1. The document discusses physiology and pathways of coagulation, as well as antiplatelet drugs, anticoagulants, and thrombolytics used to treat coagulation. 2. Standard heparin and low molecular weight heparins are compared, noting differences in molecular weight, bioavailability, monitoring needs, and clearance. 3. New oral anticoagulants are discussed as alternatives to warfarin, noting their benefits of fixed dosing, limited drug interactions and food effects, and lack of routine monitoring needs. However, concerns remain regarding a lack of monitoring methods and proven antidotes.

2. Anti-Coagulation and Concerns of low Glomerular
Rate
1- Physiology and Pathway of Coagulations.
2-Antiplatelets,Anticoagulants & Thrombolytics.
3- Heparin and Low Molecular Weight Heparin.
4- New Oral Anticoagulants in Patients with low eGFR.

3. Coagulation Mechanism
1- Activation of Clotting Factors (Coagulation cascade)
2- Requirement of a Phospholipid Surface
• Activated Platelet (platelet factor 3 phospholipid) intrinsic to blood
• Tissue Factor (TF) extrinsic to the blood
3- Vitamin-K Dependent Factors (II, VII, IX, X)
4- Formation of Reaction Complex
• Labile factors : factors V and VIII

4. FUNCTIONS OF THE COAGULATION SYSTEM
ACTION DESIRED RESULT
1- Prevent clot formation at
non-injured sites
Prevent thrombosis
2- Rapid formation of
mechanically sound clot Stop bleeding quickly
3- Gradual replacement of
clot with viable tissue
Wound healing
A) 1- is needed at the Extracorporeal Cycle
B) 2 + 3 is needed at the Arterial or Venous

5. BLOOD COAGULATION
1- Platelet Plug = Anti-platelet
2- Fibrin Clot = Anti-coagulation
The most important step in the formation of fibrin clot is the
coagulation Cascade
3- Fibrinolysis = Fibrinolytic Agent

6. A- Rapid formation of
mechanically sound clot
B- Gradual replacement
of clot with viable tissue
Either Arterial Or Venous
In Our Patient Puncture
1-3 Platelet aggregation and activation
4- Fibrin clot formation
5- Fibrinolysis

7. 1- Platelet Plug
Platelet Activation & Aggregation
Exposed Endothelial Surface
Platelets Exposed to Collagen
“Activated”
Release Contents of Cytoplasmic Granules
Adenosine Diphosphate (ADP) Thromboxane (Tx A2)
Accelerates platelet Vasoconstriction
aggregation/activation ↑ ADP release from platelets

8. PLATELETS FUNCTION
1- Stick to damaged blood vessels
• Requires von Willebrand Factor
2- Spread out to cover damaged area
3- Activate and release contents
• Partialy blocked by Aspirin
4- Aggregate ( ADP)
5- Cause blood vessel constriction (Thromboxane A2)
6- Cause retraction of clot to draw wound edges
together

9. Coagulation Mechanism
1- Activation of Clotting Factors (Coagulation
cascade)
2- Requires a Phospholipid Surface
• Activated Platelet (Platelet Factor 3 Phospholipid) intrinsic to blood
• Tissue Factor (TF) extrinsic to the blood
3- Vitamin-K Dependent Factors (II, VII, IX, X)
4- Formation of Reaction Complex
• Labile factors : factors V and VIII

10.  Ubiquitous lipoprotein (part of cell membrane)
 Initiates physiologic clotting process
 Highest concentration in Brain, Mucous Membranes,
Skin, and Immediately outside blood vessels
 Forms “Hemostatic Envelope“
 Not normally found on endothelial cells lining
blood vessels, or on circulating blood cells
Tissue damage exposes blood to Tissue Factor
Tissue Factor Initiates Fibrin Clot Formation

11. 2- Fibrin Clot
Coagulation Cascade
TF =tissue factor
PK = Prekallikrein
HK=High molecular kininogen
a = activated
- Roberts HR, et al. Current
Concepts for Hemostasis.
Anesthesiology 2004;100:3. 722-
30.
3 main steps:-
1. Formation of prothrombin activator :-
i- Intrinsic pathway
ii- Extrinsic Pathway
2. Coversion of prothrombin to thrombin(factor II):-
3. Conversion of fibrinogen to fibrin

