This document discusses recent advances in the treatment of thrombotic disorders. It describes the pathophysiology of arterial and venous thrombus formation and lists various activators and inhibitors of coagulation. It then summarizes various anticoagulant, antiplatelet and thrombolytic agents and their targets, mechanisms of action, advantages and limitations. Several newer oral anticoagulants targeting factor Xa and thrombin are discussed along with their ongoing clinical trials. The document also explores newer antiplatelet agents targeting PAR-1, P2Y12 receptors and thromboxane receptors. Various investigational agents such as RNA aptamers, monoclonal antibodies and aptamers are briefly outlined.

1. Recent Advances in
treatment of Thrombotic
Disorders

2.  Definition- The process of formation of a thrombus
 Steps involved:
1
•Platelet events
2
•Coagulation Cascade
3
•Fibrinolysis

7. Antithrombin III

9. Arterial Thrombus Venous Thrombus
White Thrombus Red thrombus
Platelets and Leucocytes in fibrin
mesh
Diffuse fibrin meshwork in which red
and white blood cells are trapped
indiscriminately
Blood flow interruption causing
ischemia/ death
Can break into an embolus and find
its way to lungs/systemic circulation

10. Activators of
Coagulation
Inhibitors of
Coagulation

11. Stasis
• Immobilizat-
ion
• Limb
paralysis
• Heart Failure
• Varicose
Vein
• Chronic
Venous
Insufficiency
Intimal
injury
• Direct
vessel
injury eg.
Surgery,
Trauma
• Indirect
vessel
injury eg.
Sepsis,
Vasculitis
Hypercoagu
lability
• Hereditary
• Acquired

12.  Treatment and Prevention of Deep Venous Thrombosis &
Pulmonary embolism
 Prevention of stroke in patients with atrial fibrillation, artificial
heart valves, cardiac thrombus.
 Ischemic heart disease
 During procedures such as cardiac catheterisation

13. Anticoagulants
• Heparin &
LMWH
• Warfarin
• DTIs- Lepirudin,
Bivalirudin,
Argatroban
• Xa inhibitors-
Fondaparinux,
Idraparinux
Antiplatelets
• Aspirin
• Clopidogrel
• Prasugrel
• Abciximab
• Eptifibatide
• Tirofiban
Fibronolytics
• Streptokinase
• Urokinase
• Alteplase
• Reteplase
• Tenecteplase

14. 1) Broad range of targets
2) Narrow therapeutic index
3) Interactions with food & other drugs
4) Slower onset of action
5) Parenteral route of delivery
6) Long term monitoring required

15.  Oral, preferably once daily
 Rapid onset and offset of action
 Predictable PK and PD
 Low propensity for food and drug interactions
 Antidote available
 Wide therapeutic window
 Easy to use with no need for monitoring

17.  Heparin is poorly absorbed across the GI mucosa
 Addition of certain chemical conjugates can aid in its
transcellular absorption
 SNAC-Heparin
 Phase III trials in hip replacement patients
 Active comparator: Enoxaparin
 Result: Failed for two reasons
a) Rates of DVT & Pulmonary embolism were higher
b) Nausea(in 30% patients) leading to poor compliance
 LHD
 Conjugate of heparin with Deoxycholic acid
 Current status: Preclinical studies

18.  Ultra-low molecular weight heparin
 Given by s.c. route
 Half life- 16 to 20 hrs; hence given once-daily
 Current status: Phase III trials ongoing

19. Ongoing Trials
SAVE-
HIP1
SAVE-
HIP2
SAVE-
KNEE
TREK
SAVE-
ABDO
SAVE-
ONCO
SAVE-
VEMED
Study
populat-
ion
Elective
total hip
replace-
ment Sx
Elective
hip
fractu-
re Sx
Elective
knee
replace-
ment Sx
Elective
total
knee
replace-
ment Sx
Major
abdo or
pelvic
surgery
Cancer
patients
at high-
risk for
VTE
Pts.
Hospital-
zed for
acute
medical
illness
No. of
Patients
2320 1000 1060 690 4400 3200 421
 Primary endpoint: Composite endpoint of any VTE & death from
any cause
 Active comparator: Enoxaparin

