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88 Cards in this Set
- Front
- Back
hemostasis
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-maintenance of blood in a fluid and clot-free state in normal vessels under normal conditions AND
-induce a rapid/localized hemostatic plug at site of vessel injury |
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thrombosis
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inappropriate clot formation <PATHOLOGIC PROCESS>
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procoagulants
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clot promoting components of blood and blood vessels
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anticoagulants
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clot inhibiting or dissolving components of blood or blood vessels
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primary hemostatic plug
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INITIAL phase of cessation of bleeding brough about at site of vessel injury by ADHESION and AGGREGATION of PLATELETS to: VESSEL WALL and to other PLATELETS
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secondary hemostatic plug
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stabilization of primary hemostatic plug by generation of FIBRIN from plasma proteins
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coagulation cascade
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series of sequential enzymatic conversions turning proenzymes into activated enzymes, culminating in the formation of FIBRIN
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Fibrinolysis
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the controlled breakdown and remodeling of fibrin at site of clot formation to reestablish blood flow in an affected blood vessel
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thrombophilia
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hereditary and acquired DEFECTS primarily in ANTICOAGULANT COMPONENTS of the blood --> result in INCREASED RISK FOR THROMBOSIS
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Principle Procoagulant Components of HOMEOSTASIS
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1. Vessel Wall (vasoconstriction)
2. The Platelet (primary hemostatic plug) 3. Plasma Proteins |
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Principle Anticoagulant Components of HOMEOSTASIS
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1. Antithrombin (III)-heparin system
2. Protein C pathway: thrombomodulin, protein C and protein S 3. Fibrinolytic System |
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Procoagulant properties of vessel wall
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A. Arterior wall (SM vasoconstriction, local factor secretion)
B. Subendothelium: ((1) ECM collagen interacts with vWF --> platelet ADHESION (2) TF triggers formation of THROMBIN) C. Endothelial Cell: (storage and release of vWF and F VIII) |
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Procoagulant properties of The Platelet
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ADHESION: to subendothelium (via vWF binding to GPIb)
ACTIVATION: secretion of ADP, TxA2, activation of surface integrin, GPIIb-IIIa, shape change/ exposure of phospholipid, release of FV, FVIII, FXIII AGGREGATION: fibrinogen x-links platelets via GPIIb-IIIa receptors, release of ADP and thromboxane recruit platelets, platelet contraction, phospholipid surface brings coag. proteins on site of injury |
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Origin and morphology of Platelets
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Bone Marrow Megacaryocytes
ALPHA GRANULES (proteins: vWF, FV, PF4) DENSE BODIES (chemicals: ADP, ATP, serotonin, Ca2+) |
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thrombomodulin
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cofactor in protein C activation
released by endothelium following release of procoagulants (that antagonize coagulation) |
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tPA
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tissue plasminogen activator
serine protease turns plasminogen --> plasmin PLASMIN = fibrolytic enzyme |
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anti-paltelet therapy
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inhibition of inappropriate platelet activation
-ASPIRIN (irreversibly inhibs. COX-1) -NSAIDS (reversible inhib COX-1) -Clopidogrel (PLAVIX) {blocks ADP receptor} -Abciximab (Reopro) and tirofiban (Aggrastat) {block GPIIb/IIIa |
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master conductor of physiologic clot formation
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THROMBIN (amplifies activation of Factors V, VIII, XI, XIII, Platelet agonist, Protein C inhibition Pathway, Fibrinogen activation to Fibrin)
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Functions of vWF
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ADHESION: binding to platelet GPIb
AGGREGATION: bins platelet GPIIb/IIa binds, protects and recruits Factor VIII to hemmorrhage site |
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Quaternary Complex
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improves efficiency of coagulation via ENZYME (activated coagulation factor)
+ COFACTOR assembly takes places on: PHOSPHOLIPID SURFACE with CALCIUM present |
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Plasma Proteins (FACTORS) involved in fibrin formation 2ndary Hemostatic Plug
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1. Ca dept: enzyme/cofactor/cell surface phospholipid interactions
2. Proenzyme: enzyme conversions (coagulation cascade) 3. Initiation via TF-FVIIa complex (generates trace amts THROMBIN) 4. Amplification and "explosive" formation of THROMBIN 5. Fibrin, cross-linked fibring End Product |
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Antithrombin inhibits
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activated factors:
FIIa (THROMBIN), FXa, tohers |
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What increases the potency of antithrombin by 1000fold
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HEPARIN
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where is heparin found
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on surface of endothelial cells
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How does anti-thrombin + heparin help localize coagulation
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neutralizes activated factors in circulation, esp. downstream from thrombus formation
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Protein C pathway
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Thrombin binds to THROMBOMODULIN on EC surface and activates PROTEIN C (vit. K dept protein on phospholipid surface near clot site)
ACTIVATED PROTEIN C interacts with cofactor (PROTEIN S) to inactivate FVa and FVIIIa, thus SHUTTING DOWN COAGULATION CASCADE |
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Fibrinolytic System involved in clot remodelling and eventually reopening of occluded vessels
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anticoagulant mechanism whereby PLASMINOGEN is converted to PLASMIN by u-PA or t-PA
PLASMIN= potent serine protease, cleaves FIBRIN and FIBRINOGEN (if uncontrolled leads to degrad. products: eg D-dimer) |
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how is the Fibrinolytic system controlled?
