Blood coagulation Flashcards
(140 cards)
1
Q
INJURY
▪ Exposes reactive subendothelial matrix proteins
such as:
A
- Collagen
- Von Willebrand Factor
2
Q
Injury Result
A
- Platelet adherence and activation
- Secretion and synthesis vasoconstrictors
- Platelet recruitment and activating proteins
3
Q
▪ Synthesized from arachidonic acid within
platelets.
▪ A platelet activator and potent vasoconstrictor.
A
THROMBOXANE A2 (TXA)
4
Q
PRODUCTS SECRETED FROM PLT GRANULES
A
▪ Adenosine diphosphate ▪ Serotonin ▪ Bind fibrinogen ▪ Cross link adjacent platelets. ▪ Aggregation and formation of platelet plug ▪ Thrombin generation and fibrin clot.
5
Q
serotonin
A
- Activation of platelet
- Conformational change in alpha and beta
integrin (IIb/IIIa) receptor.
2b3a
6
Q
DEFECTS IN FORMATION OF PLATELET PLUG
A
▪ Defects in primary hemostasis, platelet function defects, Von Willebrand Disease.
▪ Bleeding mucosal sites with injury.
- Gingiva, skin, heavy menses
7
Q
DEFECTS IN THE CLOTTING MECHANISM
A
▪ Secondary hemostasis, Hemophilia A
▪ Tend to bleed into deep tissues
- Joints, muscle, retroperitoneum
▪ No inciting event, recur unpredictably
8
Q
will do binding with fibronectin and
thrombin. This binding will produce more feedback
to produce more thrombin
A
vWF
9
Q
Platelets will be activated and release substances
like
A
ADP,5-HT, TXA2 in circulation.
10
Q
▪ Platelet rich
A
WHITE THROMBI
11
Q
Fibrin rich
A
RED THROMBI
12
Q
Form in the high
flow rate and high
shear force
environment of arteries
A
WHITE THROMBI
13
Q
▪ With large number
of trapped RBC
Venous clots
A
▪ With large number
of trapped RBC
14
Q
white thrombi is dominated by
A
platelet nidus
15
Q
red thrombi is dominated by
A
firbin tail
16
Q
white thrombi effects
A
- Downstream ischemia (of
extremities or vital organs) - Result: limb amputation
and organ failure
17
Q
Red thrombi effects
A
- Severe swelling and pain (of affected extremity) - Pulmonary Embolism – part of the clot breaks off from its location in the deep venous system and travels as an embolus; most feared consequence
18
Q
TF/VIIa
A
TFP inhibitor
19
Q
VIIIa
A
Protein C/Protein S
20
Q
IXa, XIa, Xa, Va, Thrombin
A
Antithrombin III/Heparin
21
Q
NATURAL ANTICOAGULANT SYSTEMS
A
NATURAL ANTICOAGULANT SYSTEMS
22
Q
THE IDEAL ANTI - CLOTTING DRUG
A
▪ Can preserve the tissue factor and VIIa initiation
phase
▪ Weakening the secondary pathway
23
Q
ANTIPLATELET AGENTS
A
Thromboxane A2 inhibitor Phosphodiesterase inhibitor Glycoprotein (GP) IIb/IIIa blockers ADP - receptor antagonist
24
Q
Thromboxane A2
inhibitor
A
Acetylsalicylic acid (ASA) (aspirin)
25
Phosphodiesterase
| inhibitor
Dipyridamole
26
Glycoprotein (GP)
| IIb/IIIa blockers
Abciximab
Tirofiban
Eptifibatide (“ATE”)
27
ADP - receptor antagonist
```
Clopidogrel
Prasugrel
Cangrelor
Ticlopidine
Ticagrelor
Vorapaxar (Thrombin receptor inhibitor)
```
28
Platelet function is regulated by 3 categories
1. Agents generated outside the platelets that
interact with platelet membrane receptor
2. Agents generated within the platelet that interact
with membrane receptors
3. Agents generated within the platelet that act
within the platelet
29
Agents generated outside the platelets that
| interact with platelet membrane receptor
o Catecholamines
o Collagen
o Thrombin
o Prostaglandin
30
