Coagulation Flashcards
1
Q
A balance between clot generation, thrombus formation, and regulatory mechanisms that inhibit uncontrolled thrombogenesis is called?
A
Hemostasis
2
Q
What are the goals of hemostasis?
A
- Limit blood loss from vascular injury
- Maintain intravascular blood flow
- Promote revascularization after thrombosis
3
Q
What is Primary Hemostasis?
A
Immediate platelet deposition at the endovascular injury site (adhesion, activation, and aggregation)
4
Q
What role do vascular endothelial cells play in hemostasis?
A
Antiplatelet, anticoagulant, and fibrinolytic effects to inhibit clot formation
5
Q
Are endothelial cells pro or anti clot?
A
Anti-clotting
6
Q
Endothelial cells are ___ charged to repel ______
A
Negatively charged; Repel platelets
7
Q
Endothelial cells produce platelet inhibitors such as (2)
A
Prostacyclin and nitric oxide
8
Q
What are platelets derived from? What is their lifespan?
A
Derived from bone-marrow megakaryocytes
Lifespan: 8-12 days
9
Q
How many platelets are consumed and formed daily?
A
10% consumed to support vascular integrity and 150 billion formed daily
10
Q
Damage to the endothelium exposes the underlying
A
Extracellular matrix (ECM)
11
Q
What is contained within the ECM?
A
Collagen
vWF (von Willebrands Factor)
Glycoproteins
12
Q
Platelets undergo which three phases of alteration?
A
Adhesion
activation
aggregation
13
Q
What occurs upon exposure to ECM proteins?
A
Adhesion
14
Q
This is stimulated when platelets interact with collagen and tissue factor (TF), causing the release of granular contents.
A
Activation
15
Q
What are the two types of storage granules in platelets?
A
Alpha Granules & Dense Bodies
16
Q
What do alpha granules contain?
A
Fibrinogen, factors V & VIII, vWF
17
Q
What do dense bodies contain?
A
ADP, ATP, calcium, serotonin, histamine, and epinephrine
18
Q
What occurs when released granular contents activate additional platelets, propagating plasma-mediated coagulation?
A
Aggregation
19
Q
Each stage of the clotting cascade requires assembly of membrane-bound activated ____?
A
Tenase-complexes
20
Q
What is each tenase complex composed of?
A
- Substrate (inactive precursor)
- Enzyme (activated coagulation factor)
- Cofactor (accelerator or catalyst)
- Calcium
21
Q
The extrinsic pathway of coagulation starts off with what?
A
Endothelial injury, exposing tissue factor to the plasma
22
Q
Tissue Factor forms an active complex with what other factor?
A
VIIa (TF-VIIa Complex)
23
Q
TF/VIIa complex binds to and activates what factors?
A
Factor X –> Xa
Factor 9 –> 9a (in the intrinsic pathway)
24
Q
From the intrinsic pathway, which 2 factors convert Factor X to Xa?
A
Factor 9a and Calcium
25
which factor initiates the final common pathway?
Factor Xa
26
What does Factor 10 do?
Augments the intrinsic pathway (via factor 9)
27
What is the role of factor XIIIa in coagulation?
Factor XIIIa stabilizes the fibrin clot by cross-linking.
28
The extrinsic pathway is the initiation phase of what type of homeostasis?
Plasma-mediated homeostasis
29
Activated thrombin (IIa) activates which factors to amplify thrombin generation and activate platelets?
5, 7, 8, 11
30
In the common pathway, Factor Xa binds with Factor _____ to form which complex?
Factor Xa binds with Va to form Prothrominase complex
31
Prothrombinase Complex converts ___ to ____
Prothrombin (II) to Thrombin (IIa)
32
Thrombin attaches to the _____ and converts _____ to ______
Thrombin attaches to platelets and converts fibrinogen (I) to fibrin (Ia)
33
Thrombin cleaves ________ from fibrinogen to generate _______ which polymerizes into strands to form a basic clot
Fibrinopeptides; Fibrin
34
Factor ____ crosslinks the fibrin strands to stabilize and make an insoluble clot that is resistant to fibrinolytic degredation
13a
35
Platelets adhere to _____ to become activated and recruit additional platelets
collagen
36
Fibrin molecules _______ to form a mesh that stabilizes the clot
crosslink
37
The intrinsic pathway begins with which factor?
