Coagulation (4) Flashcards
1
Q
How does hemostasis normally control bleeding?
A
Balance btw 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 2 stages of hemostasis?
A
- Primary hemostasis
- Secondary hemostasis
4
Q
What is primary hemostasis?
A
- Immediate platelet deposition at the endovascular injury site
- Leads to the initial platelet plug formation
- Only adequate for minor injury
5
Q
What is secondary homeostasis?
A
- Clotting factors activated
- Stabilized clot formed and secured with crosslinked fibrin
6
Q
What is the role of vascular endothelial cells?
A
- antiplatelet, anticoagulant, and fibrinolytic effects to inhibit clot formation
7
Q
How do vascular endothelial cells function as an antiplatelet?
A
- Endothelial cells are 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
- Synthesize tPA
8
Q
What is the function of adenosine diphosphatase?
A
Degrades adenosine diphosphate (ADP), a platelet activator
9
Q
What is the MOA of tissue factor pathway inhibitor?
A
Inhibits factor Xa & TF-VIIa complex
10
Q
What are platelets derived from?
A
Bone-marrow megakaryocytes
11
Q
What are the characteristics of inactive platelets?
A
- Disc shaped
- Anuclear (no nucleus)
- 8-12 day lifespan
12
Q
Approximately ____% of platelets are consumes to support vascular integrity
A
10%
13
Q
_________ new platelets are formed daily
A
120-150 billion
14
Q
What is the function of the platelet membrane?
A
- Contains numerous receptors
- Surface canalicular system → increases membrane surface area
15
Q
How does damage to endothelium signal for clotting cascade?
A
Damaged endothelium exposes underlying extracellular matrix (ECM): contains vWF, collagen, glycoproteins
16
Q
What happens to platelets when extracellular matrix is exposed?
A
3 phases of alteration:
- Adhesion
- Activation
- Aggregation
17
Q
When does platelet activation occur?
A
- Stimulated when platelets interact with collagen and tissue factor
- Causes release of granular contents
18
Q
What are the 2 types of granules that platelets contain?
A
- Alpha granules: contain fibrinogen, factors V & VIII, vWF, Plt-derived growth factor & more
- Dense bodies: contain ADP, ATP, calcium, serotonin, histamine, epinephrine
19
Q
When does platelet aggregation occur?
A
When the granular contents are released→ activate additional platelets and propagate plasma-mediated coagulation
20
Q
Each stage of the clotting cascade requires assembly of membrane bound activated __________ complexes
A
Tenase
21
Q
What is each activated tenase-complex composed of?
A
- Substrate (Inactive)
- Enzyme (activated coag factor)
- Cofactor (accelerator of catalyst)
- Calcium
22
Q
The _________ pathway is the initiation phase of plasma mediated hemostasis
A
Extrinsic
23
Q
What are steps of the extrinsic pathway?
A
1) Endothelial injury→ expose tissue factor to plasma
2) Tissue factor/VIIa complex
3) TF/VIIa complex binds and activates Factor X→ becomes Xa (activated)
4) TF/VIIa also activates IX→IXa
5) IXa and calcium convert X →Xa (intrinsic pathway)
6) Xa starts the common pathway
24
Q
What factor is the start of the common pathway?
A
Factor Xa
25
What factor starts the intrinsic pathway?
Factor XIIa
26
What is the role of the intrinsic pathway?
* Minor role in the initiation of homeostasis
* Functions as an AMPLIFICATION system→ propagate thrombin generation initiated from extrinsic path
27
Most thrombotic events follow ___________ pathway
Extrinsic
28
Lab coag studies rely on _________ pathway to activate the cascade (hemostasis initiation)
Intrinsic
29
Explain how intrinsic pathway initiated hemostasis:
1) Factor XII is activated when it contacts (-) charged endothelial cells
2) Factor XIIa converts XI→XIa
3) XIa + VIIIa + plt membrane + Ca2+: converts X→Xa
4) Xa initiates final common pathway
30
Which factors in the intrinsic pathway convert factor X to Xa?
- XIa
- VIIIa
- plt-membrane phospholipid
- Ca++
31
For intrinsic pathway propagation, activated thromin (IIa) activates which factors?
