Coagulation (Exam IV) Flashcards
1
Q
What is normal hemostasis?
A
A balance between clot generation, thrombus formation, and regulatory mechanisms that inhibit uncontrolled thrombogenesis.
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 are the two stages of hemostasis?
A
- Primary Hemostasis
- Secondary Hemostasis
4
Q
What occurs during primary hemostasis?
A
Immediate platelet deposition at the endovascular injury site leading to initial platelet plug formation and is only adequate for minor injury
5
Q
What occurs during secondary hemostasis?
A
Clotting factors are activated, leading to a stabilized clot formed and secured with crosslinked fibrin.
6
Q
What antiplatelet effects do vascular endothelial cells have?
A
- Negatively charged to repel platelets
- Produce platelet inhibitors such as prostacyclin and nitric oxide
- Excrete adenosine diphosphatase
- Increase protein C
- Produce Tissue Factor Pathway Inhibitor (TFPI)
- Synthesize tissue plasminogen activator (t-PA)
7
Q
What is the function of adenosine diphosphate?
A
which degrades adenosine diphosphate (ADP), a platelet activator
8
Q
What is the Tissue Factor Pathway Inhibitor
A
which inhibits factor Xa & TF-VIIa complex
9
Q
What is the lifespan of platelets?
A
8-12 days.
10
Q
What are platelets derived from?
A
bone-marrow megakaryocytes
11
Q
How many platelets are formed daily?
A
120-150 billion
12
Q
What are the phases of platelet alteration upon exposure to extracellular matrix (ECM)?
A
- Adhesion
- Activation
- Aggregation
13
Q
What do alpha granules contain?
A
- Fibrinogen
- Factors V & VIII
- von Willebrand factor (vWF)
- Platelet-derived growth factor
14
Q
What do dense bodies contain?
A
- ADP
- ATP
- Calcium
- Serotonin
- Histamine
- Epinephrine
15
Q
What is adhesion?
A
occurs upon exposure to ECM proteins
16
Q
What is activation?
A
stimulated when platelet interacts w/collagen & tissue factor (TF), causing the release of granular contents
17
Q
Aggregation
A
occurs when the granular contents are released, which activate additional platelets, propagating plasma-mediated coagulation
18
Q
Each membrane bound activated tenase complex contains:
A
1) a substrate (inactive precursor)
2) an enzyme (activated coagulation factor)
3) a cofactor (accelerator or catalyst)
4) calcium
19
Q
What does each step of the clotting cascade require?
A
assembly of membrane-bound activated tenase-complexes
20
Q
What is the extrinsic pathway of hemostasis?
A
The initiation phase of plasma-mediated hemostasis, beginning with endothelial injury and exposing tissue factor (TF) to plasma.
21
Q
What complex does tissue factor (TF) form in the extrinsic pathway?
A
TF forms an active complex with factor VIIa (TF/VIIa complex).
22
Q
List the steps of the extrinsic pathway
A
TF forms an active complex with VIIa (TF/VIIa complex)
TF/VIIa complex binds to and activates factor X, converting it to Xa
Factor Xa begins the final common pathway
23
Q
What does the intrinsic pathway primarily serve as?
A
An amplification system to propagate thrombin generation initiated by the extrinsic pathway.
24
Q
What activates factor XII in the intrinsic pathway?
A
Contact with a negatively charged surface.
25
Steps of Intrinsic Pathways
Factor XIIa converts XI to XIa
XIa and TF/VIIIa Complex convert IXto IXa
IXa and Ca++ convert X to Xa
26
Steps of the Common Pathway
*Factor X becomes Xa and binds with Va to form the prothrombinase complex.
*Prothombinase complex converts prothrombin (II) into thrombin (IIa)
*Thrombin attaches to the platelets and converts fibrinogen (I) to fibrin (Ia)
*Fibrin molecules crosslink to form a mesh that stabilizes the clot
27
What is the role of thrombin in the coagulation process?
Thrombin converts fibrinogen into fibrin, which polymerizes into strands to stabilize the clot.
28
Role of factor XIIIa
crosslinks the fibrin strands to stabilize and make an insoluble clot, resistant to fibrinolytic degradation
29
What is the key step in regulating homeostasis?
Thrombin generation
30
Initiation
Binding of platelets to collagen TF-dependent initiation of coagulation
31
Propagation
Recruitment of platelets to growing thrombus amplication of coagulation cascade
32
Stabilization
Platelet-platelet interaction
Fibrin depostion
33
What is the intrinsic Tenase Complex made up of?
Activator
IXa
VIIa
Ca++
34
What is the extrinsic Tenase Complex made up of?
