Drugs for Coagulation Disorders Flashcards
1
Q
-a process to prevent and stop bleeding
-prevention of blood loss
A
hemostasis
2
Q
HEMOSTASIS
* Steps:
A
- vascular constriction
- platelet plug formation
- formation of a blood clot as a result of blood coagulation
- fibrous organization or dissolution of the blood clot
3
Q
VASCULAR CONSTRICTION
A
- local myogenic spasm,
- local autacoid factors from the traumatized tissues and blood platelets, and
- nervous reflexes
4
Q
PLATELET PLUG FORMATION
A
a. Platelet adhesion
b. Platelet activation
c. Platelet aggregation
5
Q
a. Platelet adhesion
A
- When the endothelium is injured, platelets adhere to collagen in the tissues and to a protein
called von Willebrand factor (vWF)
that leaks into the traumatized tissue from the plasma
6
Q
von Willebrand factor (vWF)
A
a protein crucial to the blood clotting process
7
Q
the most common inherited bleeding disorder. Bleeding disorders disrupt your body’s typical healthy blood clotting process
A
von Willebrand disease (VWD)
8
Q
b. Platelet activation
A
- Morphologic changes in platelets
- Release of platelet granules adenosine diphosphate (ADP), TXA2, serotonin,
platelet-activation factor (PAF), and thrombin - These signaling molecules bind to receptors of resting platelets circulating
- The previously dormant platelets become activated and start to aggregate.
- These actions result in elevated levels of calcium and a decreased
concentration of cAMP within the platelet.
9
Q
Platelet Granules
A
Adenosine Diphosphate (ADP)
Thromboxane A₂ (TXA₂)
Serotonin
Platelet-Activating Factor (PAF)
Thrombin
10
Q
Adenosine Diphosphate (ADP) –
A
Promotes further platelet activation.
11
Q
Thromboxane A₂ (TXA₂) –
A
A potent vasoconstrictor and platelet activator.
12
Q
Serotonin –
A
Enhances vasoconstriction and platelet aggregation.
13
Q
Platelet-Activating Factor (PAF) –
A
Amplifies the activation response
14
Q
Thrombin –
A
A key enzyme in coagulation that further activates platelets.
15
Q
c. Platelet aggregation
A
- Increased cytosolic Ca2+ leads to
1) release of platelet granules containing mediators (ADP and serotonin) that activate other platelets; 2) activation of TXA2 synthesis; and
3) activation of glycoprotein (GP) IIb/IIIa receptors that bind fibrinogen and, ultimately, regulate platelet-platelet interaction and thrombus formation. - Fibrinogen, a soluble plasma GP, simultaneously binds to GP IIb/IIIa receptors on two separate platelets, resulting in platelet cross-linking and platelet aggregation.
- This leads to an avalanche of platelet aggregation, because each activated
platelet can recruit other platelets.
16
Q
Increased cytosolic Ca²⁺ leads to:
A
1- Release of platelet granules containing mediators (ADP and serotonin) that activate other platelets.
2- Activation of TXA₂ synthesis.
3- Activation of glycoprotein (GP) IIb/IIIa receptors, which bind fibrinogen and ultimately regulate platelet-platelet interaction and thrombus formation.
17
Q
a soluble plasma glycoprotein, simultaneously binds to GP IIb/IIIa receptors on two separate platelets, resulting in platelet cross-linking and platelet aggregation
A
Fibrinogen
18
Q
formation of blood clot as a result of blood coagulation
A
- The clot begins to develop in 15 to 20 seconds if the trauma to the vascular
wall has been severe, and in 1 to 2 minutes if the trauma has been minor. - Activator substances from the traumatized vascular wall, from platelets, and from blood proteins adhering to the traumatized vascular wall initiate the clotting process.
- Within 3 to 6 minutes after rupture of a vessel, if the vessel opening is not too
large, the entire opening or broken end of the vessel is filled with clot. - After 20 minutes to an hour, the clot retracts; this closes the vessel still further.
