Treatment of Hemostasis Disorders

Week 4 Luyendyk

Treatment of Hemostasis Disorders

Platelet inhibitors
Anticoagulants
Thrombolytic drugs
Drugs for bleeding disorders

Formation of a Localized Clot at the Site of Vessel Injury

4 Steps:
1.
2.
3.
4.

Vasoconstriction
Primary Hemostasis
Secondary Hemostasis
Activation of Antithrombotic Mechanisms

Step #1: Vasoconstriction

Cellular response of the neighboring cells
Mediated by reactive intermediates Endothelin

Step #2: Primary Hemostasis

Transformation of platelets into a

hemostatic plug
1. Platelet adhesion
2. Platelet granule release
3. Platelet aggregation and consolidation

Platelet Adhesion:

Platelet will bind to collagen, which is mediated by glycoproteins

(GPIa and GPIb) and Von Willebrand Factor.

Platelet Granule Release

Platelets get angry and release contents
ADP, serotonin, collagen, and thrombin will cause
platelets to release their granule contents.

Targets for Antiplatelet Drugs:

1. ADP (Plavix)
2. Cyclooxygenase -1 (aspirin)

Platelet Aggregation and Consolidation

During this process TxA2 and ADP are potent mediators of platelet aggregation
GPIIb-IIIa is a receptor on the platelet
surface that can interaction with
fibrinogen and cause platelet aggregation.
Target of Antiplatelet Therapy
GPIIb-IIIa: fibrinogen interaction is critical
for platelet aggregation.

Review: Formation of a Localized Clot at the Site of Vessel

Injury
1. Vasoconstriction
a. Neurogenic mechanisms
b. Endothelin
2. Primary Hemostasis
a. Platelet adhesion (GPIb, VWF, Collagen)
b. Platelet granule release reaction (TxA2, ADP targets of antiplatelet
therapy/ platelet inhibitors)
c. Platelet aggregation and consolidation (GPIIb-IIIa target of antiplatelet
therapy/ platelet inhibitors)

Step #3: Secondary Hemostasis

Activation of the coagulation system and a fibrin clot formation

Goal of the coagulation cascade is to form a stable fibrin clot at the site of vascular injury

Steps:

1. Tissue factor expression

2. Thrombin activation
3. Fibrin polymerization

Regulation of the Blood Coagulation

This series of catalytic reactions amplifies the process resulting in the generation of large
amounts of fibrin at the site of injury. It is highly regulated by multiple anticoagulation
factors. Also, have to have plasmin to break down the clot so that wound healing can
occur.

Extrinsic Coagulation

Requires tissue factor (tissue thromboplastin, factor III)

Tissue factor binds to factor VIIa
Tissue factor is physically separated from blood components

Intrinsic Coagulation

All required factors are present in the blood

Recent studies suggest that this pathway is primarily activated by extrinsic
pathway
Factor VIIa of the extrinsic pathway activates Factor IX of the intrinsic pathway

Coagulation Cascade Activation

In the event of damage, the tissue
factor is exposed to the blood and
finds to Factor VIIa to initiate the
coagulation cascade and produce a
clot.

Review: Secondary Hemostasis

1. Tissue factor expression
2. Thrombin activation Target of Anticoagulant Therapy
3. Fibrin polymerization

Step #4: Activation of Antithrombic Mechanisms

5 Anticoagulant and Antiplatelet Mechanisms that limit the

Propagation of Hemostasis
1)
2)
3)
4)
5)

Prostacyclin
Antithrombin III
Protein C and S
Tissue factor pathway inhibitor
Tissue type plasminogen activator

Prostacyclin (PGI2)
PGI2 from the activated endothelium can inhibit
platelet activation.

Antithrombin III
Antithrombin III is a protein that binds to and inactivates several proteins in the
coagulation cascade.
o Thrombin
o IXa
o Xa
o XIa
o XIIa
This reaction is catalyzed by heparin like molecules expressed on the surface of
endothelial cells.
Heparin given to patients prevents coagulation activation by this mechanism.

Plasmin

Produced from plasminogen when plasminogen is activated by TPA (tissue plasminogen

activator)
Thrombolytics activate plasminogen
Plasmin degrades crosslinked fibrin polymers into fibrin degradation products

Review of All 4 Steps

Thromboembolism

Risk Factors for

1. Abnormalities in Blood Flow

a.
b.
c.
d.
e.
f.

