PULM Week 5 Lectures Flashcards
(111 cards)
1
Q
what is plasma
A
obtained when blood is collected into an anticoagulant and the cells are removed (clotting factors still in inactive form)
2
Q
what is serum
A
obtained when blood is allowed to clot, clot separated into fibrin clot and serum (clotting factors activated and fibrinogen is depleted)
3
Q
what are platelets
A
“first defence”
formed from megakaryocytes (white blood cells synthesized in marrow)
non-nucleated
2-3 um in diameter
half life of 5-9 days
150-400 X 10^9 / L
activated by thrombin or ADP
4
Q
what activates platelets
A
thrombin or ADP
5
Q
half life of platelets
A
5-9 days
6
Q
where are platelets synthesized
A
formed from megakaryocytes in the marrow
7
Q
what is Virchow’s triad of normal hemostasis
A
- normal vascular epithelium
- normal blood flow
- correct hemostatic balance
8
Q
what is the mechanism of fibrin clot formation?
A
damaged endothelial layer–> platelets adhere–> platelet plug formation (aggregation) –> fibrin clot formation
9
Q
describe a primary clot
A
“platelet plug”
3 As: ADHESION, AGGREGATION, ACTIVATION
10
Q
describe a secondary clot
A
coagulation cascade + negative feedback
11
Q
describe the clotting cascade associated with a secondary clot
A
enzymes (proteases)–most of the facrors
coenzymes V and VIII
cofactors calcium and phospholipids
12
Q
describe the factors in negative feedback associated with a secondary clot
A
- anticoagulants: antithrombin–inhibits proteases; TFPI–inhibits proteases, mainly VIIa anf TF; thrombomodulin + protein C & S–breakdown coenzymes V and VIII
- fibrinolysis
13
Q
what are the 2 processes involved in thrombosis
?
A
- platelet plug formation
2. fibrin clot formation
14
Q
what leads to clotting? what is the pathway?
A
tissue damage leads to fibrin clot formation
initiator (tissue damage) –> activation of clotting factors–> FIBRINOGEN (soluble)–> [via THROMBIN]–> fibrin (insoluble) blood clot
initiator is TISSUE FACTOR (inside every cell)–lysis of cells leads to exposure of tissue factor (TF) which initiates the clot cascade
15
Q
what is thrombolysis
A
tissue repair and fibrin clot dissolution
blood clot–> [via PLASMIN] –> fibrin degredation products (soluble and cleared by liver–also called d-dimers)
16
Q
what is fibrinogen
A
very complex protein made up of 6 polypeptides
shaped like a dumbbell
three globular domains linked by triple helices
activated by CROSS LINKING–introduced to factor XIIIa, which induces a covalent bond between lysine and glutamine residues
17
Q
what is the role of vitamin K in thrombosis
A
- some clotting factors require vitamin K dependent carboxylation during their biosynthesis to be biologically active
- vitamin K is a fat soluble vitamin found in vegetable oils and green leafy veggies, also synthesized by gut flora
- normally, gut bacterial synthesis is sufficient
i. e Carboxylatin of glutamic acid residues into gamma-carboxyglutamic acid (Gla)
1. Gla binds calcium leading to conformational change
2. Ca2+-Gla-proteins can bind to phospholipid membranes (supplied by activated platelets at the site of injury)
3. ensures fibrin formation occurs at injury site instead of in flowing blood
4. the Gla is absolutely REQUIRED for the membrane binding
5. non-carboxylated kitamin K dependent proteins are biologically inactive
18
Q
list Ca2+-Gla-proteins
where can they bind?
A
factor VII, X, IX, prothrombin (“vitamin K proteins”)
only these types of proteins can bind to platelet plug
(factors Va and VIIIa can also bind but not through Gla)
complexes allow for CONCENTRATION, ORIENTATION and LOCALIZATION
19
Q
what is factor XII
A
factor XII deficient patients do not bleed–probably has non-coagulation functions
factor XIIa plays a minor role in hemostasis–activated by poly-phosphate on the activated platelet surface (negative charge)
resulting factor XIIa activates factor XI to factor XIa generating THROMBIN to further platelet activation after complex is formed
20
Q
describe the termination of clotting
A
- dilution of flowing blood
- trapping of proteases in growing fibrin clot
- serine protease inhibitors (SERPINS) such as ANTITHROMBIN binds to active site of thrombin and forms inactive complex
- antithrombin deficiency can lead to risk of thrombosis
21
Q
what initiates the coagulation system
A
tissue injury that exposes TF
22
Q
how do platelets play a role in clotting
A
support and enhance activation of the coagulation system by providing a surface onto which clotting factors assemble and by releasing stored clotting factors
23
Q
what is TF
A
membrane protein present on the subendothelial cellular components of the vessel wall (i.e smooth muscle cells and fibroblasts)
24
Q
what clotting pathway does TF activate?