12.  Tissue damage exposes blood to Tissue factor ( and
platelet to damaged endothelium which leads to platelet
activation and formation of platelet plug)
 Coagulation cascade: series of enzymatic reactions
leading to thrombin formation
• takes place mainly on membrane surface, eg
platelet membrane
 Thrombin converts Fibrinogen to fibrin on top of
platelet plug
 Fibrin polymerizes and becomes crosslinked
2- Fibrin Clot Formation

13. Coagulation Mechanism
1- Activation of Clotting Factors (Coagulation cascade)
2- Requires a Phospholipid Surface
• Activated Platelet (platelet factor 3 phospholipid) intrinsic to blood
• Tissue Factor (TF) extrinsic to the blood
3- Vitamin-K Dependent Factors (II, IX, VII, X)
4- Formation of Reaction Complex
• Labile factors : factors V and VIII

14.  Fat - soluble vitamin present in many foods
 Some made by bacteria in gut (Long use of antibiotics?)
 Necessary for synthesis of several components of
coagulation cascade.
 K dependent factors II, VII, IX, X and protein C & S
 Deficiency may lead to low levels of clotting factors,
causing a bleeding tendency
 Warfarin (Coumadin™): Anticoagulant Interferes with
vitamin K action.
3- Vitamin K is Needed For The Production Of
Several Clotting Factors

15.  Plasminogen Activators from blood vessels and other cells
convert plasminogen to plasmin to begin the process.
 Plasmin cause Degradation of fibrin clot.
 Necessary to remove clot so wound healing can proceed
 Thrombin make Fibrin Clot
 Plasmin dissolve Fibrin Clot
3- FIBRINOLYSIS

16. 1- Protein C: Degrades (activated)
factors VIIIa and Va
2- Protein S: Cofactor for
protein C
3- Antithrombin: Inhibits
thrombin and other enzymes
 Deficiency of any of these proteins can increase
risk of thrombosis
Helps Prevent Thrombosis
Confines Clot To Injured Area
Regulation Of The Coagulation
( Counter-Regulation)

17. Anti-Coagulation and Concerns with Low
eGFR
1- Physiology and Pathway of Coagulations.
2-Antiplatelets, Anticoagulants & Thrombolytics.
3- Heparin and Low Molecular Weight Heparin.
4- New OralAnticoagulants in Patients with low eGFR.

18. Anti- Platelet & Anticoagulants & Thrombolytics
HEMOSTATIC
PROCESS
AFFECTED
CLASS OF
DRUGS
SPECIFIC
DRUGS
1º platelet plug formation
inhibition
Antiplatelet drugs Reversible: NSAID
Irreversible: ASA
Thienopyridines
GpIIa/IIIb inhibitors
Coagulation cascade IV&SC anticoagulants
Oral anticoagulants
Standard and LMW heparins
Warfarin
NOAC
Fibrinolysis Fibrinolytic agents Streptokinase
Urokinase

19. Anticoagulants & Thrombolytics
DRUG SITE OF
ACTION
ROUTE PLASMA
t 1/2
EXCRE-
TION
Ø PRIOR
PROCEDURE
↑ PT /
PTT
ANTI –
DOTE
Unfraction-
ated heparin
IIa/Xa IV/SC 1.5 hrs hepatic 6 hrs No/
Yes
protamine
LMWHs Xa
IIa
SC 4.5 hrs renal 12-24 hrs No/No protamine
(partial)
Strepto -
kinase
plasmi –
nogen
IV 23 mins hepatic 3 hrs Yes/
Yes
antifibri-
Nolytics
t-PA plasmi –
nogen
IV <5 min hepatic 1 hr Yes/
Yes
antifibri-
nolytics
Oral
Anticoagu-
lants
vit-K dep.
factors
Oral 2-4days hepatic 2-4 days Yes/No Vit. K, rFVIIa
Plasma,
Prothrom.
complex
conc.
Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

20. Anti-Coagulation with concern of low eGFR
1- Physiology and Pathway of Coagulations.
2-Anticoagulants & Thrombolytics.
3- Heparin and Low Molecular Weight Heparin.
4- New Oral Anticoagulants and concerns with low eGFR.