Atrial fibrillation
Left ventricular dysfunction
Ischemic/idiopathic myocardiopathy
Congestive heart failure
Bed rest/ immobilization/ paralysis
Venous obstruction from tumor/obesity or pregnancy

2. Abnormalities of Surface in Contact with Blood

Exposure of tissue factor to the blood (not normally in contact with each other)
a. Vascular trauma/injury
b. Heart valve disease
c. Heart valve replacement
d. Atherosclerosis
e. Acute Myocardial Infarction
f. Indwelling Catheters

3. Abnormalities in Clotting Factors

a. Endogenous anticoagulants
i. Protein C deficiency (Vit K dependent)
ii. Protein S deficiency (Vit K dependent)
iii. Antithrombin III deficiency
b. Antiphospholipid Antibody Syndrome
c. Estrogen therapy
d. Pregnancy
e. Malignancy

Antiplatelet Drugs

Aspirin: inhibit COX-1 production of thromboxane A2

Ticlopidine/ Clopidogrel: inhibit ADP
Epitifibatide/Abciximab/Tirofiban: inhibit receptor
on platelet surface (IIb-IIIa) to inhibit fibrinogen
binding and platelet aggregation.

Aspirin (Acetylsalicylic Acid)

Inhibits the synthesis of thromboxane A2

(TxA2) by irreversible acetylation of
cyclooxygenase 1 in platelets.
Thromboxane A2 is a potent mediator of platelet
aggregation and degranulation and promotes
vasoconstriction.
Useful in preventing or reducing the risk of MI
and recurrent TIAs due to antithrombic events.
COX-1 is in platelets and is irreversibly inhibited
by low doses of aspirin.

Aspirin (Acetylsalicylic Acid) (antiplatelet drug)

COX-2 is in endothelial cells and produces PGI2

o PGI2 is inhibited by high doses of aspirin and COX-2 inhibitors
o PGI2 causes platelet inhibition and vasodilation
Antithrombic effects on platelets are seen 1-2 days after administration and lasts
for the duration of the platelets life span (7-10 days)

Ticlopidine (Ticlid) ADP Antagonist

Inhibits ADP receptors on platelets which prevents activation of GPIIb-IIIa.

o GPIIb-IIIa promotes platelet aggregation
Inhibits platelet adhesion and platelet-platelet interactions

Rapidly and well absorbed (>80%)

Extensively metabolized

Indicated as an alternative to aspirin to

prevent an
initial or recurrent thromboembolic
stroke
Also useful for myocardial reinfarctions
prophylaxis
Administered orally

Rare cases of severe bone marrow toxicity limits use to patients who are
intolerant or unresponsive to aspirin.
Increases liver function enzymes

Drug Interactions:
o Increased bleeding occurs when given with:
Warfarin
Heparin
Other antiplatelet drugs
NSAID drugs
Less drug-drug interactions than clopidogrel
o Cimetidine decreases its clearance
o IT decreases the clearance of theophylline
Usually clopidrogrel is preferred over ticlodipine

Clopidogrel (Plavix)

Similar mechanism to ticlopidine but has lower incidence of adverse cutaneous, GI,
or hematologic reactions
IT is used to reduce atherosclerosis in patients with a history of recent stroke,
recent MI, or established peripheral vascular diseaseused in patients with stents.
Inhibits the activity of CYP2C9 and therefore may increase the plasma
concentrations of drugs, such as:
o Fluvastatin
o Many NSAIDs
o Phenytoin
o Tamoxifen
o Tolbutamide
o Warfarin
Ticlodipine may be preferred over Clopidogrel if drug-drug interactions are difficult
to manage

Abciximab (ReoPro)

EXPENSIVE
Inhibits platelet aggregation by preventing binding of fibrinogen to glycoprotein
receptor IIb/IIIa on activated platelets.
GPIIb-IIIa: fibrinogen interaction is critical for
platelet aggregation.

Monoclonal Antibody
Given IV to high risk patients, undergoing coronary angioplasty and patients
undergoing angioplasty, atherectomy, and stent placement often with clopidogrel
Bleeding is the most common adverse effect

Other Platelet Receptor Glycoprotein Inhibitors

Phosphodiesterase Inhibitors
Prevent degradation of cAMP by inhibit PDE

Dipyridamole (Persantin)

Coronary vasodilator that also inhibits platelet aggregation.

