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90 Cards in this Set
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hemostatic mechanism processes
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1) primary hemostasis
2) coagulation (amplification and propagation) 3) termination of clotting process by antithrombotic control 4) fibrinolysis |
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primary hemostasis
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within secs of vascular injury
involves platelets and blood vessels - platelet activation |
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platelet activation
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platelets spread along surface of denuded blood vessel
- adhere via glycoprotein R (Ia/IIa to collagen) and von Willebrand factor (binds to platelet glycoprotein Ib) activation = shape change from flat to sphere, extends multiple pseudopods - release rxn - synthesize TxA2 |
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Thromboxane A2
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prostaglandin
synthesized by activated platelets stimulates further release of ADP and vasoconstrictor |
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platelet factor 3
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activated platelets expose this as a new phospholipid surface
- changes shape of platelet - creates "procoagulant" activity - interaction of clotting factors on surface - culminates in formation of fibrin |
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prostacyclin
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PGI2
prostaglandin opposite effects of TxA2 secreted by intact endothelial cells beyond site of vascular lesion to arrest further platelet activation beyond area of injury inhibits platelet activation, aggregation and secretion potent vasodilator |
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coagulation
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interaction of clotting factors (plasma proteins) to make fibrin
- series of proenzymes/procoagulant molecules cleaved to active form (serine protease) - final step: fibrinogen -> fibrin necessary component: phospholipid surface (provided by tissue factor or platelets expressing PF3) intitiated by tissue factor (TF) |
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synthesis of coagulation factors
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mostly in liver
Vitamin K dependent for proper synthesis: II, VII, IX, X (last step is addition carboxyl moiety - enables binding to phospholipid surface) ** Coumadin compete w Vit K for binding sites on hepatocyte - inhibits carboxylation Factor VIII only extrahepatic synthesis |
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mechanisms controlling coagulation
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1) clotting factors circulate in inactive form
2) normal blood flow = dilution 3) preferential removal from circulation by liver, reticuloendo system 4) requirement of phospholipid surface localizes clot formation 5) presence of circulating anti-coagulants (ATIII) |
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Antithrombin III
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Anticoagulant that circulates in blood
binds and inactivates thrombin also binds IXa, Xa, XIa, XIIa normally occurs slowly, accelerated with heparin |
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reticuloendothelial system
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mononuclear phagocyte system
all the cells able to ingest bacteria or colloidal particles etc, except for certain white blood cells primarily monocytes and macrophages, and they accumulate in lymph nodes and the spleen. The Kupffer cells of the liver and tissue histiocytes are also part of the MPS |
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fibrinolysis
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conversion of plasminogen to plasmin = active fibrinolytic enzyme
plasminogen preferentially binds fibrin clot when comes into contact with in blood stream > converted to plasmin by t-PA > creates specific binding site for fibrin (same site as for alpha2-antiplasmin) > degrades clot > releases fibrin degradation products > removed by liver, kidney or MPS |
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t-PA
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tissue plasminogen activator
released by injured tissues and vascular epithelium activates plasminogen to plamin after a few days of clot manufactured t-PA pharmacological tx for intravascular clots (directly to thrombosed areas via catheter - use within 1st hour of clot in coronary artery!) |
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alpha2-antiplasmin
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plasmin inhibitor
same binding site to plasmin as fibrin > as long as plasmin is bound to fibrin, it cant get neutralized = prevents widespread fibrinolysis |
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Fibrogen degradation products
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FDPs: products of plasmin breakdown of fibrin
removed by liver, kidney or MPS if made at rate faster than normal clearance, get accumulation: > high concentrations = anticoagulant = impair platelet fn, inhibit thrombin, prevent cross-linking fibrin strands = bleeding |
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disorders of hemostatic mechanism
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classified via:
involve platelets involve clotting factors presence of inhibitors tx often transfusion or pharmalogical |
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general pharmacologic agents used in disorders of hemostatic mechanisms
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affect function of:
1) platelets: - desmopressin - antiplatelet drugs 2) clotting factors: - vitamin K - heparin - coumadin 3) inhibitors: - antifibrinolytics - protamine - fibrinolytics |
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von Willebrand's disease