- Substances that cause or affect blood coagulation have been found in the
blood and in the tissues - Procoagulants – promote coagulation
- Anticoagulants – inhibit coagulation
- Whether blood will coagulate depends on the balance between these two
groups of substances. - In the blood stream, the anticoagulants normally predominate, so that the blood does not
coagulate while it is circulating in the blood vessels. - But when a vessel is ruptured, procoagulants from the area of tissue damage become
“activated” and override the anticoagulants, and then a clot does develop.
19
Q
- Several circulating proteins interact in a cascading series of limited proteolytic
reactions. - At each step, a clotting factor zymogen undergoes limited proteolysis and
becomes an active protease. - Each protease factor activates the next clotting factor in the sequence,
culminating in the formation of thrombin. - Blood coagulates due to the transformation of soluble fibrinogen into insoluble
fibrin by the enzyme thrombin.
A
COAGULATION CASCADE
20
Q
COAGULATION CASCADE
A
- In response to rupture of the vessel or damage to the blood itself, the
coagulation cascade results in the formation of a complex of activated
substances collectively called prothrombin activator. - The prothrombin activator catalyzes conversion of prothrombin into thrombin.
- The thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that
enmesh platelets, blood cells, and plasma to form the clot.
* Fibrin is incorporated into the plug.
* Subsequent cross-linking of the fibrin strands stabilizes the clot and forms a
hemostatic platelet-fibrin plug.
21
Q
undergoes limited proteolysis and
becomes an active protease.
A
a clotting factor zymogen
22
Q
catalyzes conversion of prothrombin into thrombin.
A
prothrombin activator
23
Q
an enzyme that convert fibrinogen into fibrin fibers that enmesh platelets, blood cells, and plasma to form the clot.
A
thrombin
24
Q
procoagulants
A
factors I-XIII
25
Anticoagulants
protein C & S
26
fibrinolytic
plasminogen
27
begins with a traumatized vascular wall or traumatized
extravascular tissues that come in contact with the blood
Extrinsic Pathway
28
begins with trauma to the blood itself or exposure of the
blood to collagen from a traumatized blood vessel wall
Intrinsic Pathway
29
EXTRINSIC PATHWAY
* Fewer steps than intrinsic
* Occurs rapidly (seconds)
* Starts when tissue factor (TF) leaks into the blood from cells outside (extrinsic to) blood vessels
* Ultimately activates clotting factor X, which combines with factor V in the
presence of Ca2+ to form the active enzyme prothrombinase
30
INTRINSIC PATHWAY
* More complex than extrinsic
* Occurs more slowly (minutes)
* Activators are either in direct contact with blood or contained within (intrinsic
to) the blood
* Starts when blood contact with collagen from damaged connective tissues in blood vessels beneath the endothelium activates clotting factor XII
* Ultimately activates clotting factor X, which combines with factor V in the
presence of Ca2+ to form the active enzyme prothrombinase
31
Steps of the Extrinsic Pathway:
1- Tissue Factor (TF) Release
When blood vessels are damaged, Tissue Factor (Factor III) is released from damaged endothelial cells
2- TF binds to Factor VII (inactive form) in plasma.
This complex, in the presence of Ca²⁺, activates Factor VII → Factor VIIa (active form).
3- Activation of Factor X (Common Pathway Initiation)
The TF–Factor VIIa complex (along with Ca²⁺) activates Factor X → Factor Xa.
4- Formation of the Prothrombinase Complex
Factor Xa binds to Factor V, forming the prothrombinase complex.
In the presence of Ca²⁺, platelet phospholipids, prothrombinase converts prothrombin (Factor II) → thrombin (Factor IIa).
Thrombin then converts fibrinogen → fibrin, leading to clot formation.
32
THROMBOSIS
is the pathological formation of a blood clot (thrombus) inside a blood vessel, obstructing blood flow. It can lead to severe conditions like heart attacks, strokes, and deep vein thrombosis (DVT).
