Blood coagulation Flashcards
INJURY
▪ Exposes reactive subendothelial matrix proteins
such as:
- Collagen
- Von Willebrand Factor
Injury Result
- Platelet adherence and activation
- Secretion and synthesis vasoconstrictors
- Platelet recruitment and activating proteins
▪ Synthesized from arachidonic acid within
platelets.
▪ A platelet activator and potent vasoconstrictor.
THROMBOXANE A2 (TXA)
PRODUCTS SECRETED FROM PLT GRANULES
▪ Adenosine diphosphate ▪ Serotonin ▪ Bind fibrinogen ▪ Cross link adjacent platelets. ▪ Aggregation and formation of platelet plug ▪ Thrombin generation and fibrin clot.
serotonin
- Activation of platelet
- Conformational change in alpha and beta
integrin (IIb/IIIa) receptor.
2b3a
DEFECTS IN FORMATION OF PLATELET PLUG
▪ Defects in primary hemostasis, platelet function defects, Von Willebrand Disease.
▪ Bleeding mucosal sites with injury.
- Gingiva, skin, heavy menses
DEFECTS IN THE CLOTTING MECHANISM
▪ Secondary hemostasis, Hemophilia A
▪ Tend to bleed into deep tissues
- Joints, muscle, retroperitoneum
▪ No inciting event, recur unpredictably
will do binding with fibronectin and
thrombin. This binding will produce more feedback
to produce more thrombin
vWF
Platelets will be activated and release substances
like
ADP,5-HT, TXA2 in circulation.
▪ Platelet rich
WHITE THROMBI
Fibrin rich
RED THROMBI
Form in the high
flow rate and high
shear force
environment of arteries
WHITE THROMBI
▪ With large number
of trapped RBC
Venous clots
▪ With large number
of trapped RBC
white thrombi is dominated by
platelet nidus
red thrombi is dominated by
firbin tail
white thrombi effects
- Downstream ischemia (of
extremities or vital organs) - Result: limb amputation
and organ failure
Red thrombi effects
- 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
TF/VIIa
TFP inhibitor
VIIIa
Protein C/Protein S
IXa, XIa, Xa, Va, Thrombin
Antithrombin III/Heparin
NATURAL ANTICOAGULANT SYSTEMS
NATURAL ANTICOAGULANT SYSTEMS
THE IDEAL ANTI - CLOTTING DRUG
▪ Can preserve the tissue factor and VIIa initiation
phase
▪ Weakening the secondary pathway
ANTIPLATELET AGENTS
Thromboxane A2 inhibitor Phosphodiesterase inhibitor Glycoprotein (GP) IIb/IIIa blockers ADP - receptor antagonist
Thromboxane A2
inhibitor
Acetylsalicylic acid (ASA) (aspirin)
Phosphodiesterase
inhibitor
Dipyridamole
Glycoprotein (GP)
IIb/IIIa blockers
Abciximab
Tirofiban
Eptifibatide (“ATE”)
ADP - receptor antagonist
Clopidogrel Prasugrel Cangrelor Ticlopidine Ticagrelor Vorapaxar (Thrombin receptor inhibitor)
Platelet function is regulated by 3 categories
- Agents generated outside the platelets that
interact with platelet membrane receptor - Agents generated within the platelet that interact
with membrane receptors - Agents generated within the platelet that act
within the platelet
Agents generated outside the platelets that
interact with platelet membrane receptor
o Catecholamines
o Collagen
o Thrombin
o Prostaglandin
Agents generated within the platelet that interact
with membrane receptors
o ADP (clopidogrel)
o Prostaglandin D2
o Prostaglandin E2
o Serotonin
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
An arachidonate product that causes platelets to change shape, release their
granules and aggregate
▪ Prostaglandin thromboxane A2
Inhibit synthesis of TXA2 ▪ By irreversible acetylation of cyclooxygenase
Aspirin
Aspirin dose approved for primary prophylaxis of AMI
325 mg/d
As an adjunct to risk factor management by
smoking cessation
Aspirin
aspirin SE
bleeding, gastritis/ gastric ulcers,
allergic reaction and Reye syndrome
▪ Antiplatelet effects by irreversibly blocking ADP
receptors on platelets
▪ No effect on prostaglandin metabolism
CLOPIDOGREL AND TICLOPIDINE
Thienopyridine derivatives
CLOPIDOGREL AND TICLOPIDINE
Ticlopidine S/E
▪ Nausea, dyspepsia and diarrhea (20%)
▪ Hemorrhage (20%)
▪ Leukopenia (1%)
Ticlopidine dose
250 mg 2x/day
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
clopidogrel is associated with
neutropenia, thrombotic
thrombocytopenic purpura
Clopidogrel loading dose
300 mg oral dose (80%of platelet
activity is inhibited)
Maintenance dose:
75 mg/d, achieve maximum
platelet inhibition
Antiplatelet effect:
7-10 days
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
Clopidogrel is Prodrug that requires activation via the
cytochrome P450 enzyme isoform CYP2C19.