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by several inhibitors:
alpha-2-antiplasmin (plasmin neutralizer) and plasminogen activator inhibitors |
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Hemophilia A
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BLEEDING DISORDER caused by a
FACTOR VIII defect X linked 1/10,000 |
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Hemophilia B
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BLEEDING DISORDER caused by a
FACTOR IX defect X linked 1/50,000 |
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Hemophilia C
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Bleeding Disorder caused by
Factor XI defect Autosomall Recessive 1/100,000 |
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vW disease
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Bleeding disorder caused by defect in vWF
AD, AR inheritance 0.1 to 1.0% frequency |
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Virchow's Triad of Thrombosis
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1) Changes in vessel wall (atherosclerosis, hypertension, smoking)
2) changes in blood flow (stasis, turbulance) 3) changes in coagulability of blood (hereditary or quired hypercoagulability) |
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Hereditary Thrombophilia
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Activated Protein C resistance (FACTOR V LEIDEN MUTATION)
Prothrombin 20210 mutation |
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hypercoagulability can be aquired from
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ANTIPHOSPHOLIPID Abs
CANCER ORAL CONTRACEPTIVES |
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Prothombin Time
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Recombinant TF, Ca2+, Phospholipid
+ Patient's Plasma --> time to CLOT FORMATION |
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Activated Partial Thromboplastin Time (aPTT or PTT)
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used to measure INTRINSIC PATHWAY
Contact activator, Phospholipid + Patient's plasma -(incubate 2-5 minutes w/ CaCl2) --> Clot formation |
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INR
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international normalized ratio
each THROMBOPLASTIN (reagent) is assigned an international sensitivity index (ISI) (Patient PT/ Normal PT )^ISI = INR |
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Thrombin time measures what?
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measures conversion of fibrinogen --> fibrin
prolonged by: heparin (UFH and LMWH), low or dysfunctional fibrinogen, D-dimer, paraprotein |
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vitamin K dependent Factors
(coagulation proteins) |
Factor 2
Factor 7 Factor 9 Factor 10 |
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Coagulation Proteins
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Enzymes: Factors 11, 2, 7, 9, 10, Protein C, tPA, Plasmin
Cofactors: Tissue Factor, F5, F8, Protein S Misc: Fibrinogen, F13, Alpha2-antiplasmin, PAI-1, Antithrombin |
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Intrinsic Coagulation Pathway
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XII--> XIIa
XI --> XIa IX ---> IXa (VIIIa + Ca) X ---> Xa (Va + Ca) II--->IIa (Ca) fibrinogen ---> fibrin Fibrin --(XIII)--> X-linked fibrin |
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COMMON coagulation Pathway
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X ---> Xa
(Va + Ca) II--->IIa (Ca) fibrinogen ---> fibrin Fibrin --(XIII)--> X-linked fibrin |
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Extrinsic coagulation Pathway
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X -(TF+FVIIa)--> Xa
(Va + Ca) II--->IIa (Ca) fibrinogen ---> fibrin Fibrin --(XIII)--> X-linked fibrin |
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FACTOR XIII
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functions to stabilize the fibrin clot by crosslinking the Lysine and glutamine side chains of α- and γ-chains of fibrin to form homopolymers
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quaternary complex
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Enzyme (activated coagulation factor) + cofactor (reaction accelerator) assembled on phospholipid surface by calcium ions
Improves efficiency (keeps activation local-- at site of injury) |
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Anticoagulant Mechanisms
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ANTITHROMBIN SYSTEM:
-antithrombin III + heparins PROTEIN C SYSTEM: -thrombomodulin, protein C, protein S FIBRINOLYTIC SYSTEM -plasminogen activators -plasmin -plasminogen activator inhibitors -plasmin neutralizers |
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Antithrombin Action
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AT + Heparin Like molecule complex
binds and neutralizes Factors IXa, Xa, XIa, XIIaA via conformational change |
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Activated Protein C + Protein S
inactivate what? |
inactivate FVa and FVIIIa
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Protein C is activated by
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the binding of Thrombin and Protein C to Thrombomodulin
Active Protein C is released |
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How does APC exert its anticoagulant effects?