- Factor V
- Factor VII
- Factor VIII
- Factor XI
all these factors amplify thrombin generation and activates platelets to lead to common pathway
32
What happens in the common pathway?
1) Factor X→Xa
2) Xa binds with Va→ prothrombinase complex
3) Prothrombinase complex converts Prothrombin (II)→ thrombin (IIa)
4) IIa attaches to plts and converts fibrinogen (I)→ fibrin (Ia)
5) Fibrin crosslink to form mesh/stabilize clot
33
What is the function of thrombin?
* Converts fibrinogen (I) to Fibrin (Ia)
(Cleaves fibrinopeptides from fibrinogen to generate fibrin)
34
How does fibrin form a stabilized clot?
Fibrin polymerizes into strands to form a basic clot
35
Which factor crosslinks the fibrin strands to stabilize and make an insoluble clot that is resistant to fibrinolytics?
Factor XIIIa
36
_________ generation is the key-step in regulating hemostasis
Thrombin
37
Both intrinsic and extrinsic tenase complexes facilitate the formation of __________ __________
Prothrombinase complexes
38
What are the 4 major coagulation counter-mechanisms?
* Fibrinolysis
* Tissue factor pathway inhibitor (TFPI)
* Protein C
* Serine protease inhibitors (SERPINs)
39
What is the MOA of fibrinolysis?
- TPA and urokinase→ convert plasminogen to plasmin which breaks down the clot enzymatically
40
Which factors does plasmin degrade?
Factor V and VIII
41
What is the MOA of tissue factor pathway inhibitor?
Forms complex with Xa→ inhibits tissue factor/VIIa complex, Xa, and downregulates the extrinsic pathway
42
What is the MOA of protein C?
Inhibits factors:
- 2
- 5
- 8
43
What are examples of serine protease inhibitors?
* Antithrombin
* Heparin
* Heparin Cofactor II
44
What factors does an antithrombin inhibit?
- Thrombin
- 9, 10, 11, 12
45
What is the MOA of heparin and what factors does heparin inhibit?
- Binds to antithrombin causing conformational change
- accelerates antithrombin
46
What is MOA of heparin cofactor II?
Inhibits thrombin alone
47
What test is the most effective predictor of bleeding?
Bleeding time
48
What should be asked about to assess bleeding risk in preop?
- Nose bleeds
- Bleeding gums
- easy bruising
- excessive bleeding w/dental extraction
- excessive bleeding with past surgery
- trauma
- childbirth
- blood transfusions
- fam hx
- use of blood thinners
- co-morbidities (liver, renal, thyroid, bone marrow disorders)
49
What should you do if you suspect bleeding disorder?
PT and aPTT are standard first-line labs
50
What is the most common inherited bleeding disorder?
Von Willebrands Disease: effects 1% of population
51
What lab tests are good for detecting vWD?
- vWF level
- vWF plt binding activity
- Factor 8 level
- Plt function test
52
What is a common medical treatment for mild vWD?
DDAVP (increases vWF)
53
If a patient with vWD has intraop bleeding, what way be required?
vWF administration and factor 8 concentrates
54
vWF plays a critical role in platelet adhesion and prevents degradation of factor ____.
8
55
What is hemophilia A?
Factor 8 deficiency
occurs 1:5,000
56
What is hemophilia B?
Factor 9 deficiency
Occurs 1: 30,000
57
Is hemophilia genetic?
- 2/3 genetic
- 1/3 mutation with no family history
58
How does hemophilia usually present?
In childhood as spontaneous hemorrhage involving joints and muscles
59
What do labs show with hemophilia?
- Normal PT, Plt, and bleeding time
- PTT prolonged
60
What can be used in preop to prophylactically treat patient with hemophilia?
- DDAVP
- Factor 8
- Factor 9
61
______ meds are the most significant cause of intraoperative bleeding
Anticoagulants
62
What herb can prolong bleeding time?
Garlic
* d/c 7-10 days before surgery
63
Common herbs/supplements that impact bleeding risk:
64
The liver is the primary source of which factors?
5, 7, 9, 10, 11, 12
65
How does liver disease lead to hemostatic issues?