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hereditary platelet disorder
- most common congenital bleeding disorder plasma deficiency of vWF = impaired platelet function ^ levels with: transfusion FFP cryoprecipitate desmopressin |
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major functions of von Willebrand Factor
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1) mediates platelet adhesion to collagen in subendothelial layers of injured bv
2) carrier protein for small moiety of factor VIII molec - contains VIII coagulant activity (VIIIC) |
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Causes of thrombocytopenia
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1) inadequate platelet production by bone marrow
2) sequestration in spleen 3) consumption from tissue injury or platelet activation 4) dilution due to massive transfusion of colloids or crystalloid or blood (would also decrease clotting factors etc) 5) destruction by immune mechanisms |
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definition thrombocytopenia
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platelet count falls below 150,000/mm^3
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causes of platelet dysfunction
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1) myeloproliferative and myelodysplastic syndromes = intrinsic defects
2) systemic conditions: liver disease, kidney failure, DIC, cardiopulm bypass (alters milieu platelets circulate in) **3) drug administration (ASA, NSAID) |
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hemophilia types and deficiencies
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A: factor VIII
B: factor IX C: factor XI |
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treatment vitamin K deficiency
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IM or IV vit K
(Aquamephyton) dose 10-20 mg 3-5 hours for correction of coagulopathy before surgery, if vit K deficient, can give 4-8 hours before OR and as long as at least 1/2 liver cells functioning, can get sufficient clotting factors to prevent excessive bleeding |
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vitamin K absorption and malabsoption causes
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fat soluble, requires bile salts for absorption from jejunum
(produced by bacteria in intestinal tract so rarely diet deficient unless newborn w/o established flora) malabsorption syndromes pancreatic insufficiency biliary obstruction GI obstruction rapid GI transit time |
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Disseminated Intravascular Coagulation (DIC)
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- excessive deposition of fibrin throughout the vascular tree,
- simultaneous depression of the normal coagulation inhibitory mechanisms - impaired fibrin degradation triggered by overwhelming amounts procoagulant material in blood stream for mechs that normally restrain and localize clot formation (could be large area of tissue damage = lots of tissue factor released; could be speticemia w endotoxins activating clotting) causes both tissue ischemia and, ultimately, critical depletion of platelets and factors (can see bleeding); leads to or exacerbates circulatory shock lethal 85% or more tx transfusion, try to get platelets over 80, plasma to replace clotting factors (esp labile 5 and 8) |
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hemostasis
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A system to control blood loss from spontaneous or traumatic breaks in the blood vessel
outside vessel physiological (compare to thrombosis) |
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thrombosis
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The formation of a blood clot within a blood vessel
within vessel pathological (compare to hemostasis) |
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arterial clots
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fast flowing arteries
platelets pushed to edge (think laminar planes of flow) = platelet rich therefore tx with antiplatelets (stroke, heart attack) |
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venous clots
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slow flowing veins
fibrin/red-cells rich more of problem = use antithrombotics (DVT) |
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platelet production/turnover
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constitutively secreted TPO regulatory hormone of platelet production
originate from megakaryocytes survive ~ week, mostly cleared by RES without utilization |
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Thrombopoietin
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TPO
constitutively secreted to regulate platelet production binds to c-mpl on platelet and is cleared w no effect binds to megakaryocytes to ^ production platelets if low platelets, less TPO mopped up and more available to stim megakaryocytes |
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Platelet functions in hemostasis
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Adhesion
Aggregation (secretion) Coagulation (site assembly coag factors) |
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platelet aggregation
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platelets binding to each other
- via GP IIb/IIIa (heterodimer) - once activated, changes shape so can recognize fibrillary molecules at arginine, glycine and aspartate |
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action of platelets
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Immediate:
plugs damaged vessel wall long term: promotes vessel wall repair PDGF |
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PDGF
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Platelet derived growth factor
oncogene derived product for vessel wall to repair itself chronic PDGF -> atheroscelrosis |
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Antiplatelet agents
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ASA
Ticlopidine GP IIb/IIIa Inhib. |
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Thinking low platelets due to underproduction?
