Bleeding, Coagulopathy, and Anticoagulation Flashcards
(230 cards)
1
Q
What is the “Hemostasis Tripod”?
A
Primary hemostasis
Coagulation
Vasoconstriction
2
Q
Define “Primary Hemostasis”
A
Mediated by platelets
3
Q
Define “Coagulation”
A
A chemical process
4
Q
Define “Vasoconstriction”
A
A mechanical process
5
Q
Platelets adhere to disrupted vessel wall via?
A
Platelet surface membrane glycoprotein receptor Ib and vWF
6
Q
Platelets also adhere to one another via?
A
Surface receptor glycoprotein IIb/IIIa and fibrinogen
7
Q
Name three actions of platelets
A
Production of arachidonic acid vasoconstrictors, release of various proteins from platelet storage granules, and provide site for generation of thrombin and subsequent fibrin formation
8
Q
Name two arachidonic acid vasoconstrictors
A
Thromboxane A2 and prostaglandins
9
Q
What types of proteins are released from platelet storage granules?
A
Platelet agonists ADP and serotonin, coagulation factors vWF and coagulation factor V, heparin-binding proteins, growth factor/chemokines PDGF
10
Q
Platelet surface provides site for?
A
Generation of thrombin and subsequent fibrin formation
11
Q
What is the “extrinsic system”?
A
Tissue Factor-Factor VII pathway
12
Q
In the extrinsic system, complex forms between?
A
Tissue factor and factor VII after tissue factor is exposed to blood
13
Q
In the extrinsic system, after factor VII is activated, what happens?
A
Tissue factor-factor VIIa complex binds and activates factor X
14
Q
In the extrinsic system, factor Xa is responsible for what conversion?
A
Converts prothrombin (factor II) to thrombin (factor IIa)
15
Q
The conversion of prothrombin to thrombin requires what cofactor?
A
Factor V
16
Q
The conversion of prothrombin to thrombin is most efficient in the presence of?
A
A phospholipid surface, e.g., activated platelet
17
Q
What is the alternate (“secondary”) pathway of coagulation?
A
Amplifies the effects of the first pathway, same initiating factors
18
Q
In the secondary pathway, what activates factor IX?
A
Tissue factor VIIa complex activates factor IX
19
Q
Factor IX and cofactor VIII activate what?
A
Factor X
20
Q
The secondary pathway results in the formation of?
A
Thrombin
21
Q
What is the first step in the third coagulation pathway?
A
Thrombin itself activates factor XI
22
Q
What does factor XIa activate?
A
Factor IX
23
Q
What does the third pathway result in?
A
Pathway proceeds to additional thrombin formation
24
Q
What is necessary for the conversion of fibrinogen into fibrin?
A
Thrombin and coagulation
25
Thrombin and coagulation facilitates its own formation by?
Activating coagulation factors and cofactors
26
Thrombin and coagulation is a strong activator of?
Platelet aggregation
27
How does thrombin and coagulation mediate fibrinogen cleavage?
Forms fibrin monomers and subsequent polymers; cross linking of fibrin takes place by thrombin-activated factor XIII (the ultimate step in the coagulation cascade)
28
What does Tissue factor pathway inhibitor (TFPI) do?
Inhibits the impact of tissue factor, which stops the whole cascade from beginning
29
What activates circulating protein C?
Endothelial cell-bound enzyme thrombomodulin in association with thrombin
30
Activated protein C degrades what?
Cofactors V and VIII
31
Activation of protein C requires what essential cofactor?
Protein S
32
What forms complexes and inactivates thrombin and factor Xa?
Antithrombin III
33
Antithrombin III is strongly enhanced by the presence of?
Heparin
34
Protein C inhibits which pathway of coagulation?
Secondary pathway and final pathway (breaks down activated factors V and VIII)
35
Protein C initiates the breakdown of?
Fibrin clot
36
How does Protein C shut down the coagulation cascade?