In combination with aspirin, reduces thrombosis in patients with thrombotic
disease
In combination with warfarin, inhibits embolism from prosthetic heart valves (main
use)

Cilostazol (Pletal)

Antithrombotic, antiplatelet, and vasodilatory action

Inhibits PDE type III and thereby, increases cAMP levels
Used for intermittent claudication and peripheral vascular disease

Anagrelide (Agrylin)

Reduces elevated platelet counts in patients with essential thrombocytosis (too

many platelets)
Used if platelet number is too HIGH
Inhibits megakaryocyte development in the late postmitotic stage
Inhibits the formation of platelets
Approved for treatment of thrombocytosis secondary to myeloproliferative
disorders, such as Polycythemia Vera and CML to reduce the risk of stroke and MI.

General Mechanisms of Anticoagulation

1. Calcium Chelators: Inhibits blood coagulation in vitro

a. Oxalic acid, sodium citrate, disodium edetate
2. Heparins: Accelerates action of Antithrombin III to neutralize thrombin and other
coagulation factors
a. Any drugs that end in INS
3. Rudins: Direct thrombin inhibitors
4. Coumarin: Interfere with hepatic synthesis of functional vitamin K dependent
clotting factors
a. Warfarin

Standard Heparin (UFH)

Source: Porcine intestinal mucosa and bovine lung
Structure: sulfated mucopolysaccharide (acidic molecule)
Route of Administration:
o Continuous (infusion pump)
o Intermittent (subcutaneous)
o Not oral due to lack of absorption
o Not IM due to risk of hematoma at injection site
Onset of Action: Immediate
Endothelial cell/protein binding:
o Extensive: sticky molecule
o Clearance is dose dependent because plasma levels of heparin increase
considerably once binding sites are saturated (most drugs are dose
independent)
o Dose Dependent Pharmacokinetics
Therapeutic Goal:
Prolonged PTT to 1.5-2.5 times normal
Mechanism of Action
o Protease inhibitor, antithrombin III, forms a 1:1 complex with clotting factor
proteases
o Interaction is slow but is stimulated 1000 fold by heparin, which binds
antithrombin III
o This complex inactivates factor IIa (thrombin) main mechanism
o This complex also inactivates factor Xa, which occurs earlier in cascade

Standard Heparin (continued)

Contraindications
o Bleeding disorders and disorders that predispose to bleeding (hemophilia,
thrombocytopenia), hemorrhage, and several other diseases
o Patients with advanced liver or kidney disease, severe HTN, and certain
infections (active TB, infectious endocarditis)
o Preferable to other anticoagulants during pregnancy due to lack of placental
transfer (contrast to warfarin)
Adverse Effects

Antidote: Protamine Sulfate

LMWH: Low Molecular Weight

Heparins
Enoxaparin MW: 2000-6000
Dalteparin MW: 2000-9000
Tinzaparin MW: 3000-8000
Properties of LMWH
o First approved for primary prevention of DVT after hip replacement therapy
o Evaluated and used for treatment of other thromboembolic diseases
o Advantages of UFH:
o Pharmacokinetics (DOSE INDEPENDENT)
o Safety
o Also contraindicated in HIT: Heparin Induced Thrombocytopenia
o Not readily reversed with protamine sulfate
o Monitored by anti-Xa activity assay, when needed

LMWH: inhibits 10a better than thrombin

Know:
Unfractionated heparin goes away very
quickly but LMWH has a longer half life.

Fondaparinux (Arixtra)

o Synthetic pentasaccharide

o
o
o
o

anticoagulant
Unlike UHF or LMWH, it has NO EFFECT on thrombin (IIa)
It exerts antithrombotic activity as a result of ATIII-mediated selective inhibition
of factor Xa
Elimination half life is 18 hours allows 1x daily dosing subcutaneously
Should not cause HIT
o Does not bind to platelet 4
o However, clinical trials are needed to determine if it is a safe alternative to
heparin in patients at risk for HIT
Uses

o
o
o
o

Venous thromboembolism prophylaxis after ortho surgery

Treatment of PE
Treatment of DVT
Treatment of coronary artery thromboembolism promising but still under
study

Direct Thrombin Inhibitors (rubins)