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Check peripheral blood: all reduced or just platelets?
Bone marrow: megakaryocytes? |
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causes platelet destruction
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almost always only platelets reduced
non-immune: -DIC -Infection Immune: - Drug (Heparin, Quinine/Quinidine) - Infection (Bacteria, HIV) - Idiopathic (ITP) |
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Immune thrombocytopenia purpura (ITP)
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common autoimmune disorder
(1/2,000-1/10,000) peaks in early children (acute, transient gone in few months) and older, usually women 20-40 mild to severe thrombocytopenia splenectomy often curative (2/3) see in lupus, HIV... |
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management of thrombocytopenic patient
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1) estimate bleeding risk
- looking for signs - petechiae high sens and spec for platelet bleeding disorders - blood blisters (high risk high sens and high spec) (bruise is non-specific) 2) determine cause: - Underproduction - Increased destruction - Sequestration |
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Treatment for ITP
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initial:
1) RE blockade: IV-IgG (effective, temporary but $$$) 2) Prednisone (50-60mg, stops Ab production; cheap, many side effects) 3) Splenectomy: definitive tx; early rather than later |
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Pentad of TTP
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1) Schistocytic Hemolytic Anemia (Fragmentation hemolysis)
2) Thrombocytopenia - destructive 3) Acute neurological events: stroke 4) Renal Impairment 5) Fever |
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possible cause TTP
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Defect in ADAMTS 13 (cleaves large vWF) - get large vWF grabbing onto lots of platelets in circulation
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hemolytic uremic syndrome
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like TTP but much more likely to occur in children, and epidemic (rather than episodic)
1) schistocytic hemolytic anemia/ fragmented hemolysis 2) thrombocytopenia 3) renal impairment caused by e. coli toxin |
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contraceptives and thrombus
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VTE and ATE risk
prothrombotic alter lipid component of platelet = little bit stickier - more likely to cause thrombotic event even newest generations (almost always VTE) but not related to platelets |
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Vascular constriction after blood vessel injury due to:
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1) local myogenic spasm
2) local autacoid factors from traumatized tissues and platelets (TxA2) 3) nervous reflexes (initiated by pain or other sensory impulses) |
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platelet cytoplasm contents
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1) actin, myosin, thrombosthenin
2) ER and golgi residuals (synthesize enzymes, store Ca2+) 3) mitochondria (ATP, ADP) 4) enzyme systems (synth prostaglandins) 5) fibrin-stabilizing factor protein 6) growth factor |
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platelet cell membrane
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- surface coat of glycoproteins - adhere to injured areas
- phospholipids |
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events when platelet comes into contact with injured epithelium
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-swell, irregular shape, pseudopods
- contractile proteins contract forcefully to cause granule release - become sticky: adhere to collagen and vWF - secrete large quantities ADP - start manufacturing TxA2 |
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Timeline of blood clotting
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beginning of clot:
- mild 1-2 min - severe 15-20 sec extrinsic faster than intrinsic entire opening of ruptured vessel closed within 3-6 min clot retraction ~ 20min to 1 hr (serum expressed from clot, requires platelets) complete organization of clot into fibrous tissue within 1-2 wks |
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clotting factors and synonyms
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I - Fibrinogen
II - Prothrombin III - Tissue Factor IV - Calcium V - Proaccelerin; labile factor VII - Serum prothrombin conversion accelerator (SPCA); proconvertin VIII - Antihemophilic factor (AHF) IX - Plasma thromboplastin component (PTC) X - Stuart factor XI - Plasma thromboplasting antecedent (PTA) XII - Hageman factor XIII - Fibrin-stabilizing factor |
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proteolytic actions of thrombin
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cleaves proteins into smaller, active components
fibrinogen -> fibrin prothrombin ->more thrombin VIII IX X XI XII aggregation of platelets |
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mechanisms leading to prothrombin activator
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1) trauma to vascular wall and adjacent tissue