Injury
TF
VIIa
Ca++
35
What is the Prothrombinase Complex made up of and what is it's function?
Xa
Va
Ca++
Converts prothrombin (II) to thrombin (IIa)
36
What are the four major coagulation counter-mechanisms?
* Fibrinolysis
* Tissue factor pathway inhibitor (TFPI)
* Protein C system
* Serine Protease Inhibitors (SERPINs)
37
Fibrinolysis
endovascular TPA & urokinase convert plasminogen to plasmin
38
Plasmin
breaks down clots enzymatically, and degrades factors V & VIII
39
Tissue factor pathway inhibitor (TFPI)
forms complex w/Xa that inhibits TF/7a complex, along with Xa; thereby downregulating the extrinsic pathway
40
Protein C
Inhibits factors II,Va, &VIIIa
41
Serine Protease Inhibitors (SERPINs)
Antithrombin (AT) inhibits thrombin, factors 9a (IXa), 10a (Xa), 11a (XIa), 12a (XIIa)
Heparin binds to AT, causing a conformational change that accelerates AT activity
Heparin cofactor II inhibits thrombin alone
42
What is the most common inherited bleeding disorder?
Von Willebrand's Disease.
43
Von Willebrand's Disease
Deficiency in vWF, causing defective plt adhesion/aggregation
Best labs to perform: vWF level, vWF-plt binding activity, Factor 8 level, Plt function assay
Products to correct with: DDAVP, vWF, Factor VIII concentrates
44
Drugs that induce bleeding
ASA
NSAIDs
Heparin
Warfarin
Beta-Lactam Abx
Nitroprusside
NTG
NO
SSRIs
45
Supplements that affect coagulation
Vitamin E
Ginko
Ginger
Garlic
St Johns Wort
Tumeric
Grapeseed oil
Cayenne
46
What are the standard first line labs if a bleeding disorder is suspected?
PT & aPTT
47
What factors do Hemophillia A and B affect?
A: Factor VIII deficiency
B: Factor IX deficiency
48
Lab to monitor for Hemophilia
prolonged PTT
49
Products for Hemophilia
DDAVP
Factors VIII and/or factor IX
50
What is the most common cause of intraoperative bleeding?
Anticoagulant medications.
51
What does liver disease impair in terms of hemostasis?
Synthesis of coagulation factors and causes quantitative and qualitative platelet dysfunction and Impaired clearance of clotting and fibrinolytic proteins
52
What clotting factors does the liver produce?
All except III, IV, VIII, XIII
53
Abnormal Coag labs with liver disease
prolonged PT and PTT
TEG & ROTEM may be valuable
54
How does CKD affect coagulation?
Baseline anemia due to lack of erythropoietin and Platelet dysfunction
55
Tx for CKD Coagulopathy
Dialysis and correction of anemia to shorten bleeding times
Platelet dysfunction tx through:
Cryoprecipitate (rich in vWF)
DDAVP
Conjugated estrogens given pre-operatively x 5 days
56
What is Disseminated Intravascular Coagulation (DIC)?
A pathological hemostatic response causing excessive activation of the extrinsic pathway overwhelming anticoagulant mechanisms generating intravascular thrombin
Coagulation factors & platelets become depleted during widespread microvascular thrombotic activity, causing multi-organ dysfunction
57
What is DIC precipitated by and what is the best tx?
trauma
amniotic fluid embolus
malignancy
sepsis
incompatible blood transfusion
TREAT THE UNDERLYING CAUSE
58
What is trauma-induced coagulopathy?
acute coagulopathy seen in trauma pts, which is thought to be related to activated protein C decreasing thrombin generation
59
How does hypoperfusion cause TIC?
Hypoperfusion is thought to be the driving factor for protein C activation
The endothelial glycocalyx, which contains proteoglycans, degrades resulting in "auto-heparinization"
Platelet dysfunction contributes to the increased bleeding
60
What causes Trauma-Induced Coagulopathy (TIC)?
Acidosis, hypothermia, and/or hemodilution.
61
What are the most common inherited prothrombotic diseases?
* Factor V Leiden mutation
* Prothrombin mutation
62
Factor V Leiden mutation
leads to activated protein C resistance-excess fibrin is laid
63
Prothrombin mutation
↑PT concentration, leading to hypercoagulation
64
Thrombophilia
inherited or acquired predisposition for thrombotic events that generally manifests as venous thrombosis and is highly susceptible to Virschows Triad
65
Antiphospholipid Syndrome
autoimmune disorder w/antibodies against the phospholipid-binding proteins in the coagulation system.