DO NOT REQUIRE ANTITHROMBIN III

Hirudin: the rudins

65 amino acid peptide

This is a specific thrombin inhibitor obtained from leeches

Lepirudin (Refludan)

Recombinant yeast-derived form of hirudin

It is approved for anticoagulation in patients with heparin-induced thrombocytopenia
(HIT)

Desirudin (Ipivask) and Bivalirudin (Angiomax)

New recombinant hirudin analogs that may be used instead of heparins in the
future

Argatroban (Acova)

2nd agent (1st is lepirudin) approved for HIT

Unlike lepirudin, it is cleared by liver and can be used in patients with end-stage
renal disease

Warfarin
Coumarin derivative
100% oral bioavailability
Plasma Protein Binding is Extensive
o Low volume of distribution (albumin space)
o Long half-life (36 hours)
o Lack of urinary excretion of unchanged drug
Metabolism
o Metabolized to inactive metabolites by cytochrome P450
(CYP2C9) in liver
o Site of numerous drug interactions
Mechanism of Action
o Inhibitor of Vitamin K epoxide reductase
o Impairs livers capacity to produce reduced Vitamin K
Essential cofactor in the production of Vit K dependent coagulation
factors
Clotting factors 2,7,9,10 are dead factors dont work
Resistance: mutations in Vitamin K epoxide reductase confers heritable resistance to
warfarin

Warfarin (continued)
Speed of Onset: SLOW
o Warfarin half like = 1.5 days (36 hours)

o 8-12 hours for initial anticoagulant effect, several days to reach maximum
hypoprothrombinemia.
o The delay represents time to replace normal clotting factors with
incompletely gamma-carboxylated factors and the time to reach steady state
levels of drug
Antidote:
o Discontinue drug
o Administer large doses of vitamin K and fresh frozen plasma or factor IX
concentrates containing prothrombin complex

Drug Drug Interactions with Warfarin

Drugs that diminish the response to oral anticoagulants:

Inhibition of oral warfarin absorption
Cholestyramine (also affects vitamin K absorption)

Induction of hepatic microsomal enzymes: (Cytochrome Inducers)

Barbituates
Carbamazepine
Primidone
Rifampin
St. Johns Wart
Stimualtion of clotting factor synthesis
Vitamin K diet and bacteria
Estrogens

Drugs that enhance the response to oral anticoagulants

Displacement from plasma albumin:
Sulfonamides
Inhibition of anticoagulant metabolism:
Amiodarone
Allopurinol
Cimeditine
Ciprofloxacin
Erythromycin
Co-trimoxazole
Metronidazole (selective for S warfarin)
Fluconazole(selective for S warfarin)
Reduction in availability of Vitamin K:
Broad spectrum antibiotics

Uses of Warfarin
o Heparin and warfarin are both used to treat both arterial and venous thrombi
o Heparin is used for the first 7-10 days, with a 3-5 day overlap with warfarin, which
may be continued for up to 6 months.
o Warfarin is also used to prevent blood clots in patients with chronic atrial fibrillation

Therapeutic Goal with Warfarin

o Prolong the PT time above normal

o 1.2-1.5 fold increase if tissue factor (thromboplastin) is used
o 1.503.5 if you use human tissue factor in INR
This can be achieved in about
1
week but remember that the
onset is slow.

Limitations of Warfarin

Adverse effect:
Serious and possibly fatal bleeding occurs in brain, pericardium, stomach and
intestine
Pregnancy:
Warfarin is contraindicated (category X)
Fetal warfarin syndrome (FWS)
Teratogen 1st trimester
in utero fetal hemorrhage throughout pregnancy
Contraindications:
Pregnancy (risk of fetal hemorrhage/malformation)
Patients with bleeding disorders
Liver disease (impaired drug metabolism)

Know this table!!!

