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88 Cards in this Set

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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
inappropriate clot formation <PATHOLOGIC PROCESS>
clot promoting components of blood and blood vessels
clot inhibiting or dissolving components of blood or blood vessels
primary hemostatic plug
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
secondary hemostatic plug
stabilization of primary hemostatic plug by generation of FIBRIN from plasma proteins
coagulation cascade
series of sequential enzymatic conversions turning proenzymes into activated enzymes, culminating in the formation of FIBRIN
the controlled breakdown and remodeling of fibrin at site of clot formation to reestablish blood flow in an affected blood vessel
hereditary and acquired DEFECTS primarily in ANTICOAGULANT COMPONENTS of the blood --> result in INCREASED RISK FOR THROMBOSIS
Principle Procoagulant Components of HOMEOSTASIS
1. Vessel Wall (vasoconstriction)
2. The Platelet (primary hemostatic plug)
3. Plasma Proteins
Principle Anticoagulant Components of HOMEOSTASIS
1. Antithrombin (III)-heparin system
2. Protein C pathway: thrombomodulin, protein C and protein S
3. Fibrinolytic System
Procoagulant properties of vessel wall
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)
Procoagulant properties of The Platelet
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
Origin and morphology of Platelets
Bone Marrow Megacaryocytes
ALPHA GRANULES (proteins: vWF, FV, PF4)
DENSE BODIES (chemicals: ADP, ATP, serotonin, Ca2+)
cofactor in protein C activation
released by endothelium following release of procoagulants (that antagonize coagulation)
tissue plasminogen activator
serine protease
turns plasminogen --> plasmin
PLASMIN = fibrolytic enzyme
anti-paltelet therapy
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
master conductor of physiologic clot formation
THROMBIN (amplifies activation of Factors V, VIII, XI, XIII, Platelet agonist, Protein C inhibition Pathway, Fibrinogen activation to Fibrin)
Functions of vWF
ADHESION: binding to platelet GPIb
AGGREGATION: bins platelet GPIIb/IIa
binds, protects and recruits Factor VIII to hemmorrhage site
Quaternary Complex
improves efficiency of coagulation via ENZYME (activated coagulation factor)
+ COFACTOR assembly takes places on: PHOSPHOLIPID SURFACE with CALCIUM present
Plasma Proteins (FACTORS) involved in fibrin formation 2ndary Hemostatic Plug
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
Antithrombin inhibits
activated factors:
FIIa (THROMBIN), FXa, tohers
What increases the potency of antithrombin by 1000fold
where is heparin found
on surface of endothelial cells
How does anti-thrombin + heparin help localize coagulation
neutralizes activated factors in circulation, esp. downstream from thrombus formation
Protein C pathway
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
Fibrinolytic System involved in clot remodelling and eventually reopening of occluded vessels
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)
how is the Fibrinolytic system controlled?
by several inhibitors:
alpha-2-antiplasmin (plasmin neutralizer)
and plasminogen activator inhibitors
Hemophilia A
X linked
Hemophilia B
FACTOR IX defect
X linked
Hemophilia C
Bleeding Disorder caused by
Factor XI defect
Autosomall Recessive
vW disease
Bleeding disorder caused by defect in vWF
AD, AR inheritance
0.1 to 1.0% frequency
Virchow's Triad of Thrombosis
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)
Hereditary Thrombophilia
Activated Protein C resistance (FACTOR V LEIDEN MUTATION)

Prothrombin 20210 mutation
hypercoagulability can be aquired from
Prothombin Time
Recombinant TF, Ca2+, Phospholipid
+ Patient's Plasma --> time to CLOT FORMATION
Activated Partial Thromboplastin Time (aPTT or PTT)
used to measure INTRINSIC PATHWAY
Contact activator, Phospholipid + Patient's plasma -(incubate 2-5 minutes w/ CaCl2) --> Clot formation
international normalized ratio
each THROMBOPLASTIN (reagent) is assigned an international sensitivity index (ISI)

(Patient PT/ Normal PT )^ISI = INR
Thrombin time measures what?
measures conversion of fibrinogen --> fibrin

prolonged by: heparin (UFH and LMWH), low or dysfunctional fibrinogen, D-dimer, paraprotein
vitamin K dependent Factors
(coagulation proteins)
Factor 2
Factor 7
Factor 9
Factor 10
Coagulation Proteins
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
Intrinsic Coagulation Pathway
XI --> XIa
IX ---> IXa
(VIIIa + Ca)
X ---> Xa
(Va + Ca)
fibrinogen ---> fibrin
Fibrin --(XIII)--> X-linked fibrin
COMMON coagulation Pathway
X ---> Xa
(Va + Ca)
fibrinogen ---> fibrin

Fibrin --(XIII)--> X-linked fibrin
Extrinsic coagulation Pathway
X -(TF+FVIIa)--> Xa
(Va + Ca)
fibrinogen ---> fibrin

