Beruflich Dokumente
Kultur Dokumente
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Antibodies:
Antigen binding site, variable region and constant region, heavy chain and light chain, Fab fragment and Fc fragment over hinge
region
IgA, IgD, IgD, IgE, IgG, IgM
Test question:
IgG - 80% total, cross placenta, opsonization (Ab adheres to bacterial susceptible for phagocytosis)
IgM – first produced – precursor for IgG, 10-15% total activate complement (Complement system of protein that lyses target
cells’ plasma membrane);
Most antibodies are either IgG or IgM
margination – sticking process; entire moving of leukocyte out of the blood vessel.
IgD – Not known, may help CD4 Th (Helper T cells)
IgA – Body fluid, tears, bronchiole secretions, saliva
IgE – Allergic reactions, histamine release.
Production:
Virgen cells first/second exposure to antigen memory cells + activated, combat ready cells
Primary response:
Antibody titer (arbitrary units) IgM is not amplified but IgG is amplified.
Second exposure: IgG related
T-Cells:
Act over a short range
Interact with another cell in body
Can kill or signal other cell
Only recognize antigen when presented on surface of target cell
Helper cells – 2 types:
Activate macrophage and B-cells:
Cytotoxic cells – kill infected cells
Suppressor cells – regulate activity
MHC-I
Present foreign peptides to cytotoxic cells
Cytotoxic T-cells
Cytotoxic T-Cells recognize viral protein fragments on surface of infected cells
Cytotoxic T-Cells induce infected cells to kill themselves:
(i) Bind to infected cells
(ii) Induce cell death
(iii) Punch hole in cell membrane
(iv) With CD8 perforin discharge.
MHC-II
Present foreign peptides to helper cells
Helper T-cells
Activation of helper T-cells:
(i) Antigen interact with antigen-presenting cell
(ii) Interact and bind to CD4 – Th activation : Il-2 receptor proliferation Effector T-Cell
(iii) Helper T-cells stimulate macrophages and B-cells
(iv) Helper T-cells recognize foreign antigen bound to MHC-II proteins on surface of antigen-presenting cells
Natural Killer cells:
Destroy virus-infected cells
Do not express antigen specific receptors
Cells with low levels of MHC I
Induce cells to undergo apoptosis
MHC-I + CD8 infection
5 cells horizontal: RBC, neutrophils, eosinophils, basophils,
Lymphocytes, monocytes, platelets (thrombocytes)
Platelets:
General:
Formed in bone marrow
Production regulated by thrombopoietin (liver and kidney)
Sequestered in spleen (30%)
2-4 um in diameter, life span 8-12 days (RBC 100 days~)
No nucleus
Have mitochondria, make ATP, ADP
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Have enzymes that make prostaglandins (bleed out with aspirin prostaglandins is vasodilator)
Regulate smooth muscle contraction
Cytoplasm has fibrin-stabilizing factor (in Common pathway)
Activation of platelets:
Collagen and microfibrillar proteins (vWF)
ADP released from damaged RBCs and activated platelets
ADP makes stickiness of platelets
Thromboxane from activated platelets (vasoconstricted promote clotting)
Platelet activating factor from basophils
Epinephrine (stress)
Thrombin
Clotting process:
Hemostasis – prevents hemorrhage by:
Vascular spasms
Platelet plug formation
Blood clotting
Steps in traumatized blood vessel: severed vessel platelets agglutinate fibrin appears fibrin clot forms clot retraction
occurs to seal the bleeding, tight the clot.
Platelet formation:
Has early stage, intermediate stage, late stage
Platelets have PDGF (Platelet derived growth factor) which causes proliferation of vascular endothelial cells
1. Platelet adhesion
2. Platelet release reaction – Liberated ADP, serotonin, and thromboxane A2
(i) ADP and thromboxane A2 – activate nearby platelets
(ii) Serotonin and thromboxane A2 – vasoconstrictors (constrict vascular smooth muscle), reduce blood flow through
vessel
(iii) Release of ADP – makes nearby platelets sticky to adhere together and promote platelet plug
3. Platelet aggregation
Detailed diagram:
Injured tissues and platelets release the clotting factor prothrombin activator and calcium ions
Prothrombin activator converts the blood protein prothrombin to thrombin
Thrombin splits fibrinogen to form fibrin
Other way: Blood-Clotting Cascade:
Extrinsic and intrinsic pathways converge in the Common pathway
Prothrombinase converts Prothrombin into the enzyme, thrombin
Thrombin converts soluble fibrinogen into insoluble fibrin
(i) Fibrin form the thread of the clot
(ii) All step needs Calcium
Extrinsic vs. Intrinsic pathways
they need activation, activated by previous factors of cascade effect and related Calcium in all steps.
