Exam 4: 4/3 Coagulation Flashcards
Test 4
1
Q
What is normal hemostasis a balance between?
A
Balance between:
-clot generation
-thrombus formation
-regulatory mechanisms
All of these should inhibit uncontrolled thrombosis
2
Q
What are the goals of hemostasis? (3)
A
- Limit blood flow from vascular injury.
- Maintain intravascular blood flow.
- Promote revascularization after thrombosis.
3
Q
What are the two different stages of hemostasis? Describe them.
A
Primary: initial platelet plug formation at the endovascular injury site
-only adequate for minor injuries
Seconday: clotting factors activated
-clot form, stabilized and secured with cross-linked fibrin
4
Q
Vascular endothelium cells have _________ (3) affects. What do these effects do? What are the mechanisms of the endothelial cells to achieve these effects? (6)
A
Anti platelet, anticoagulant, fibrolytic effects → inhibit clot formation
- Negatively charged → repel platelet.
- Produce Prostacyclin & Nitric Oxide = platelet inhibitors
- Excrete adenosine diphosphatase → degrades ADP (platelet activator)
- Increases Protein C (anticoagulant)
- Produce tissue factor pathway inhibitor (TFPI) → inhibits factor Xa & TF-VIIa complex
- Synthesizes tPA
5
Q
Platelets are derived from bone marrow ________
A
megakaryocytes
6
Q
Inactivated platelet circulate as ____-shaped _______ cells. What is their lifespan?
A
disc-shaped
anuclear cells
8-12 days
7
Q
___% a platelets are consumed to support vascular integrity
A
10%
8
Q
_______billion new platelets are formed daily
A
120-150 billion
9
Q
T/F: the surface area membrane of a platelet can increase
A
T
10
Q
What does a platelet have on its surface?
A
Numerous receptors and a canalicular system (channel & ducts to increase membrane surface area)
11
Q
Damage to endothelium exposes the underlying __________ which contains what? (3)
A
Extracellular matrix (ECM)
- Collagen
- von Willebrand’s factor (vWBF)
- Glycoprotein
12
Q
When platelets are exposed to contents in the extracellular matrix (ECM) what three phases do they undergo?
A
- Adhesion (adhere to vascualr surface area)
- Activation (spill out contents)
- Aggregation (the contents enourage aggregation)
13
Q
Adhesion of platelets occurs when exposed to _______
A
ECM proteins
14
Q
Activation of platelets occurs when platelets interact with _____ & _______. What does this cause?
A
collagen
tissue factor (TF)
release of granular contents
15
Q
What are the two types of platelet storage granules? What do they contain?
A
Alpha granules:
* Fibrinogen
* Factors V & VIII (5 & 8)
* vWF
* Platelet derived growth factors
Dense bodies:
* ADP
* ATP
* Calcium
* Serotonin
* Histamine
* Epinephrine
16
Q
When does aggregation of platelets occurs?
A
Granular contents are released → additional platelets are activated
17
Q
Each stage of the clotting cascade requires assembly of membrane bound activated ___________. What does this consist of?(4)
A
Tenase-complexes:
-A substrate (inactivated precursor)
-an enzyme (activated coagulation factor)
-a cofactor (accelerator/catalyst)
-calcium
18
Q
Clotting factors: Factor I (1)
A
Fibrinogen
19
Q
Clotting factors: Factor II (2)
A
Prothrombin
20
Q
Clotting factors: Factor III (3)
A
Tissue thromboplastin
21
Q
Clotting factors: Factor IV (4)
A
Calcium ions
22
Q
Clotting factors: Factor V (5)
A
Labile factor
23
Q
Clotting factors: Factor VII (7)
A
Stable factor
24
Q
Clotting factors: Factor VIII (8)
A
Anti-hemophilic factor
25
Clotting factors: Factor IX (9)
Christmas factor
Plasma thromboplastin component (PTC)
26
Clotting factors: Factor X (10)
Stuart-Prower Factor
27
Clotting factors: Factor XI (11)
Plasma thromboplastin antecedent (PTA)
28
Clotting factors: Factor XII (12)
Hageman factor
29
Clotting factors: Factor XIII (13)
Fibrin stabilizing factor
30
Describe the extrinsic pathway of the clotting cascade
1. Trauma exposes tissue factors → Tissue Factors + Factor VII (7) = TFIIa Complex
2. TFIIa Complex → Activates Factor X (10) → Factor Xa (start of common pathway)
4. Prothrombin (F II) → Thrombin → activates plates & converts fibrinogen of fibrin
31
What two things does TFIIa Complex do?