By inactivating Factors V and VIII
37
What are tPA and uPA and where are they found?
Plasminogen activator molecules found in endothelial cells
38
What causes the release of tPa and uPA?
Several stimuli, including hypoxia, acidosis
39
At what two levels is fibrinolysis inhibited at?
Activator inhibitors (PAIs) and circulating protease inhibitors (e.g., alpha 2-antiplasmin)
40
What is the most common congenital coagulation disease?
von Willebrand disease
41
What is Type I vWD?
Reduced concentration (10-45% normal levels)
42
What is Type II vWD?
Dysfunctional vWF
43
What is IIa subtype of vWD?
Variable qualitative defect in GP-1 binding and multimer formation (quality not good)
44
What is IIb subtype of vWD?
"Gain of function" defect, excessive binding to platelet GP-1 (vWF works too well and you get MORE platelet aggregation) -- makes you hyper-coaguble, the opposite problem)
45
What is IIm subtype of vWD?
Monomers have decreased GP-1 binding, multimers normal
46
What is IIn subtype of vWD?
Defect in binding to factor VIII, may be diagnosed as hemophilia A
47
What is type III vWD?
Absent vWF (homozygous for gene defect); don't make any vWF
48
In which type of vWD do patients know they have it because they are symptomatic early on and likely experience severe disease?
Type III
49
Desmopressin (DDAVP) is used to treat which types of vWD?
Type I and IIa
50
DDAVP is an analogue of?
Vasopressin
51
DDAVP promotes the release of vWF stored in?
Endothelial cell-associated Weibel-Palade bodies
52
vWF links exposed collagen to?
Platelets
53
How is DDAVP given?
Nasal spray (Stimate)
54
DDAVP is contraindicated in which type of vWD?
Type IIb
55
How do you treat more severe forms of vWD?
Replacement with transfused factors
56
How long does treatment continue after surgery?
4-7 days
57
Initially, clotting is mostly dependent on?
Platelets
58
Coagulation disease results in?
Late re-bleeding after fibrinolysis (clots don't stabilize- these patients need to be treated with something that ensures clot stays long enough to prevent late re-bleeding)
59
What is the most commonly inherited coagulation disorder?
Hemophilia A (classic hemophilia)
60
How is Hemophilia A inherited?
Sex-linked recessive, 1 of 10k male births
61
Levels of which factor are variable in Hemophilia A?
Factor VIII; mild hemophilia up to 40% of normal, severe <1%
62
Patients with factor VIII greater than what percentage rarely bleed spontaneously, but will have bleeding problems after surgery or trauma?
5%
63
What develops in 10-15% of severely affected hemophiliacs?
Anti-factor VIII antibodies (factor VIII inhibitors)
64
Factor VIII levels are also decreased in what disease? Why?
vWD because vWF acts as a carrier molecule for factor VIII
65
How do you treat mild-moderate Hemophilia A?
DDAVP
66
DDAVP releases endogenous factor VIII from where?
Liver sinusoids and endothelial cells
67
DDAVP also releases what?
vWF resulting in a transient increase in factor VIII levels
68
How do you treat severe Hemophilia A?
Factor VIII transfusion
69
What does Hemophilia B is also known as?
Christmas disease
70
Hemophilia B affects what?
Factor IX
71
Name 3 hypercoaguable coagulation diseases
Protein C deficiency, Protein S deficiency, Factor V Leiden
72
Where are Proteins C and S synthesized?
Liver
73
Proteins C and S depend on?
Vitamin K
74
Mild forms of Protein C/S deficiency predispose individuals too?
Thrombosis
75
Severe forms of Protein C/S deficiency lead to?
Not compatible with life
76
What is Factor V Leiden disease?
Polymorphic factor V which resists inactivation by activated protein C (protein C not able to bind normally to factor V)
77
Factor V Leiden is present in what % of people of what descent?
5% of North American Caucasians
78
Factor V Leiden is rare in people of what descent?