example of Drug that impair CYP2C19 function
Omeprazole
T or F
▪ In contrast to clopidogrel, cytochrome P450 genotype status is not an important factor in prasugrel pharmacology
T
▪ Similar to clopidogrel
▪ Given orally
▪ Approved for patients with acute coronary
syndrome
PRASUGREL
▪ Newer type of ADP inhibitor (cyclopentyl
triazolopyrimidine)
▪ Approved for oral use in combination with aspirin
in patients with acute coronary syndrome
TICAGRELOR
▪ Parenteral P2Y12 inhibitor
▪ Approved for IV use of coronary interventions in
patients without previous ADP P2Y12 inhibitor
therapy.
CANGRELOR
▪ Used in patients with Acute Coronary Syndrome
▪ Target the platelet IIb/IIIa receptor complex
PLATELET GLYCOPROTEIN IIb/ IIIa BLOCKERS
▪ IIb/IIIa complex: function as receptor
- Fibronectin and von Willebrand factor
- Glanzmann’s thrombasthenia
▪ Chimeric monoclonal antibody directed against
IIb/IIIa complex
▪ Include vibronectin receptor
▪ First agent approved in this class of drugs
ABCIXIMAB
Abciximab is used in
- Percutaneous Coronary Intervention
- Acute Coronary Syndrome
T or F
EPTIFIBATIDE AND TIROFIBAN Do not block the vibronectin receptor
T
▪ Inhibit ligand binding to IIb/IIIa receptor by
occupancy of receptor
EPTIFIBATIDE AND TIROFIBAN
cyclic peptide derived from rattlesnake venom that contains a variation of the RGD motif (KGD).
Eptifibatide
peptidomimetic inhibitor with RGD sequence motif.
Tirofiban
▪ Vasodilator that inhibits platelet function
▪ Inhibit adenosine uptake and cGMP phosphodiesterase activity
DIPYRIDAMOLE
as combination therapy with
aspirin to prevent cerebrovascular ischemia
DIPYRIDAMOLE
DIPYRIDAMOLE May also be used in combination with warfarin for
primary prophylaxis of thromboemboli in patients
with prosthetic heart valves.
▪ Used to perform cardiac stress test.
DIPYRIDAMOLE
▪ Newer phosphodiesterase inhibitor
▪ Promotes vasodilation
▪ Inhibit platelet aggregation
CILOSTAZOL
cilostazol is used to treat
intermittent claudication
ANTICOAGULANTS
▪ Unfractionated Heparin
▪ Fondaparinux
▪ LMWH (low molecular weight heparins)
▪ Direct Thrombin Inhibitors (Parenteral)
LMWH (low molecular weight heparins)
- Enoxaparin
- Dalteparin
- Tinzaparin
▪ Direct Thrombin Inhibitors (Parenteral)
- Argatroban
- Bivalirudin
- Hirudin (Desirudin/Lepirudin)
▪ Fondaparinux is a specific factor
Xa inhibitor
Fondaparinux will only involve factor Xa but
heparin will involve
Factor XIIa, XIa, IXa, Xa and IIa.
key step in the coagulation pathway.
Inhibition of one molecule of ______ can inhibit
the generation of 50 molecules of thrombin (IIa).
Factor Xa
factor Xa will be affected by
low molecular weight
heparins and unfractionated heparin.