Factor 12a
38
Initially, the intrinsic pathway was thought to occur due to endovascular contact with _____ _____ substances
negatively charged (glass, dextran)
39
Now we know that the intrinsic pathway plays a minor role in initiation of hemostasis and is more of an _____ ______ for thrombin generation intitiated by the ______ ______
Amplification system; extrinsic pathway
40
Most thrombotic events follow which pathway?
Extrinsic pathway
41
Lab coag studies rely on which pathway to activate the pathway?
Intrinsic pathway
42
Contact with what surface causes Factor 12 to be activated?
Negatively charged surface
43
Factor 12a converts ____ to _____
Factor 11 to 11a
44
4 Things convert Factor X to Xa, what are they?
1. Factor 9a
2. Factor 8a
3. Platelet membrane phospholipid
4. Calcium
45
What is the common pathway in coagulation?
In the common pathway, factor X becomes Xa and binds with Va to form the prothrombinase complex, converting prothrombin into thrombin.
46
Both intrinsic and extrinsic tenase complexes facilitate formation of
Prothrombinase complexes
47
The intrinsic Tenase complex is made up of
1. an activator (the catalyst)
2. Factor 9a
3. Factor 8a
4. Calcium
48
The extrinsic tenase complexes are made up of
1. Injury (the catalyst)
2. TF
3. Factor 7a
4. Calcium
49
What are the four major coagulation counter-mechanisms?
* Fibrinolysis
* Tissue factor pathway inhibitor (TFPI)
* Protein C system
* Serine Protease Inhibitors (SERPINs)
50
Fibrinolysis: endovascular TPA and urokinase convert ___ to ___
plasminogen to plasmin
51
During Fibrinolysis,_____ breaks down clots enzymatically, and degrades Factors 5 and 8
Plasmin
52
Protein C system inhibits which factors? (3)
1. Factor 2
2. Factor 5a
3. Factor 8a
53
Tissue factor pathway inhibitor (TFPI) forms a complex with Xa that inhibits _____ complex along with Xa; thereby ________ the extrinsic pathway
Inhibits TF/7a complex; thereby downregulating the extrinsic pathway
54
Serine protease inhibitors (SERPIN) consist of what 3 things
1. Antithormbin
2. Heparin
3. Heparin cofactor II
55
Antithrombin inhibits (5)
Thrombin, Factors 9a, 10a, 11a, 12a
56
What is the mechanism of Heparin?
Binds to antithrombin causing a conformational change that accelerates AT activity
57
What is the mechanism of action of Heparin cofactor II?
Inhibits thrombin alone
58
What is the most effective predictor of bleeding?
Careful bleeding history
59
What should you ask about in pre-op assessment?
History of:
nose bleeds
bleeding gums
easy bruising
excessive bleeding during dental extraction
surgery
trauma
childbirth and blood transfusions
60
vWF is the most common inherited bleeding disorder which leads to defective ____ ______
Platelet adhesion
61
How does vWF help with platelet adhesion?
Prevents degradation of Factor 8
62
What are common laboratory findings in von Willebrand's disease?
Platelets and PT will be normal
aPTT might be prolonged depending on the level of factor VIII.
63
What are better tests to asses for vWF?
Factor 8 level, Plt function assay
64
What drug increases vWF?
Desmopressin (DDAVP)
65
What do you give for intraop bleeding?
vWF and Factor 8 concentrates
66
What characterizes hemophilia A?
Factor VIII (8) deficiency
67
What characterizes hemophilia B?
Factor 9 deficiency
68
What fraction of hemophilia is genetically inherited?
2/3
69
Hemophilia presents in childhood as spontaneous hemorrhage in the
joints and muscles
70
What do hemophilia labs show?
Normal PT, platelets, bleeding time
Prolonged PTT
71
What should you do if your patient shows up and has hemophilia?
Consult hematologist
Consider DDAVP and Factor 8/9 before surgery
72
What is the most significant cause of intra-op bleeding?