Agents generated within the platelet that interact
| with membrane receptors
o ADP (clopidogrel)
o Prostaglandin D2
o Prostaglandin E2
o Serotonin
31
Agents generated within the platelet that act
| within the platelet
```
o Prostaglandin endopoxides
o Thromboxane A2 (aspirin)
o Cyclic nucleosides
o CAMP
o CGMP
o Calcium Ions
```
32
An arachidonate product that causes platelets to change shape, release their
granules and aggregate
▪ Prostaglandin thromboxane A2
33
Inhibit synthesis of TXA2 ▪ By irreversible acetylation of cyclooxygenase
Aspirin
34
Aspirin dose approved for primary prophylaxis of AMI
325 mg/d
35
As an adjunct to risk factor management by
| smoking cessation
Aspirin
36
aspirin SE
bleeding, gastritis/ gastric ulcers,
| allergic reaction and Reye syndrome
37
▪ Antiplatelet effects by irreversibly blocking ADP
receptors on platelets
▪ No effect on prostaglandin metabolism
CLOPIDOGREL AND TICLOPIDINE
38
Thienopyridine derivatives
CLOPIDOGREL AND TICLOPIDINE
39
Ticlopidine S/E
▪ Nausea, dyspepsia and diarrhea (20%)
▪ Hemorrhage (20%)
▪ Leukopenia (1%)
40
Ticlopidine dose
250 mg 2x/day
41
Approved for prevention of stroke in patients with
history of transient ischemic arrack (TIA) or
thrombotic stroke, and in combination with aspirin
for the prevention of coronary stent thrombosis.
Ticlopidine
42
clopidogrel is associated with
neutropenia, thrombotic
| thrombocytopenic purpura
43
Clopidogrel loading dose
300 mg oral dose (80%of platelet
| activity is inhibited)
44
Maintenance dose:
75 mg/d, achieve maximum
| platelet inhibition
45
Antiplatelet effect:
7-10 days
46
Approved for patients with unstable angina or nonST-elevation acute myocardial infarction (NSTEMI) in combination with aspirin; for patients with STEMI; recent MI, stroke or established peripheral arterial disease
CLOPIDOGREL
47
Clopidogrel is Prodrug that requires activation via the
cytochrome P450 enzyme isoform CYP2C19.
48
example of Drug that impair CYP2C19 function
Omeprazole
49
T or F
▪ In contrast to clopidogrel, cytochrome P450 genotype status is not an important factor in prasugrel pharmacology
T
50
▪ Similar to clopidogrel
▪ Given orally
▪ Approved for patients with acute coronary
syndrome
PRASUGREL
51
▪ Newer type of ADP inhibitor (cyclopentyl
triazolopyrimidine)
▪ Approved for oral use in combination with aspirin
in patients with acute coronary syndrome
TICAGRELOR
52
▪ Parenteral P2Y12 inhibitor
▪ Approved for IV use of coronary interventions in
patients without previous ADP P2Y12 inhibitor
therapy.
CANGRELOR
53
▪ Used in patients with Acute Coronary Syndrome
| ▪ Target the platelet IIb/IIIa receptor complex
PLATELET GLYCOPROTEIN IIb/ IIIa BLOCKERS
54
▪ IIb/IIIa complex: function as receptor
- Fibronectin and von Willebrand factor
| - Glanzmann’s thrombasthenia
55
▪ Chimeric monoclonal antibody directed against
IIb/IIIa complex
▪ Include vibronectin receptor
▪ First agent approved in this class of drugs
ABCIXIMAB
56
Abciximab is used in
- Percutaneous Coronary Intervention
| - Acute Coronary Syndrome
57
T or F
| EPTIFIBATIDE AND TIROFIBAN Do not block the vibronectin receptor
T
58
▪ Inhibit ligand binding to IIb/IIIa receptor by
| occupancy of receptor
EPTIFIBATIDE AND TIROFIBAN
59
```
cyclic peptide derived from rattlesnake venom that contains a variation of the
RGD motif (KGD).