33
Steps of the Intrinsic Pathway:
1- Contact Activation (Factor XII Activation)
When blood comes into contact with collagen from damaged connective tissues beneath the endothelium, in the presence of HMW Kininogen, Prekallikrein, Factor XII (Hageman Factor) is activated → Factor XIIa.
2- Activation of Factor XI
Factor XIIa converts Factor XI → Factor XIa.
3- Activation of Factor IX
Factor XIa activates Factor IX → Factor IXa in the presence of Ca²⁺.
4- Formation of the Tenase Complex (Factor X Activation)
Factor IXa, along with Factor VIIIa, Ca²⁺, and phospholipids, activates Factor X → Factor Xa.
5- Formation of the Prothrombinase Complex
Factor Xa combines with Factor V, forming prothrombinase in the presence of Ca²⁺.
Prothrombinase converts prothrombin (Factor II) → thrombin (Factor IIa).
6- Fibrin Clot Formation
Thrombin converts fibrinogen → fibrin, leading to clot stabilization.
34
common pathway
* Starts with formation of prothrombinase from extrinsic and intrinsic pathways
* Prothrombinase and Ca2+ catalyze the conversion of prothrombin to thrombin
* Thrombin, in the presence of Ca2+, converts fibrinogen, which is soluble, to
loose fibrin threads, which are insoluble.
* Thrombin also activates factor XIII (fibrin stabilizing factor), which strengthens and stabilizes the fibrin threads into a sturdy clot.
35
extrinsic pathway of clotting is stimulated by ________________ released by damaged tissue
thromboplastin
36
NATURAL ANTICOAGULANTS
Antithrombin
Heparan sulfate proteoglycans
Protein C and Protein S,
37
is a plasma protein that inhibits coagulation factors of the
intrinsic and common pathways (inactivates the serine proteases IIa, IXa, Xa, XIa, and XIIa).
Antithrombin
38
synthesized by endothelial cells stimulate the
activity of antithrombin.
Heparan sulfate proteoglycans
39
proteolyzes cofactors Va and VIIIa and thereby greatly diminishes the activation of prothrombin and factor X.
Protein C and Protein S
40
*the process of fibrin digestion by the fibrin-specific protease,
plasmin (fibrinolysin)
* dissolves the polymerized clot and restores blood flow
FIBRINOLYSIS
41
converts plasminogen into plasmin, which then degrades fibrin and dissolves the clot.
tPA
Tissue Plasminogen Activator
42
Blood clot can become invaded by _________ which subsequently form connective tissue all through the clot,
fibroblasts
43
LABORATORY TESTS
Bleeding time
identifies
platelet number and function
44
LABORATORY TESTS
Prothrombin time (PT)
identifies
factors I,II,V,VII,X
45
LABORATORY TESTS
activated partial thromboplastin time (aPTT)
identifies
factors I,II,V,VIII,IX,X
46
LABORATORY TESTS
Thrombin time (TT)
identifies
HMWK, prekallikrein
factor XI, XII
fibrinogen
inhibitors of fibrin aggregation
47
COAGULATION
DISORDERS
THROMBOEMBOLIC
DISORDERS
BLEEDING
DISORDERS
48
– an abnormal clot that develops in a blood vessel
Thrombus
49
– an abnormal clot flowing with the blood
Embolus
50
Any roughened endothelial surface of a vessel—as may be caused by
arteriosclerosis, infection, or trauma—is likely to
initiate the clotting process.
51
Blood often clots when it flows very slowly through blood vessels, where small quantities of
thrombin and other procoagulants are always being formed.