1. Activates Factor Xa (start of common pathway)
2. Augments (helps/makes more effective) the Intrinsic pathway
32
What happens when Factor Xa, Va, and calcium are together, what Factor is activated?
Factor II (Prothrombin)
Factor II (Prothrombin)
→ Thrombin → Fibrinogen → Cross-linked Fibrin (via Factor XIIIa)
33
The extrinsic pathway is the initiation phase of __________ homeostasis
Plasma mediated
34
Factor ______ begins the final common pathway
Xa (10a)
35
What was previously thought to initiate the intrinsic pathway of the clotting cascade?
Damage to the endothelial; contact with negatively charged surface → factor XII becomes activated
36
What is currently understood about the role of the intrinsic pathway in the clotting cascade?
That is plays a minor role in the initiation of hemostasis.
It's more of an **amplification system** to increase thrombin generation initiated by the extrinisic pathway
37
Describe the intrinsic pathway of the clotting cascade
1. Upon contact with a negatively charged surface, Factor XII becomes activated into XIIa
2. Factor XIIa → Activates Factor XI (11) into Factor XIa
3. Factor XIa → activates Factor IX (9) into Factor IXa
4. Factor IXa → Activates Factor X (10) into Factor Xa with the help of Factor VIIIa Xa. This is the start of the common pathway
5. Factor Xa → Activates Prothrombin (F II) into Thrombin (IIa)
6. Thrombin → Activates Fibrinogen into Cross-linked Fibrin via Factor XIIIa
38
What additional factors does Thrombin (2a) activate?
V - 5
VII - 7
VIII - 8
XI - 11
39
What forms the prothrombinase complex? What does this do?
Factor Xa & Factor Va
Converts prothrombin → thrombin
40
Describe the common pathway
1. Factor Xa & Factor Va → Prothrombin to thrombin
2. Thrombin attaches to platelet → converts fibrinogen to fibrin
3. Fibrin cross link → stabilize clot
41
Thrombin cleaves ____________ from Fibrinogen to generate Fibrin which polymerizes into strands to form a basic clot.
fibrinopeptides
42
_________ is the key step in regulating hemostasis
Thrombin generation
43
What are the 4 major anticoagulation mechanisms? Describe them
1. Fibrinolysis: TPA & Urokinase
Convert plasminogen to plasmin
Breaks down clots
Degrades factors V & VIII
2. Tissue factor pathway inhibitor (TFPI): forms complex with Xa --> inhibits VIIa/TF complex & Xa
Down regulates the extrinsic pathway
3. Protein C system: inhibits factors II, Va, VIIIa
4. Serine Protease inhibitors (SERPINs):
-antithrombin (AT): inhibits thrombin, factors IXa, Xa, XIa, XIIa,
-Heparin: Bonds to antithrombin --> confirmational change that accelerates antithrombin activity
-heparin cofactor II: inhibits thrombin alone
44
_______ are first line labs if bleeding disorder is suspected
PT, aPTT
45
Pinpoint important things from vWBF disease
**Most common bleeding disorder**
Deficiency in vWBF --> defective platelet adhesion/aggregation
vWBF prevents degradation of Factor 8 --> decreased Factor 8
aPTT prolonged (platelets/PT normal)
Mild cases will respond to DDAVP
Tx: vWBF & Factor 8 concentrates
46
Most common inheritied bleeding disorder
von Willebrand's Disease
47
von Willebrand's Disease effects ____% of the population
1%
48
von Willebrand's Factor prevents the degradation of what factor?
VIII (8)
49
T/F: Routine coagulation labs are helpful for patient's with von Willebrand's Disease
False
They are not helpful.
Better tests include:
1. vWF level
2. vWF-platelet binding activity
3. Factor 8 level
4. Platelet function assay
50
What will the labs look like for patients with von Willebrand's disease?
Platelets and pT will be normal
Only aPTT might be prolonged due to no Factor VIII (8)
51
T/F: Mild von Willebrand's disease is often response to DDVAP (increased vWF)
True
52
Describe Hemophilia
Hemophilia A: Factor 8 deficiency (1/5000)
Hemophilia B: Factor 9 deficiency (1/30000)
**2/3 genetic**
**1/3 present as a new mutation w/o family hx**
Presents in childhood as spontaneous hemorrhage involving joints & muscles
**Labs: PTT prolonged**
Normal PT & bleeding time
Tx: DDAVP
Factors 8/9 concentrates before Sx
53
Hemophilia A is a Factor ________ deficiency that occurs in 1 in ____ patients.
Factor 8; 1 in 5000
54
Hemophilia B is a Factor ________ deficiency that occurs in 1 in ____ patients.
Factor 9; 1 in 30k
55
Which Hemophilia disease is more rare?