2) trauma to blood 3) contact of blood with damaged endothelial cells or with collagen and other tissue elements outside the blood vessel extrinsic = trauma to vascular wall and surrounding tissues intrinsic = begins in blood itself |
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positive feedback effects of thrombin
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proteolytic action on prothrombin
activates factor V which accelerates production of prothrombin activator (Xa + Va) |
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factors preventing clotting in normal vascular system
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1) smoothness of endothelial cell surface (prevents contact activation of intrinsic)
2)layer of glycocalyx on endothelium 3) thrombomodulin bound w endothelial membrane (binds thrombin, activates protein C) |
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glycocalyx
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mucopolysaccharide
adsorbed to surface of endothelial cells repels clotting factors and platelets, preventing activation |
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thrombomodulin
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bound to endothelial membrane
binds to thrombin = removes thrombin from clotting process thrombomodulin-thrombin complex activates protein C = anticoagulant that inactivates Va and VIIIa |
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anticoagulants
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fibrin fibers (absorb 85-90% fibrin when clot is forming)
antithrombin III (aka antithrombin-heparin cofactor) -> combines with thrombin heparin (low in body, used pharmacologically) - combines with antithrombin III to increase its effects 100-1000 fold (also removes IX, X, XI, XII) |
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production of physiological heparin
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mast cells (pericapillary connective tissue; esp lungs and liver w slower moving blood w often embolic microclots)
basophils |
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plasmin digests:
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fibrin fibers
fibrinogen Factor V Factor VIII Factor XII Prothrombin |
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hemophilia
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bleeding disease that occurs almost exclusively in males
1 in 10,000 in US 85% A (factor VIII small MW affected) 15% B (factor IX affected) **transmitted by X chromosome! recessive, females only carriers variable severity w genetic deficiency - amount of trauma needed to cause bleeding tx: factor VIII |
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abnormal clot in blood vessel
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thrombus
free flowing = embolus |
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causes of thromboembolic conditions
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1) any roughened endothelial surface of a vessel
- arteriosclerosis - infection - trauma 2) very slow blood flow through vessels |
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heparin
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commercially extracted from animal tissues
injection 0.5 - 1mg/kg blood clotting time ^ from 6 min to 30 min - occurs instantaneously lasts 1,5-4 hours broken down by heparinase |
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warfarin
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inhibits enzyme vitamin K epoxide reductase complex 1 (VKOR c1)
- enzyme that converts inactive (oxidized) vit K to active form (reduced) decrease of 50% coagulant activity by end of 12 hrs decrease to 20% by 24hrs (need to wait to degredation of already active forms in blood) 1-3 days return to normal after discontinue |
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measurement of PT
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- blood removed, immediately oxalated (so no thrombin)
- given XS Ca2+ and TF (usually phospholipid-protein extract of tissue eg lung, brain; TF and PL) = activation of prothrombin to thrombin via extrinsic pathway = clot more prothrombin = faster clot formation normal 12 sec *varies w prep of tissue factor |
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INR
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international normalized ratio
- devised to standardize measurements of prothrombin time (which is affected by tissue factor preparation) - each TF batch has ISI (international sensitivity unit) normal = 0.8 - 1.2 high= 4-5 = high risk bleeding low = 0.5 = chance of clot warfarin tx = 2.0 - 3.0 |
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aPTT
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partial thromboplastin time
- blood collected with oxalate or citrate - activate intrinsic pathway by adding a phospholipid and calcium and contact activating agent (ellagic acid, silica, kaolin) - time measured until clot formed typical 25-39s can follow with "mixing test" when mix pts blood with normal plasma and see if clot (deficiency disappears) if not = contains inhibitor (ie heparin) good screening test for inherited or acquired factor deficiencies in intrinsic pathway |
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extrinsic tenase
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FVIIa
TF PL Ca2+ Activates FX to FXa and FIX to FIXa |
