Term
| List the antithrombotic properties of the endothelium |
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Definition
1. Antiplatelet: PGI2, NO produced by endothelial cells impede adhesion (stimulated by thrombin, cytokines); ADPase
2. Anticoagulant: heparin-like molecules (via AT-III), thrombomodulin (activates protein C, which inactivates Va & VIIIa), protein S (co-factor for protein C), tissue factor pathway inhibitor
3. Fibrinolytic effects: endothelial cells make t-PA (tissue-type plasminogen activator), cleaves plasminogen -> plasmin --> cleaves fibrin to degrade thrombi |
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Term
| List the prothrombotic properties of the endothelium |
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Definition
1. Platelet effects: adhesion via vWf (which is made by endothelial cells)
2. Procoagulant: in response to cytokines, EC make tissue factor (activates extrinsic pathway), EC also augments fn of IXa and Xa
3. Antifibrinolytic: EC secrete plasminogen activator inhibitors (PAIs), favor thrombosis |
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Term
| Recognize that platelets originate in red bone marrow by _________. |
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Definition
fragmentation of megakaryocytes
-megaK come from megakaryoblasts
-maturation occurs in the BM |
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Term
| Recognize platelets in peripheral blood |
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Definition
small, irregularly shaped anuclear cells
2-4 mcm diameter
life span 8-12 days |
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Term
| Describe the general function of platelets |
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Definition
Primary Hemostasis!
Primary H occurs BEFORE clotting factors (VIII, IX, etc)
platelets are attracted to the exposed subendothelial matrix
adhesion via vWf
activation to change shape, release cytoplasmic granules
aggregation of more platelets forms the plug |
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Term
| Define primary hemostasis and the role of endothelial injury and the initial platelet plug has in stopping the bleeding |
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Definition
Endothelial injury exposes ECM, to which platelets adhere via vWf.
Platelet adhesion
Shape change (flatter)
Granule release (ADP, TxA2)
Recruitment of more platelets
Aggregation (hemostatic plug) |
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Term
| Define von Willebrand factor, explain its role in platelet function and clotting factor function |
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Definition
Following endothelial injury, vWf (secreted by platelets) facilitates adhesion of platelets to ECM
An "adhesion bridge" between subendothelial collagen and GpIb platelet receptor |
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Term
| List the three steps of platelet rxn after activated |
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Definition
Platelet adhesion to ECM
Secretion (release rxn)
Platelet aggregation |
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Term
| Explain the purpose of platelet secretion (release rxn) |
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Definition
Occurs soon after adhesion
Dense bodies - Ca++, ADP |
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Term
| Explain the purpose of platelet aggregation |
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Definition
Follows adhesion and granule release
TxA2 & ADP amplify aggregation --> primary plug (reversible)
Activation of coag cascade makes thrombin (stabilizes plug)
-thrombin binds PAR, causes more aggregation
-platelet contraction --> secondary plug
-thrombin converts fibrinogen to fibrin |
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Term
| Differentiate primary hemostatic plug from the secondary hemostatic plug |
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Definition
Primary - done by platelets, reversible
Secondary - stabilized by thrombin, "cemented" |
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Term
| What does aspirin impair? |
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Definition
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Term
| Explain the role fibrinogen has in platelet aggregation |
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Definition
Platelet activation by ADP triggers a conformational change in the platelet GpIIb-IIIa receptors that induces binding to fibrinogen, a large protein that forms bridging interactions between platelets that promote platelet aggregation
A mesh network that cross-links platelets |
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Term
List the major numbered coag factors and their role in the common pathway, extrinsic, and intrinsic pathways
-which conversions require Ca++?