Anticoagulation medication
73
What factors does the liver produce?
Factors: 5,7,9,10,11,12
Protein C & S
Antithrombin
74
Liver disease leads to what implication on hemostasis?
1. Impaired synthesis of coagulation factors
2. Quantitative and qualitative platelet dysfunction
3. Impaired clearance of clotting and fibrinolytic proteins
75
What do labs show in liver disease?
Prolonged PT and possible prolonged PTT
76
Lab values only reflect the lack of _____ ______ factors, and do not account for the lack of _______ _____Factors
Pro-coagulation; Anticoagulation
77
Liver Disease patients have sufficient amounts of _____ production
thrombin
78
CKD patients have anemia due to: (2)
1. Lack of EPO
2. Platelet dysfunction (d/t uremic environment)
79
Treatment of CKD platelet dysfunction includes:
1. Cryo (rich in vWF)
2. DDAVP (tachyphylaxis)
3. Conjugated estrogens (give 5 days preop)
80
What is pathological hemostatic response to ______ causing excessive activation of the extrinsic pathway, which generates intravascular _____
DIC
TF/7a Complex; Thrombin
81
What triggers Trauma-Induced Coagulopathy (TIC)?
Trauma, Amniotic fluid embolism, malignancy, sepsis, incompatible blood transfusion
82
DIC Labs?
Decreased Platelets
Prolonged: PT/PTT/Thrombin time
Increased soluble fibrin & Increased FDP
83
What are causes of coagulopathies?
Acidosis
Hypothermia
Hemodilution
84
Trauma induced coagulopathy (TIC) is thought to be related to ..?
Activated protein C decreasing thrombin generation
85
What is the driving factor for Protein C activation in TIC?
Hypoperfusion
86
In TIC, the endothelial glycocalyx degrades which might result in
Auto-heparinization
87
The most common inherited prothrombin diseases are caused by mutations in which 2 factors?
Factor 5 and 2 (Prothrombin)
88
Factor V Leiden mutation leads to ______ ______ resistance, present in 5% of the Caucasian population.
Activated Protein C
89
Prothrombin mutation causes increased ____ concentration, leading to hypercoagulation
PT
90
Thrombophilia is an inherited or acquired predisposition for
Thrombotic events, generally manifesting as a venous thrombus
91
Thrombophilia pt. are highly susceptible to
Virchow's triad
92
Antiphospholipid syndrome is an AI disorder that creates antibodies against
Phospholipid binding proteins in the coagulation system
-Characterized by recurrent thrombosis and pregnancy loss
-Requires lifetime anti-coagulants
93
What greatly increases the risk of thrombosis in pro-thrombotic prone patients?
Oral contraceptives
Pregnancy
immobility
infection
trauma
Surgery
94
HIT is associated with _______ occurring _____ days after heparin treatment
Thrombocytopenia; 5-14 days (*for the first time you experience it), can be within 1 day if seen heparin prior
95
Who is at a high risk for HIT?
Women
High-dose patients (Cardiopulmonary bypass)
Unfractionated heparin over LMWH
96
What drug is contraindicated in HIT?
Warfarin (decreases Protein C and S synthesis)
97
How long does it take the HIT antibodies to clear from the circulation?
3 months
98
What are the laboratory tests used to assess coagulation?
* Prothrombin Time (PT)
* Activated Partial Thromboplastin Time (aPTT)
* Anti-factor Xa activity assay
* Platelet Count
* Activated Clotting Time (ACT)
99
What does Prothrombin Time (PT) assess and how is the test performed?
What does it monitor?
Plasma mixed with TF and number of seconds to clot is measured
-Assesses the integrity of the extrinsic and common pathways, reflecting deficiencies in factors 1,2,5,7,10
Monitors: Vitamin K antagonists (Warfarin)
100
What does Activated Partial Thromboplastin Time (aPTT) measure?
aPTT measures seconds until clot formation after mixing plasma with phospholipid, Ca², and an activator of the intrinsic pathway.
-Assesses integrity of the intrinsic and common pathway
-more sensitive for 8 & 9 deficiency
-May be used to measure heparin
101
How is Xa activity assay performed?