Characterized by recurrent thrombosis and pregnancy loss that require life-long anticoagulants
66
Increased Risk of thrombosis for prothrombotic disease populations
Oral contraceptives
pregnancy
immobility
infection
surgery & trauma
67
What is Heparin Induced Thrombocytopenia (HIT)?
Mild-moderate thrombocytopenia associated with heparin, often occurring 5-14 days after treatment that results in platelet count reduction as well as activation of the remaining platelets and potential thrombosis
68
Risk Factors for HIT
women
pts receiving high heparin doses such as w/CPB
Unfractionated heparin > LMWH
69
What anticoagulant would you want to avoid if HIT is suspected (other than heparin)?
Warfarin b/c it decreases protein C and S synthesis
70
How is HIT confirmed?
HIT antibody testing
-antibodies typically cleared from circulation in 3 months
71
What does Prothrombin Time (PT) assess and what factors?
Integrity of extrinsic and common pathways of coagulation.
I, II, V, VII, X
72
What lab do you use for wafarin?
PT
73
What factors are aPTT sensitive for and what medication do we use it for?
VIII & IX
Heparin
74
What labs do we assess for heparin effect?
aPTT, ACT, Anti-factor Xa assay
75
What does Activated Partial Thromboplastin Time (aPTT) measure?
Integrity of intrinsic and common pathways of coagulation.
76
What does the Anti-factor Xa activity assay assess?
Functional assessment of heparin's anticoagulant effect
and can be used to assess LMWH, Fondaparinux, factor Xa inhibitors
77
What is activated clotting time (ACT) and normal level?
Used to assess intrinsic and common pathways
107+/- 13 seconds
78
What is the normal platelet count?
Greater than 100,000 platelets per microliter.
79
What is the purpose of viscoelastic coagulation tests?
Measures all aspects of clot formation from early fibrin generation to clot retraction and fibrinolysis.
80
What do POC analyzers measure in the context of heparin concentration?
Determines perioperative heparin concentration
81
How much protamine is needed to inhibit 1mg of heparin?
1mg protamine will inhibit 1mg heparin
82
What is the effect of adding increasing amounts of protamine to heparinized blood?
Time to clot decreases until protamine concentration > heparin concentration
83
What do viscoelastic coagulation tests measure?
Measures all aspects of clot formation from early fibrin generation to clot retraction & fibrinolysis
84
Name two types of viscoelastic coagulation tests.
* TEG (Thromboelastogram)
* ROTEM (Rotational Thromboelastometry)
85
R time
Measures:
Normal:
Problem With:
Treated with:
Time to start forming clot
5-10 minutes
Problem with coagulation factors
Treated with FFP
86
K time
Measures:
Normal:
Problem With:
Treated with:
Measures: Time until clot reaches a fixed strength
Normal:1-3 min
Problem With: Fibrinogen
Treated with: Cryo
87
Alpha angle
Measures:
Normal:
Problem With:
Treated with:
Alpha angle
Measures: speed of fibrin accumulation
Normal: 53-72 degrees
Problem With: Fibrinogen
Treated with:Cryo
88
Maximum Amplitude (MA)
Measures:
Normal:
Problem With:
Treated with:
Measures: highest veritcal amplitude of TEG
Normal: 50-70 mm
Problem With: Platelets
Treated with: plts and/or DDAVP
89
LY30
Measures:
Normal:
Problem With:
Treated with:
Measures: % of amplitude reduction 30 minutes after max amplitude
Normal: 0-8% ?
Problem With: Excess fibrinolysis
Treated with:TXA and/or aminocaproic acid
90
What do antiplatelet agents inhibit?
Platelet aggregation and/or adhesion
91
What are the three main classes of antiplatelet agents?
* Cyclooxygenase Inhibitors
* P2Y12 receptor antagonists
* Platelet GIIb/IIIa receptor antagonists
92
Cyclooxygenase inhibitors and MOA
Block Cox 1 from forming TxA₂, which is important in plt aggregation
ASA
NSAIDS
93
P2Y12 receptor antagonist Medications in order of shortest to longest duration
Ticagrelor & Cangrelor: Short-acting, <24h activity
Clopidogrel: anti-plt effects x 7 days after d/c
Ticlopidine: anti-plt effects x 14-21 days after d/c
94
How long do ASA's antiplatelet effects last after discontinuation?
7-10 days
95
What do P2Y12 receptor antagonists prevent?
Prevent GIIb/IIIa expression
96
What is the duration of antiplatelet effects for Clopidogrel after discontinuation?
7 days
97
Platelet GIIb/IIIa R antagonists medication
Abciximab, Eptifibatide, Tirofiban
98
What type of anticoagulants inhibit the synthesis of Vitamin K dependent factors and what is the most common?