20.  Oral Vitamin K antagonist
 Hydrolyzed by esterases & not by CYP450 enzymes
 Not affected by CYP-mediated drug-drug interactions or by
genetic variations in CYP450 system
 Current status:
 In Phase II trials
 Study population: Patients with atrial fibrillation

22. Property Advantage
Do not bind to plasma proteins
More predictable anticoagulant
responase
Do not bind to Platelet factor 4
Activity unaffected by large
quantities of PF4 released in
the vicinity of platelet-rich
arterial thrombi
Inhibit fibrin-bound as well as
fluid phase thrombin
Greater anticoagulation than
heparin

23.  An oral, reversible Direct Thrombin inhibitor
 Oral bioavailability is about 5%
 Prodrug ; converted to active drug dabigatran by plasma
esterases
 Excreted mainly by renal route
 Is a substrate of P-gp, an efflux transporter
 Hence has drug interactions with quinidine & amiodarone
which increase its plasma levels by reducing clearance
 Current status: Approved in 2010 for prevention of stroke in
atrial fibrillation

24.  Reversible Direct Thrombin Inhibitor
 Short t1/2 with predictable pharmacokinetics
 Clearance by non-renal route
 Can be used as an alternative in patients who have developed
antibodies to heparin/PF4 complex
 Current status: Phase II trials ongoing in CRF patients on
hemodialysis

25.  Consists of 2 polyethylene side-chains coupled to recombinant
hirudin
 Has a prolonged t1/2 of 12 hrs
 Renal clearance & hence t1/2 is even more prolonged in renal
insufficiency
 Current Status: Phase II trials ongoing
 Study population: Renal failure patients undergoing
hemodialysis
 Active comparator: Heparin

27.  Hypermethylated version of Fondaparinux
 t1/2 – 80 hrs ; given once-weekly
 Contains Biotin moeity, which can be neutralized by exogenous
avidin
 Current status: Phase III trials ongoing (CASSIOPEA)
 Study population - Patients of symptomatic pulmonary
embolism
 Active comparator- Warfarin
 Primary endpoint - Recurrent venous thromboembolism at 99
days after randomisation

28.  Orally active, Reversible factor Xa inhibitor
 Rapid onset of action with 80% bioavailability
 Given once-daily
 Dual mode of elimination- renal & hepatic route
 Current status: Approved as
1) Prophylaxis of deep vein thrombosis during knee or hip
replacement surgery (RECORD trial)
2) Stroke prevention in Atrial fibrillation( ATLAS & ROCKET-AF
trial)

29.  Orally active, small-molecule drug
 Target: Direct factor Xa inhibitor
 Curent status:
Phase III trials underway:
1) Prevention of stroke in Atrial fibrillation patients:
• Comparison with warfarin
ARISTOTLE
trial
• Comparison with aspirin in patients who are
intolerant/ ineligible for warfarin treatment
AVERROES
trial

30. 2) Secondary Thromboprophylaxis in patients of knee
replacement
• Comparison with enoxaparin+warfarin
in patients acute DVT or pulmonary
embolism
AMPLIFY
trial
• Comparison with placebo in patients
who have completed 6-12 months
treatment for thrombotic events
AMPLIFY-
EXT trial

31.  Orally active, small-molecule drug
 Target: Direct factor Xa inhibitor
 Curent status: Phase III trial ongoing (ENGAGE AF-TIMI 48)
 Study population: Patients with atrial fibrillation
 Primary endpoint: Composite of stroke & systemic embolic
events
 Active comparator: Warfarin

32.  Parenteral drug (i.v.) with Half life of 2 to 3 hrs
 Target: Direct factor Xa inhibitor
 Excreted unchanged in urine and metabolites excreted in faeces
 Current status: Phase II dose-finding trial completed (SEPIA-
ACS1-TIMI42)
 Patient population: Non-ST segment elevation ACS
 Active comparator: Heparin + Eptifibatide
 Primary efficacy outcome: composite of death, MI, urgent
revacularization
 Primary safety outcome: Major & minor bleeding episodes
 Results: Intermediate dose group selected for phase III trials