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activated protein C (in presence of Protein S on phospholipid) inactivates FV and FVIII
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PLASMINOGEN (the inactive precursor of PLASMIN) is produced by what organ?
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the liver
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PLASMINOGEN is activated to PLASMIN by what?
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-t-PA (made in endothelial cells; high binding affinity for fibrin (at clot site))
-u-PA; (made in kidney, free in plasma) -streptokinase; pharmacologic agent |
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PLASMIN is a serine protease that does what?
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cleaves FIBRIN -->D-D dimer, other fragments
and can cleave FIBRINOGEN --> DIC |
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Plasminogen activator inhibitor-1 (PAI-1)
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regulator of plasmin:
inactivates excess t-PA that escapes into plasma |
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Alpha-2 antiplasmin
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regulator of plasmin:
inactivates plasmin that escapes into plasma |
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Primary Hemostasis related abnormalities
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vWD, Bernard-Soulier, Glanzman, Thrombasthenia
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Secondary Hemostasis related abnormalities
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Deficiencies in factors (Hemophilia, Christmas Disease)
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Hemorrhage (Acquired Disorders)
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-Blood loss (platelet and clotting factor depletion)
-Excess anticoagulation (selective decrease or inhibition of clotting factors) -DIC (platelet or clotting factor consumption, excess fibrinolysis) -Inhibitors (rare) Abs to clotting factors, usually factor VIII |
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von Willibrand Disease
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-most common bleeding disorder 1-3%
-Dec/Absent or abnormal vW multimers -S/S epitaxis, bruising, menorrhagia, GI, gingival bleeding -3 types -Dx: BT, FVIII, vWAg, RIPA -Rx: DDAVP |
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Bernard Soulier Syndrome
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-Deficiency of GPIB, AR
-Early childhood bruising, mucosal bleeding -Dx: Increased bleeding time, giant platelets, thrombocytopenia, Aggregation studies -Rx: platelets, DDAVP |
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Glanzmann's Thrombasthenia
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-AR, Deficiency of GPIIbIIIa
-Early childhood bruising, bleeding -Dx: BT, Plt aggregation studies |
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Thrombosis: Virchow's Triad
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ENDOTHELIAL INJURY (atherosclerosis, smoking, hypertension, vasculitis)
ABNORMAL BLOODFLOW (turbulence, venous stasis, atrial fibrillation) HYPERCOAGULABILITY (hereditary acquired (hormones, cancer, Abs) |
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Endothelial Injury can be caused by:
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MI, valvulitis (HEART), atherosclerotic ulcerated plaques, vasculitis (vessels)
bacterial endotoxins, radiation, cigarette smoke |
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Endothelial injury disturbs hemostasis due to...
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exposure of sub-endothelial collagen, platelet activation, adherence...