21. Blood Coagulation: Fibrin Clot Platelet Plug
Clopidogrel
Abciximab
Tirofiban(Agrastat)
Fibrinolytic

22. Mechanism
of Action
Weitz. NEJM 1997
.

23. Standard Heparin vs. LMWH
Parameters Standard Heparin LMWH
MOLECULAR WEIGHT 3, 000 - 30,000 daltons 4,000-6,500 daltons
BIOAVAILABILITY variable due to binding to plasma
protein & macrophages
predictable
MONITORING PTT
dose adjusted based on PTT
no need for monitoring
no dose adjustments
HALF – LIFE variable; dose-dependent (30
min for 25 u/kg, 150 mins with
400 u/kg)
4-6 hrs
CLEARANCE hepatic renal

24. Standard Heparin vs. LMWH
PARAMETERS STANDARD HEPARIN LMWH
EFFECT ON
PLATELETS
Higher incidence of HIT
Inhibition of platelet function
Inhibits platelet-endothelium
interaction
Lower incidence of HIT
Less inhibition
No interaction
RISK OF BLEEDING higher Lower
ANTI Xa: IIa
ACTIVITY
1:1 2:1
REVERSAL protamine Only anti-IIa (90%) but
not anti-Xa (60%) activity
reversed by protamine (1
mg/100 anti-Xa units
LMWH
COST inexpensive expensive

25. Robert E. Cronin and Robert F. Reilly. Unfractionated Heparin for Hemodialysis: Still the Best
Option. Semin Dial. 2010 ; 23(5): 510–515. doi:10.1111/j.1525-139X.2010.00770.x

26. Anti-Coagulation with concern of low eGFR
1- Physiology and Pathway of Coagulations.
2-Anticoagulants & Thrombolytics.
3- Heparin and Low Molecular Weight Heparin.
4- New Oral Anticoagulants and concerns with low
eGFR.

27. Known Problems With Warfarin
1 - Unpredictable dose response
2 - Narrow therapeutic index
3 - Drug-drug, drug-food interactions
4 - Problematic monitoring
5 - High bleeding rate
6 - Slow reversibility

28. Properties Benefit
Oral, once-daily dosing Ease of administration
Rapid onset of action
No need for overlapping parenteral
anticoagulant
Minimal food or drug interactions Simplified dosing
Predictable anticoagulant effect No coagulation monitoring
Extra renal clearance Safe in patients with renal disease
Rapid offset in action
Simplifies management in case of
bleeding or intervention
Antidote For emergencies
Properties of an Ideal Anticoagulant

29. Novel Oral Anticoagulants
Important Comparative Features
• Oral direct thrombin inhibitor
• Twice daily dosing
• Renal clearance
Dabigatran
• Direct factor Xa inhibitor
• Once daily (maintenance), twice daily (loading)
• Renal clearance
Rivaroxaban
• Direct factor Xa inhibitor
• Twice daily dosing
• Hepatic clearance
Apixaban
• Direct factor Xa inhibitor
• Once daily dosing
• Hepatic clearance
Edoxaban
Circulation 2010;121:1523

30. Comparison Overview of New
Anti-Coagulants with Warfarin
Features Warfarin New Agents
Onset Slow Rapid
Dosing Variable Fixed
Food effect Yes No
Drug interactions Many Few
Monitoring Yes No
Half-life Long Short
Antidote Yes
No (except
Dabigatran)

31. Comparison of Phase 3 SPAF Trials
for NOACs: A Robust Trial Base
Rivaroxaban Apixaban Edoxaban
Open Label
Two Doses
Twice Daily
RE-LY
Double Blind
Two Doses
Once Daily
ROCKET-AF
Double Blind
Two Doses
Twice Daily
ARISTOTLE
Double Blind
Two Doses
Once Daily
ENGAGE
Dabigatran
Novel Anticoagulants
F IIa Inhibitor F xa Inhibitor

32. Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14
Ericksson BI, et al. Clin Pharmacokinet 2009;48:1-22
Dabigatran Apixaban Rivaroxaban Edoxaban
Target IIa (thrombin) Xa Xa Xa
Hrs to Cmax 2 1-3 2-4 1-2
CYP metabolism None 15% 32% NR
Bioavailability 7% 66% 80% > 45%
Transporters P-gp P-gp P-gp/BCRP P-gp
Protein binding 35% 87% >90% 55%
Half-life 12-14h 8-15h 9-13h 8-10h
Renal elimination 80% 25% 33% 35%
Linear PK Yes Yes No Yes
BCRP = breast cancer resistance protein; CYP = cytochrome P450; NR = not reported;
P-gp = P-glycoprotein
Comparative Pharmacokinetics/
Pharmacodynamics of Novel Agents