A
the extrinsic pathway, which then in turn activates the intrinsic pathway
both pathways meet at the common pathway–> THROMBIN activation–> fibrin activation and crosslinking
25
what compounds are produced by endothelial cells that play a role in termination of clotting
thrombomoduling
antithrombin
TFPI
endothelial cells also activate fibrinolytic mechanisms through production of tissue plasminogen activator 1, urokinase, plasminogen activator inhibitor and annexin 2
26
what does thrombomodulin do
binds to thrombin, activates proteins C & S, and inactivates factors Va and VIIIa
27
what does antithrombin do
inhibits the proteases VIIa, IXa, IIa (thrombin)
28
what does TFPI do
inhibtis proteases, mainly VIIa, TF
29
what does plasminogen do
plasminogen-->plasmin-->cleaves fibrin to FDPS, D dimers
30
describe the extrinsic pathway
vascular injury-->TF -->factor VII-TF--> factor VIIa-tissue factor --> factor IX converts to factor IXa and factor X to factor Xa, both of which feed into the intrinsic pathway
the two pathways meet at Factor Xa production
31
describe the intrinsic pathway
factor XI-->factor XIa-->converts Factor IX to factor IXa, which works with Factor VIIIa to convert Factor X to factor Xa
32
describe the common pathway
starts with the meeting of the intrinsic and extrinsic pathways at factor Xa, which then converts prothrombin to thrombin
thrombin converts fibrinogen to fibrin which then goes on to be cross linked fibrin
33
what are clot busters
break up fibrin polymer network to restore normal blood flow
34
how is plasminogen activated?
the inactive plasminogen form is activated due to plasminogen activator--tPA, uPA, streptokinase
after activation it becomes plasmin which is an enzyme
35
uPA
urokinase plasminogen activator
converts plasminogen to plasmin through TISSUE REMODELLING
not most important enzyme to make plasmin for clot busting
36
tPA
tissue plasminogen activator
interacts with cofactor molecule (actual clot)
problems with tPA result in stroke due to too much bleeding
>40% of patients clots are resistant
37
what does plasmin do?
it is a protease and it cleaves the triple helix of the fibrin polymer --produces d dimers that are soluble and cleared by the liver
38
what can be used as a marker for thrombosis
d dimer presence
39
describe the protein C-protein S pathway
1. thrombomodulin appears on endothelial cell plasma membranes
2. once enough thrombin has accumulated, it interacts with thrombomodulin
3. through negative feedback mechanisms, converts thrombin from procoagulant to anti-coagulant
4. does this by exposing a new active site on the thrombin molecule and blocking procoagulant binding site
5. leads to activation of protein C (a protease) with protein S
6. this leads to inactivation and cleavage of factor Va, VIII (cofactors on platelet membranes)
deficiency of protein C or S results in increased risk of thrombosis
40
how does antithrombin work?
it is a glycoprotein that is found free floating in the blood
produced by the liver
*most important and prevalent*
particularly inhibits THROMBIN/Xa
negative feedback--binds to active site of thrombin and forms and inactive complex--does not allow thrombin to activate fibrin formation
41
how does heparin work
accelerates the antithrombin-thrombin association
42
list the tests used to monitor coagulation
1. D-dimer test
2. prothrombin time (PT)
3. activated partial thromboplastin time (aPTT)
43
d dimer test
- detects for the presence of a THROMBUS
| - normal values are
44
Prothrombin time (PT) test
- used to monitor coagulation state when patient is on WARFARIN
- measures the time required for coagulation from the EXTRINSIC and common pathways
- involves addition of thromboplastin and Ca2+ into plasma sample
- now given as the International Normalized Ratio
- measurement of clotting time
- prothrombin time (in seconds) for a normal individual varies from lab to lab, country to country--caused problems
- INR created to standardize the test--each manufacturer assigns an ISI value
- normal INR = 1
- on anticoagulant drugs, INR is >1
45
Activated partial thromboplastin time (aPTTT)
used to monitor coagulation state when patient is on HEPARIN
measures the time required for coagulation from the INTRINSIC and common pathways
involves addition of partial thromboplastin and Ca2+ and kaolin into plasma sample
also called partial thromboplastin time
thromboplastin is a crude brain extract of phospholipid and tissue factor
partial thromboplastin consists of phospholipid but no tissue factor
46
what are the important hereditary risk factors for venous thrombosis?