-which require thrombin? |
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Definition
EXTRINSIC PATHWAY:
Initiated by tissue factor (thromboplastin)
VII -> VIIa
INTRINSIC PATHWAY:
XII -HMWK collagen-> XIIa
XI -thrombin-> XIa
VIII -thrombin-> VIIIa
IX -XIa or VIIa-> IXa
COMMON:
X -VIIa-> Xa
V -thrombin-> Va
II (promthrombin) -Xa, Va-> IIa
XIII -thrombin-> XIIIa
I (fibrinogen) -thrombin-> fibrin
XIIIa helps cross-link fibrin
Require Ca++:
X -> Xa
II -> IIa
XIII -> XIIIa
I -> Ia
Require thrombin:
XI
VIII
V |
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Term
| Describe the activation of the factors in intrinsic and extrinsic pathways (4-10) |
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Definition
Extrinsic: activated by tissue factor (aka thromboplastin), released from damaged tissue
Intrinsic: activated by intrinsic blood vessel derived platelet factor |
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Term
| Explain the effects coumadin and heparin have on the intrinsic and extrinsic pathways |
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Definition
Coumadin - widely used anticoagulant, antagonizes the reaction involving the binding of certain coag factors to Ca++
Heparin - activates Antithrombin-III (inhibits the activity of thrombin as well as IXa, Xa, XIa, XIIa). Administer heparin to minimize thrombosis |
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Term
What does mucosal bleeding indicate?
Bleeding into deep soft tissue/joints?
Symptoms of liver disease? |
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Definition
Platelet disorder
Clotting factor disorder
Factor VII |
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Term
| Define "coagulation cascade" |
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Definition
the third arm of the hemostatic process
intrinsic (XII, XI, IV, VIII)
extrinsic (VII)
common (X, V, II, I, XIII) |
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Term
Where is factor VII synthesized?
What does it initiate?
What test is used to measure factor VII, and is important in liver disease? |
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Definition
In the liver
-if liver isn't functioning properly, it may stop making VII
-imp in coagulation and liver disease
-has the *shortest half-life of all the coag factors* in chronic liver disease, this is the one whose def will manifest first
Promthrombin time (PT)
The extrinsic pathway |
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Term
In the intrinsic pathway, which deficiency are we most familiar with?
What test do you use to evaluate the intrinsic pathway? |
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Definition
Factor VIII - Hemophilia A
Factor IX def - Hemophilia B
Partial Thromboplastin Test (PTT) - look for VIII and IX |
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Term
| How will a clotting factor deficiency manifest in a patient? |
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Definition
Hematoma
Ecchymoses
Hemathroses (joints)
*NOT petechiae* |
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Term
| Robbins 4.11 - the fibrinolytic system |
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Definition
Fibrinolysis is accomplished through activity of *plasmin* - breaks down fibrin, interferes with its polymerization
fibrin degradation products act as weak anticoagulants
-elevated FDPs, esp D-dimers, can diagnose abnormal thrombotic states inc DIC, DVT, pulmonary embolism
t-PA, urokinase, streptokinase are all plasminogen activators -> plasmin
Plasminogen activator inhibitor blocks fibrinolysis |
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Term
| The role of thrombin in hemostasis and cellular activation |
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Definition
| I/c platelet aggregation & TxA2 production Generates cross-linked fibrin (inc activating factor XIIIa) Activates ECs to express: -adhesion molecules (neutrophils) -fibrinolytic mediators (t-PA) -vasoactive mediators (PGI2, NO) -cytokine mediators (PDGF) Activates lymphocytes, monocytes |
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Term
| Define the natural anti-thrombins that restrict clotting |
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Definition
AT-III
Proteins S and C
tissue factor pathway inhibitor |
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Term
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Definition
plasmin
plasminogen
plasminogen activators
alpha-2 anti-plasmin |
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Term
| The role of the therapeutic use of thrombolytic agents in acute MI, acute massive pulmonary embolism, and DVT |
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Definition
| DVT - anticoagulant meds, e.g. heparin - "turn off" the clotting system in the body |
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Term
| How will thrombocytopenia manifest? |
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Definition
Petechiae (rashes)
Platelet disorder
Increased bleeding time
Low platelet count
<50,000 mm3 is severe
<20,000 risk for spontaneous bleeding |
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Term
Which lab test can tell you about platelet function?