52
Inherited Disorders
* tendency to form thrombi (thrombophilia)
* quantitative/qualitative abnormalities of the natural anticoagulant system (antithrombin, proteins C and S) and procoagulant system (factor V Leiden, the prothrombin 20210 mutation, elevated clotting factor and cofactor levels, hyperhomocysteinemia)
53
Acquired Disease
* atrial fibrillation and with the placement of mechanical heart valves
* prolonged bed rest
* high-risk surgical procedures
* cancer
* antiphospholipid antibody syndrome
54
PREVENTION OF
CLOTTING
ANTICOAGULANTS
ANTIPLATELETS
55
DISSOLUTION OF
CLOT
FIBRINOLYTICS
56
* inhibit either the action of the coagulation factors (the thrombin inhibitors, such as heparin and heparin-related agents) or interfere with the synthesis of the coagulation factors (the vitamin K antagonists such as warfarin)
ANTICOAGULANTS
57
INDIRECT THROMBIN INHIBITORS:
HEPARINS
58
exert antithrombotic effect via antithrombin
INDIRECT THROMBIN INHIBITORS:
59
* a glycosylated, single-chain polypeptide (432 amino acids)
* inhibits clotting factor proteases thrombin (IIa), IXa, and Xa, by forming
equimolar stable complexes with them
antithrombin
60
Indirect Thrombin
Inhibitors:
Heparins
Unfractionated
Heparin (UFH)
Low Molecular-
weight Heparin
(LMWH)
Synthetic
Heparin
Derivatives
61
* a heterogeneous mixture of sulfated mucopolysaccharides
(glycosaminoglycans) found in the secretory granules of mast cells
* binds to endothelial cell surfaces and variety of plasma proteins
* synthesized from UDP-sugar precursors as a polymer of alternating D-glucuronic acid and N-acetyl-D-glucosamine residues
* MW: 5000–30,000 Da
HEPARIN
62
* porcine intestinal mucosa or bovine lung
* heterogeneous in composition but biological activities are similar (~150
USP units/mg)
* USP unit is the quantity of heparin that prevents 1 mL of citrated sheep
plasma from clotting for 1 hour after the addition of 0.2 mL of 1% CaCl2
UNFRACTIONATED HEPARIN* Source:
63
UNFRACTIONATED HEPARIN
* MOA:
* catalyzes inhibition of coagulation proteases (Xa and thrombin) by antithrombin by ≥1000-fold
* antithrombin acts as a “suicide substrate” for these proteases
* inhibition occurs when the protease attacks a specific Arg-Ser peptide bond in the reactive site of antithrombin and becomes trapped as a stable 1:1 complex
* binding of heparin induces a conformational change in antithrombin that makes the reactive site more accessible to the protease
* functions as a cofactor for the antithrombin-protease reaction without being consumed
64
UNFRACTIONATED HEPARIN
* Other Effects:
* interfere with platelet aggregation
* Monitoring Pharmacologic Effects:
* increase in aPTT (target:1.8–2.5x the normal value)
* increase in bleeding time
* Pharmacokinetics:
* Given IV or SC
* Immediate onset of action when given IV
65
UNFRACTIONATED HEPARIN
* Clinical Uses:
* DOC for anticoagulation in pregnancy
* initial treatment of venous thrombosis and pulmonary embolism because of rapid onset of action (an oral anticoagulant usually is started concurrently, and heparin is continued for at least 4–5 days to allow the oral anticoagulant to achieve its full therapeutic effect)
* long-term treatment of recurrent thromboembolism despite adequate oral anticoagulation
* initial management of UA or AMI, during and after coronary angioplasty or stent placement, and during surgery requiring cardiopulmonary bypass
* treatment of selected patients with disseminated intravascular coagulation
* low-dose heparin regimens – for prevention of venous thromboembolism in certain high-risk
patients
66
UNFRACTIONATED HEPARIN
* Toxicity: bleeding, hypersensitivity, heparin-induced thrombocytopenia (HIT)
* CI: HIT, hypersensitivity, active bleeding, hemophilia, significant