33. Dosing Options for Renal Dysfunction
► Dabigatran 75 mg bid (USA) 50%
► Dabigatran 110 mg bid (non-USA)
► Rivaroxaban 15 mg daily 25%
► Apixaban 2.5 mg bid 50%
ESC 2012
Consider also for age ≥80, weight ≤ 60 KG (frailty)

34. Properties of Ideal Anticoagulant
Do NOACS Fit the Bill?
• Proven efficacy √
• Low bleeding risk √
• Fixed dosing √
• Good oral bioavailability √
• No routine monitoring needed √
• Reversibility: ?PCC, FEIBA, rVIIa
• Rapid onset of action √
• Few drug or food interactions √

35. NOACs vs Warfarin —
A Top Sky View
• NOACs generally more effective than warfarin for
stroke prevention
• NOACs are generally safer (less bleeding, with
some exceptions, but NOACs uniformly cause less
intracranial hemorrhage, most devastating and
mortality-inducing bleeding complication of OAC)
• NOACs, overall, reduce mortality
• NOACs are more convenient for patient/clinician

36. Unresolved Issues with NOACs
• No established methods of monitoring
• No known therapeutic ranges
• Lack of a proven antidote
• Uncertain management of bleeding
• Long term safety: to be determined
• No head-to-head comparisons of new agents

37. Conclusion
• All of the newer anticoagulants currently available for the
management of VTE and ACS have approved labeling for use
in patients with mild-moderate CKD.
• Currently available LMWHs, factor Xa inhibitors, and Direct
Thrombin Inhibitors ( Dabigatran) (excluding
argatroban) are eliminated primarily by the kidneys, so dosing
in patients with severe renal impairment may require
cautious dosage reduction or increased monitoring for
bleeding and thromboembolic complications or both.
• Appropriate anticoagulation in patients with lower eGFR
• requires that the patient's risk of thrombosis be carefully
balanced against the risk of bleeding.
• Bob L. Lobo. Use of Newer Anticoagulants in Patients With Chronic Kidney Disease. Am J Health Syst
Pharm. 2007;64(19):2017-2026.

39. Patient Selection for Anticoagulation
Additional Considerations
► Risk of bleeding
► Newly anticoagulated vs established therapy
► Availability of high-quality anticoagulation
management program
► Patient preferences

40. The CHADS2 Score
Stroke Risk Score for Atrial Fibrillation
Congestive Heart failure 1 32
Hypertension 1 65
Age > 75 years 1 28
Diabetes mellitus 1 18
Stroke or TIA 2 10
Moderate-High risk >2 50-60
Low risk 0-1 40-50
VanWalraven C, et al. Arch Intern Med 2003; 163:936.
* Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).
Prevalence (%)*Score (points)

41. The CHA2DS2-VASc Score
Stroke Risk Score for Atrial Fibrillation
Congestive heart failure or LVEF < 35% 1
Hypertension 1
Age > 75 years 2
Diabetes mellitus 1
Stroke/TIA/systemic embolism 2
Vascular Disease (MI/PAD/Aortic plaque) 1
Age 65-74 years 1
Sex category (female) 1
Moderate-High risk > 2
Low risk 0-1
Lip GYH, Halperin JL. Am J Med 2010; 123: 484.
Weight (points)

42. Importance of the HAS-BLED Score
Hypertension (> 160 mm Hg systolic) 1
Abnormal renal or hepatic function 1-2
Stroke 1
Bleeding history or anemia 1
Labile INR (TTR < 60%) 1
Elderly (age > 75 years) 1
Drugs (antiplatelet, NSAID) or alcohol 1-2
High risk (> 4%/year) > 4
Moderate risk (2-4%/year) 2-3
Low risk (< 2%.year) 0-1
Pisters R, et al. Chest 2010; 138: 1093.
Lip GYH, et al. J Am Coll Cardiol 2010; 57: 173.
Weight (points)
Risk Score for Predicting Bleeding in
Anticoagulated Patients with Atrial Fibrillation

43. OAC, oral anticoagulant
Nieuwlaat et al. Eur Heart J 2006; Gage et al. JAMA 2001
CHADS2 score
OACtherapy(%)
58 59
64 61
0
20
40
60
80
100
1 2 3 4
5333 AF patients in 35 countries: 2003–2004
Modest Use of Vitamin K Antagonists
Even in High-Risk Patients
European Heart Survey

45. Reinecke H et al.,. in the Management of Atrial
Fibrillation in Chronic Kidney Disease.
J Am Soc Nephrol 20: 705–711, 2009
Many physiologic mechanisms are altered in CKD
which lead to substantial changes in hemostasis with
the paradox that patients in all stages of CKD but
especially with ESRD have both a prothrombotic state
predisposing to high risk for thromboembolism and a
coagulopathy with an increased tendency for bleeding.
This explains the high rate of ischemic strokes and also
the high rate of bleeding.

