anticoagulants in plastic surgery

1. ANTICOAGULANTS

2. ANTICOAGULANTS
Drugs that help preventing the clotting (coagulation) of blood
Coagulation will occur instantaneously once a blood vessel has been
severed
Blood begins to solidify to prevent
excessive blood loss and to prevent
invasive substances from entering
the blood stream.

3. CLASSIFICATION
ANTICOAGULANTS
USED IN VIVO
PARENTERAL ORAL
USED IN VITRO
HEPARIN
CALCIUM COMPLEXING
AGENTS

5. - DIRECT THROMBIN
Lepirudin
Bivalirudin
Argatroban
1) USED IN VIVO:
A) PARENTERAL ANTICOAGULANTS:
- INDIRECT THROMBIN INHIBITORS:
Heparin
Low molecular weight heparins
Fondaparinux
Danaparoid

6. -INDANDIONE DERIVATIVE:
Phenindione
B) ORAL ANTICOAGULANTS:
- COUMARIN DERIVATIVES:
Bishydroxcoumarin (dicumarol)
Warfarin sodium
Acenocoumarol
Ethylbiscoumacetate
-DIRECT FACTOR Xa INHIBITORS:
Rivaroxaban
-ORAL DIRECT THROMBIN INHIBITOR:
Dabigatran etexilate

7. 2) USED IN VITRO:
A) HEPARIN:
B) CALCIUM COMPLEXING AGENTS:
Sodium citrate
Sodium oxalate
Sodium edetate

8. 1930s
Heparin
1950s 1990s 2002
1970s
Warfarin LMWHs Factor Xa
inhibitor
DTIs
Argatroban
Bivalirudin
Lepirudin
Iprivask
Fondaparinux
Enoxaparin
Dalteparin
Tinzaparin
1980s 2010-12
DTI and
Factor Xa
inhibitors
Dabigatran
Rivaroxaban
Apixaban
Developmental History –
Current FDA Approved Anticoagulants

9. HEPARIN
Heparin is a non-uniform mixture of straight chain mucopolysaccharides
with MW 10,000 to 20,000.
It contains polymers of two sulfated disaccharide units:
D-glucosamine-L-iduronic acid
D-glucosamine-D-glucuronic acid
It is present in all tissues containing mast cells; richest sources are lung,
liver and intestinal mucosa.

10. ANTICOAGULANT ACTION OF
HEPARIN
HEPARIN
Activates plasma ATIII
Heparin-AT III complex
Binds to clotting factors of intrinsic and common pathways
(Xa, IIa, IXa, XIa, XIIa and XIIIa) and inactivates them

11. OTHER ACTIONS OF HEPARIN
Heparin in higher doses inhibits platelet aggregation and prolongs
bleeding time.
Heparin in lower doses helps in lipaemia clearing
(lipo protein , hepatic lipases stimulants)

12. PHARMACOKINETICS
Heparin is not absorbed orally.
If Injected i.v. - acts instantaneously.
After s.c. injection anticoagulant effect develops after ~60 min.
Bioavailability of s.c. heparin is inconsistent.
Heparin does not cross blood-brain barrier or placenta (it is the
anticoagulant of choice during pregnancy).
It is metabolized in liver by heparinase.
Fragments are excreted in urine.

13. Heparin should not be mixed with penicillin, tetracyclines,
hydrocortisone in the same syringe or infusion bottle.
Heparinized blood is not suitable for blood counts (alters the
shape of RBCs and WBCs), fragility testing and complement
fixation tests.

15. ADVERSE EFFECTS
Bleeding due to overdose - most serious complication.
Thrombocytopenia - mild and transient.
Transient and reversible alopecia is infrequent. Serum transaminase
levels may rise.
Osteoporosis - long-term use of relatively high doses.
Hypersensitivity reactions – rare.

16. CONTRAINDICATIONS
Bleeding disorders, history of heparin induced thrombocytopenia.
Severe hypertension, threatened abortion, piles, g.i. ulcers..
lumbar puncture.
Chronic alcoholics, cirrhosis, renal failure.

17. Low molecular weight (LMW) heparins
Heparin has been fractionated into LMW forms (MW 3000–7000) by
different techniques.
LMWHs are defined as heparin salts having an average molecular
weight of less than 8000 Da.
These are obtained by various methods of fractionation or
depolymerisation of polymeric heparin.