Hemophilia B
56
How many Hemophilia cases are genetically inheritied vs presented as a new mutation without a family history?
2/3 inheritied
1/3 new mutation
57
How does hemophilia frequently present?
In childhood as spontaneous hemorrhage (nose bleeds) involving joints and muscles
58
What labs will be abnormal with Hemophilia patients?
Normal: PT, bleeding time
Abnormal: PTT prolonged
(abnormal aPTT is for vWD!!!)
59
What drugs induce bleeding?
Heparin
Warfarin
PO anticoags
Beta-lactam abx
Nitroprusside
Nitroglycerin
NO
SSRIs
60
What herbs induce bleeding?
Cayenne
Garlic (stop 7 to 10 days before surgery)
Ginger
Ginkgo Biloba
Grapeseed oil
St. John wort
Turmeric (Warfarin is a derivative of this)
Vitamin E
61
How does liver disease affect bleeding in patients? (3)
Hemostatic issues:
-Impaired synthesis of coagulation factors
-quantitative and qualitative platelet dysfunction
-impaired clearance of clotting in fibrinolytic proteins
**Labs: prolonged PT/PTT**
62
The liver is the primary source of what factors?
Factors:
5
7
9
10
11
12
Protein C & S
Antithrombin
63
How do chronic liver disease patient's "rebalanced hemostasis"?
They lack pro-coag factors but also lack anti-coag factors so they balances out and they also have sufficient production of thrombin
However, they are still very susceptible to disruption in coagulation. Use **TEG & ROTEM as guides** This will tell you what factors to treat the patient with.
64
How does Chronic Kidney Disease affect coagulation? How do we Tx this?
CKD --> anemia at base dt:
-lack of erythopoietin
-platelet dysfunction dt uremic environment
Tx: Dialysis
Correction of anemia
(Both shorten bleeding time)
Cryo
DDAVP
Conjugated estrogen preop x5days
(these are for platelet dysfunction only)
65
CKD patient's display a baseline anemia due to what? (2)
1. Lack of erythropoietin production
2. Platelet dysfunction (due to uremic environment)
66
________ and correction of ________ are both done to shorten bleeding times in chronic renal disease patients.
Dialysis; anemia
67
Treatment of platelet dysfunction in chronic renal disease patients includes:
1. Give Cryo (rich in vWF)
2. DDVAP (caution with tachyphlaxis)
3. Conjugated estrogens given pre-operatively for 5 days
68
Describe DIC
Disseminated intravascular coagulation
Pathologic hemostatic response to TF/7a complex --> excessive activation of extrinsic pathway
Coagulation factors & platelets become depleted --> widespread microvascular thrombosis --> multiorgan dysfunction
causes: trauma, amniotic fluid in embolus, malignancy, sepsis, incompatible blood transfusion
labs: decreased platelets,
Prolonged PT/PTT/TT/Soluble fibrin/fibrin degration products
Tx: correct underlying condition
Administer appropriate blood products
69
DIC is pathological hemostatis response to ____________ causing excessive activation of the ____________ pathway, which overwhelms the anticoagulant mechanisms and generates intravascular thrombin.
TFIIa; extrinsic
70
What are somethings that can precipitate DIC?
Amniotic fluid emboli
Trauma
Malognancy
Sepsis
Incompatible blood transfusion
71
How is DIC treated?
Treat the underlying condition
Administer blood products
72
Coagulopathies occur dt ______ (3)
Acidosis
Hypothermia
Hemodilution
73
What is trauma induced coagulopathy?
Acute coagulopathy scene and trauma patient thought to be related to **activated protein C decreasing thrombin generation**
Hypoperfusion is thought to be the driving factor for protein C activation
74
This coagulopathy is an acute uncontrolled hemorrhage that is thought to be related to activated ________ decreasing thrombin generation and it is a common cause of death.
trauma induced coagulopathy ; Protein C
75
________is thought to be the driving factor for ____________ activation
Hypoperfusion; Protein C
76
Preoteoglycan-shedding results in "________________"
auto-heparinization
77
What are some causes of trauma induced coagulopathy?
Acidosis, hypothermia, and/or hemodiution
78
Decribe the Prothrombotic disorders (4). Which are most common?
**Inherited/genetic**
Factor V Leiden mutation: activated, protein C resistance
-present 5% Caucasian population
Prothrombin mutation: increase prothrombin concentration --> hypercoagulation
Thrombophilia: can be inherited or acquired
-highly susceptible to Virchow's triad (blood stasis, endothelial injury, hypercoagulability)
Antiphospholipid syndrome: autoimmune disorder with antibodies against phospholipid binding proteins in the coagulation system
-recurrent thrombosis and pregnancy loss
Requires lifelong anticoagulant
**PO contraceptives, pregnancy, and mobility, infection, surgery and trauma, greatly increased the risk of thrombosis**
79
What are three types of Prothrombotic diseases?