46. Eric Black-Maier; Jonathan P Piccini. Oral Anticoagulation in End-
stage Renal Disease and Atrial Fibrillation: Is it Time to Just Say No to
Drugs? Heart. 2017;103(11):807-808.
• Little is understood about how to safely reduce the risk of thromboembolic events in
patients with AF and ESRD. Prospective trials of AF have uniformly excluded patients with a
glomerular filtration rate (GFR) <30 mL/hour.
• ESRD produces alterations in haemostasis that predispose patients to haemorrhagic
(platelet α granule depletion, reduced endothelial cell adhesion molecule expression) and
thrombotic (increased circulating fibrinogen) complications, limiting extrapolation of data
from patients with normal renal function. Data on the net clinical effect of warfarin in
patients with ESRD are limited to observational studies.
• Many experiences have suggested harm in the form of excess stroke and death, while others
have suggested benefit.
• Reflecting uncertainty in the available body of evidence, KDIGO modified their 2011
consensus statement on cardiovascular disease to recommend against routine oral
anticoagulation in dialysis patients with AF.
• In contrast, the most recent 2014 American College of Cardiology (ACC)/American Heart
Association (AHA)/Heart Rhythm Society guidelines on AF provide a grade IIa
recommendation for use of warfarin in ESRD.
• It is time to investigate the hypothesis that LAA occlusion may be superior to oral
anticoagulation in these high-risk patients. We need to know if we should 'just say no to
drugs' for stroke prevention in patients with AF and ESRD.

47. LMWH in USA
LMWH TRADE
NAME
MOLECULAR
WEIGHT
(daltons)
HALF - LIFE
(minutes)
Anti Xa: Anti
IIa
Dalteparin Fragmin 5,000 120 2:1
Enoxaparin Clexane
(Lovenox)
4,500 150 2.7:1
Danaparoid Orgaran 6,500 1,100 20:1
Ardeparin Normiflo 6,000 200 2:1
Standard
Heparin
14,000 60-90 1:1

48. Stroke Risk and Renal Disease
Olesen JB. NEJM 2012; 367:625-635
Aspirin does not prevent stroke
Characteristic
Total Population
(n = 132,372)
No Renal Disease
(n = 127,884)
Hazard Ratio
(95% CI)
P Value
Hazard Ratio
(95% CI)
P Value
All participants 1.00
Antithrombotic
Therapy
None 1.00 1.00
Warfarin 0.59 (0.57-0.62) < 0.001 1.10 (1.06-1.14) < 0.001
Aspirin 1.11 (1.07-1.15) < 0.001 1.10(1.06-1.14) < 0.001
Warfarin and
aspirin
0.70(0.65-0.75) < 0.001 0.69(0.64-0.74) < 0.001

49. References
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50. References
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51. Oral Anticoagulants
Warfarin
• inhibits synthesis of vitamin - k dependent factors II,
VII, IX, X and protein C & S
• reversal:
• stopping medication and waiting for ~4 days for PT
normalization
• vitamin K PO or IV (1-2mg)
• immediate: rFVIIa, FFP (1-2 units),
prothrombin complex concentrate
• check PT prior to surgery

52. Results:Reinhard Klingel et al;. Safety and Efficacy of Single Bolus Anticoagulation with Enoxaparin
for Chronic Hemodialysis. Kidney Blood Press Res 2004;27:211–217
• 24,117 HD treatments with enoxaparin at a
median dose of 70.1 IU/kg (5,000 IU median total
dose) for single bolus anticoagulation.
• In 83.0% of HD treatments, enoxaparin was given
as single bolus.
• In 98.3% of patients no adverse event was
reported.
• No drug-related severe adverse event occurred.
• Significant clotting problems were observed in
only 0.3% of HD treatments with single bolus
anticoagulation.