thrombocytopenia, purpura, severe hypertension, infective endocarditis, active tuberculosis, ulcerative lesions of the gastrointestinal tract, threatened
abortion, visceral carcinoma, advanced hepatic or renal disease
Antidote: Protamine Sulfate
* a highly basic, positively charged peptide that combines with negatively
charged heparin as an ion pair to form a stable complex devoid of
anticoagulant activity
* For every 100 units of heparin remaining in the patient, 1 mg of protamine sulfate is given IV
67
LOW MOLECULAR-WEIGHT HEPARIN (LMWH)
* Enoxaparin (LOVENOX)
* Dalteparin (FRAGMIN)
* Tinzaparin (INNOHEP, others)
* Ardeparin (NORMIFLO)
* Nadroparin (FRAXIPARINE)
* Reviparin (CLIVARINE)
68
* isolated from standard heparin by gel filtration chromatography, precipitation
with ethanol, or partial depolymerization with nitrous acid and other chemical or enzymatic reagents
* MW: <5400 Da
LOW MOLECULAR-WEIGHT HEPARIN (LMWH)
69
LOW MOLECULAR-WEIGHT HEPARIN (LMWH)
* MOA:
* catalyzes inhibition of factor Xa by antithrombin
* induces of a conformational change in antithrombin that facilitates reaction with the protease, Xa
* Monitoring Pharmacologic Effects:
* factor Xa inhibition assay, which is mediated by antithrombin
* Pharmacokinetics:
* more predictable pharmacokinetic properties (allows weight-adjusted subcutaneous administration without laboratory monitoring [outpatient setting])
* SC
70
LOW MOLECULAR-WEIGHT HEPARIN (LMWH)
* Clinical Uses:
* prevention of venous thromboembolism
* treatment of venous thrombosis, pulmonary embolism, and unstable angina
* Toxicity:
* lower incidence of heparin-induced thrombocytopenia and possibly lower
risks of bleeding
* incomplete neutralization with protamine sulfate
71
SYNTHETIC HEPARIN DERIVATIVES:
FONDAPARINUX
(ARIXTRA)
72
a synthetic pentasaccharide based on the structure of the antithrombin binding region of heparin
SYNTHETIC HEPARIN DERIVATIVES:
73
SYNTHETIC HEPARIN DERIVATIVES: FONDAPARINUX
(ARIXTRA)
* MOA: mediates inhibition of factor Xa by antithrombin
* Pharmacokinetics:
* SC
* OD at a fixed dose without coagulation monitoring
* Clinical Uses: thromboprophylaxis of patients undergoing hip or knee surgery and for the therapy of pulmonary embolism and deep venous thrombosis
* Toxicity: less likely than heparin or low-molecular-weight heparin to trigger HIT
* CI: renal failure
74
DIRECT THROMBIN INHIBITORS
* Parenteral
* Lepirudin
* Bivalirudin
* Argatroban
* Oral
* Dabigatran etexilate mesylate
75
* a recombinant derivative of hirudin, a direct thrombin inhibitor present in the salivary glands of the medicinal leech (Hirudo medicinalis)
LEPIRUDIN (REFLUDAN)
76
LEPIRUDIN (REFLUDAN)
* MOA: binds tightly to both the catalytic site and the extended substrate recognition site of thrombin (bivalent)
* PK: given IV
* Clinical Uses: treatment of patients with HIT
* Monitoring: aPTT
* Toxicity: hypersensitivity
* SP: kidney disease
77
BIVALIRUDIN (ANGIOMAX)
* a synthetic, 20-amino-acid polypeptide that directly inhibits thrombin
* MOA: binds tightly to both the catalytic site and the extended substrate
recognition site of thrombin (bivalent)
* PK: rapid onset and rapid offset of action; given IV; dose reduction in kidney disease
* Clinical Uses: used as an alternative to heparin in percutaneous coronary
angioplasty
78
ARGATROBAN
* a synthetic compound based on the structure of L-Arg
* MOA: binds reversibly to the catalytic site of thrombin
* PK: rapid onset of action; given IV infusion; dose reduction in liver disease
* Clinical Uses: an alternative to lepirudin for prophylaxis or treatment of patients with or at risk of developing HIT
* Monitoring: aPTT
79
DABIGATRAN ETEXILATE MESYLATE
* MOA: binds to the active site of thrombin