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Alterations in normal blood flow can be produced by:
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TURBULANCE (arterial or cardiac thrombosis)
STASIS (venous thrombosis) Mechanism: disrupt laminar flow, prevent dilution of activated factors by fresh flowing blood, retard clotting factors inhibitors, promote endothelial cell activation -ulcerated atherosclerotic plaques, aneurysms-local stasis, MI, Mitral valve stenosis |
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FACTOR V LEIDEN
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*AA replacement (Arg506Gln) at one of three APC (activated protein C {that inactivates factor V and VIII}) cleavage sites in the factor Va molecule
*Factor V Leiden inactivated ~ ten times slower than normal factor V *Persists longer in the circulation results in increased thrombin generation and a mild hypercoagulable state *Individuals heterozygous for the factor V Leiden mutation have a slightly increased risk for venous thrombosis; homozygous individuals have a much greater thrombotic risk |
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Factor V Leiden Mutation
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-almost exclusively in Caucasians
-Heterozygous mutation prevalence ≈ 4-10% in gen. Caucasian pop -Increased risk of venous thrombosis ≈ 5-fold -Prophylaxis during immobilization, pregnancy -Increased risk with oral contraceptives (≈ 30-fold vs. non-carriers not using OCP) |
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Prothrombin 20210 mutation
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-28 families with venous thrombosis (w/o known defect)
-Found same G20210A substitution in 3’-untranslated region in 5/28 (18%) probands vs 1% of controls -prevalence (heterozygous) ≈ 1-3% of Caucasians, relative risk of thrombosis ≈2-4% -Increased Prothrombin levels (mean 135% vs. 100%) due to increased mRNA stability |
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Hereditary Thrombophilia: risk factors
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Factor V Leiden
Prothrombin 20210 Protein C deficiency Protein S deficiency Antithrombin deficiency Elevated homocysteine |
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Heparin–induced Thrombocytopenia Syndrome
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-Incidence :5% of population
-Unfractionated heparin preparations -Mechanism: generation of antibodies that bind PF4 -Antibodies bind to heparin-like molecules present on platelet surface and endothelium -Platelet activation or endothelial injury -Prothrombotic state -Avoid by LMW heparin |
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Antiphospholipid Antibody Syndrome (HUGHES SYNDROME)
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Definition: Positive antiphospholipid antibody ; persistent, atleast 6 weeks apart + 1 CF
Arterial or venous thrombosis Thrombocytopenia Frequent miscarriages APLA are abs directed against phospholipids Two classifications- Secondary APS; underlying autoimmune disorder, such as SLE Primary APS; No known underlying autoimmune disorder |
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Antiphospholipid Antibody Syndrome
Mechanism CF??? Diagnosis Rx |
Mechanism of hypercoaguable state: unknown
Direct platelet activation Inhibition of PGI2 by endothelial cells Inhibit functions of Protein C or S CF : protean ; depending on vascular bed Venous thrombosis: LE, Cerebral Vein, retinal Neurologic disease: stroke , dementia Preg complications: Miscarriages, HELLP Hypoprothrombinemia Diagnosis: Anticardiolipin Abs, Lupus inhibitor Treatment: Warfarin , heparin, steroids |
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ANTICOAGULANT THERAPY
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partially decrease the syntehsis of procoagulant factors
-COUMADIN = ORAL vit. K antagonist (decreases factors II, VII, IX, X) -Inhibit action of THROMBIN and factor Xa: (Heparin and derivatives, R-hirudin) -Fibrinolytic agents to lyse clot (t-PA, urokinase, streptokinase) |
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Screening Tests for Hemostasis
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Personal/Family History/PE**
First Level Testing: Platelets: -Platelet count -Bleeding Time Plasmatic Coagulation Factors -(PT,APTT, TT) |
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2nd Level Tests of Hemostasis
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Platelet Function (Aggregometry,)
Von Willebrands Disease Testing Coagulation Inhibitors Fibrinolysis Testing |
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Problems with using Bleeding Time in diagnostic or clinical applications
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-Poor predictive value for hemostatic problems during surgery
-Does not correlate in a linear fashion with platelet dysfunction -Not useful Dx/exclusion Bleeding diathesis -Useful DX pts with bleeding history |
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Platelet Count can be useful because
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-Quantitative/Quantitative defects lead to bleeding problems
-Myeloproliferative disorders elevated platelet ->Thrombosis or bleeding |
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Instrinsic Coagulation Pathway is measured by what kind of test?
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aPTT
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Exstrinsic Coagulation Pathway is measured by what kind of test?
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PT Test
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Prothombin time reference range
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12-14 secs to fibrin formation
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PT prolonged by:
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Deficiencies of VII, X, V, II, fibrinogen
Inhibitors (D-dimer, paraprotein, lupus anticoagulant |
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Application of PT
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Warfarin (interferes with Vit K dependent factors (2,7,9,10) : Prolongs PT
PT can be used to monitor warfarin therapy |
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problems with using PT to monitor oral anticoagulation therapy?
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-PT clotting time depends on plasma factor levels & strength of the lab reagent
-PT expressed in seconds is not standardized across different labs ( discrepant results between different labs, and should therefore not be used to monitor warfarin therapy ) |
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PTT range
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23-33 seconds to fibrin formation
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PTT prolonged by
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Deficiencies in VIII, IX, XI, XII, (HMWK,pre-kallikrein);
inhibitors heparin (unfractionated ; less sensitive to LMWH) lupus anticoagulant specific acquired factor inhibitor (esp. VIII) |
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Thrombin time measures
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conversion fibrinogen to fibrin
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thrombin time prolonged by
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heparin (both UFH and LMWH)
low or dysfunctional fibrinogen D-dimer paraprotein |