How will it be affected if you have thrombocytopenia? |
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Definition
Bleeding time
will be prolonged |
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Term
Bleeding due to thrombocytopenia: how do you tell if it's due to:
-increased destruction
-increased utilization
-impaired production
-what do you suspect if in PMS, RBC, WBC, PT/PTT all normal? |
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Definition
need BM biopsy/aspirate
increased destruction: *BM megakaryocytes* present in pt due to peripheral destruction
Autoimmune issue
impaired production: few or no megakaryocytes in BM. if PMS normal:
-cytopenias, suspect BM disease - BM needed to exclude leukemia, aplastic anemia, metes, B12 def
all normal: immune mediated thrombocytopenia or drug-induced destruction |
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Term
| What are the three main components of a blood clot? |
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Definition
Platelets
Thrombin
Fibrin
RBCs |
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Term
Robbins 4-12
Explain thrombosis using Virchow's triad |
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Definition
Hemostatis is normal physiology
Thrombosis is a pathological condition
ENDOTHELIAL INJURY (heart wall, atherosclerosis)
ABNORMAL BLOOD FLOW (turbulence and stasis in dilated veins and arterial aneurysms)
HYPERCOAGULABILITY (increased tendency to form thrombi) |
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Term
Define thrombus as it relates to:
-mural thrombi
-arterial thrombi
-venous thrombi
-heart valve vegetation (valvular) |
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Definition
Thrombi cause obstruction within the vascular space --> occlude lumen and produces ischemia/MI
may break off, travel to another vascular space & obstruct vessels at a site distant from site of origin (embolize)
arterial: superimposed on atherosclerotic lesions
venous: stasis, form in slow moving blood
mural: attached to the wall of the heart, either ventricular or atrial
-ex: stenosis of mitral valve, followed by stroke (right parietal infarct embolization)
valvular: formed on infected and damaged heart valves or sterile valves in systemic disorders |
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Term
| Define hypercoagulability, list major disorders |
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Definition
Any alteration of the coag pathways that predisposes to thrombosis
1. Primary (genetic)
-point mutations in factor V gene or prothrombin gene
-i/c VIII, IX, XI, or fibrinogen
-def in AT-III, proteins C or S
2. Secondary (acquired)
-prolonged bed rest/immobilization
-MI
-A fib
-tissue injury
-DIC
-heparin use
-cardiomyopathy
-nephrotic syndrome
-pregnancy, postpartum high estrogen
-oral contraceptives
-sickle cell anemia
-smoking |
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Term
| Explain how protein S and C deficiencies are associated with thrombosis |
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Definition
C inhibits clotting by inactivating Va and VIIIa
S is a cofactor for C
Deficiency in either leads to hypercoagulable state |
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Term
| Describe the complications of venous and arterial thrombi |
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Definition
Venous thrombi - phlebothrombosis
most: superficial & deep leg veins
risk factors: immobilization, old age, injury to BV, hypercoagulability
Risk of pulmonary emboli
Pulmonary thromboembolus - saddle thromboembolus
Arterial thrombi
most: coronary, cerebral, mesentary, renal, lower leg arteries
risks for: *infarction, chronic ischemia*
frequently occlusive |
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Term
Explain the clinical sig of:
migratory thrombophlebitis (Trousseau's)
arterial
valvular
intramural
microvascular (capillaries) thrombosis |
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Definition
migratory:
arterial: coronary atherosclerosis with thrombosis (atherosclerotic aorta) - arterial lumen completely obstructed, thrombus develops on an ulcerated atherosclerotic (fibrous) plaque; aortic aneurysm with thrombus; pulmonary artery
valvular: risk factors include bacterial endocarditis, nonbacterial thrombotic endocarditis
intramural: risk factors include MI, atrial fibrillation, cardiomyopathy, ulcerated atherosclerotic plaque, aneurysmal dilation (precursors for aortic mural thrombus) |
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Term
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Definition
affects mainly the veins in the lower leg and thigh
formation of a clot (thrombus) in the larger veins of the area
Area may be tender and warm, or no symptoms at all
Iliac, femoral, popliteal, tibial veins |
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Term
Pulmonary thromboembolus
-typical source?