1. gain of function factor
2. loss of function factor
1. factor V Leiden
prothrombin gene mutation
increased factor VIII
2. protein C deficiency
antithrombin deficiency
increased homocysteine
47
what are the three overall groups of acquired risk factors for venous thrombosis
1. stasis
2. vascular injury
3. hypercoagulative state
48
what risk factors for venous thrombosis are associated with stasis
1. obesity
2. pregnancy
3. age
4. immobility--usually inpatients; rarely due to airline travel
5. hospitalization
49
what risk factors for venous thrombosis are associated with vascular injury
1. surgery--hip and knee replacements
2. trauma
3. malignancy
4. inflammation
50
what risk factors for venous thrombosis are associated with hypercoagulative state
1. pregnancy
2. age
3. malignancy
4. hyperviscosity--i.e due to rare cancer of RBCs
5. meds--Oral contraceptives
6. post-partum--natural increase in factor VIII post-labor to prevent excessive bleeding can upset the pro/anticoagulant balance and result in thrombosis
51
what are some other risk factors for venous thrombosis
1. hormonal--> estrogen is a stronger risk factor than progesterone
2. antiphospholipid antibody syndrome (APLS)-->body forms autoantibodies towards phospholipids; lupus anticoagulant, anticardiolipin antibodies; B2 glycoprotein antibodies--> interferes with PTT test so it looks like theyre at greater risk of bleeding but actually are at greater risk of clotting
52
what % of people with first unprovoked VTE have a hereditary disorder?
50%
53
how do hereditary and acquired risk factors come together to provide total risk for VTE?
if an individual has both, the effects are supra-additive, in that the relative risk due to having both is more than the sum of the individual risks
54
what are hypercoagulable states
increased clotting factors, decreased anticoagulants and fibrinolysis
occur in the setting of:
1. hereditary thrombophilias
2. pregnancy
3. post partum period
4. age
5. malignancy
6. hyperviscosity (polycythemia)
7. meds (oral contraceptives)
55
name two hereditary thrombophilias
1. factor V leiden
| 2. AT-III deficiency
56
list 5 lab tests used to test for hypercoagulable states
1. dRVVT (dilute Russell venom viper test)
2. testing for antiphospholipid antibodies
3. prothrombin time
4. aPTT
5. thrombin time
57
what does the dRVVT test?
- assessed presence of LUPUS anticoagulant (antiphospholipid syndrome)
- mixing studies--> distinguish between clotting factor deficiency and presence of lupus anticoagulant
1. if prolonged dRVVT coagulation time, mix patients blood with normal blood (which has clotting factors)
2. if coagulation time is now corrected, patient has deficiency in clotting factors
3. if the coagulation time is NOT corrected, patient likely has lupus anticoagulant
- -> antiphospholipid syndrome
58
how do you test for antiphospholipid antibodies
ELISA--> detect Ab to phospholipids (CARDIOLIPIN) or phospholipid binding proteins (B2-MICROGLOBULIN)
when antibodies interfere with phospholipid-dependent coagulation tests--> lupus anticoagulants
59
what are you measuring when you test thrombin time
you incubate the plasma with thrombin (IIa) and this measures FIBRINOGEN FUNCTION only
60
when do you test for hereditary factors?
- unprovoked +/- recurrent VTE
- strong family Hx
- purpura fulminans in neonates and children--requires URGENT protein C&S testing
61
what is the definition of acute heart failure
(acute decompensated HF)
defined as a short term or rapid change in heart failure signs and symptoms resulting in need for urgent therapy
examples include MI, arrhythmias, or sudden loss of valve function
62
how does acute left ventricular failure affect pulmonary pathophysiology
in acute HF, there is a sudden shift of blood volume from systemic to pulmonary circulation
this causes:
1. dilation of vessels
2. heavy, wet, frothy lungs when cut
3. hyaline granular fluid
4. acute pulmonary edema--acute build up of fluid in the lungs
5. potential pneumonia because it is an ideal culture medium
6. frothy sputum because of surfactant
63
what is the pathogenesis of chronic left ventricular failure
incapacity of the left heart to pump away all blood presented to it by RV
64
what are diagnostic features of chronic LV failure
fluid accumulation in alveolar spaces
congestion
rales
microhemorrhages
rusty sputum
65
what are the typical etiologies of chronic pulmonary congestion
- moderate LV failure
| - stenotic mitral valves
66
what is the pathology of chronic LV failure in the pulmonary system?