Asians
79
Factor V Leiden may predispose individuals to?
Deep venous thrombosis
80
What is the source of coagulation factors?
Liver
81
What is the source of Protein C, Protein S, and fibrinogen?
Liver
82
Thrombocytopenia, sometimes seen in liver disease patients, is the result of?
Portal hypertension and associated splenomegaly
83
Function of what is impaired in cirrhotic patients?
Thrombocyte
84
What is MELD score?
Model for end-stage liver disease score
85
What is the formula of MELD score based on?
Serum bilirubin, serum creatinine, INR
86
MELD score predicts how many month mortality?
3 month (how likely are you to still live in 3 months if you don't get a new liver)
87
Higher MELD score indicates?
Worse liver
88
What disease also presents with coagulation abnormalities and risk for enhanced bleeding?
Renal failure
89
In patients with renal failure, low levels of what may contribute to the impaired function of primary hemostasis?
Hematocrit
90
Is low hematocrit frequently an important factor in renal disease patients?
Less frequently because most patients are regularly treated with erythropoietin
91
How can you test the extent of hematocrit defect?
Platelet Function Assay
92
Why do renal failure patients have coagulation abnormalities?
Attributed to impaired platelet adhesion, aggregation, and release
93
What has been shown to correct prolonged bleeding time in patients with uremia?
DDAVP
94
If insufficient correction of bleeding is achieved with DDAVP, what can be used?
Platelet concentrates
95
What additional measures need to be corrected in patients with uremia?
Anemia and hemodialysis
96
What is Aspirin's mechanism of action?
Irreversible inhibitor of platelet membrane-associated cyclooxygenase
97
Aspirin blocks the formation of what?
Thromboxane A2
98
What is Thromboxane A2?
A potent platelet agonist and vasoconstrictor
99
Do high or low doses of aspirin preferentially inhibit Thromboxane A2?
Low
100
What does aspirin do to platelet aggregation?
Irreversible (and relatively weak) inhibition of platelet aggregation
101
Aspirin may be associated with?
Significant impairment of primary hemostasis and mild enhancement of bleeding
102
What is the life span of a platelet?
10 days
103
How many days are usually required after termination of aspirin use to restore adequate platelet function and effective hemostasis?
5-7 days
104
How long will the effect of aspirin last?
For the interval needed to produce a sufficient number of new platelets not affected
105
What are the two more important adverse effects of aspirin?
Bleeding and the occurrence of hemorrhagic gastritis (or even gastric ulceration)
106
For most dental procedures, we want to continue/discontinue aspirin?
Continue (risks > benefits)
107
Clopidogrel is AKA?
Plavix
108
Clopidogrel is an oral prodrug metabolized by?
Liver
109
What % of the absorbed drug becomes active form?
15%
110
Clopidogrel is subject to?
Cytochrome genetic polymorphisms
111
What is the half life of Clopidogrel?
8 hours
112
The effects of Clopidogrel last how long in relation to a platelet?
For the platelet's lifetime
113
Clopidogrel binds irreversibly to what receptor on the platelet surface?
P2Y12 ADP receptor (prevents ADP-mediated platelet aggregation)
114
Clopidogrel is comparable to aspirin as secondary prophylaxis in patients with what three conditions?
MI, stroke, or peripheral arterial disease
115
Is there any benefit to combining clopidogrel with aspirin vs aspirin alone?
Combination superior after acute coronary event, PCI, and coronary stent placement
116
Is clopidogrel or aspirin more expensive?
Clopidogrel- much more expensive
117
Does clopidogrel or aspirin result in more clinical bruising/bleeding?
Clopidogrel
118
Is clopidogrel safe to continue through most oral surgery?
Yes, like aspirin
119
Name three other P2Y12 blockers
Ticlopidine (Ticlid), Prasugrel (Efient), and direct-acting reversible inhibitors
120
Name two direct-acting reversible inhibitors
Ticragelor (Brilinta), Cangrelor (Kengreal)
121
Do Ticlopidine and Prasugrel have a more or less rapid onset compared to clopidogrel?