-clinical stuff |
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Definition
-large veins in the legs and pelvis
-asymptomatic small emboli
massive saddle embolus @ bifurcation of main pulmonary artery (cardiogenic shock, sudden death)
pulmonary hemorrhage
pulmonary infarct (red) |
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Term
| Recognize the fate of thrombi, special emphasis to lysis and embolization |
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Definition
Lysis (dissolution) - resolution, fibrinolysis, rapid shrinkage & total disappearance of recent thrombi
Propagation (growth) - thrombi accumulate more platelets and fibrin
Organization/recanalization (new lumen) - older thrombi become organized, capillary channels eventually form & re-establish the continuity of the original lumen
Embolization - thrombi dislodge, travel to other sites in the vasculature
Other: infxn-seeding with bacteria |
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Term
| Define, differentiate thrombus and embolus |
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Definition
thrombotic stroke: clot blocks flow of blood in brain
embolitic stroke: fatty plaque or blood clot breaks away and flows to brain where it blocks an artery |
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Term
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Definition
An embolus is often a piece of a thrombus that breaks off, danger of pulmonary artery embolization
Arterial, venous |
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Term
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Definition
venous thromboembolus passes through atrial septal defect into systemic circulation
clot enters vein on right side of the heart, passes through a hole into the left side. clot can move to artery, block blood flow to brain (stroke) and other organs |
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Term
Define, give clinical ex of:
-systemic
-thromboemboli
-fat emboli
-amniotic fluid emboli
-gas emboli |
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Definition
systemic: mural thrombosis of left ventricle following acute MI can progress to systemic embolism
thromboemboli: arterial, venous. Leg embolism can lead to gangrene
fat: broken bone (bone marrow fat), or trauma to fat-laden tissues. microglobules of fat from BM obstruct microvasculature -> ischemia, hemorrhage. fatty acids damage vessel endothelium -> formation of platelet thrombi in areas of injury
amniotic fluid: delivery. tears in placental membranes or uterine veins --> infusion of amniotic fluid with procoagulants into maternal circulation. Sx: cyanosis, dyspnea (pulmonary edema), hypotension, bleeding (DIC)
gas: thoracic trauma (rib), deep sea. Decompression sickness (N gas forced out of alveoli, dissolves in blood & tissues, rapid ascent -> N expands, forms gas bubbles in tissue & vessel lumen, "the bends," pneumothorax, pulmonary embolus |
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Term
| Define infarction, explain the main differences b/t white and red infarcts (4-18) |
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Definition
Risk in arterial thrombi
Necrosis due to total occlusion or loss of blood supply
-red: loose spongy tissue (lung) or dual blood supply
-white: solid tissue; kidney/heart |
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Term
| Define shock, explain the three major types of shock (4-3) |
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Definition
blood volume isn't sufficient to occupy the vascular space (hypoperfusion) due to either reduced CO or d/c BV
-hypotension
-hypoxia
-organ failure
1. cardiogenic: heart failure due to MI
2. hypovolemic: massive fluid loss (think kids), loss of circulating BV -> d/c preload -> d/c CO. dehydration, hemorrhage
3. septic: bacteria release of cytokines; induce systemic hypotension, impaired contractility, endothelial injury and thrombosis |
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Term
| The 4 stages of hemostasis |
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Definition
1. Vasoconstriction (neurogenic; transient)
2. Hemostatic plug formation (primary hemostasis)
3. fibrin clot formation (secondary hemostasis)
4. thrombolysis (limits the clotting) |
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Term
| You see bone marrow megakaryoctes. What's your ddx? |
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Definition
| Thrombocytopenia due to peripheral destruction |
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Term
| In PMS, RBC/WBC are normal, PT/PTT normal; you have bleeding due to thrombocytopenia. Ddx? |
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Definition
| Immune mediated thrombocytopenia or drug-induced (increased destruction) |
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Term
| Bleeding due to thrombocytopenia. Abnormal PMS - cytopenias (WBCs, RBCs). What's your ddx? |
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Definition
Decreased production
BM disease - do a biopsy
Other ddx:
-leukemia
-aplastic anemia
-metes
-B12 deficiency |
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Term
Abnormal platelet function.
Platelet count is normal.
Mucosal bleeding/petechiae present.
What do you suspect? |
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Definition
Qualitative disorder
Check RxHx - NSAIDS, aspirin
Check BUN, Cr, evaluate for uremia
congenital defect |
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Term
Endocarditis
what's a vegetation?
describe how a bacterial endocarditis might manifest (heart) |
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Definition
most common: aortic and mitral valves
-IV drug abusers: right heart
vegetation = thrombi on heart valves
vegetations are friable -> systemic emboli -> infarcts in brain, kidneys, myocardium, etc.
vegetations can form on the left, right or both sides of heart, can embolize and travel.
-emboli from left heart valves (mitral or aortic) -> aorta --> rest of body
-emboli from tricuspid or pulmonic --> lungs
emboli in lungs -> shortness of breath
emboli in brain -> stroke
emboli can carry infections to other parts of the body
bacterial endocarditis: large, friable vegetation on mitral heart valve
-from bacteremic exposure or immunocompromised pt |
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