1. gross
2. microscopic
```
chronic lesions
1. i.e rheumatic fever' heavy wet lungs
2. congested capillaries
microhemorrhages
3. "heart failure" cells (macrophages engulf hemoglobin)
4. lower lobe edema
5. CAPILLARIES UNDER PRESSURE
```
67
what happens as a result of obstruction in the pulmonary vasculature
whether due to something like a pulmonary embolus or anything else--> may result in changes within the right ventricle as well as the left ventricle secondarily
an increase in the afterload for the right ventricle will cause the right ventricle to first dilate (if acute) and then overtime/chronically hypertrophy (pressure overload, so concentric hypertrophy)
the hypertrophy will ultimately increase the O2 demand of the right heart
the dilation will cause a number of different malformations--i.e tricuspid regurgitation or deviation of the interventricular septum into the left ventricular chamber, reducing its volume
68
what is the result of a deviated interventricular septum as a result of RV hypertrophy from pulmonary obstruction?
reduces the LV chamber size
this will decrease the amount of filling for the LV, which compounds the problem of less filling due to pulm obstruction
also means there is less blood to pump out to rest of body, making exercise more difficult
would also decrease coronary blood flow--> less perfusion leads to problems in overworked RV
69
what is cor pulmonale
right sided heart failure due to pulmonary hypertension
70
symptoms of cor pulmonale
breathlessness
peripheral edema
JVC distension
hepatomegaly
71
causes of cor pulmonale/pulmonary obstruction
1. PULM EMBOLISM--acute and massive--very serious
2. acute pulmonary infection--may lead to rapid worsening of cor pulmonale
3. chronic obstructive pulmonary disease--chronic bronchitis, emphysema (MOST COMMON CAUSE)
4. diseases of the pulmonary vasculature (chronic thromboembolic disease)
5. diffuse interstitial lung disease (pulm fibrosis)
6. obstructive sleep apnea
7. obesity hypoventilation syndrome
72
name an antiplatelet agent
aspirin
73
name an anticoagulant that is a calcium ion chelator
citrate
EDTA
74
name an anticoagulant that accelerates inhibition of thrombin and factor Xa by antithrombin
heparin
75
name an anticoagulant that inhibits liver carboxylation of Gla proteins
coumarol drugs (warfarin)
aka blood thinners
76
name an anticoagulant that directly inhibits thrombin and factor Xa
new oral anticoagulants
77
name a thrombolytic agent
tPA (clot busters)
78
MOA of unfractionated heparin
-amplifies the anticoagulant effect of antithrombin III
(which is a natural plasma protease inhibitor of thrombin and factor Xa)
-inhibits factor Xa by binding only antithrombin III
-inhibits thrombin by binding antithrombin III and thrombin
79
pharmacokinetics of of unfractionated heparin
- very complex
- dose-response curve is difficult to predict, therefore Tx must be individualized and monitored with aPTT
- reduced bioavailability because it binds to a variety of plasma proteins
- shorter half life
- administered via IV or SC
80
side effects of both unfractionated and low molecular weight heparin
1. heparin-induced thrombocytopenia (HITS)--> antibodies against heparin/platelet factor 4 complex--> platelets become activated and sticky leading to thrombocytopenia, bleeding due to this, +/- thrombosis (greater chance with unfractionated heparin due to increased plasma protein binding)
2. hemorrhage--unfractionated heparin is reversible with protamine sulfate
3. osteoperosis
4. hyperkalemia
5. fever
81
MOA of LMW heparin
- amplifies the antigoaculant effect of antithrombin III
- most molecules are too small to bind both antithrombin III and thrombin at the same time
- mediates most of the anticoagulant effects through inhibition of factor Xa which minimal effects on factor IIa
82
pharmacokinetics of LMW heparin
- more predictable dose response curve than unfractionated
- does not need to monitor with aPTT
- less plasma protein binding
- longer half life
- administered SC
83
indications for both heparin types
1. treatment and prevention of inappropriate thrombosis such as VTE, PE, DVT caused by stasis, endothelial damage, or a hypercoagulable state
2. treatment and prevention of arterial thrombosis
3. initial management of: unstable angina, acute MI, coronary angioplasty or stent placement, cardiac surgery requiring bypass machine
4. disseminated intravascular coagulation (DIC)
84
which type of heparin is best for
1. sick inpatients?
2. outpatients?
3. concern of bleeding risk and need for invasive procedures
4. stable inpatients?