```
Eptifibatide
60
peptidomimetic inhibitor with RGD sequence motif.
Tirofiban
61
▪ Vasodilator that inhibits platelet function
| ▪ Inhibit adenosine uptake and cGMP phosphodiesterase activity
DIPYRIDAMOLE
62
as combination therapy with
| aspirin to prevent cerebrovascular ischemia
DIPYRIDAMOLE
63
DIPYRIDAMOLE May also be used in combination with warfarin for
primary prophylaxis of thromboemboli in patients
| with prosthetic heart valves.
64
▪ Used to perform cardiac stress test.
DIPYRIDAMOLE
65
▪ Newer phosphodiesterase inhibitor
▪ Promotes vasodilation
▪ Inhibit platelet aggregation
CILOSTAZOL
66
cilostazol is used to treat
intermittent claudication
67
ANTICOAGULANTS
▪ Unfractionated Heparin
▪ Fondaparinux
▪ LMWH (low molecular weight heparins)
▪ Direct Thrombin Inhibitors (Parenteral)
68
LMWH (low molecular weight heparins)
- Enoxaparin
- Dalteparin
- Tinzaparin
69
▪ Direct Thrombin Inhibitors (Parenteral)
- Argatroban
- Bivalirudin
- Hirudin (Desirudin/Lepirudin)
70
▪ Fondaparinux is a specific factor
Xa inhibitor
71
Fondaparinux will only involve factor Xa but
| heparin will involve
Factor XIIa, XIa, IXa, Xa and IIa.
72
key step in the coagulation pathway.
Inhibition of one molecule of ______ can inhibit
the generation of 50 molecules of thrombin (IIa).
Factor Xa
73
factor Xa will be affected by
low molecular weight
| heparins and unfractionated heparin.
74
TOXICITY OF HEPARIN
```
Bleeding
▪ Reversible alopecia
▪ Osteoporosis
▪ Spontaneous fractures
▪ Accelerated clearing of postprandial lipemia
▪ Mineralocorticoid deficiency
▪ Heparin-induced Thrombocytopenia
```
75
HIT is High in UHF treatment of what source
bovine
76
HIT clinical manifestations
o Venous thrombosis and occlusion of arteries
o Risk of thrombosis for indwelling catheters
o Skin necrosis
77
Tx HIT
o Discontinue heparin
| o Use fondaparinux
78
CONTRAINDICATIONS OF HEPARIN
```
▪ HIT
▪ Hypersensitivity
▪ Active bleeding
▪ Hemophilia
▪ Significant thrombocytopenia
▪ Purpura
▪ Severe hypertension
▪ Intracranial hemorrhage
▪ Infective endocarditis
▪ Active tuberculosis
▪ Ulcerative lesions of the GIT
▪ Threatened abortion
▪ Visceral carcinoma
▪ Advance renal disease
▪ Recent surgery of the brain, spinal cord and eye
▪ Lumbar puncture
▪ Regional anesthetic block
▪ Caution:
- In pregnancy used only when clinically indicated
```
79
PLASMA CONCENTRATION OF HEPARIN
▪ 0.2 to 0.4 unit/mL (protamine titration)
| ▪ 0.3 to 0.7 unit/mL (anti Xa unit)
80
Heparin initial bolus injection
80-100 unit/kg/hr
81
Heparin continuous infusion:
15 to 22 unit/kg/hr
82
Heparin low dose prophylaxis
▪ Subcutaneous administration
| ▪ 5000 units every 8 to 12 hours
83
T or F
***Heparin is not administered by IM because it causes
necrosis
T
84
Enoxaparin frequency
30mg 2x daily or 40mg once daily subQ
85
Correspond to therapeutic anti Xa level of 0.5 to 1 unit/mL
Enoxaparin Full dose: 1mg/kg subQ every 12 hours
86
Target anti Xa level of 1.5 units/mL
1.5 mg/kg once a day
87
Prophylactic dose: ________subQ once daily
5000 units
88
Dalteparin Therapeutic dose for venous disease:
200 units/kg
| once a day
89
Dalteparin Therapeutic dose for acute coronary syndrome:
120 units/kg every 12 hours
90