TOXICITY OF HEPARIN
Bleeding ▪ Reversible alopecia ▪ Osteoporosis ▪ Spontaneous fractures ▪ Accelerated clearing of postprandial lipemia ▪ Mineralocorticoid deficiency ▪ Heparin-induced Thrombocytopenia
HIT is High in UHF treatment of what source
bovine
HIT clinical manifestations
o Venous thrombosis and occlusion of arteries
o Risk of thrombosis for indwelling catheters
o Skin necrosis
Tx HIT
o Discontinue heparin
o Use fondaparinux
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
PLASMA CONCENTRATION OF HEPARIN
▪ 0.2 to 0.4 unit/mL (protamine titration)
▪ 0.3 to 0.7 unit/mL (anti Xa unit)
Heparin initial bolus injection
80-100 unit/kg/hr
Heparin continuous infusion:
15 to 22 unit/kg/hr
Heparin low dose prophylaxis
▪ Subcutaneous administration
▪ 5000 units every 8 to 12 hours
T or F
***Heparin is not administered by IM because it causes
necrosis
T
Enoxaparin frequency
30mg 2x daily or 40mg once daily subQ
Correspond to therapeutic anti Xa level of 0.5 to 1 unit/mL
Enoxaparin Full dose: 1mg/kg subQ every 12 hours
Target anti Xa level of 1.5 units/mL
1.5 mg/kg once a day
Prophylactic dose: ________subQ once daily
5000 units
Dalteparin Therapeutic dose for venous disease:
200 units/kg
once a day
Dalteparin Therapeutic dose for acute coronary syndrome:
120 units/kg every 12 hours
LMWH is used with caution in px with
renal insufficiency
▪ For venous thromboembolism
▪ Bind antithrombin with high specific activity = less
bleeding
▪ Efficient inactivation of factor Xa
FONDAPARINUX
▪ Long half-life of 15 hours
▪ Alternative anticoagulant for HIT
Fondaparinux
o A highly basic peptide; antagonist
o Combines with heparin as an ion pair to form stable complex devoid of anticoagulant activity
Protamine s04
__ mg of protamine sulfate IV for every 100 units of heparin
1
Rate of infusion should not exceed
50mg in any 10-minute
period
- For excess Dalteparin, it is removed by
plasmapheresis
T or F
Protamine does not reverse the
activity of fondaparinux
T
Bind at both catalytic and active site of thrombin and substrate recognition site
▪ HIRUDIN and BIVALIRUDIN
Bind only at thrombin site
ARGATROBAN and MELAGATRAN
▪ Specific irreversible thrombin inhibitor from leech saliva
HIRUDIN
Hirudin recombinant form
Lepirudin
▪ Bivalent inhibitor of thrombin and platelet
activation
▪ Administered IV
BIVALIRUDIN
▪ FDA approved for percutaneous coronary
angioplasty
BIVALIRUDIN
▪ Reach and inactivate fibrin bound thrombin in
thrombi
▪ Has little effect on platelets or the bleeding time
LEPIRUDIN
FDA approved for
thrombosis related to HIT
LEPIRUDIN
▪ 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
▪ An oral prodrug metabolized to the DTI
melagatran
XIMELAGATRAN
Vitamin K Antagonist
Warfarin
WARFARIN
▪ A synthesized agent from
BISHYDROXYCOUMARIN
99% of racemic warfarin is bound to
plasma albumin
T or F
The levorotatory S-warfarin is four times more
potent than the dextrorotatory R-warfarin
T
Warfarin ▪ Mechanism of Action
- Block the gamma- carboxylation of
several glutamate residues in prothrombin
and factors VII, IX, and X
Resistance to warfarin:
presence of Vitamin K
reductase
Four Vitamin K dependent factors includes:
II, VII, IX, and X
Half-life: VII (__), IX (__hours), X (__
hours), II (__ hours)
6, 24, 40, 60
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
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
warfarin
▪ Cutaneous necrosis
- First weeks of therapy
- Frank infarction of the breast, fatty
tissues, intestine, and extremities
Defined as progression or recurrence of a
thrombotic event while in the therapeutic range
These individuals may have their INR target raised
WARFARIN RESISTANCE
Most commonly seen in patients with advanced
cancers, typically of gastrointestinal origin
(Trousseau’s syndrome)
WARFARIN RESISTANCE
Reversal of warfarin action
- Discontinue the drug
- Oral or parenteral vitamin K1
(phytonadione) - Fresh-frozen plasma
- Prothrombin complex concentration
o BEBULIN and Proplex T
▪ Direct thrombin inhibitors (Oral)
Dabigatran
▪ Direct Oral Factor Xa inhibitors
- Rivaroxaban
- Apixaban
- Edoxaban
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
FIBRINOLYTIC AGENTS
▪ Streptokinase
▪ Recombinant tissue plasminogen activator
▪ Inhibitors of Fibrinolysis
▪ Fibrinolytic Drugs
▪ Recombinant tissue plasminogen activator
- Alteplase
- Reteplase
- Tenecteplase
Inhibitors of Fibrinolysis
- E-aminocaproic acid
- Tranexamic acid
Rapidly lyses thrombi by catalyzing the
formation of serene protease PLASMIN
▪ Fibrinolytic Drugs
FIBRINOLYTIC AGENTS
includes
Streptokinase, Urokinase,
Anistreplase, t-PA
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
▪ 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
▪ 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
▪ 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
▪ Plasminogen activated endogenously
▪ Activate plasminogen bound to fibrin
▪ Confines fibrinolysis to the formed thrombus and
avoids systemic activation
TISSUE PLASMINOGEN ACTIVATOR (t-PA)
▪ Human t-PA, manufactured by recombinant DNA
technology
ALTEPLASE
▪ 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
FIBRINOLYTIC INHIBITORS
AMINOCAPROIC ACID
TRANEXAMIC ACID
SERINE PROTEASE INHIBITORS
▪ Similar to amino acid Lysine ▪ A synthetic inhibitor of fibrinolysis ▪ Completely inhibits plasminogen activation ▪ Rapidly absorbed orally ▪ Cleared by kidney
AMINOCAPROIC ACID
▪ 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
▪ 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