Vitamin K antagonists
Warfarin
99
Vitamin K anticoagulants inhibit synthesis of:
II,VII,IX,X Protein C and S
100
DOC for Afib and valve replacements
Warfarin
101
Does protamine reverse all the heparin anticoagulant meds?
Unfractionated: Fully
LMWH: Partial
Fondaparinux: NO
102
What is the direct thrombin inhibitor of choice for liver or renal impairment?
Bivalirudin
103
Direct Thrombin Inhibitor Meds
Hirudin
Bivalirudin
Dabigatran
104
What is the usual therapeutic INR range for Warfarin?
2-3
105
What is required for monitoring therapeutic effect of Warfarin?
Frequent lab monitoring (PT/INR)
106
What is the reversal agent for Warfarin?
Vitamin K
107
Does Unfractionated heparin or LMWH have a shorter half life?
Unfractionated heparin
108
How is Unfractionated Heparin administered?
Given IV
109
What is the reversal agent for Unfractionated Heparin?
Protamine
110
How is LMWH administered?
Dosed BID SQ
111
What is the half-life of Fondaparinux?
17-21 hours
112
What is the first Direct Oral Anticoagulant (DOAC)?
Dabigatran (Pradaxa)
113
114
What is the advantage of Direct Oral Anticoagulants (DOACs) compared to Warfarin?
More predictable pharmacokinetics/dynamics
lower mortality
less lab monitoring required
shorter half-life
less drug interaction
115
What are the two categories of thrombolytics?
* Fibrin-Specific
* Non-Fibrin-Specific
116
Name Fibrin-Specific thrombolytics.
Alteplase (tPA)
Reteplase
Tenecteplase
117
What drug is non-fibrin specific and why is it not used very often?
Streptokinase
allergic reactions
118
Surgery is contraindicated within_____days of thrombolytic tx
10
119
What class of drugs is used to mitigate blood loss?
Procoagulants
120
What are the 2 classes of procoagulants?
Antifibrinolytics
Factor Replacements
121
Name the Factor replacements and their function
Recombinant VIIa (RfVIIa): ↑’s thrombin generation via intrinsic & extrinsic paths
Prothrombin Complex Concentrate (PCC): contain vitamin-K factors
Fibrinogen Concentrate: derived from pooled plasma.
Cryoprecipitate & FFP: Cheaper & contain more coag factors, but less specific composition
122
What are the two subclasses of Antifibrinolytics?
* Lysine analogues
* SERPIN
123
What is a common lysine analogue used as an antifibrinolytic?
Tranexamic Acid (TXA)
124
What does Prothrombin Complex Concentrate (PCC) contain?
Vitamin-K factors
125
What is the recommendation for low-risk patients on Warfarin prior to surgery?
D/c 5 days prior to surgery & restart 12-24h postop
126
What should be done for high-risk patients on Warfarin before surgery?
Stop 5 days prior & bridge with UFH or LMWH
127
When should UFH be discontinued prior to surgery?
4-6 hours
128
What is the recommended wait time for elective surgery after placement of a bare-metal stent?
6 weeks
129
What is the DOC for emergent reversal from Warfarin?
Prothrombin Complex Concentrates
130
What antidote is available for Dabigatran (Pradaxa)?
Idarucizumab
131
What may reverse DOAC Factor Xa Inhibitors?
Andexanet
132
What are the absolute contraindications for thrombolytics?
Vascular lesions
Severe, uncontrolled HTN (SBP>180 or DBP>110)
Recent cranial surgery or trauma
Brain Tumor
Ischemic stroke<3 months
Active bleeding
133
Relative Contraindications for Thrombolytics
Ischemic stroke >3m prior
Active Peptic ulcer
current use of anticoagulants
pregnancy
Prolonged/traumatic CPR<3 weeks prior
Major surgery <3 weeks prior
134
When should Warfarin be d/c prior to surgery?
Low risk: 5 days and resume within 24 hours
High risk: 5 days and bridge with UFH or LMWH
135
When should heparin be d/c prior to surgery?
UFH should be d/c’d 4-6h prior to surgery & resumed (no bolus) ≥12h postop
LWMH should be d/c’d 24h prior to surgery & resumed 24h postop
136
When should ASA be d/c prior to surgery?
mod/high rx pts- current recommendation is to continue ASA
low rx pts- stop 7-10 days prior to surgery
137
How long should bare metal coronary stents wait for elective surgery?
6 weeks
138
How long should drug eluding coronary stents wait for elective surgery?
6 months
139
Which anticoagulants aren't contraindicated concerned with neuraxial anesthesia?
NSAIDs/ASA
Heparin
Lovenox