LMWH is used with caution in px with
renal insufficiency
91
▪ For venous thromboembolism
▪ Bind antithrombin with high specific activity = less
bleeding
▪ Efficient inactivation of factor Xa
FONDAPARINUX
92
▪ Long half-life of 15 hours
| ▪ Alternative anticoagulant for HIT
Fondaparinux
93
o A highly basic peptide; antagonist
| o Combines with heparin as an ion pair to form stable complex devoid of anticoagulant activity
Protamine s04
94
__ mg of protamine sulfate IV for every 100 units of heparin
1
95
Rate of infusion should not exceed
50mg in any 10-minute
| period
96
- For excess Dalteparin, it is removed by
plasmapheresis
97
T or F
Protamine does not reverse the
activity of fondaparinux
T
98
Bind at both catalytic and active site of thrombin and substrate recognition site
▪ HIRUDIN and BIVALIRUDIN
99
Bind only at thrombin site
ARGATROBAN and MELAGATRAN
100
▪ Specific irreversible thrombin inhibitor from leech saliva
HIRUDIN
101
Hirudin recombinant form
Lepirudin
102
▪ Bivalent inhibitor of thrombin and platelet
activation
▪ Administered IV
BIVALIRUDIN
103
▪ FDA approved for percutaneous coronary
| angioplasty
BIVALIRUDIN
104
▪ Reach and inactivate fibrin bound thrombin in
thrombi
▪ Has little effect on platelets or the bleeding time
LEPIRUDIN
105
FDA approved for
| thrombosis related to HIT
LEPIRUDIN
106
```
▪ Small molecule thrombin inhibitor
▪ FDA approved in patients with HIT
▪ Has a short half-life
▪ Needs aPTT monitoring
▪ Clearance is dependent on liver function
```
ARGATROBAN
107
▪ An oral prodrug metabolized to the DTI
| melagatran
XIMELAGATRAN
108
Vitamin K Antagonist
Warfarin
109
WARFARIN
| ▪ A synthesized agent from
BISHYDROXYCOUMARIN
110
99% of racemic warfarin is bound to
plasma albumin
111
T or F
The levorotatory S-warfarin is four times more
potent than the dextrorotatory R-warfarin
T
112
Warfarin ▪ Mechanism of Action
- Block the gamma- carboxylation of
several glutamate residues in prothrombin
and factors VII, IX, and X
113
Resistance to warfarin:
presence of Vitamin K
| reductase
114
Four Vitamin K dependent factors includes:
II, VII, IX, and X
115
Half-life: VII (__), IX (__hours), X (__
| hours), II (__ hours)
6, 24, 40, 60
116
For you to completely coagulate a patient,
if a half-life of prothrombin is 60 hours and
there is a presence of protein C and S,
you need to overlap it with a short acting
anti-coagulant (heparin)
- There is a tendency to clot if you do not
overlap it with heparin
117
warfain
| ▪ Crosses the placenta
- Cause a hemorrhagic disorder in the fetus
- Affect fetal proteins with gammacarboxyglutamate residues found in bone
and blood
- Cause a serious birth defect
118
warfarin
| ▪ Cutaneous necrosis
- First weeks of therapy
- Frank infarction of the breast, fatty
tissues, intestine, and extremities
119
Defined as progression or recurrence of a
thrombotic event while in the therapeutic range
These individuals may have their INR target raised
WARFARIN RESISTANCE
120
Most commonly seen in patients with advanced
cancers, typically of gastrointestinal origin
(Trousseau’s syndrome)
WARFARIN RESISTANCE
121
Reversal of warfarin action
- Discontinue the drug
- Oral or parenteral vitamin K1
(phytonadione)
- Fresh-frozen plasma