More rapid onset
122
Which P2Y12 blocker is also a prodrug but with rapid conversion to active form?
Prasugrel (Efient)
123
What is the benefit of direct-acting, reversible inhibitors?
Direct acting = more rapid onset
| Reversible binding = shorter half-lie
124
What is Dipyramidole's mechanism of action?
Has anti platelet effect by inhibition of phosphodiesterase
125
Inhibition of phosphodiesterase results in?
Intracellular accumulation of cyclic AMP
126
Dipyramidole has shown what effects in clinical trails?
No significant efficacy on the prevention of thromboembolic disease
127
Dipyramidole how shown what effects in vitro?
Potent inhibitor of platelet aggregation
128
What are the most potent inhibitors of platelet aggregation?
Glycoprotein Receptor IIb/IIIa inhibitors
129
What is the mechanism of action of Glycoprotein Receptor IIb/IIIa inhibitors?
Competitive inhibitors for fibrinogen binding to the platelet IIb/IIIa receptor
130
Are IV or oral forms of Glycoprotein Receptor IIb/IIIa inhibitors most effective?
IV forms highly effective in interventional cardiology, oral forms not effective
131
Coumadin is what class of drug?
Anti-coagulant
132
Coumadin is an antagonist of?
Vitamin K
133
What is Coumadin's mechanism of action?
Blocks the essential vitamin K-dependent carboxylation of coagulation factors II, VII, IX, and X
134
By blocking these coagulation factors, Coumadin results in?
Formation of biologically inactive proteins and decreases the coagulant activity of these factors in plasma
135
Effect of Coumadin is a function of what?
The decay in the concentration of the coagulation factors, not the drug itself
136
The half-life of vitamin K-dependent coagulation factors ranges from?
6 h to 60 h
137
The full effect of Coumadin therapy is delayed for how long?
2 or 3 days
138
Full restoration of normal coagulation after termination of Coumadin therapy requires how many days?
At least 3-5 days
139
Dose-effect relationship of Coumadin varies considerably due to what three factors?
Binding to plasma albumin, variable vitamin K intake, variable clearance by the liver
140
What is the most important side effect of Coumadin treatment?
Bleeding
141
What may occur with an associated protein C deficiency in patients on Coumadin?
Rare Coumadin-induced skin necrosis
142
In rare Coumadin-induced skin necrosis, are levels of coagulation factors still normal?
Yes; a net pro-coagulant state results
143
The new oral anticoagulants are inhibitors of what factor?
Xa
144
What new drug is a direct thrombin inhibitor?
Pradaxa
145
What three new drugs are factor Xa inhibitors?
Xarelto, Eliquis, Savaysa
146
Are the new oral anticoagulants affected by diet, liver function, etc. or require regular lab monitoring?
No
147
What is the onset and half-life of new oral antiocoagulants?
Relatively rapid onset (2-3 hours) and short half-life (8-12 hours)
148
Impaired renal function affects new oral anticoagulants how?
Increases and prolongs drug effect
149
How do the new oral anticoagulants compare to Coumadin with stroke prevention?
Comparable
150
How do the new oral anticoagulants compare to Coumadin with risk of extra cranial bleeding?
Same, oral anticoagulants possibly higher
151
Is routine testing of effect available for new oral anticoagulants?
No
152
Can you reverse new oral anticoagulants?
Very limited
153
How much is known about the safety of new oral anticoagulants?
Little- once bleeding starts, there may be little to do but wait
154
Discontinuing new oral anticoagulant for how many days before oral surgery is prudent?
1-2 days
155
Discontinuing new oral anticoagulant before oral surgery is longer in which patients?
Renal patients
156
What is Idarucizamab (Praxbind)?