Novel Orally Bioavailable Anticoagulants

Thrombolytic Drugs

Lyse thrombi by catalyzing the formation of serine

protease (plasmin) from its precursor zymogen
(plasminogen)
Thrombolytic Drugs end in ase (kinase or
plase)
Plasmin degrades cross linked fibrin

Thrombolytic therapy is directed towards the conversion of plasminogen to

plasmin, which degrades fibrin and lyses thrombi.
Circulating antiplasmins preclude the possibility of using plasmin itself for
thrombolytic therapy
Plasma does not contain inhibitors of urokinase (human kidney protease) or the
complex formed between plasminogen and streptokinase (streptococcal enzyme)
These activators convert plasminogen to plasmin inside the thrombus,
where plasmin is protected from the inhibitory effects of circulating antiplasmins
o Activate local to bypass the systemic antiplasmin
Preferential conversion of fibrin-bound plasminogen to plasmin also occurs with
tissue plasminogen activator (t-PA)
t-PA is more efficacious than streptokinase or anistreplase for thrombolytic therapy
in myocardial infarction, but it carries a higher risk of hemorrhagic stroke.

Streptokinase

Nonenzymatic protein produced by group C beta-hemolytic streptococci

Facilitates thrombolysis through formation of activator complex with plasminogen
results in formation of plasmin
Plasmin degrades fibrin, fibrinogen, and procoagulant factors V and VIII
Aspirin plus streptokinase may be as effective as t-PA
Hypersensitivity to streptokinase may occur

Urokinase

o Parenteral thrombolytic agent (from human cultured kidney cells)

o Indicated for lysis of pulmonary emboli, lysis of coronary artery thrombi associated
with evolving transmural myocardial infarction
o Hypersensitivity reactions occur less frequently than with streptokinase

Recombinant Thrombolytic Agents

Alteplase: biosynthetic recombinant form of human tissue plasminogen activator (tPA)

Considerably more expensive than streptokinase

Alteplase is not associated with hypersensitivity reactions

Reteplase

Recombinant plasminogen activator

Longer half-life than alteplase

Tenecteplase, TNK-t-PA

Modified human t-PA

Compared to Alteplase, it has a prolonged half-life, increased specificity for
fibrin and increased resistance to plasminogen activator inhibitor-1

Uses of Thrombolytic Agents

Thrombolytic drugs were only used for deep-vein thrombosis and serious
pulmonary embolism
Today they are used for the treatment of acute peripheral arterial thrombosis
(including myocardial infarction patients who meet certain criteria) and emboli,
and for unclogging catheters and shunts
In 1996, approved for treatment of acute ischemic stroke
Rule out intracranial bleeding (CT scan)
September 2001, approved for the restoration of function to central venous access
devices
Thrombolytic therapy should be followed with anticoagulant therapy with
heparin (rapid onset) and then warfarin (orally effective)
For myocardial infarction, aspirin may be an adjuvant therapy because of its antiplatelet effect.

Contraindications to Thrombolytic Therapies

Surgery within 10 days

Serious G.I. bleeding within 3 months
History of hypertension (diastolic pressure > 110 mm Hg)
Active bleeding or hemorrhagic disorder
Previous cerebrovascular accident or active intracranial process
Aortic dissection
Acute pericarditis

LMWH Low Molecular Weight Heparin

and Fondaparinux
Not warfarin because it will take too
long.

Drugs Used in Bleeding Disorders

Vitamin K:

Fat soluble vitamin from green leafy vegetables

Produced by bacteria colonizing human intestine: needs bile salts for absorption
Required for gamma carboxylation of glutamine resides in prothrombin and
Factors VII, IX, and X
Treats warfarin excess and vitamin K deficiency
Prevents hemorrhagic disease of Vitamin K deficiency in newborns

Plasma Fractions/ Clotting Factors

Deficiencies in plasma coagulation factors can cause bleeding (hemophilia)
o Concentrated plasma fractions treat these deficiencies
o Threat of AIDS and viral hepatitis discourages use of plasma fractions in
treatment of patients with hemophilia

Recombinant factors are preferred:

o Antihemophilic factor (AHF, Factor VIII): commercially prepared to secrete

factor VIII

Fibrinolytic Inhibitors:
Aminocaproic Acid treats:

o Systemic or urinary hyperfibrinolysis (aplastic anemia, abruption placentae,

hepatic cirrhosis)
o Bleeding associated with neoplastic disease (carcinoma of prostate, lung,
stomach, or cervix)
o Bleeding following cardiac surgery

Summary:

Know the pharmacology and uses of:

1. Platelet inhibitors

2. Anticoagulants

Recognize that heparins require antithrombin III for their mechanism of action.

2. Drugs for bleeding disorders

Recombinant Factor 8 to treat Hemophilia

3. Thrombolytic drugs