of that specific mature T cell. Follicular dendritic cells (FDCs) are also found within the lymph node and bind antigen. B cells bind antigen on the FDCs which causes a cascade to occur within the B cell resulting in expression of MHC II on the B cell surface causing the B cell to become mature. The mature B cell then binds to a mature T cell (Th1, etc.) allowing the B cell to undergo isotype/class switching (i.e. IgM to IgG). The mature B cell then becomes either a plasma cell or a memory B cell. The plasma cell pumps out antibody used to mark invading organisms (think mast cell and innate immunity) and memory B cells are used in response to a secondary infection of the invading organism in the future.
What immune cell types are derived from the lymphoid progenitor cell and what type of immunity are they associated with?
Innate immunity: NK cells and dendritic cells (also can be derived from myeloid progenitor cell too)
Adaptive immunity: T cells (CD4 helper, CD8 killer, and memory T cells) and B cells (memory B cells and plasma cells)
What immune cell types are derived from the myeloid progenitor cell and what type of immunity are they associated with?
Erythroid progenitor cells –> RBCs
Granulocyte macrophage progenitors which become PMNs, eosinophils, and basophils; monocytes –> macrophages and dendritic cells
What are cytokines?
Cytokines are soluble messenger molecules that are secreted by cells of the immune system when activated as a part of the response to infection. I.e. IFNs (a and B), TNFa
What are chemokines?
Chemokines are a large class of cytokines that attract cells into inflamed tissues and play a role in leukocyte homing.
What is the function of erythrocytes?
Transport O2 and CO2
What is the function of neutrophils?
First line of cellular defense - phagocytose invading microorganisms and becomes pus
What is the function of eosinophils?
Eosinophils secrete histamine and heparin and are found at the site of an allergic reaction, inflammatory reaction, or parasitic worm invasion.
What is the function of basophils?
Basophils mediate allergic and inflammatory reactions and bind IgE molecules.
What is the function of T cells?
T cells are involved in cell mediate immunity and assist in humoral immunity.
What is the function of B cells?
B cells become plasma cells which are involved in the humoral antibody response and B cells become memory B cells which are used in the secondary immune response.
What is the function of NK cells?
NK cells respond to virally infected cells and certain tumor cells.
What is the function of monocytes?
Monocytes are the second line of cellular defense and phagocytose organisms to present antigen to dendritic cells to continue the immune response.
What is the function of platelets?
Platelets are involved in clotting mechanisms.
What is the difference between blood plasma, serum, and lymph plasma?
Blood plasma is composed of water, plasma protein (albumin, globulins, fibrinogen), and organic and inorganic molecules
Serum contains everything that blood plasma does except for fibrinogen (thus it does not clot!!)
Lymph plasma carries carbonic acid but little O2; also coagulates slower than blood
Difference = clotting ability
Blood plasma > lymph plasma > serum
What is the progression of hematopoiesis sites during embryological/fetal development?
Week 2-3: yolk sac
Week6: liver
Month 3: spleen
Month 5: bone, thymus
What are the characteristics of proerythroblasts (blast cells) in regards to their nucleus, cytoplasm, and mitotic activity?
Nucleus: round, 1+ nucleoli
Cytoplasm: basophilic
Mitotic activity: Yes
What are the characteristics of basophilic erythroblast in regards to their nucleus, cytoplasm, and mitotic activity?
Nucleus: round, condensed chromatin; no nucleoli
Cytoplasm: basophilic (more than proerythroblast)
Mitotic activity: Yes
What are the characteristics of polychromatophilic erythroblast in regards to their nucleus, cytoplasm, and mitotic activity?
Nucleus: round, smaller than basophilic erythroblast
Cytoplasm: basophilic to eosinophilic depending on amount of ribosomes and hemoglobin, respectively, within the cell
Mitotic activity: Yes
What are the characteristics of orthochromatophilic erythroblast in regards to their nucleus, cytoplasm, and mitotic activity?