Factor V Leiden Mutation
Prothrombin Mutation
Thrombophilia
80
Factor V Leiden mutation leads to ____________ resistance and is present in ____% of the caucasian population
Protein C
5%
81
Prothrombin mutation causes increased ________ production leading to ________
prothrombin; hypercoagulation
82
Thrombophilia is an ____________ predispisition for thrombotic events that genenerallly manifests as ________ thrombosis and is highly susceptible to ________
inherited; venous; Virchow's Triad
83
Prothrombotic diseases are caused by a mutation in what?
Factor V or Prothrombin
84
________ is an auto immune disorder with antibodies against phospholipid binding proteins in the coagulation system. Characterized by recurrent thrombosis and ________, where patients often require lifelong anticoagulants
Antiphospholipid Syndrome; pregnancy loss
85
Describe HIT
Heparin induced thrombocytopenia
Occurs 5 to 14 days after heparin treatment
Platelet count reduction --> potential thrombosis
Auto immune response in 5% patient receiving heparin
**Response can occur within 1 day if previously had heparin before**
Infraction heparin >> LMWH risk
Cannot bridge to warfarin
Dx confirmed with HIT antibody testing
Antibodies cleared within 3 months
86
When do the symptoms of HIT generally occur?
5-14 days after treatment
87
____% of patient receiving Heparin will go on to develop HIT.
5%
88
________ carries a greater risk than ________ in HIT
UFH; LMWH
89
Why is warfarin contraindicated in HIT therapy?
Because it decreases Protein C & S synthesis
90
HIT diagnosis is confirmed with HIT ________ and these are typically cleared from ciruclation in ___________
antibody testing; 3 months
91
What gender is more at risk for HIT?
women
92
# Labs:
**PT** looks at the ____________ pathways.
The lab will mix ____________ with ____________ and look at the number of seconds measured until a clot forms.
This will show deficiencies in factors _______________
This is used to monitor _______________
**extrinsic/common**
Plasma mixed with tissue factor
Deficiencies in factors: 1, 2, 5, 7, 10
**Vit-K antagonists like Warfarin**
93
# Labs:
**aPTT** looks at the ____________ pathways.
The lab will mix ____________ with ____________ and look at the number of seconds measured until a clost forms.
Deficiencies in factors _______________
This is used to monitor _______________
**intrinsic/ common**
plasma with phospholipid, Ca++, and an activator of the intrinsic pathway
Deficiencies in factors: 8, 9
**Heparin**
94
Anti-factor Xa
Functional assessment of heparins anticoagulant effects
Plasma + Xa
used to monitor Fondaparinux, LMWH, and other Factor Xa inhibitors
95
# Labs:
What is a normal platelet count?
Normal: >100,000plts/microliter
96
# Labs:
Activated clotting time (ACT)
Normal: 107 (+/- 13seconds)
Addition of clotting activator to accelerate clotting time
**intrinsic/common**
Measure responsiveness to heparin
97
________ is a variation of whole blood clotting time. A normal value is ________ seconds (+/- ________ seconds)
ACT (activated clotting time); 107
13
98
Labs: heparin concentration measurements
Determines preoperative heparin concentration
99
1mg protamine will inhibit ____ heparin
1mg
100
What are my Viscoelastic coagulation test?
TEG
ROTEM
101
TEG values/Tx: R time
Time to start forming clot
Normal: 5-10minutes
>10min --> FFP
102
TEG values/Tx: K time
Time until clot reaches a fixed strength
Normal: 1-3 mins
>3min --> cryo
103
TEG values/Tx: Alpha angle
Speed of fibrin accumulation
Normal: 53 - 72 degrees
Tx: cryo
104
TEG values/Tx: maximum amplitude (MA)
Highest vertical amplitude of the TEG
Normal: 50 - 70 mm
Tx: Platelets
DDAVP
105
TEG values/Tx: LY30
Percentage of amplitude reduction 30 minutes after maximum amplitude (percentage of clot dissolved after 30 minutes)
Normal: 0-8%
>8% --> TXA or Aminocaproic acid
106
What are the three classes of anti-platelets? How do they work? How long do their anti-platelet effects last after stopping the drug?