33.  Nematode anticoagulant protein
 Isolated from Ankylostoma caninum
 Target: Inhibits Factor VIIa/TF complex
 Current status:
 Phase 2 trial completed (ANTHEM –TIMI-32)
 Subjects: Patients with non-ST elevation ACS
 Active comparator: UFH
 Primary endpoint: Rate of major plus minor bleeding
 Results: No significant increase in bleeding rates

34.  Recombinant human Activated Protein C(APC)
 Mechanism of action:
1. Activates Protein C & promotes degradation of factors V &
VIII
2. Has a profibrinolytic effect by inhibiting Plasminogen
activator inhibitor-1
 FDA Approval: To reduce sepsis in patients of organ
dysfunction
 Withdrawal: A Cochrane Review of earlier trials failed to show
any survival benefit in sepsis patients
 Eli-Lily, in October, voluntarily withdrew the drug from
worldwide markets

35.  Current status:
 Undergoing Phase II trial
 Patient population: Patients of acute Pulmonary embolism
 Study groups: Drotrecogin plus Enoxaparin(4 dose escalating
groups) compared with Enoxaparin alone
 Primary endpoint: No. of patients with major bleeding events
 Secondary Endpoint: Plasma levels of APC, soluble fibrin & FDP

37.  Definition: the persistent activity of clopidogrel target (i.e.
P2Y12 receptors of the platelet) despite an adequate antiplatelet
regime
 Mechanisms
•CYP2C19*2 alleleGenetic
polymorphisms
•With OmeprazoleDrug-Drug
Interactions

38. Genetic Testing
Who should be tested?
 Those undergoing multi vessel PCI
procedures
 H/o stent thrombosis
 Other co-morbid conditions like DM &
CRF

39. Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450-2C19 (CYP2C19 )
Genotype and Clopidogrel Therapy

41. Vorapaxar & Atopaxar

42. Selective PAR-1 antagonists:
 No effect on ADP-induced or collagen-induced platelet
aggregation(reqd. for normal hemostasis)
 Bleeding time, PT & aPTT not affected- unlike Argatroban &
Cangrelor
 Leave PAR-4 function intact
 Theoretically safer than Direct Thrombin Inhibitors & Factor Xa
inhibitors

44.  DSMB evaluation found increase in
incidence of intracranial hemorrhage in
stroke patients.
 TRACER trial- Discontinued
prematurely
 TRA2P-TIMI 50 : Trial continued, but
patients with h/o stroke were excluded
from the study

45. LANCELOT-ACS Trial:
 Phase II study to assess safety
 Comparison with placebo
 Results:
A. No significant increase in major bleeding
B. Major cardiac events were lower in atopaxar group
C. Adverse effects(Dyspepsia, Liver enzyme elevation)- Did not
differ significantly between the 2 groups
 Phase III trials are being planned for further evaluation

46.  ADP analogue
 Intravenous P2Y12 inhibitor
 Plasma half-life: 3-6 minutes
 Full recovery of platelet function within 60 minutes

47.  CHAMPION-PCI : Comparison with Clopidogrel (600 mg loading
dose)
 CHAMPION-PLATFORM : Cangrelor- Clopidogrel combination
compared with clopidogrel alone
 Patient population: Those undergoing PCI
 Primary endpoint: All cause mortality, MI & ischemia-driven
revascularization 48 hrs post-PCI
 Both trials halted: Efficacy endpoints not met according to
Interim analysis

48.  Phase II study
 Aim: To determine whether cangrelor could be used as a
“bridge” between discontinuing thienopyridines and surgery.
 Active comparator: None; placebo group used
 Primary efficacy endpoint: Platelet reactivity (expressed in
PRU) measured by an in-vitro assay
 Primary safety endpoint: Excessive-CABG related bleeding
events
 Results: a) 98% cangrelor patients(v/s 19% placebo patients)
had low levels of platelet reactivity
b) No significant differences in major bleeding events
BRIDGE Trial