1. unfractionated
2. LMW
3. unfractionated because is rapidly reversible protamine sulfate
4. LMW
85
which type of heparin should be used in the context of renal failure
unfractionated (because LMW accumulates in renal failure)
86
what are the two new oral anticoagulants
rivaroxaban
dibigatran
87
what does rivaroxaban do
inhibits factor Xa
88
what does dibigatran do
inhibits thrombin
89
advantages of the new oral anticoagulants
do not require continuous monitoring of clotting time
90
disadvantage of new oral anticoagulants
no current antidote (bind very tightly--requires 10 hrs to clear from patient or treat with fresh frozen plasma)
91
what does warfarin do? (generally)
inhibits liver carboxylation of Gla proteins
i.e inhibits prothrombin, factor IX, factor X, factor VII, protein C&S
92
will warfarin break down already formed clots?
no
93
MOA of warfarin
- vitamin K is a key factor in hepatic activation of 4 coagulation factors (II, VII, IX, and X)
- to act as a cofactor vitamin K must be in the reduced form (converted by VKOR
- warfarin inhibits VKOR by blocking formation for reduced vitamin K and inhibiting activation of the 4 clotting factors
- highly plasma protein bound--fat soluble vitamin
- warfarin is a vitamin K analogue, so it competitively inhibits the vitamin K epoxidase (VKOR?)
- this means that the vitamin K dependent clotting factors cant get the gamma-carboxylate group and they are unable to be activated
94
pharmacokinetics of warfarin
- readily and completely absorbed from the GI tract
- inactivated by the liver and excreted through the kidneys
- takes around 3 days to work since the relative turnover of these clotting factors is about 72 hours on average
- it is metabolized by many different CYP450 enzymes (hence the large number of side effects)
95
how is warfarin administered
orally (100% bioavailable)
96
how is warfarin reversed
replacement of drug with vitamin K
97
SEs of warfarin
1. hemorrhage
2. skin necrosis
3. purple toe syndrome
4. microembolization
5. teratogenicity
6. less common: agranulocytosis, leukopenia, diarrhea, nausea, vomiting
98
drug interactions with warfarin
MANY
99
indications for warfarin
1. prophylaxis and treatment of VTE
2. prophylaxis and treatment of atrial fibrillation
3. valvular stenosis
4. heart valve replacement
5. MI
6. antiphospholipid syndrome
* replaces heparin at discharge
* most common treatment for PE or DVT
100
contraindications for warfarin
1. pregnancy
2. recent events that predispose to bleeding (stroke,surgery)
3. platelet disorder
4. hypersensitivity
5. vitamin K deficiency
6. non-steroidal anti-inflammatory drugs
101
give 3 examples of thrombolytic agents
1. tPA (tissue plasminogen activator)
2. streptokinase, staphylokinase (bacteria)
3. uPA (urokinase)
102
indications for thrombolytic therapy
submassive PE (hypotension, severe hypoxemia, right heart failure)
selective cases of massive DVT
ischemic stroke
103
MOA of thrombolytic agents
activate plasminogen--> plasmin
| fibrin--> D2E/d dimer
104
limitations of thrombolytic agents
bleeding risk is 3X higher than anticoagulant therapy, especially intracranial bleeding
105
DDx for DVT
1. varicose veins
2. ruptured baker's cyst
3. muscle or tendon
4. joint
5. peripheral edema
*need to distinguish between deep (iliac, femoral, popliteal, tibeal) and superficial (greater/lesser saphenous vein)
106
Well's criteria for DVT
| clinical likelihood for having a DVT
1. active cancer
2. paralysis or casting
3. bedridden >3d or surgery within 3 months
4. Hx of DVT
5. likely alternative diagnosis (-2)
6. calf swelling >3cm
7. superficial veins
8. unilateral edema
9. swelling of entire leg
10. localized pain over deep venous system
high risk = >4
107
imaging to evaluate VTE/DVT
doppler ultrasound
indicated when low clinical probability with + d dimer
indicated when moderate to high Wells score
+ confirms Dx
- repeat in 5-7 days
108
DDx for pulmonary embolism
1. MI
2. pericarditis
3. pneumonia
4. pneumothorax
5. chest wall pain
6. CHF
7. pleuritis
8. pericardial tamponade
109
what is the PE imaging protocol
CT scan
VQ scan can also be performed
110
which anticoagulants are immediate acting? delayed acting?
immediate = heparin
delayed = warfarin
111
which patients with diagnosed venous thromboembolism should be investigated for hypercoagulable states
1. idiopathic VTE
| 2. VTE at young age (