* Impaired coagulation factor synthesis
* Platelet dysfunction (quantity and quality)
* Impaired clearance of clotting and fibrinolytic proteins
66
What are common lab findings in pts with liver disease?
- Prolonged PT
- possible prolonged PTT
Only accounting for lack of pro-coagulation factors no accounting for lack of anticoagulation factors
67
Do chronic liver patients suffer from insufficient thrombin production?
No, they often have rebalanced hemostasis as well as sufficient amounts of thrombin
Compensated but not optimal (susceptible to disruption in coagulation)
68
What tests are valuable guides for patient with chronic liver disease to assess risk for bleeding?
* TEG
* ROTEM (rotational thromboelastometry)
69
What causes baseline anemia in pts with CKD?
- Lack EPO
- Platelet dysfunction (d/t uremic environment)
70
_________ and correction of anemia are both shown to shorted bleeding times
Dialysis
71
What are treatments for platelet dysfunction associated with CKD?
- Cryo
- DDAVP
- Conjugated estrogens given preop (x5 days)
72
What is DIC?
* Pathological hemostatic response to TF/7a complex causing excessive activation of the extrinsic pathway, which overwhelms the anticoagulant mechanisms and generates intravascular thrombin
* Coagulation factors & platelets become depleted during widespread microvascular thrombotic activity, causing multi-organ dysfunction
73
What may precipitate DIC?
* Trauma
* Amniotic fluid embolus
* Malignancy
* Sepsis
* Incompatible blood transfusion
74
What are lab findings indicative of DIC?
- Low platelets
- prolonged PT/PTT/thrombin time
- increased soluble fibrin
- fibrin degradation products
75
What are primary actions in management of a pt in DIC/
- Correct underlying condition
- Administer appropriate blood products
76
Uncontrolled _____________ is a common cause of trauma related death
hemorrhage
77
What are common reasons for coagulopathies to occur in the trauma patient?
- Acidosis
- Hypothermia
- Hemodilution
78
What is Trauma induced coagulopathy (TIC)? What is thought to cause it?
- Acute coagulopathy seen in trauma
- Thought to be related to activated protein C decreasing thrombin generation
79
What is the driving factor for protein C activation associated with trauma induced coagulopathy?
- Hypoperfusion causing endothelial glycocalyx to degrade
- proteoglycan-shedding results in "auto-heparinization"
- platelet dysfunction contributes to the increased bleeding
80
The most common inherited prothrombotic diseases are cause by a mutation in factor ______ or ______
V or Prothrombin
81
What mutation leads to activated protein C resistance?
Factor V Leiden mutation
- present in 5% caucasion population
82
What mutation causes increase prothrombin concentration leading to hypercoagulation?
Prothrombin mutation
83
Inherited or acquired predisposition for thrombotic events:
Thrombophilia
84
What is a typical presentation of thrombophilia?
- Manifests as venous thrombosis
- Highly susceptible to Virchows Triad (stasis, endothelial injury, hypercoagulability)
85
Autoimmune disorder with antibodies against the phospholipid-binding proteins in the coagulation system:
Antiphospholipid Syndrome
86
How is antiphospholipid syndrome characterized and what is often required?
- Characterized by recurrent thrombosis and pregnancy loss
- Often require life-long anticoagulants
87
When is HIT likely to occur?
5-14 days after heparin treatment
88
What is the MOA of HIT?
Autoimmune response occurring in up to 5% of pts receiving heparin
89
What happens to platelets with HIT?
Platelet count reduction and activation of remaining platelets causing potential thrombosis
90
If HIT is occurring: If a patient received a prior heparin dose __________ or __________ may occur with in 1 day of a subsequent dose
Thrombocytopenia
Thrombosis
91
What are risk factors for development of HIT?
- Women
- Pt on high dose heparin (cardiopulm bypass)
- unfractionated heparin carried higher risk than LMWH
92
What are the step if HIT is suspected?
- D/C all heparin
- Convert to alternative AC (warfarin contraindicated because it decreases protein C and S synthesis)
93
How is HIT diagnosis confirmed?