Plasma mixed with Xa and an artificial substrate that releases a signal after Xa is cleaved
-Functional assessment of Heparin's effect
-Also used to test LMWH, Fondapurinux, Factor Xa inhibitors
102
What is the normal platelet count?
> 100,000 platelets /microliter
103
What does Activated Clotting Time (ACT) measure?
Measures responsiveness to heparin
-Variation to whole blood clotting time, adds a clotting activator to accelerate the time
-Addresses intrinsic and common
104
What is the normal range for Activated Clotting Time (ACT)?
107 +/- 13 seconds
105
What does Heparin Concentration Measurement estimate?
Estimates preoperative plasma heparin concentration
106
1 mg protamine will inhibit ____ mg of heparin
1 mg heparin
107
What do Viscoelastic Coagulation Tests measure?
All aspects of clot formation from early fibrin generation to clot retraction & fibrinolysis
108
Name two types of Viscoelastic Coagulation Tests.
* TEG (Thromboelastogram)
* ROTEM (Rotational Thromboelastometry)
109
What are the three main classes of Antiplatelet Agents?
* Cyclooxygenase Inhibitors
* P2Y12 receptor antagonists
* Platelet GIIb/IIIa Receptor antagonists
110
What is the mechanism of action for Cyclooxygenase Inhibitors?
Block Cox 1 from forming TxA₂ (which is important in platelet aggregation)
-ASA and NSAIDS
111
How long do the anti-platelet effects of Aspirin last after discontinuation? NSAIDs?
Aspirin: 7-10 days
NSAIDs: 3 days
112
What is the mechanism of action for P2Y12 Receptor antagonists?
Inhibit P2Y22-R preventing GIIb/IIIa expression
-Clopidogrel, Ticlopidine, Ticragrelor, Cangrelor
113
How long do the anti-platelet effects of ____ last after discontinuation?
Clopidogrel
Ticlopidine
Ticagrelor & Cangrelor
Clopidogrel: 7 days
Ticlopidine: 14-21 days
Ticagrelor & Cangrelor: < 24 hours
114
MOA for Platelet GIIb/IIIa -R Antagonists?
Prevent vWF and fibrinogen from binding to the GIIb/IIIa -R
-Abciximab, Eptifibatide, Tirofiban
115
What are the main types of Anticoagulants?
* Vitamin K antagonists
* Heparin
* Direct Thrombin Inhibitors
* Direct Oral Anticoagulants (DOACs)
116
What is the most common Vitamin K antagonist? MOA?
Warfarin - inhibits synthesis of vit. K dep. clotting factors (2,7,9,10, Protein C & S)
117
What is the DOC for Afib and Valve replacements?
Warfarin
118
What is the half-life of Warfarin? What labs do you use to monitor warfarin?
40 hours, can take 3-4 days to reach goal INR (2-3)
Lab: PT/INR, requ. frequent monitoring
119
MOA of Heparin?
Binds to antithrombin and inhibits soluble thrombin and Xa
120
What is a key characteristic of Low Molecular Weight Heparin (LMWH)?
NO coagulation testing needed, longer half-life
-protamine is only partially effective
121
What is the main difference between Unfractionated Heparin and LMWH?
Unfractionated Heparin has a short half-life and requires close monitoring
122
What is the MOA of Fondaparinux and Half life?
Direct Xa inhibitor
Long Half-life (17-21 hrs)
-Protamine is not effective
123
Name some direct thrombin inhibitors and the drug class MOA
MOA: Bind/block thrombin in both soluble and fibrin-bound states
Hirudin, Argatroban, Bivalirudin, Dabigatran
124
Which direct thrombin inhibitor is found in leeches
Hirudin
125
Which direct thrombin inhibitor reversibly binds to thrombin with a half life of 45 min?
Argatroban (measure intraop with PTT and ACT)
126
Which direct thrombin inhibitor has the shortest half life and is the drug of choice for renal or liver impairment?
Bivalirudin
127
Which direct thrombin inhibitor is the first DOAC approved for CVA prevention and non-valvular Afib?
Dabigatran (Pradexa)
128
What is beneficial about DOAC?
New class with predictable PK properties, fewer drug interactions, dosed daily with NO lab monitoring, shorter half life than warfarin, fewer: thrombotic events, ICH, and lower mortality than warfarin
129
What are the DOAC that are DIrect Xa inhibitors?
1. Rivaroxaban (Xarelto)
2. Apixaban (Eliquis)
3. Edoxaban (Savaysa)
130
What is the primary use of Thrombolytics?
To dissolve blood clots via serine proteases that convert plasminogen to plasmin, breaking down fibrinogen to fibrin
131
Name a Fibrin-Specific Thrombolytic.
Non-specific?
Altepase (tPA)
Non-specific: Streptokinase (allergic reactions)
132
Surgery is contraindicated within ____ days of receiving a thrombolytic
10 days
133
What are Procoagulants used for?
To mitigate blood loss
-Antifibrinolytics and Factor replacements
134
Name two types of antifibrinolytics that are lysine analogues. MOA?
* Epsilon-amino-caproic acid (EACA)
* Tranexamic Acid (TXA)
MOA: Bind and inhibit plasminogen from binding to fibrin impairing fibrinolysis
135
TXA is used for what surgery frequently?
ortho surgery
136
Factor replacements such as Recombinant 7a increase _____ generation via intrinsic and extrinsic path
thrombin
137
Prothrombin Complex Concentrates contain _____ Factors
vitamin-K factors
138
Fibrinogen concentrates are derived from _____
pooled plasma at a standard concentration
139
Cryo and FFP contain _____ coagulation factors, but ______ specific composition
more; less specific
(cheaper though)
140
What should be done with Warfarin in low risk patients before surgery?
High risk patients?
Low risk: Stop 5 days prior to surgery & restart 12-24h postop
High risk: Stop 5 days prior and bridge UFH/LMWH
141
UFH should be discontinued ____ hours prior to surgery and resumed with no bolus ____ than 12 hours postop
Discontinue heparin 4-6 hours before surgery
start no sooner than 12 hours postop
142
Discontinue LMWH ____ hours prior to surgery and resume ___ hours postop
24 hours and 24 hours
143
Current recommendations from the AHA suggest that moderate to high risk patients _____ their aspirin thru the periop period
continue
143
Post-bare metal stent, delay elective surgery
Drug eluding stent?
Bare metal: 6 weeks after placement
Drug eluding: 6 months
144
What is the emergency reversal agent for Warfarin?
Prothrombin Complex Concentrates (PCC) - works fast, but short half life so also give Vitamin K to restore liver carboxylation of factors
145
What is the emergency reversal agent for direct thrombin inhibitors
No reversal but they have a short half life (besides dabigatran)
146
What is the antidote for Dabigatran (Pradaxa)?
Idarucizumab
147
True or False: Surgery is contraindicated within 10 days of thrombolytic treatment.
True
148
Fill in the blank: Direct Oral Anticoagulants (DOACs) have ______ pharmacokinetics/dynamics.
more predictable
149
What is a characteristic of Direct Thrombin Inhibitors?
Bind/block thrombin in both soluble & fibrin-bound states
150
What is the effect of adding protamine to heparinized blood?
Time to clot decreases until protamine concentration > heparin concentration
151
What is the key action of P2Y12 receptor antagonists?
Prevent GIIb/IIIa expression
152
What is the main function of Factor Replacements?
Increase thrombin generation via intrinsic & extrinsic pathways
153
What is the half-life of Argatroban?
45 minutes
154
What is secondary hemostasis?
Clotting factors activated, stabilizing the clot with crosslinked fibrin
155
Adenosine Diphosphate (ADP) is a ________
Platelet activator
156
Endothelial cells excrete this enzyme which degrades ADP
Adenosine diphosphatase (inactivating platelets)
157
Endothelial cells increase ______ which is an anticoagulant
Protein C
158
Tissue Factor Pathway Inhibitor (TFPI) inhibits which factors?
Factor Xa and TF-7a complex
159
Endothelial cells synthesize what "clot buster"
t-PA (tissue plasminogen activator)
160
DOAC Factor Xa inhibiors might be reversed by _____, a derivative of Factor Xa
Andexanet