Fibrin --(XIII)--> X-linked fibrin
functions to stabilize the fibrin clot by crosslinking the Lysine and glutamine side chains of α- and γ-chains of fibrin to form homopolymers
quaternary complex
Enzyme (activated coagulation factor) + cofactor (reaction accelerator) assembled on phospholipid surface by calcium ions
Improves efficiency (keeps activation local-- at site of injury)
Anticoagulant Mechanisms
-antithrombin III + heparins
-thrombomodulin, protein C, protein S
-plasminogen activators
-plasminogen activator inhibitors
-plasmin neutralizers
Antithrombin Action
AT + Heparin Like molecule complex
binds and neutralizes Factors IXa, Xa, XIa, XIIaA via conformational change
Activated Protein C + Protein S
inactivate what?
inactivate FVa and FVIIIa
Protein C is activated by
the binding of Thrombin and Protein C to Thrombomodulin

Active Protein C is released
How does APC exert its anticoagulant effects?
activated protein C (in presence of Protein S on phospholipid) inactivates FV and FVIII
PLASMINOGEN (the inactive precursor of PLASMIN) is produced by what organ?
the liver
PLASMINOGEN is activated to PLASMIN by what?
-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
PLASMIN is a serine protease that does what?
cleaves FIBRIN -->D-D dimer, other fragments
can cleave FIBRINOGEN --> DIC
Plasminogen activator inhibitor-1 (PAI-1)
regulator of plasmin:
inactivates excess t-PA that escapes into plasma
Alpha-2 antiplasmin
regulator of plasmin:
inactivates plasmin that escapes into plasma
Primary Hemostasis related abnormalities
vWD, Bernard-Soulier, Glanzman, Thrombasthenia
Secondary Hemostasis related abnormalities
Deficiencies in factors (Hemophilia, Christmas Disease)
Hemorrhage (Acquired Disorders)
-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
von Willibrand Disease
-most common bleeding disorder 1-3%
-Dec/Absent or abnormal vW multimers
-S/S epitaxis, bruising, menorrhagia, GI, gingival bleeding
-3 types
Bernard Soulier Syndrome
-Deficiency of GPIB, AR
-Early childhood bruising, mucosal bleeding
-Dx: Increased bleeding time, giant platelets, thrombocytopenia, Aggregation studies
-Rx: platelets, DDAVP
Glanzmann's Thrombasthenia
-AR, Deficiency of GPIIbIIIa
-Early childhood bruising, bleeding
-Dx: BT, Plt aggregation studies
Thrombosis: Virchow's Triad
ENDOTHELIAL INJURY (atherosclerosis, smoking, hypertension, vasculitis)
ABNORMAL BLOODFLOW (turbulence, venous stasis, atrial fibrillation)
HYPERCOAGULABILITY (hereditary acquired (hormones, cancer, Abs)
Endothelial Injury can be caused by:
MI, valvulitis (HEART), atherosclerotic ulcerated plaques, vasculitis (vessels)
bacterial endotoxins, radiation, cigarette smoke
Endothelial injury disturbs hemostasis due to...
exposure of sub-endothelial collagen, platelet activation, adherence...
Alterations in normal blood flow can be produced by:
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
*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
Factor V Leiden Mutation
-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)
Prothrombin 20210 mutation
-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
Hereditary Thrombophilia: risk factors
Factor V Leiden
Prothrombin 20210
Protein C deficiency
Protein S deficiency
Antithrombin deficiency
Elevated homocysteine
Heparin–induced Thrombocytopenia Syndrome
-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
Antiphospholipid Antibody Syndrome (HUGHES SYNDROME)
Definition: Positive antiphospholipid antibody ; persistent, atleast 6 weeks apart + 1 CF
Arterial or venous thrombosis
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
Antiphospholipid Antibody Syndrome
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
Diagnosis: Anticardiolipin Abs, Lupus inhibitor
Treatment: Warfarin , heparin, steroids
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,
-Fibrinolytic agents to lyse clot
(t-PA, urokinase, streptokinase)
Screening Tests for Hemostasis
Personal/Family History/PE**
First Level Testing:
-Platelet count
-Bleeding Time
Plasmatic Coagulation Factors
2nd Level Tests of Hemostasis
Platelet Function (Aggregometry,)
Von Willebrands Disease Testing
Coagulation Inhibitors
Fibrinolysis Testing
Problems with using Bleeding Time in diagnostic or clinical applications
-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
Platelet Count can be useful because
-Quantitative/Quantitative defects lead to bleeding problems
-Myeloproliferative disorders elevated platelet ->Thrombosis or bleeding
Instrinsic Coagulation Pathway is measured by what kind of test?
Exstrinsic Coagulation Pathway is measured by what kind of test?
PT Test
Prothombin time reference range
12-14 secs to fibrin formation
PT prolonged by:
Deficiencies of VII, X, V, II, fibrinogen
Inhibitors (D-dimer, paraprotein, lupus anticoagulant
Application of PT
Warfarin (interferes with Vit K dependent factors (2,7,9,10) : Prolongs PT
PT can be used to monitor warfarin therapy
problems with using PT to monitor oral anticoagulation therapy?
-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 )
PTT range
23-33 seconds to fibrin formation
PTT prolonged by
Deficiencies in VIII, IX, XI, XII, (HMWK,pre-kallikrein);
heparin (unfractionated ; less sensitive to LMWH)
lupus anticoagulant
specific acquired factor inhibitor (esp. VIII)
Thrombin time measures
conversion fibrinogen to fibrin
thrombin time prolonged by
heparin (both UFH and LMWH)
low or dysfunctional fibrinogen