* PK: it is a prodrug, converted to the active moiety, dabigatran; predictable
pharmacokinetics and bioavailability, which allow for fixed dosing; do not
interact with P450-interacting drugs; rapid onset and offset of action allow
for immediate anticoagulation, thus avoiding the need for overlap with
additional anticoagulant drugs
* Clinical Uses: prevention of stroke and systemic embolism in patients with
atrial fibrillation;
alternative to enoxaparin for thromboprophylaxis in
orthopaedic surgery
80
DABIGATRAN ETEXILATE MESYLATE
* Monitoring: not required
* Toxicity: bleeding (especially GI)
* Antidote: Idarucizumab
* humanized monoclonal antibody Fab fragment that binds to dabigatran and
reverses the anticoagulant effect
* approved for use in emergent surgery or for life-threatening bleeding
81
VITAMIN K ANTAGONISTS
* Bishydroxycoumarin – natural form
* Dicoumarol – synthetic derivative
* Warfarin (COUMADIN)
* Wisconsin Alumni Research Foundation, with “arin” from coumarin
82
VITAMIN K ANTAGONISTS
* MOA:
* Coagulation factors II, VII, IX, and X and the anticoagulant proteins C and S are biologically inactive unless the amino-terminal glutamate residues are carboxylated to form the Ca2+-
binding γ-carboxyglutamate residues
* The reaction of the descarboxy precursor protein requires CO2, O2
and reduced vitamin K, and is
catalyzed by γ-glutamyl carboxylase in the RER
* Carboxylation is directly coupled to the oxidation of vitamin K to its corresponding epoxide
83
VITAMIN K ANTAGONISTS
* PK:
* Warfarin Na is completely absorbed
* 90% bound to plasma proteins; long half-life
* Monitoring Pharmacologic Effects:
* PT
* International Normalized Ratio (INR)
INR =(patient prothrombin time / mean of normal prothrombin time for lab) ISI
where ISI = International Sensitivity Index
84
VITAMIN K ANTAGONISTS
* PD:
* 8-12-hour delay in the action of warfarin
* Inhibition of coagulation is dependent on their degradation half-lives in the
circulation (VII: 6h; IX: 24h; X: 40h; II: 60h)
* Loading doses are of limited value.
* Heparin is co-administered for 4-5 days.
85
VITAMIN K ANTAGONISTS
* Clinical Uses:
* prophylaxis and treatment of thrombotic disease (target INR: 2–3)
* prevention of progression or recurrence of acute DVT or pulmonary embolism following an initial course of heparin
* prophylaxis and treatment of thrombotic disease w/ artificial heart valves or other medical conditions increasing thrombotic risk (target INR: 2.5–3.5)
* prevention of venous thromboembolism in patients undergoing orthopedic or gynecological
surgery and in preventing systemic embolization in patients with AMI, prosthetic heart valves,
or chronic atrial fibrillation.
86
VITAMIN K ANTAGONISTS
* Toxicity:
* Bleeding
* Birth defects and abortion, fetal or neonatal hemorrhage and intrauterine death
* Antidote: Vitamin K1 (phytonadione) PO/IV
87
Xa INHIBITORS
* Rivaroxaban (XARELTO)
* Apixaban
88
Xa INHIBITORS
* MOA:
blocks the active site of factor Xa
* PK: rapid onset of action and shorter half-lives than warfarin; given PO
* Monitoring: not needed
* Clinical Uses:
* prevention of venous thromboembolism following hip or knee surgery
* treatment of DVT and PE
89
ANTIPLATELETS
*Inhibit platelet function
ASPIRIN - Inhibition of PG synthesis
CLOPIDOGREL, TICLOPIDINE - Inhibition of ADP-induced platelet aggregation
ABCIXIMAB, EFTIFIBATIDE, - Blockade of GPIIB/IIIA receptors
TIROFIBANDIPYRIDAMOLE, CILOSTAZOL - Others
90
ASPIRIN
* MOA: irreversible acetylation of COX-1, preventing the synthesis of TXA2, an inducer of platelet aggregation
* PD: 50-325 mg (81 mg) PO; effect lasts 7-10 days; effect is cumulative
* Monitoring: bleeding time
* Clinical Uses:
* primary prophylaxis of myocardial infarction
* secondary prevention of vascular events among patients with a history of