49.  Orally active, non-thienopyridine drug
 Mechanism of action: Reversible inhibition of P2Y12 receptors
 Advantages over thienopyridines:
 Greater platelet inhibition
 Does not require metabolic conversion for activation
 Faster onset of action(2 hrs)
 Faster offset of action due to reversibility

50.  Adverse effects: Dyspnoea, arrythmia, Increase in S.creatinine
& uric acid levels
 Current status: Approved in July 2011 for reducing CV death &
MI in patients of acute coronary syndrome
 Boxed warning: Decreased efficacy with aspirin doses > 100
mg/day

51.  Direct-acting reversible P2Y12 antagonist.
 Can be administered both intravenously and orally
 Predictable, dose-dependent platelet inhibition
 Current Status: Phase II Trial (INNOVATE-PCI) is currently
ongoing in patients undergoing elective PCI

52.  Platelet 5-HT2A receptor antagonist
 CURRENT STATUS:- Phase III trial completed(S-ACCESS)
 Active comparator: Aspirin(81 mg OD)
 Study population: Patients with recent cerebral infarction
 Primary endpoint: Recurrence of Cerebral infarction
 Results: Sarpogrelate was not non-inferior to aspirin i.e. No
significant difference in outcome between sarpogrelate and
aspirin was found

53.  Orally active, Thromboxane Receptor antagonist
 Blocks thromboxane-induced platelet aggregation and
vasoconstriction
 Current status: Phase III trial(PERFORM) halted
 Study population: Patients with ischemic stroke or TIA
 Primary endpoint: Composite of fatal & nonfatal stroke, MI &
other vascular death
 Active comparator: Aspirin 100 mg
 Results:
A. Similar rates of primary endpoint in both groups
B. Increase in incidence of minor bleeding compared to aspirin

54.  A Nitric-Oxide (NO) releasing aspirin
 Antithrombotic
 Antiatherogenic – Decreases monocyte activation
 Vasodilatory & Cardioprotective properties
 Current status: Preclinical testing

55.  Dimeric Gp. VI fusion protein
 Blocks interaction between Gp VI and vascular collagen thus
preventing further platelet events
 Current status: Phase I studies underway
 Monoclonal antibody to Gp VI receptor
 Only targets receptors on activated platelets, thus reducing
chances of bleeding
 Current status: Phase I studies underway

56.  Single stranded nucleic ligands (DNA or RNA based)
 Highly specific- bind with high specificity to their target
 Advantages over antibodies:
a. Stable structure
b. Non immunogenic
c. Can be easily modified
 Drawbacks :
a. Degradation by nucleases- overcome by base substitution
b. Rapid renal clearance- overcome by conjugation with
Polyethylene glycol to augment its size

57.  RNA aptamer
 Consists of Pegnivacogin (the therapeutic component) &
Anivamersen (its antidote)
 Target: Factor IXa
 Current status:
 Phase IIb studies ongoing (RADAR Trial)
 Subjects: Patients of Acute Coronary Syndrome undergoing
elective PCI
 Active comparator: Unfractionated heparin
 Primary endpoint: Major bleeding episodes upto 48 hrs/
discharge, whichever is earlier

58.  DNA Aptamer
 Target: Anti-vWF; inhibits binding to Gp Ib on platelets
 Current status:
 Phase II trial ongoing
 Subjects: Patients of congenital TTP( characterized by
increased vWF activity)
 Primary endpoint: Serum ARC 1779 concentrations
 Secondary endpoint: vWF & platelet function assays

59.  DNA aptamer
 Has no structural modifications
 Unstable in vivo & hence given by continuous i.v. infusion
 Target: Thrombin-inhibitor
 Current status: Phase I trial ongoing

60. New Oral anticoagulants are in a
fierce competition with Heparin &
LMWH for VTE prevention
The search for an alternative to
warfarin for stroke prophylaxis in atrial
fibrillation appears nearing completion
Not yet clear whether thrombin or
Factor Xa is the best target
Head-to-head comparisons & cost-
effectiveness analyses will be
necessary