Intrinsic need more time (slower process), more steps
Blood trauma, contact with collagen or activated platelets
Not in number order, XIIXIIX (+VIII) X activation
Slower (2-6) minutes), cascade, many components
Need to know order of factor:
(i) Trauma to the blood converts Factor XII to the proteolytic active Factor XIIa.
(ii) Enzymatic activation of Factor XI.
(iii) Enzymatic activation of Factor IX.
(iv) Activated factor IX and activated factor VIII work together to activate factor X.
(v) Factor Xa combines with Factor V and phospholipids to form Prothrombin Activator.
Extrinsic pathway
Tissue trauma releases “tissue factore” which functions as a proteolytic enzyme tissue thromboplastin (VII): Tissue
factor complexes with factor VII and with Calcium converts Factor X to activated Factor X X activation: Factor Xa
combines with factor V and phospholipids to form Prothrombin Activator
Rapid and explosive in nature (15s)
Common pathway:
Xa combined wih V and platelet phospholipids (PF3) + Ca++
Prothrombin activator:
(i) prothrombin thrombin;
(ii) fibrinogen fibrin
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Pathway (Test question):
(i) Formation of Prothrombin Activator
(ii) Conversion of Prothrombin (Factor II) to Thrombin
Prothrombin splits into → Thrombin (proteolytic enzyme}
a) acts on fibrinogen
b) stimulates fibrin stabilizing factor
c) acts on prothrombin + clotting factors (positive feedback)
(iii) Conversion of Fibrinogen (Factor I) to Fibrin
Intravascular anticoagulants:
1. Endothelial Cells
thrombomodulin (protein bound to endothelial membrane)
- binds thrombin and stops clotting process
2. Antithrombin III (alpha-globulin, combines with heparin)
inhibits factors II, X, VII, XI, and XII
antithrombin III inactivates thrombin
3. Heparin: conjugated polysaccharide, negative charge
little action alone, when combined with antithrombin III
increased affinity of antithrombin III for thrombin by 100-1000-fold
We want majorly amplify it.
Fibrinolytic system:
Plasminogen = circulating globulin
Plasmin =proteolytic enzyme, similar to trypsin
digest fibrin threads, fibrinogen, and other clotting factors
Significance: removal of small clots
Plasminogen activators:
Tissue Plasminogen Activator (TPA) – break down fibrin for stroke, clot in brain; urokinase; streptokinase
Plasminogen inhibitors:
plasminogen activator inhibitor (PAI-1) inhibits TPA
Blood coagulation tests:
Pathways:
Intrinsic: XII-XI-IX-VIIIX
Extrinsic: VIIVIIaXXa
Common pathway: V
aPPT - activated Partial Thromboplastin Time and PT – Prothrombin Time
Prothrombin (II) Thrombin
Blood coagulation tests
PROTHROMBIN TIME (PT)
Form tissue
time to form clot when tissue-thromboplastin is added
~12-14 seconds, test of extrinsic and common pathway,
factors II,V,VII,X
vitamin K factors – make the blood clot, warfarin therapy (commonly use, has to monitor)
small salad everyday incorporated into PT-INR measurement.
ACTIVATED PARTIAL THROMBOPLASTIN TIME (aPTT)
For plasma
time to form clot when plasma-thromboplastin is added
~30 seconds, test of intrinsic pathway and common pathway
Not VII, but VIII, IX, XI
Good to test for heparinzed patients
PT-INR: Prothrombin Time-International normalized ratio
INR = PT test/PT normal
INR – 0.9-1.3 for normal people
INR = 2-3 people on anticoagulation therapy (Warfarin)
Lower clotting process slower the bleeding could bleeding out
Longer time but not too long
Xarelto (Rivaroxaban) is an oral anticoagulant that is a direct factor Xa inhibitor. With its use, we cannot measure PT-INR
Effect both in-, ex- and common pathway.
Monitor but can’t measure
Coagulation defects:
Vitamin C deficiency
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causes a lack of stable collagen (elderly, alcoholics)
Hepatic failure
almost all clotting factors are made in the liver
Vitamin K deficiency
required for II (prothrombin), VII, IX, and X
caused by fat malabsorption due to lack of bile secretion
von Willebrand Disease
most common congenital bleeding disorder,
affects 1% population
Results from loss of the large component of Factor VIII
symptoms in vWD similar to platelet disorders
bleeding time is prolonged.
Hemophilia – bleeding that occurs due to a clotting factor deficiency
Hemophilia A, affects 1/10,000
Deficiency of/nonfunctional VIII (intrinsic pathway)
X-linked, almost exclusively in males
Hemophilia B affects 1/100,000
Deficiency of /nonfunctional IX (intrinsic pathway)
Thrombocytopenia
presence of low numbers of platelets
Tendency to bleed, however bleeding comes from many small venules rather than large vessels as in hemophiliacs.
Disseminated Intravascular Clotting
Abnormal bleeding and clot formation in critically ill patients.