18. MECHANISM OF ACTION
Selectively inhibit factor Xa with little effect on IIa.
Act only by inducing conformational change in AntiThrombine III
Hence LMW heparins have smaller effect on aPTT and whole
blood clotting time than unfractionated heparin (UFH)
Also, they have lesser antiplatelet action—less interference with
haemostasis.
Lower incidence of haemorrhagic complications compared to UFH
Elimination - primarily by renal excretion.

19. ADVANTAGES OF LMW HEPARIN
Better subcutaneous bioavailability (70–90%) compared to UFH
(20–30%)
Longer and more consistent t½(4–6 hours)
Since aPTT/clotting times are not prolonged, laboratory monitoring
is not needed.
Risk of osteoporosis after long term use is much less.

20. INDICATIONS
Prophylaxis of deep vein thrombosis and pulmonary
embolism in high-risk patients undergoing surgery.
Treatment of established deep vein thrombosis.
Unstable angina and MI: they have largely replaced
continuous infusion of UFH.
To maintain patency of cannulae and shunts in dialysis
patients.

21. A number of LMW heparins have been marketed-
Enoxaparin
Reviparin
Nadroparin
Dalteparin
Parnaparin
Ardeparin

22. FONDAPARINUX
The pentasaccharide with specific sequence that binds to AT III with
high affinity to selectively inactivate factor Xa without binding
thrombin (factor IIa), has been recently produced synthetically.
Bioavailability - If injected s.c. is 100%
Excreted unchanged by the kidney.

23. DIRECT THROMBIN INHIBITORS
Unlike heparin, these recently developed anticoagulants bind directly
to thrombin and inactivate it without the need to combine with and
activate ATIII.
Lepirudin
Bivalirudin
Argatroban

24. ORAL ANTICOAGULANTS
Act indirectly by interfering with the synthesis of vit K dependent
clotting factors in liver.
Apparently behave as competitive antagonists of vit K and lower the
plasma levels of functional clotting factors in a dose-dependent
manner.
they inhibit the enzyme vit K epoxide reductase (VKOR) and interfere
with regeneration of the active hydroquinone form of vit K which acts
as a cofactor for the enzyme γ-glutamyl carboxylase.
The half-life of warfarin is 36 to 42 hours

25. MECHANISM OF ACTION OF ORAL
ANTICOAGULANTS

26. DIRECT FACTOR XA INHIBITORS
Act rapidly without a lag time
Have short-lasting action.
Rivaroxaban

27. ORAL DIRECT THROMBIN INHIBITOR
Dabigatran etexilate
Reversibly blocks the catalytic site of thrombin and produces a rapid
(within 2 hours) anticoagulant action.
Oral bioavailability is low.
No laboratory monitoring is required.
The plasma t½ is 12–14 hours.
Duration of action 24 hours.

28. USES OF ANTICOAGULANTS
Deep vein thrombosis (DVT) and pulmonary embolism (PE)
Myocardial infarction (MI)
Unstable angina
Rheumatic heart disease; Atrial fibrillation(AF)
Cerebrovascular disease
Vascular surgery, prosthetic heart valves, retinal vessel thrombosis,
extracorporeal circulation, haemodialysis
Defibrination syndrome or ‘disseminated intravascular coagulation’

29. Aspirin (Acetylsalicylic Acid)
mechanism of action is the irreversible inhibition of the cyclooxygenase (COX) 1
and 2 enzymes.
The action of COX is necessary for the conversion of arachidonic acid to
prostaglandin (PG) H2.
The PGH2 is rapidly converted to several bioactive prostanoids, including
thromboxane A2, a potent vasoconstrictor, and an inductor of platelet
aggregation.
Despite the short half-life of aspirin (3 to 6 hours), its irreversible effects will last
for the complete lifetime of the platelet (8 to 9 days). After the interruption of
aspirin therapy, recovery of platelet function depends on its turnover
(approximately 10% per day)

30. Non-steroidal Anti-inflammatory Drugs
(NSAIDs)
These drugs act by the inhibition of COX enzymes, depending on the particular
drug. Some NSAIDs can selectively inhibit the COX 2 enzyme that mediates
pain and inflammation,
simultaneously limiting the undesirable effects of COX 1 inhibition.
The effect of NSAIDs on platelet function is considered a short-term effect that
normalizes within three days; nonetheless, this can vary between drugs in the
class.
For short-acting drugs like ibuprofen, diclofenac, and indomethacin, 50% of
platelet function is restored 6 hours after the last dose and normalized after 24
hours