1. Cyclooxygenase inhibitors: Block COX1 from forming TXA2
-ASA: 7-10 days
-NSAIDS: 3 days
2. P2Y12-Receptor antagonists: Inhibit those receptors & prevent IIb/IIIa granulation/aggregation
-Clopidogrel: 7 days
-Ticopidine: 14-21 days
-Ticagrelor & Cangrelor: 24 hrs
3. Platelet GIIb/IIIa antagonists: prevents vWF & fibrinogen from binding to those receptors
-Abciximab, Eptifibatide, Tirofiban
107
What are the vitamin K dependent factors?
2
7
9
10
Protein C & S
108
Anticoagulants: Warfarin
Long 1/2 life (40h)
3-4 days to reach therapeutic INR (2-3)
Reversible with vitamin K
109
Anticoagulants: Heparin
MOA: binds to ANTITHROMBIN!!!! --> inhibits thrombin & Xa
(indirect thrombin inhibitor)
UFH:
Short 1/2 life
fully reversable w/ protamine
Close monitoring required
LMWH:
Longer HL
Dose BID SQ
Partially reversed w/ protamine
Fondaparinux:
Much longer half life (17-21h)
Dose once a day
Not reversible
110
Anticoagulants: direct thrombin inhibitors
MOA: bind/block thrombin
Hirudin: found in leeches
Argatroban: reversible
Bivalirudin: shortest half life
Dabigatran (Pradaxa): 1st DOAC (PO)
111
This Direct Thrombin Inhibitor drug is synthetic and reversibly binds to Thrombin. It has a half-life of ________________ minutes.
Argatroban; 45 minutes
112
This Direct Thrombin Inhibitor drug is synthetic and is has the shortest half-life of any in this class which makes it the DOC for patients with ________ impariment
Biva**L**rudin
**L**iver or renal patients
113
This drug was approved for CVA prevention and non-valvular A-**fib**
Da**big**atran (Pradaxa)
114
T/F: Dabigatran (Pradaxa) is both a DTI and DOAC.
True
115
DOAC =
Direct Oral anticoagulants
116
Direct Xa inhibitors: Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa) are all examples of what drug class?
DOAC
117
What are the benefits of DOAC? What drugs are they?
More predictable pharmacokinetics/ pharmacodynamics
-fewer drug interactions
-does daily without lab monitoring
-shorter half life
-fewer embolic events
-lower mortality
Direct thrombin inhibitors: Dabigatran (Pradaxa)
Direct Xa inhibitors: Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
118
What are the 2 categories of thrombolytics?
Fibrin-Specific: tPA, Reteplase, Tenecteplase
Non-Fibrin-Specific: Streptokinase (has allergic reactions sometimes)
119
Why isn't Streptokinase widely used?
allergic reactions
120
Surgery is contraindicated within _______ of thrombolytic treatment
10 days
121
What are absolute contraindications for thrombolytic treatment?
Vascular lesions
-severe uncontrolled hypertension (SBP >185; DBP >110)
-recent cranial surgery or trauma
-brain tumor
-ischemic stroke <3 months
-Active bleeding
122
What are relative contraindications for thrombolytic treatment?
Ischemic stroke >3 months
-Active Pepcid ulcer
-current use of anticoagulant drug drugs
-pregnancy
-prolonged or traumatic CPR <3 weeks prior
-major surgery <3 weeks prior
123
What are the 2 Procoagulant classes? Describe them. What is included in them?
Antifibrinolytics:
-Lysine analogues: Epsilon-amino-caproic acid (EACA) & Tranexamic acid (TXA) - inhibits plasminogen from binding to fibrin --> impairs fibrinolysis
-SERPIN: Aprotinin - removed from market dt renal/cardio toxicity
Factor Replacements:
-Recombinant VIIa
-prothrombin complex concentrates (PCC): has vit K factors
-fibrinogen concentrates
-cryoprecipitate & FFP: more coag factors but less specific
124
When should you stop/start taking this med for Sx: Warfarin
low risk:
stop: 5 days prior
start: 12-24 h
high risk:
Stop: 5 days prior & bridge to heparin
125
When should you stop/start taking this med for Sx: Heparin
UFH:
Stop: 4-6h
Start: 12h
LMWH:
Stop: 24h
start: 24h
126
When should you stop/start taking this med for Sx: aspirin
mod/high risk: continue
low risk:
stop: 7-10 days
127
We delay elective Sx for _____ with bare metal stents & ______ for drug eluding stents
6 weeks
6 months
128
What are the reversals for warfarin?
Prothrombin complex concentrates (PCC) = for emergent reversal
vitamin K = more sustained reversal (slower)
129
The reversal for DOAC Dabigatran (Pradaxa) is ________
Idarucizumab
130
The reversal for DOAC factor Xa inhibitors is __________
Andexanet