Due to massive tissue damage
Depletion of clotting factors
In vivo coagulation
Thromboembolic conditions
venous thrombosis, pulmonary embolism
artificial heart valves, by-pass surgery
long-term bed immobilization
As blood flows, the clot detaches, causing a freely flowing clot = embolus
Deep venous thrombosis:
Deep Vein Thrombosis (DVT)
Anticoagulants for clinical use:
HEPARIN
Activates antithrombin III by binding to its inhibitor
Causes blood clotting time to increase from ~6 min to ~30 min
Change in clotting time occurs instantaneously
Action lasts 1.5 -4 hrs (inactivated by heparinase)
WARFARIN (Coumadin)
Decreases the available form of vitamin K
Decreases the amount of prothrombin, factors VII, IX, X
Delay for activity (~24 hrs), time for degradation of active prothrombin
XARELTO (rivaroxaban)
Inhibition of Factor Xa interrupts both the intrinsic and extrinsic pathways
Associated with lower rates of serious and fatal bleeding events than warfarin yet higher rates of G.I. bleeding
Differentiate classes of Immunoglobulins.
Identify the clotting factors involved in the Extrinsic, Intrinsic, and Common Pathways.
Intrinsic clotting: within the blood vessels
Extrinsic clotting: outside of the blood vessels, which is in muscles
Common pathways:
Calculate PT-INR
Understand anticoagulation and diseases caused by coagulation defects
Understand the role of blood typing and the role in transfusions, immune responses.
Blood types A, B, AB, O
RBC has A-antigen on its surface and anti-B antibody in plasma
Blood groups:
Genotypes: OO – O types – Agglutinogens: None – Agglutinins: Anti-A and Anti-B
Case report from 1939 Levine and Stetson:
Woman (type O) gave birth to stillborn fetus who had died from hemolytic anemia
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Second pregnancy for the woman
Transfused with blood from husband (type O) following delivery and developed a severe transfusion reaction (O- and O+
complication)
Hypothesis
Fetus inherits antigen from father
A few fetal red cells crossed the placenta into mother’s circulation
Mother made antibody against foreign antigen
Antibody crosses the placenta and attacked fetal red cells
Fetus dies from severe hemolytic anemia
Hemolytic Disease of the Newborn Erythroblastosis fetalis
ABO incompatibility
O mother and A or B fetus
(i) Most anti-A is IgM which does not cross placenta
(ii) ABO antigens are not well developed in fetus
Rh incompatibility
Rh positive fetus and a Rh negative mother
(i) 0.1 ml fetal blood crossing placenta cause immunization
(ii) due to fetal-maternal bleeding during delivery
(iii) Mother develops Anti-Rh agglutinins
(iv) More critical with 2nd Rh positive child
Treatment - mild cases simple transfusion
severe cases exchange transfusion
(i) corrects fetal anemia
(ii) removes mothers antibodies
Prevention - Rh immunoglobin injection into mother after delivery destroys fetal cells in mother
Blood Transfusion:
1. Packed Red Cells
Increase O2 carrying capacity
2. Platelets
Single donation or apheresis (separates 1 constituent of blood from donor)
if count is <20,000/ml, add platelets with plasma
3. Plasma
Single donation or apheresis
Usually for coagulation deficiency where platelet counts are sufficient
Transfusion reaction:
Transfusion reaction due to agglutination of donor blood
Agglutination of red blood cells due to antigen-antibody reaction
Activation of complement system
Agglutination destroyed by white cells, with hemoglobin
released into plasma
Shock, chills, fever, shortness of breath, renal shutdown
Know the role of the drug targets presented for anticoagulation.
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- renal erythropoietic factor
- 1,25 dihydroxycholecalciferol (Vitamin D)
- renin
Regulation of acid-base balance
Gluconeogenesis: glucose synthesis from amino acids
Control of arterial pressure
Regulation of water & electrolyte excretion
High Creatinine – Kidney is not function well (should filter out creatinine as product of muscle break down)
Edema: water in extracellular
Plasma filtration: 60 times per day
Renal Blood Flow = RBF
Glomerular Flow Rate
Both can be affected.
Explain the multiple functions of the kidney
Describe the process of glomerular filtration
Understand the role of hydrostatic pressure and oncotic pressure in determining the glomerular filtration rate
Calculate the glomerular filtration rate and the amount excreted by the kidneys.
Explain examples of changes in GFR and associated disorders
Review a brief background on edema
Illustrate the mechanisms of tubular reabsorption and secretion throughout the Loop of Henle
Characterize specific transporters and their locations
Calculate changes in peritubular hydrostatic pressure and capillary colloid osmotic pressure
Describe the mechanisms for hormonal regulation of ion secretion/reabsorption (angiotensin, aldosterone, ADH, Atrial natriuretic peptide )
Classify the diseases associated with defects in transporters with relevant drug classes and targets
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