Reversal of dabigatran (Pradaxa); is is an anti-dabigatran mAb fragment
157
When is Praxbind indicated?
For emergency surgery or life-threatening bleeding
158
Peak effect of Praxbind is?
Within 4 hours; reverses anticoagulation immediately
159
Patients on Praxbind remain in normal coagulation state in how much time?
24 hours (Pradaxa may be resumed at that time)
160
What risk is associated with Praxbind?
Exposure to underlying thrombotic disease consequence
161
Serious risk of Praxbind in patients with?
Hereditary fructose intolerance because solution contains Sorbitol
162
What is Andexanet Alfa?
Not yet approved; Factor Xa decoy protein given as infusion
163
Andexanet Alfa reverses anticoagulation in?
Less than 5 minutes
164
What is PER977 (ciraparantag, aripazine)?
Nonspecific agent for anti-Xa and anti-thrombin agents (heparin, dabigatran)
165
How is Heparin given?
Parenterally
166
What is Heparin a mixture of?
Glycosaminoglycans of various molecular sizes isolated from intestines or lungs of pig, cow or other cattle
167
What does Heparin bind to?
Antithrombin III
168
Binding to Antithrombin III causes?
Potentiates inhibition of factors IIa (thrombin) and Xa more than 1000-fold
169
Effect of heparin after IV administration is?
Immediate
170
What kind of half-life does Heparin have?
Dose-dependent half-life
171
After IV administration of a 5000U bolus of Heparin, the mean half life is?
60-90 min
172
Heparin is often given as?
Continuous IV infusion
173
How is Heparin monitored?
Frequent laboratory monitoring, usually by aPTT (because anticoagulant effect of heparin may be highly variable)
174
In special conditions like surgery, what can be used to monitor heparin?
Whole blood activated clotting time (ACT)
175
When must heparin be given parenterally?
When used as prophylaxis against thrombosis, requires frequent subcutaneous injections
176
How are LMWHs given?
Parenterally- usually subcutaneous
177
What is the average MW of LMWHs?
4-6 kDa
178
What type of effects can be seen with LMWHs?
In some situations have a more favorable antithrombotic effect and induce fewer bleeding complications than unfractionated heparin
179
What two benefits are associated with LMWHs?
Predictable inter- and intraindividual bioavailability and clearance & much longer half-life compared to unfractionated heparin
180
Predictable inter- and intraindividual bioavailability reduces the need for?
Frequent laboratory monitoring and frequent dose adjustments
181
Much longer half-life compared to unfractionated heparin is advantageous when?
When stable anticoagulation is required over a long period of time
182
much longer half-life compared to unfractionated heparin may complicate situations that require?
Easily adjustable anticoagulation, like patients at high risk for bleeding
183
Large randomized controlled trials have demonstrated the efficacy and safety of LMWH in the postoperative prevention of?
Venous thromboembolism in surgical patients
184
What are pentasaccharides?
Parenteral drugs
185
What is the prototype of pentasaccharides?
Arixtra (fondaparinux)
186
When are pentasaccharides indicated?
For DVT prophylaxis or DVT/PE treatment
187
What is the mechanism of action of pentasaccharides?
Synthetic compounds that exert antithrombin-dependent exclusive inhibition of factor Xa
188
Is Xa inhibition direct or indirect by pentasaccharides?
Indirect
189
Some evidence that pentasaccharides are superior to LMWH for prophylaxis of?
Venous thromboembolism in patients undergoing hip or knee replacement
190
What is the most frequent adverse effect of heparin or heparin derivative treatment?
Bleeding
191
What is heparin-induced thrombocytopenia (HIT)?
An immunological response to heparin characterized by thrombocytopenia and thromboembolism
192
When does HIT occur?
5-7 days after initial exposure to heparin, but may be an immediate complication if the patient has received heparin previously
193
Alternative anticoagulant therapy may consist of treatment with hirudin or heparinoids but not with coumarin derivatives, which may cause?