vascular events
* Toxicity:
* GI bleeding
* Hemorrhagic stroke
91
* Ticlopidine
* Clopidogrel (Plavix)
* Prasugrel
* Ticagrelor
ADP-INDUCED PLATELET AGGREGATION
INHIBITORS
92
ADP-INDUCED PLATELET AGGREGATION
INHIBITORS
* Chemistry: thienopyridines
* MOA: irreversibly inhibit the binding of ADP to its receptors on platelets
and, thereby, inhibit the activation of GP IIb/IIIa receptors required for
platelets to bind to fibrinogen and to each other
93
ADP-INDUCED PLATELET AGGREGATION
INHIBITORS
* Clinical Uses:
* Ticlopidine:
prevention of stroke in patients with a history of a transient ischemic attack (TIA) or thrombotic stroke, and in combination with aspirin for
prevention of coronary stent thrombosis
* Clopidogrel:
for patients with unstable angina or non-ST-elevation acute
myocardial infarction (NSTEMI) in combination with aspirin; for patients with ST-elevation myocardial infarction (STEMI); or recent myocardial infarction,
stroke, or established peripheral arterial disease
94
ADP-INDUCED PLATELET AGGREGATION
INHIBITORS
* Toxicity:
* Ticlopidine:
-nausea, vomiting, and diarrhea; severe neutropenia (absolute
neutrophil count <1500/mL), thrombotic thrombocytopenic purpura (TTP)- hemolytic uremic syndrome
* Clopidogrel:
-less A/E than ticlopidine, TTP
95
GP IIB/IIIA BLOCKERS
* Glycoprotein IIb/IIIa is a platelet-surface integrin designated
ɑIIbβ3
* This dimeric glycoprotein is a receptor for fibrinogen and von Willebrand factor, which anchor platelets to foreign surfaces and to each other, thereby mediating aggregation
96
* Abciximab
* Eptifibatide
* Tirofiban
GP IIB/IIIA BLOCKERS
97
ABCIXIMAB
* a Fab fragment of a humanized monoclonal antibody directed against
the ɑIIbβ3 receptor
* Clinical Uses:
-used in conjunction with percutaneous angioplasty for
coronary thromboses, and when used in conjunction with aspirin and
heparin, has been shown to be quite effective in preventing restenosis,
recurrent myocardial infarction, and death
* ADR: bleeding
98
EPTIFIBATIDE
* a cyclic peptide inhibitor of the fibrinogen binding site on ɑIIbβ3
* Clinical Uses:
-treatment of acute coronary syndrome and for angioplastic coronary interventions
* ADR: bleeding
99
TIROFIBAN
* a nonpeptide, small-molecule inhibitor of ɑIIbβ3
* Clinical Uses:
-has efficacy in non-Q-wave myocardial infarction and unstable angina
* ADR: bleeding
100
DIPYRIDAMOLE
* a vasodilator that also inhibits platelet function by inhibiting adenosine
uptake and phosphodiesterase activity, thereby increasing cAMP
* Clinical Uses:
* in combination with warfarin for postoperative primary prophylaxis of
thromboemboli in patients with prosthetic heart valves
* in combination with aspirin to prevent cerebrovascular ischemia
101
CILOSTAZOL
* a newer phosphodiesterase inhibitor that promotes vasodilation and
inhibition of platelet aggregation
* Clinical Use: treatment of intermittent claudication
102
rapidly lyse thrombi by catalyzing the formation of the serine protease
plasmin from its precursor zymogen,
plasminogen
FIBRINOLYTICS
103
FIBRINOLYTICS
* Streptokinase, Urokinase, Anistreplase
* Tissue Plasminogen Activators (t-PAs): Alteplase, Reteplase, Tenecteplase
104
STREPTOKINASE
* Source: a protein (but not an enzyme in itself) synthesized by Group C β-hemolytic streptococci that combines with the proactivator plasminogen
* MOA:
* forms a stable, noncovalent 1:1 complex with plasminogen, producing a
conformational change that exposes the active site on plasminogen that cleaves Arg 560 on free plasminogen to form free plasmin
* Clinical Uses: in acute pulmonary embolism, deep vein thrombosis, acute myocardial infarction, arterial thrombosis, and occluded access shunts
* ADR: bleeding, hypersensitivity
105
UROKINASE