31. Thienopyridines (Clopidogrel and
Prasugrel)
These are inhibitors of the adenosine diphosphate (ADP) receptor,
Physiologically, the union of ADP with its receptor increases levels of intracellular
calcium and activates platelet receptor that promotes the stabilization of the
platelet clot through fibrinogen bonds.
Clopidogrel and prasugrel are prodrugs in which active metabolites irreversibly
affect the platelet function in a time- and dose-dependent fashion.
A clopidogrel dose of 75 mg daily produces a 60% decrease of platelet function in
3 to 5 days; in contrast,
Due to the irreversible mechanism of action, it is recommended to interrupt these
drugs 5 to 7 days before non-cardiac elective surgery.

32. Non-thienopyridines (Ticagrelor and
Cangrelor)
Ticagrelor is a reversible, non-competitive ATP analog that binds to a G-protein in the
P2Y12 receptor, preventing its activation and signaling.
After a loading dose of ticagrelor, the maximum antiplatelet effect is achieved within 2
hours, plasma half-life is 8 to 12 hours, and steady-state concentration in 2 to 3 days.
Due to the reversible effect of ticagrelor on platelets, it is recommended to be
suspended 5 days before surgery.
On the other hand, cangrelor is a direct, reversible, and intravenously administered
drug that inhibits the P2Y12 receptor. Cangrelor can inhibit 95% to 100% of platelet
activity within the first two minutes of administration; the plasma half-life of cangrelor (3
to 6 minutes) allows recovery of 80% to 90% platelet function within 60 to 90 minutes
of discontinuing the intravenous infusion.

33. surgery in patient on anticoagulants
according to the American Society of Regional Anesthesia (ASRA) 2018 guidelines
and the American College of Surgeons 2018 guidelines.
During the preoperative period:
Discontinue warfarin five days before surgery.
Three days before surgery, start subcutaneous LMWH or unfractionated heparin
(UFH), depending on the renal function of the patient at therapeutic doses.
Two days before surgery assess INR, if greater than 1.5 vitamin K can be
administered at a dose of 1 to 2 mg.
Discontinue LMWH 24 hours before surgery or 4 to 6 hours before surgery if UFH.

34. During the postoperative period:
If the patient is tolerating oral intake, and there are no unexpected surgical issues
that would increase bleeding risk, restart warfarin 12 to 24 hours after surgery.
If the patient received preoperative bridging therapy (high thromboembolic risk) and
underwent a minor surgical procedure, resume LMWH or UFH 24 hours after
surgery.
If the patient underwent a major surgical procedure, resume LMWH or UFH 48 to 72
hours after surgery.
Always assess the bleeding risk and adequacy of homeostasis before the
resumption of LMWH or UFH

35. as a common recommendation among guidelines, DOACs should be
held 3 half-life times before low-risk procedures and 5 half-life times
before high-risk procedures.

36. How to Perform Emergency Reversal of
Anticoagulation
An urgent procedure is defined as one that can be delayed up to 24 hours, giving
time to the physician to conduct anticoagulation reversal based on repeated
coagulation tests.
On the other hand, the emergent scenario can be defined as one in which the
patient requires surgical intervention in less than 1 hour or is experiencing life-
threatening bleeding.
In emergent cases, the amount of time, number of coagulation tests that can be
performed, and opportunities to delay the procedure until the bleeding risk is lower
are limited.
Reversal of warfarin: For non-significant bleeding with alterations of the INR,
conservative strategies such as interruption of the drug and oral vitamin K are
suitable options.

37. in the emergent scenario, the reversal of warfarin anticoagulation is based on
prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP) administration
as follows:
INR 2-4: PCC 25 IU/kg IV
INR ≥4-6: PCC 35 IU/kg IV
INR >6: PCC 50 IU/kg IV
Vitamin K: 10 mg IV administered slowly
FFP: 10 to 20 ml/kg
Trauma patients: 1 gm of tranexamic acid can be used at arrival and repeat dose of 1
gm in 8 hours
PCC is commercially available as prothrombin complex concentrate both contain
heparin and are thus contraindicated in patients with a past medical history of heparin-

38. -THANK YOU