Nucleus: pyknotic (condensed), karyorrhexis (extrusion of nucleus)
Cytoplasm: eosinophilic (more hemoglobin)
Mitotic activity: No
What are the characteristics of reticulocyte in regards to their nucleus, cytoplasm, and mitotic activity?
Nucleus: anucleate
Cytoplasm: eosinophilic
Mitotic activity: No
What are the characteristics of mature RBC in regards to their nucleus, cytoplasm, and mitotic activity?
Nucleus: anucleate
Cytoplasm: eosinophilic
Mitotic activity: No
How long does it take a CFU-E progenitor cell to go from the basophilic erythroblast stage to a mature RBC in erythropoiesis?
1 week
Granulopoiesis is the development of granulocytes from their progenitor cell (CFU-G). What cell types come from CFU-G?
Eosinophils, basophils, neutrophils
How long does it take for a CFU-G cell to go through granulopoiesis to become a mature granulocyte?
14 days
Note, 1.25 million WBCs are released into circulation/sec
How long do granulocytes remain in peripheral blood and how long do they remain in CT after leaving the vascular system?
Peripheral blood: 6-10 hours
CT: 1-2 days
Blast cells have what of the following: shape of nucleus, nucleoli, granules, and mitotic activity.
Shape of nucleus: round
Nucleoli: absent
Granules: present
Mitotic Activity: Yes
Promyelocytes have what of the following: shape of nucleus, nucleoli, granules, and mitotic activity.
Shape of nucleus: round
Nucleoli: present
Granules: present
Mitotic Activity: Yes
Myelocytes have what of the following: shape of nucleus, nucleoli, granules, and mitotic activity.
Shape of nucleus: round
Nucleoli: absent
Granules: present
Mitotic Activity: Yes
Metamyelocytes have what of the following: shape of nucleus, nucleoli, granules, and mitotic activity.
Shape of nucleus: indented
Nucleoli: absent
Granules: present
Mitotic Activity: No
Band/stab cells have what of the following: shape of nucleus, nucleoli, granules, and mitotic activity.
Shape of nucleus: U-shaped
Nucleoli: absent
Granules: present
Mitotic Activity: No
Mature granulocytes have what of the following: shape of nucleus, nucleoli, granules, and mitotic activity.
Shape of nucleus: multi-lobed
Nucleoli: absent
Granules: present
Mitotic Activity: No
What are some features of yellow marrow?
Yellow marrow is derived from myeloid tissue and it occupies much of the diaphysis of long bones. It consists of mostly fat cells with blood vessels. Yellow marrow is primarily present in almost all marrow of limbs by the age of 18.
What are some features of red marrow?
Red marrow is derived from myeloid tissue and is located in the ribs, sternum, long and short bones, and iliac crest, etc. It is the site of hemopoiesis and is present in neonates and children until the ages of 5-7 years old.
What are the components of bone marrow?
Stroma (cells and fibers), sinusoids (vascular channels), and developing blood cells (EPO).
What are the types of cells in stroma and type of fiber?
Cells: fibroblasts, macrophages, fat-storing cells, osteogenic cells, and endothelial cells
Fibers: collagenous, reticular –> support blood vessels
Erythropoetin (EPO) is an example of a differentiating and growth regulating factor. Where is it produced, what stimulates its formation, and what does it stimulate?
Produced in the kidney
Formation stimulated by hypoxia
Stimulates erythroblasts to multiply and differentiate into hemoglobin-syntheszing cells (proerythroblasts, etc.)
What are colony forming units (CFUs) and when are they formed, what do they become, and what structures do they seed?
Formed in weeks 2-3 of embryological development.
Become erythrocytes, granulocytes, monocytes, lymphocytes, megakaryotes (platelets), etc.
CFUs seed the liver, spleen, and bone marrow with mesenchymal cells to make bone marrow