* Source: a human enzyme synthesized by the kidney that directly converts
plasminogen to active plasmin
* MOA: directly cleaves the arginine-valine bond of plasminogen to yield active plasmin
* Clinical Uses: lysis of pulmonary emboli
* ADR: bleeding, low antigenicity
106
ANISTREPLASE
* anisoylated plasminogen streptokinase activator complex (APSAC)
* a preformed complex of purified human plasminogen and bacterial
streptokinase that has been acylated to protect the enzyme’s active site
* considered to be a prodrug
* Streptokinase must be released, and only plasminogen (to which it was
associated) will get converted to plasmin
107
Alteplase
– recombinant human t-PA
108
Reteplase –
another recombinant human t-PA from which several amino acid
sequences have been deleted; less fibrin specific than alteplase
109
Tenecteplase –
mutant form of t-PA that has a longer half-life; more fibrin-specific than alteplase
110
t-PAs
* MOA: preferentially activate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation
* Clinical Uses: treatment of myocardial infarction, massive pulmonary
embolism, and acute ischemic stroke
111
ANTIFIBRINOLYTICS
* Aminocaproic Acid
* Tranexamic Acid (Hemostan)
* Aprotinin
112
Aminocaproic Acid
* a synthetic inhibitor of fibrinolysis
* competitively inhibits plasminogen activation
* Blocks binding sites on plasminogen and plasmin, thus blocking the interaction of plasmin with fibrin
* PO, IV
113
Tranexamic Acid (Hemostan)
* an analog of aminocaproic acid and has the same properties; 10x more potent
* PO
114
Aprotinin
* a serine protease inhibitor that inhibits fibrinolysis by free plasmin
* also inhibits the plasmin-streptokinase complex in patients who have received that thrombolytic agent
* may cause renal dysfunction, heart attack, stroke, hypersensitivity (anaphylactic) reactions
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ANTIFIBRINOLYTICS
* Clinical Uses:
* adjunctive therapy in hemophilia
* therapy for bleeding from fibrinolytic therapy
* prophylaxis for rebleeding from intracranial aneurysms
* postsurgical gastrointestinal bleeding
* postprostatectomy bleeding
* bladder hemorrhage secondary to radiation- and drug-induced cystitis
* Toxicity:
* intravascular thrombosis from inhibition of plasminogen activator, hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness
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* may have their origin in naturally occurring pathologic conditions, such as
hemophilia, or as a result of fibrinolytic states that may arise after GI surgery
or prostatectomy
* use of anticoagulants may also give rise to hemorrhage
BLEEDING DISORDERS
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* Vitamin K
* Plasma Fractions
* Recombinant Factor VIIa
TREATMENT OF BLEEDING DISORDERS
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VITAMIN K
* fat-soluble substance found primarily in leafy green vegetables
* dietary requirement is low, because the vitamin is additionally synthesized by bacteria that colonize the human intestine
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VITAMIN K
2 natural forms:
* Vitamin K1
: Phytonadione (food)
* Vitamin K2: Menaquinone (synthesized by intestinal bacteria)
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VITAMIN K
* PK: PO, IV
* Clinical Uses:
* administered to all newborns
* warfarin toxicity
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PLASMA FRACTIONS
* Used in hemophilia (bleeding disorder that results from a congenital
deficiency in a plasma coagulation protein)
* Fresh Frozen Plasma – contains all clotting factors
* Cryoprecipitate – contains fibrinogen, factor VIII, vWF, factor XIII
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*For Factor VII deficiency
RECOMBINANT FACTOR VIIa
