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Steps in Hemostasis (order the steps and explain your logic)
Clot retraction – contraction of platelets via actin and myosin pull fibrin threads together strengthening clot Vascular spasm – vasoconstriction of damaged vessel Fibrinolysis – breakdown and removal of the fibrin meshwork of the clot Coagulation – activation of plasma proteins that result in the formation of a clot Platelet plug formation - aggregation of platelets at the site of vessel damage What do you think are the most important aspects of hemostasis that you need to know and understand?
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Vascular spasm – vasoconstriction of damaged vessel
Platelet plug formation - aggregation of platelets at the site of damage Coagulation – activation of plasma proteins that result in clot formation Clot retraction – contraction of platelets pulls fibrin threads together strengthening clot Fibrinolysis – breakdown and removal of the fibrin meshwork of the clot
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Hemostasis: stoppage of bleeding
Objective Hemostasis Hemostasis: stoppage of bleeding Mechanisms: Vascular Spasm: constriction of the damaged blood vessel Platelet Plug: platelets adhere to each other and to the wall of the injured vessel to form a temporary seal Coagulation: blood is transformed into a semisolid mass that surrounds and strengthens the platelet plug
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+ + Primary Hemostasis: Vascular Spasm/Platelet Plug Blood flow
Blood vessel damage Platelet Plug (2-4 mins) Vascular Spasm Platelets release ADP Platelets adhere serotonin and to each other thromboxane A2 forming a plug (dense granules) Serotonin, Thromboxane A2 ADP + +
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Vascular spasm - vasoconstriction
Neurogenic reflex mediated by pain receptors Endothelin - released by endothelial cells Serotonin (released by platelets) Thromboxane A2
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+ + Blood flow Platelet Plug Vascular Spasm Blood vessel damage
(2-4 mins) Vascular Spasm Platelets release ADP Platelets adhere serotonin and to each other thromboxane A2 forming a plug (dense granules) Serotonin, Thromboxane A2 ADP + +
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Platelet plug formation – upon exposure to extracellular matrix molecules
Adhesion – von Willibrand’s factor Shape change - swelling Release reaction- granules release contents Aggregation- mediated by thromboxane A2 , ADP, and thrombin
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The Structure of A Blood Vessel
Platelets adhere to exposed sub-endothelial collagen fibers and other ECM components Anything that interferes with collagen synthesis (aging, vitamin C deficiency, corticosteroid use) can lead to bleeding
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Platelet Adhesion depends on the presence of Von Willibrands Factor, made by platelets and endothelial cells
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Most common inherited bleeding disorder
Normal platelet count, but defective adhesion Resulting in prolonged bleeding time
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Secondary Hemostasis: Coagulation
The goal of coagulation is to form a fibrin meshwork! The formation of a blood clot takes place in three phases: 1. Formation of Prothrombin Activator (prothrombinase) 2. Conversion of Prothrombin to Thrombin 3. Polymerization of Fibrinogen to Fibrin slower pathway (3-6 minutes) shorter pathway (about 15 seconds) all necessary factors are injured cells external to the blood in the blood release tissue factor (TF) which shortens the process Intrinsic Pathway Extrinsic Pathway
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Intrinsic Pathway Extrinsic Pathway
a combination of activated factor X, Ca2+, PF3 and activated factor V Prothrombin (inactive) Fibrin (active) Prothrombin Activator Complex Thrombin (active) Fibrinogen (inactive)
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Ca2+ intrinsic What ion is needed in both pathways?
When blood coagulates in a test tube, is the extrinsic or the intrinsic pathway activated? Antithrombin III inhibits activated Factor X – which pathway is inhibited – intrinsic, extrinsic or both? Ca2+ intrinsic both pathways
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Why are newborns given a shot of Vitamin K?
Factor Common name(s) I Fibrinogen - has the highest concentration of all the clotting factors * II Prothrombin * III Tissue Factor, Tissue Thromboplastin - released from injured endothelial cells * V Labile Factor, Proaccelerin VII Stable Factor, Proconvertin ) VIII - sex linked Hemophilia A factor, * IX - sex linked Christmas Factor, Hemophilia B Factor, Plasma Thromboplastin Component * X Stuart Prower Factor * XI Hemophilia C factor, Plasma Thromboplastin Antecedent * XII Hageman Factor XIII Fibrin Stabilizing Factor, Laki-Lorand Factor PK - clot! Prekallekrein, Fletcher Factor - also acts on plasminogen to form plasmin; HMWK High Molecular Weight Kininogen, Fitzgerald Factor Note: 1. Factors I, II, V, VII, VIII, IX, X, XI, XII, XIII are made by the liver 2. The synthesis of factors II, VII, IX and X requires vitamin K * The ones you have to know Why are newborns given a shot of Vitamin K?