Skin necrosis
194
Long-term use of heparin has been associated with?
Osteopenia
195
Is there a higher or lower incidence of osteopenia with LMWH?
Lower incidence
196
What is a thrombolytic agent?
Plasminogen activators (recombinant endogenous plasminogen activators, tPA)
197
How are plasminogen activators administered?
At a dose 1000x physiological concentration
198
What is the most important side effect of thrombolytic treatment?
Bleeding
199
What 3 signs on a physical exam might point to a defect in the coagulation system?
Abnormal bruising, petechiae, splenomegaly
200
Preoperative screening in patients with signs or symptoms of a bleeding tendency includes what three tests?
A platelet count, a PTT, and PT/INR
201
If an abnormality in primary hemostasis is suspected, what is tested and what is measured?
Platelet function is tested and vWF is measured
202
Is platelet function testing widely clinically relevant?
No
203
What is PT/INR?
Prothrombin time test; mixture of calcium and thromboplastin is added to citrated blood and the time to clot formation is measured
204
What does the PT value reflect?
The coagulation ability of the TF-VIIa coagulation pathway
205
Tissue thromboplastin is a mixture of?
TF and phospholipid membrane fragments
206
What is normal PT?
Averages 12 +/- 2 seconds
207
Define INR
Ratio of patient's PT to the individual laboratory standard; provides a standardized way to report the PT time relative to control
208
Are PT or INR values comparable between laboratories?
INR values are comparable between laboratories, but PT values are not
209
PT is prolonged by deficiencies in what 5 things?
Factors VII, X, V, prothrombin, fibrinogen
210
PTT measures?
Slower "intrinsic" pathway: normal is roughly 25-40 sec
211
PTT is used commonly to monitor?
Anticoagulation with heparin
212
Deficiencies in what two factors will not be detected with PTT test?
VII or XIII
213
PTT is used commonly to monitor?
Anticoagulation with heparin
214
In vitro, PTT requires all clotting factors except?
Factor VII
215
Prolonged aPTT (activated partial thromboplastin time) may indicate?
Use of heparin, antiphospholipid antibody (esp lupus anticoagulant), coagulation factor deficiency, sepsis, or presence of antibodies against coagulation factors
216
What was the standard method for assessing primary hemostasis for many years?
Bleeding time
217
Bleeding time can be affected by ingestion of?
Aspirin
218
Is bleeding time sensitive or specific?
Neither
219
What is used in place of bleeding time?
Platelet function analyzer-100 (PFA-100)
220
How does PFA-100 work?
Blood sample put into test cartridge, vacuum draws blood through thin glass coated with collagen and E/ADP, coating activates platelets in the moving sample and promotes platelet adherence and aggregation
221
Closure time is measured by?
Time it takes for a clot to form inside the glass tube and prevent further blood flow
222
An initial screen for PFA-100 is done with?
Collagen/EPI
223
If CT is normal on initial screen, what does this indicate?
Unlikely that a platelet dysfunction exists
224
What is used to confirm an abnormal collagen/EPI test?
A collagen/ADP test is run
225
If the collagen/ADP test is normal, then the abnormal collagen/EPI test may be due to?
Aspirin ingestion
226
If both collagen/ADP and collagen/EPI tests are abnormal, then what does this indicate?
Patient likely has a platelet dysfunction
227
What is the gold standard for platelet function analysis?
Platelet aggregometry (PAA)
228
What is studied in PAA?
The response of either whole blood or platelet-rich plasma to specific agents known to induce aggregation of platelets is studied
229
How does PAA work?
A beam of light passes through a suspension of stirred platelets and the percent transmission is measured.
When an agonist such as thrombin is added, a small initial drop in light transmission typically occurs as platelets change shape from discs to spheres.
As platelet aggregation occurs, light transmission increases
230
Platelet aggregation tests use a battery of agonists like?
ADP, collagen, ristocetin, and arachidonic acid