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Intrinsic tenase
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FIXa
FVIIIa PL Ca2+ Activates FX to FXa |
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Prothrombinase
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FXa
FV PL Ca2+ Converts FII to FIIa (thrombin) |
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Antithrombotic control mechanisms
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Main occur via circulating enzyme inhibitors in the body
Antithrombin Protein C Protein S Tissue Factor Pathway Inhibitor (TFPI) |
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activation of protein C
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XS thrombin binds thrombomodulin
- loses ability to convert I to Ia, - instead changes protein C to APC - APC plus cofactor protein S inhibits FVa and FVIIIa - slows down coag |
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Thrombin clotting time (TCT)
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Useful when both aPTT and PT/IINR are prolonged - can localize defect to final step of cascade
- deficiency/defect in fibrinogen - decreased activity of FIIa thrombin test via adding thrombin directly - should cause clotting 15-20s most common for ^ in hospitalized pts = heparin |
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hypercoagulable
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Increased levels of any one or more factors in the
cascade can result in an increased tendency to form a fibrin clot Defects in the antithrombotic control mechanisms can also increase tendency to form clots clinically manifest as VTE congenital or acquired |
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Virchow's Triad
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Prothrombotic factorws:
1) Stasis: immobility 2) vascular injury: surgery, trauma 3) Hypercoagulability: inherited or acquired defects in coag cascade |
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Overall cause VTE
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activation of coagulation exceeds
ability of natural anticoagulant systems prothrombotic vs antithrombotic |
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Clinical presentation PE
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• Dyspnea (shortness of breath)
• Chest pain/discomfort • Hemoptysis • Tachycardia If massive: • Syncope • Hypotension • Low oxygen levels in blood May have symptoms of leg DVT |
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Clinical presentation DVT
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usually unilateral
- leg pain/heaviness - swelling - discolouration (erythema) - leg may be warm to touch |
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Inherited thrombophilia classification
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1) Deficiencies in coagulation inhibitors
- antithrombin, APC, Protein S 2) Resistance to inhibitors of coagulation (ie factor V Leiden) 3) Increased levels of coagulation factors - prothrombin gene mutation - ^ FVIII, FIX, FXI |
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Activated Protein C resistance
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most common mutation will see
Mutation in FV (arginine to glutamine substitution at aa 506) prevents proteolytic inactivation of FV by APC |
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Prognosis DVT
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proximal DVT untreated associated with 40-50% ^ risk PE
10% PE are fatal! |
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dabigatran
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direct inhibitor of FIIa
= antithrombotic agent |
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rivaroxaban
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direct inhibitor of FXa
= antithrombotic agent |
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main mechanisms of anticoagulants
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1) Increase effectiveness of antithrombin (indirect FIIa and FXa inhibitors)
- heparin 2) Direct inhibitors of FIIa and FXa 3) Vitamin K antagonists (eg Warfarin) |
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overlapping therapy for VTE
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start with heparin and warfarin at same time
- heparin discontinued when warfarin reaches therapeutic levels as measured by INR |
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Inherited Risk factors for VTE
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"thrombophilias"
- Antithrombin deficiency - Protein C def - Protein S def - APC resistance (factor V Leiden) - Prothrombin gene mutation - Elevated levels of FVIII (FIX, FXI) |
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Aquired risk factors for VTE
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- immobility (lower extremity fracture)
- surgery/trauma - cancer - oral contraceptives/hormone replacement - pregnancy - other conditions |
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Tissue factor pathway inhibitor
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Circulates in plasma at very low concentrations, most bound to endothelial cell surface
- binds and inactivates FXa - FXa-TFPI can also inhibit TF-FVIIa heparin can increase TFPI plasma levels |