HIT antibody testing
antibodies typically cleared from circulation in 3 months
94
How is Prothrombin time (PT) measured?
Plasma is mixed with TF and the number of seconds is measured until a clot forms
95
What are PT measurements used to assess?
- Assess integrity of extrinsic and common pathways
- Used to monitor vitamin K antagonists s/a warfarin
96
PT measurements can show deficiencies in which factors?
1, 2, 5, 7, 10
97
What is activated partial thromboplastin time (aPTT) measuring?
Measures seconds until clot forms after mixing plasma w/ phospholipid, Ca, and an activator of the intrinsic pathway
98
What are aPTT measurements used to assess?
- Assess integrity of intrinsic and common pathways
- May be used to measure the effect of heparin
99
aPTT measurements are more sensitive to deficiencies in what factors?
8 and 9
100
How is anti-factor Xa activity assay measured?
Plasma combined with Xa and an artificial substrate that releases a colorimetric signal after factor Xa is cleaved
101
What are anti-factor Xa activity assays used to assess?
- Functional assessment of heparin's anticoagulant effect
- Can also be used to assess effect of LMWH, fondaparinux, factor Xa inhibitors
102
What is a normal platelet count?
>100,000 plts/microliter
(POC testing is available)
103
How is Activated Clotting Time (ACT) measured?
Variation of whole blood clotting time, with the addition of a clotting activator to accelerate clotting time
104
What is ACT measurements used to assess?
- Intrinsic and common pathway
- Used to measure responsiveness to heparin
105
What is a normal ACT?
107 +/- 13 seconds
106
1 mg of protamine will inhibit ___ heparin
1 mg
107
What happens to heparin concentration if more protamine is added?
As increasing amounts of protamine are added to heparinized blood, time to clot decreases until protamine concentration > heparin concentration
108
What is heparin concentration measurement used for?
- Determines perioperative heparin concentration
- Estimates plasma heparin concentration
109
What does viscoelastic coagulation tests measure?
Measures all aspects clot formation from early fibrin generation to clot retraction and fibrinolysis - coagulation diagrams generated
110
Why are viscoelastic coagulation test used? What are they?
Allows for more precise blood product administration
- TEG
- ROTEM (rotational thromboelastometry)
111
What are the 3 main classes of antiplatelet agents?
- Cyclooxygenase inhibitors
- P2Y12 receptor antagonists
- Platelet GIIb/IIIa R antagonists
112
How do cyclooxygenase inhibitors work?
Block Cox1 from forming TxA2, which is important in platelet aggregation
113
What are examples of COX inhibitors?
- ASA: anti-platelets x 7-10 days after d/c
- NSAIDs: anti-platelet effects x3 days
114
How do P2Y12 receptor antagonists work?
Inhibit P2Y12-R→ preventing GIIb/IIIa expression
115
What are some examples of P2Y12 antagonists?
- Clopidogrel: anti-plt effects x7 days after d/c
- Ticlopidine: anti-plt effects x14-21 days after d/c
- Ticagrelor & Cangrelor: short acting, <24h activity
116
How do Platelet GIIb/IIIa R antagonists work?
Prevent vWF & fibrinogen from binding to GIIb/IIIa-R
117
What are examples of Platelet GIIb/IIIa R antagonists?
- Abciximab
- Eptifibatide
- Tirofiban
118
How do vitamin k antagonists work?
Inhibit synthesis of vit-k dependent factors 2, 7, 9, 10, protein C & S
119
What is the most common vitamin k antagonist?
Warfarin
120
Warfarin is the drug of choice for what?
Valvular Afib and valve replacements
121
How long is the half life for warfarin?
40 hours - can take 3-4 days to reach therapeutic INR (2-3)
- Usually requires heparin until therapeutic effect achieved
122
Considerations for patients on warfarin:
- Need frequent lab monitoring required (PT/INR)
- Reversable w/ vitamin K
123
How does heparin work?
Binds to antithrombin→ directly inhibits soluble thrombin and Xa
124
Unfractionated heparin:
- Short half life, given IV
- Fully reversable with protamine
- Close monitoring required
125
LMWH:
- Longer half life than unfractionated
- Dosed BID SQ
- No coag testing needed
- Protamine only partially effective
126
Fondaparinux:
- Much longer half life (17-21h), dosed once/day
- Protamine not effective
127
How do direct thrombin inhibitors work?