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1. platelets contain actin and myosin
Clot Retraction 1. platelets contain actin and myosin Question: What other cells contain actin and myosin? What are these proteins used for? 2. platelets trapped within the clot contract and pull the fibrin threads together 3. Results: 1. the clot is strengthened and condensed 2. serum is squeezed out 3. the edges of the wound are drawn together What is the difference between serum and plasma ??????? Muscle; Contraction Serum = plasma minus clotting factors
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Vessel Healing Endothelial cells, vascular smooth muscle cells and fibroblasts undergo mitosis to repair the wall of the vessel Mitosis is stimulated by: 1. platelet derived growth factor (PDGF), produced by platelets 2. vascular endothelial growth factor (VEGF) produced by many cell types
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Recombinant PDGF can be used to promote wound healing
74 year old white male with sensory neuropathy and poor fitting footwear developed a non-healing ulcer for 15 months on his right lateral foot. On his initial visit, saucerization of the ulcer was performed. Daily topical Regranex was applied After 6 weeks, the ulcer was completely healed.
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Fibrin Degradation Products Plasminogen
Fibrinolysis Enzymatic degradation of fibrin removes the clot when healing has occurred Plasmin Fibrin Degradation Products Plasminogen Fibrin Plasminogen activators include: 1. TPA released by endothelial cells 2. Activated thrombin and factor XII 3. Urokinase released by endothelial cells, kidney cells, epithelial cells and cancer cells 4. Cytofibrokinase, a tissue enzyme Streptokinase, bacterial product
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Preventing Unwanted Clots
Smooth, intact endothelium (Which pathway?) Circulation (movement) of the blood Chemical factors a. Prostacyclin, NO b. Vitamin E Quinone Leg Massagers Help To Prevent Clots
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Objective 11 Clot Control Factor That Limit the size of Clots
1. Circulation of Blood 2. Inhibition of Activated Clotting Factors - adsorption of thrombin into the clot removes it from circulation - liver products that limit coagulation: antithrombin III protein C heparin TFPI = tissue factor protein inhibitor
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Agents Used Clinically To prevent Clotting
Aspirin (reduces thromboxane production) Heparin Sulfate (activates antithrombin III) Warfarin and Coumadin, vitamin K inhibitors (How do these work?) Blood banks routinely add calcium chelators to blood. Calcium chelators remove calcium from solution. Why do they add these chelators?
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The medicinal leech, Hirudo medicinalis, produces hirudin which encircles and inactivates thrombin
Hirudin based anticoagulant pharmaceutical products - Lepirudin (Refludan) , hirudin derived from Hansenula (Thrombexx, Extrauma) and Desirudin (Revasc/Iprivask)
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Important factors in hemostasis and where they are produced
1. Vascular spasm Factor Source Endothelin endothelial cells Serotonin platelets Thromboxane A2 platelets 4. Fibrinolysis Factor Source Tissue plasminogen factor(TPA)-endothelial cells Activated XII liver Thrombin indirectly liver Urokinase endothelial cells, kidney cells 2. Platelet plug formation Factor Source Von Willebrand factor platelets, endothelial cells Thromboxane A2-platelets ADP platelets Collagen (in vessel wall) fibroblasts 5. Clot prevention Factor Source Prostacyclin endothelial cells NO endothelial cells, hemoglobin Vitamin E quinone Antithrombin III liver Protein C liver Heparin mast cells, basophils 3. Coagulation Factor Source * Prothrombin activator complex* Prothrombin* Thrombin* Fibrinogen* Fibrin Tissue factor damaged tissue cells PF3 activated platelets Calcium diet, bones Vitamin K intestinal bacteria * Source for clotting factors is liver
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Objective 14 Disorders Related to Hemostasis
Thrombus: a clot that develops and persists in an unbroken vessel or chamber of the heart
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Embolus : an intravascular clot that is floating free in the plasma
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Disseminated Intravascular Coagulation:
a systemic thrombohemorrhagic disorder involving unregulated fibrin formation and accelerated fibrinolysis
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Thrombocytopenia A platelet count of <50,000 /mm3 blood which may cause spontaneous bleeding Deficient coagulation factor VII (hemophilia A), IX (hemophilia B), factor (XI) or others Hemophilia
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Prothrombin Time (PT) Measures clotting time of plasma in the presence of an optimal concentration of tissue factor Measures the overall efficiency of the extrinsic clotting system and the common pathway Increased PT time may indicate deficiency of prothrombin, fibrinogen, or factors V, VII, or X Partial Thromboplastin Time (PTT) Measures the overall efficiency of the intrinsic pathway and the common pathway PTT is prolonged in deficiencies of factors V, VIII, IX, X, XI, XII, HMW kininogen, heparin, prekallikrein, prothrombin, fibrinogen
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Objective 15 Blood Groups
Agglutinogen: a glyoprotein found on the surfaces of RBCs - agglutinogens elicit immunologic responses, such as antibody formation, when introduced into a non-compatible host
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49 of 50 : 17-T04ABOBlood_TAB.jpg 49 of 50 : 17-T04ABOBlood_TAB.jpg
Agglutinin: a glyoprotein antibody produced by plasma cells and found in body fluids Agglutinins are produced by non-compatible hosts when they are exposed to foreign aglgutinogens Agglutination: a clumping reaction that occurs when agglutinogens are linked to agglutinins © 2006 Pearson Education, Inc., publishing as Benjamin Cummings © 2006 Pearson Education, Inc., publishing as Benjamin Cummings
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Human Blood Groups 1. ABO 10. Diego 19. Kx 2. MNS 11. Cartwright (or Yt) 20. Gerbich 3. P 12. Xg 21. Cromer 4. Rh 13. Scianna 22. Knops 5. Lutheran 14. Dombrock 23. Indian 6. Kell 15. Colton 24. Ok 7. Lewis 16. Landsteiner-Weiner 25. Raph 8. Duffy 17. Chido/Rodgers 26. Auberger 9. Kidd 18. Hh 27. Sutter
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Clinically Important Blood Groups - The ABO System and the Rh System
A. The ABO System
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49 of 50 : 17-T04ABOBlood_TAB.jpg
© 2006 Pearson Education, Inc., publishing as Benjamin Cummings
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Agglutinigens and agglutinins
ABO Blood Types Agglutinigens and agglutinins Blood typing
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The Rh System Landsteiner was back at it again, along with Alexander Weiner…. Together, they discovered the Rh factor The Rh Systen includes several agglutinogens: Include C,D,E,c,e D is the most immunogenic even though C and E are somewhat immunogenic
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It was called the Rh factor because it was first found on blood cells isolated from a Rhesus monkey …..
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Rh positive individuals have C,D,E in some combination
Rh negative individuals have no C, D or E Rh negative individuals will develop anti Rh agglutinin (usually anti-D) if exposed to Rh positive blood Inject Rh + blood Produce anti-D agglutinin
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Let’s practice:
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Objective 18 Hemolytic Anemia of the Newborn -HDN
(Erythroblastosis Fetalis) A disorder that may arise when a mother lacks an agglutinogen that is present on the RBCs of her fetus. The usual cause is an Rh incompatibility. Mother: Rh negative Father: Rh positive Fetus: Rh positive The process: Rh negative mother carrying an Rh positive fetus: Fetal Rh+ cells pass into the mothers bloodstream as a result of bleeding either during the pregnancy or during the birth process
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Note: normally fetal RBCs and maternal blood are separated by a layer of placental cells (trophoblast)
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Mother’s plasma cells produce anti-D agglutinin
Anti-D agglutinin can diffuse through the placenta and into the fetus during subsequent pregnancies The anti D agglutinin will attack the fetal cells, causing hemolysis
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The severity of the symptoms will depend on the amount of agglutinin produced by the mother and the amount of time that the the fetus is exposed to it. Specific problems include: 1. Anemia, hypoxia (can lead to brain damage, death) 2. Hyperbilirubinemia 3. Kernitcterus 4. Hepatosplenomegaly 5. Fetal ascites/edema
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kernicterus Fetal ascites Erythroblasts in fetal blood
Neonatal jaundice
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Treatment includes in utero transfusions, early induction of labor and exchange transfusions, phototherapy after birth Prevention involves the administration of Rhogam to Rh negative mothers
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Hemolytic Transfusion Reactions:
Reasons for Mismatches: Human Error Weak agglutinogens missed in typing Atypical groups
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