- Prothrombin complex concentration
o BEBULIN and Proplex T
122
▪ Direct thrombin inhibitors (Oral)
Dabigatran
123
▪ Direct Oral Factor Xa inhibitors
- Rivaroxaban
- Apixaban
- Edoxaban
124
Reversal Agents for Direct Oral Anticoagulant
- Idarucizumab (reversal agent for dabigatran alone)
- Andexanet alfa (is a factor Xa “decoy” molecule without procoagulant activity that competes for binding to anti-Xa drugs)
- Ciraparantag
125
FIBRINOLYTIC AGENTS
▪ Streptokinase
▪ Recombinant tissue plasminogen activator
▪ Inhibitors of Fibrinolysis
▪ Fibrinolytic Drugs
126
▪ Recombinant tissue plasminogen activator
- Alteplase
- Reteplase
- Tenecteplase
127
Inhibitors of Fibrinolysis
- E-aminocaproic acid
| - Tranexamic acid
128
Rapidly lyses thrombi by catalyzing the
| formation of serene protease PLASMIN
▪ Fibrinolytic Drugs
129
FIBRINOLYTIC AGENTS
| includes
Streptokinase, Urokinase,
| Anistreplase, t-PA
130
A protein (but not an enzyme in itself) synthesized
by streptococci that combines with the
proactivator plasminogen. This enzymatic
complex catalyzes the conversion of inactive
plasminogen to active plasmin.
STREPTOKINASE
131
▪ A human enzyme synthesized by the kidney that directly converts plasminogen to active
plasmin. Plasmin itself cannot be used because
naturally occurring inhibitors (antiplasmins) in
plasma prevent its effects.
▪ The absence of inhibitors for Urokinase permits its
use.
▪ Lyse thrombin from within.
UROKINASE
132
▪ Another recombinant human t-PA from which
several amino acid sequences have been
deleted.
▪ Less expensive recombinant human t-PA.
▪ Leads to major fibrin – binding domain, less fibrin
specific.
RETEPLASE
133
▪ A mutant form of t-PA that has a longer half-life,
and it can be given as an intravenous bolus.
Reteplase and Tenecteplase are as effective as
alteplase and have simpler dosing schemes
because of their longer half-lives.
▪ More fibrin – specific than t-PA.
TENECTEPLASE
134
▪ Plasminogen activated endogenously
▪ Activate plasminogen bound to fibrin
▪ Confines fibrinolysis to the formed thrombus and
avoids systemic activation
TISSUE PLASMINOGEN ACTIVATOR (t-PA)
135
▪ Human t-PA, manufactured by recombinant DNA
| technology
ALTEPLASE
136
▪ An Isolated plasminogen streptokinase activator
complex
▪ Consist of complex of purified human
plasminogen and bacterial streptokinase
▪ Acylated to protect enzyme site
▪ Acyl group hydrolyzes, free the streptokinase pro
activator complex
ANISTREPLASE
137
FIBRINOLYTIC INHIBITORS
AMINOCAPROIC ACID
TRANEXAMIC ACID
SERINE PROTEASE INHIBITORS
138
```
▪ Similar to amino acid Lysine
▪ A synthetic inhibitor of fibrinolysis
▪ Completely inhibits plasminogen activation
▪ Rapidly absorbed orally
▪ Cleared by kidney
```
AMINOCAPROIC ACID
139
▪ Analog of aminocaproic acid with the same
chemical properties
▪ Orally administered
▪ Loading dose - 15mg/kg
▪ Following dose - 30 mg/kg every 6 hours
TRANEXAMIC ACID
140
▪ Aprotinin is a serine protease inhibitor
▪ Inhibit fibrinolysis by free plasmin
▪ Inhibit plasmin- streptokinase complex in patient
who received thrombolytic agent
▪ Reduces bleeding by as much as 50%
▪ For open heart procedures
▪ Liver transplantation
SERINE PROTEASE INHIBITORS