Bind/block thrombin in both soluble & fibrin-bound states
128
What are examples of direct thrombin inhibitors?
- Hirudin
- Argatroban
- Bivalirudin
- Dabigatran (pradaxa)
129
Where is hirudin naturally found?
Leeches
130
How is argatroban monitored?
Intraop with PTT or ACT
131
Half life of argatroban:
45 minutes
132
Which direct thrombin inhibitor has the shortest half life?
Bivalirudin
133
What is bivalirudin the drug of choice for?
Renal or liver impairment
134
What is the first direct oral anticoagulant?
Dabigatran (Pradaxa)
135
What is dabigatran approved for?
CVA prevention and non-valvular a-fib
136
What are the benefits to direct oral anticoagulants?
- Have more predictable pharmacokinetics/dynamics
- Fewer drug interactions
- Dosed daily w/o lab monitoring
- Efficacy similar to warfarin, but much shorter half-life
- Fewer embolic events, intracranial hemorrhages, and lower mortality than warfarin
137
What are examples of Direct Xa inhibitors?
Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
138
What are most thrombolytics?
Serine proteases that convert plasminogen to plasmin, which breaks down fibrinogen to fibrin
139
What are the 2 categories of thrombolytics?
- Fibrin-specific: Altepase (tPA), Tenecteplase
- Non-fibrin-specific: Streptokinase (not widely used d/t allergic reaction)
140
Surgery is contraindicated within ___ days of thrombolytic tx
10
141
Absolute and relative contraindications for thrombolytics:
142
What are procoagulants used for?
To mitigate blood loss
143
What are the 2 classes of procoagulants?
Antifibrinolytics and factor replacements
144
What are the 2 subclasses of antifibrinolytics?
- Lysine analogues
- SERPIN
145
What do lysine analogues do?
What are the lysine analogues?
Bind and inhibit plasminogen from binding to fibrin and impairs fibrinolysis
- Epsilon-amino-caprioc acid (EACA) & tranexamic acid (TXA)
146
What is an example of a SERPIN?
Aprotinin (removed from market d/t renal & cardio toxicity)
147
What are the factor replacements?
- Recombinant VIIa
- Prothrombin Complex Concentrate (PCC)
- Fibrinogen concentrate
- Cryoprecipitate and FFP
148
What does recombinant VIIa do?
Increases thrombin generation via intrinsic and extrinsic pathways
149
What does Prothrombin complex concentrate contain?
Contain vitamin-k factors
150
One negative and positive of crycoprecipitate and FFP:
- Cheaper and contain more coag factors
- Less specific composition
151
When to stop Warfarin prior to surgery:
- Low rx pts should d/c 5 days prior to surgery & restart 12-24 hours postop
- High rx pts should d/c 5 days prior & bridge w/ UFH or LMWH
152
When to stop heparins prior to surgery:
- UFH should be d/c'd 4-6h prior to surgery & resumed (no bolus) > 12h postop
- LMWH should be d/c'd 24h prior to surgery & resumed 24h postop
153
When to stop aspirin prior to surgery:
*not as defined
- Mod/high rx pts - current recommendation is to continue ASA
- Low rx pts - stop 7-10 days prior to surgery
154
Preop guidelines for pts post coronary stent placement:
- Bare-metal stents→ delay elective surgery 6 weeks after placement
- Drug-eluding stents→ delay elective surgery 6 months after placement
155
When might warfarin reversal be required?
For excessive bleeding or emergent surgery
156
What is the drug of choice for emergent coumadin reversal?
Prothrombin complex concentrates
157
What does vitamin k restore for reversal?
Vitamin K restores liver carboxylation of vit-k dependent factors for more sustained correction
158
Is there a reversal for direct thrombin inhibitors?
No reversal for most, but half life is short
159
What is the antidote for Dabigatran?
Idarucizumab
160
What can direct factor Xa inhibitors be reversed by?
Andexanet - a derivative of factor Xa
161
Common anticoagulants graph:
