anticoagulation in orthopaedics

1. Anticoagulation in Orthopaedics
By
Ihab El-Desouky (M.D.)
Asst. Prof. Orthopaedics & Traumatology
Pelvis and Joints Reconstruction Unit
Kasr Al-Ainy School of Medicine
Cairo University

2. DVT & Anticoagulation in Orthopedics
Why : Prophylaxis against Deep Venous thrombosis
To avoid fatal Pulmonary Embolism (PE)
Without prophylaxis:--- Deep venous thrombosis (DVT)
Historic fatal PE
1- 2%
Current fatal PE
0.1-0.2%

3. DVT & Anticoagulation in Orthopedics
Pathogenesis for Deep Venous Thrombosis (DVT)
Rudolf Virchow Germany (1821-1902): HIS triad
All these---- activation of coagulation mechanism +
formation of blood clot+ propagation of the clot.

4. DVT & Anticoagulation in Orthopedics
Thrombotic Stimuli During Total Hip and Knee
Arthroplasty:
Venous Stasis: Tourniquet placement + immobility during
the postoperative period
Tissue Injury: Manipulation during preparation of the
femoral prosthesis releases tissue thrombo-plastin
and other thrombogenic molecules
Hypercoagulability: Thrombogenic stimuli + reduction in
antithrombin III and fibrinolysins due to blood loss by
bleeding.

5. DVT & Anticoagulation in Orthopedics
Risk Factors:
Primary Hypercoagulopathies
(inherited)
• Gene Mutation
• Factor V Leiden Mutation
• Antithrombin III Deficiency
• Protein C Deficiency
• Protein S Deficiency
• Activated Protein C Resistance

6. DVT & Anticoagulation in Orthopedics
Secondary factors (acquired)
• Malignancy
• Elevated Hormone Conditions
• Hormone Replacement .Oral Contraceptive therapy &Late Pregnancy
• Elevated Antiphospholipid Antibody Conditions
• Lupus
• History Of Thromboembolism
• Major surgery with tourniquet
• Obesity
• Aging
• CHF
• Varicose Veins
• Smoking
• General Anesthetics (Vs. Epidural And Spinal)
• Immobilization

7. DVT & Anticoagulation in Orthopedics
Diagnosis:
• DVT
– Leg swelling/erythema
– Leg pain
– Superficial venous
congestion
– Homan’s sign?
• PE
– Symptoms:
• Dyspnoea
• Tachypnea
• Tachycardia
• Pleuritic chest
pain
-ECG:
-Blood gases: PO2

8. DVT & Anticoagulation in Orthopedics
Diagnostic tools:
1-Clinical: Well’s clinical prediction guide:
High : Score 3 or more
Moderate : Score = 1 or 2
Low probability: Score 0

9. DVT & Anticoagulation in Orthopedics
2-Blood testing:
-D-dimer :degradation product of cross-linked fibrin of
the blood clot . Elevated levels of D-dimer in DVT.
Detection by:
1-ELISA
2- latex agglutination
3- blood agglutination test
False positive: pregnancy , acute trauma, myocardial
infarction, DIC

10. DVT & Anticoagulation in Orthopedics
3-Imaging:
DVT: Imaging
• Venography is gold
standard (direct
imaging)
• Non-invasive
– Venous Duplex
Ultrasound is 96%
sensitive, 98% specific
– plethysmography is 75%
sensitive, 90% specific
PE: Imaging
-Chest X-ray
-Nuclear medicine
ventilation-perfusion scan
(V/Q)
• Pulmonary angiography
• is gold standard
• Helical chest CT
• widely considered first
line imaging modality

11. DVT & Anticoagulation in Orthopedics
DVT: management
Prophylaxis: ANTI-COAGULATION
Treatment:
In-bedding for 10 days
• LMWH /12 h (5 ds with 3 days
overlap) followed by long
term Warfarin ( 3 months )
• Vena cava filter placement
indications
1-when anticoagulation is
contraindicated
2-Recurrent DVT despite
adequate anticoagulation
PE: management
ICU admission:
• O2
• continuous IV heparin
infusion followed by
warfarin therapy
– continuous IV heparin
infusion (7-10 days )+warfarin
therapy typically given for 3
months
• Thrombolytics; streptokinase
– in specific cases
(hypotensive)
– Surgery:Pulmonary
embolectomy

12. Anticoagulation in Orthopedics
Clot formation:
(Intrinsic pathway by damage of B.V. endothelium ).
( Extrinsic pathway by tissue trauma—thrombo-plastin)
+ protein C &S
(Extrinsic pathway)
Antithrombin III (AT) : is a small protein by liver inhibits several factors
thrombin (IIa) + IXa+ Xa

13. Anticoagulation in Orthopedics
How to prevent DVT:
1- Lower hypercoagulability: by anticoagulant & blood
loss.
2-Minimize tissue injury: shorter operation time & bone
and soft tissue manipulation.
3-Prevent stasis: mechanical measures &mobilization of
the limb and patient.

14. Anticoagulation in Orthopedics
Anticoagulation (AC)methods:
1-Mechanical (non-pharmacological) measures:
- Graduated Compression (elastic) Stockings (GCS).
- Intermittent Pneumatic Compression (IPC) devices.
- Venous Foot Pumps (VFP) + combined (IPC+VFP)
Action:IPC venous stasis- blood flow velocity+ circulating fibrinolysins.
Advantage: no monitoring, no bleeding risk, tolerated.
Disadvantage: patient dependant + not effective alone
Not in ischemia or neuropathy
Stratification: ( which Risk Group?)
Combined in high and highest risk groups.
Alone in high risk of bleeding (AC over-dose, hepatic, haemophilia)

15. Anticoagulation in Orthopedics
2-Pharmacological anticoagulants: (affect coagulation factors)
The evolution of anticoagulant therapy
UFH: unfractionated heparin; LMWH: low molecular weight heparin; VKA: vitamin K
antagonists
Parenteral Oral
-Heparins
(UFH, LMWH)
-VKA
-Thrombin
inhibitors
(Hirudin,
Bivalirudin)
-Thrombin
inhibitors
(Dabigatran)
- Factor Xa
inhibitor
Fondaparinux
-Factor Xa
inhibitors
(Rivaroxaban,
Apixaban,
Edoxaban)

16. Anticoagulation in Orthopedics(Parenteral)
1-Heparin: (father of parenteral AC)
History: 1916;McLean , USA,
started discovery from canine liver.
April 1937 (Unfractionated Heparin) UFH: 1st
safe injection in human.
Late 1980s: Low Molecular Weight heparin
(LMWH) derived from heparin.
Action: activates AT III
inhibits thrombin and Xa (equally).
(flooding of anticoagulation--- requires monitoring)
LMWH: short chains---mainly Xa+ thrombin

17. Anticoagulation in Orthopedics(Parenteral)
Advantages: UFH : anticoagulant & antithrombotic DVT by 60-75%
Disadvantages: of UFH
1- Bleeding with increased dose ( not suitable for high risk )
2-Heparin Induced Thrombocytopenia (HIT): 2-4% , antibody induced--- Thrombosis
(gangrene) and DIC. !!!! (HIT& Thrombosis)-ttt Hirudin analogue. (no platelet)
3- OSteoporosis: & spontaneous fracture (prolonged use, vertebrae, pregnant).
4- Monitoring & dose adjustment.
Route of administration: 5000 U /S.C (I.V.)/ 8 hours.
Monitoring: APTT N= 25-35 sec warning levels above 75 sec
Antidote: Bleeding: protamine sulphate (Protam): 1mg for 100 units slow IV /10 min
HIT&T: Bivalirudin (Angiomax)
Stratification: moderate risk group only (higher dose for high risk---complications)
Not recommended by AAOS

18. Anticoagulation in Orthopedics(Parenteral)
2-Low Molecular Weight Heparin (LMWH):
Family : Enoxaprin (Clexane), Nadroparin (Fraxiparine)
By depolymerization of UFH --- reduce chain length .
Advantages:
-Specific activatation of AT III on Xa mainly (+ thrombin less ).
-No prolonged APTT- no monitoring
-Better bio-avaibility and t ½ -- can given once.
-Renal & liver metabolism.
But: retroperitoneal hematoma + surgical site haemorrhage (1.7%)
(If given too early after operation before 1st clot)
Antidote: protamine sulphate or factor VII (r-VIIa)
Route of administration: Enoxaparin 40 mg/ once S.C. ( start 12-24h post-
operative
Stratification: moderate, high & highest –risk groups with dose
adjustment (according to B.W.)
Duration: up to 35 days.

19. Anticoagulation in Orthopedics(Parenteral)
3-Fondaparinux : (Arixtra 2.5 & 7.5mg) ( Year: 2002)
synthetic penta-saccharide similar to LMWH.
Activate AT III for Xa selectively.
(indirect Xa Inhibitior)
So:
-More powerful than enoxaparine.
-Longer t ½ ( up to 20 h)- once daily -No monitoring
BUT:
- Episodes of Major bleeding (2.7% vs 1.7%)+ no antidote ( ?? R
FVIIa)
-Renal metabolism only: so creatinine clearance (CrCl) should be >
30 ml/min.
Route of administration: 2.5 mg once S.C.
Stratification: high and highest- risk groups. Duration: 35 d.

20. Anticoagulation in Orthopedics(Parenteral)
4-Direct Thrombin Inhibitors:
1-Hirudin: extract of blood-sucking leeches(Hirudo medicinalis)
-Binds to thrombin directly --- inactivation.
-Recombinant hirudin (Thrombexx)
for S.C injection:15mg/ 12h/ max 12 d
-Renal excretion (not in renal ptn) + hypersensitivity.
-Bleeding episodes- no antidote.
No specific risk stratification by AAOS or ACCP.
2-Bivalirudin: (Angiomax) synthetic analogue
-with shorter half-life, less renal metabolism,
-and low immunogenicity
-IV for treating HIT+T

21. Anticoagulation in Orthopedics(Oral)
1-Warfarin: (the father of oral AC):
History: Great Depression in USA 1929:
Farmers fed cattle & sheep by
mouldy sweet clover hay bleeding and death.(sweet clover
disease)
In 1933 : research started in Wisconsin University, USA.
In late 1940s: was promoted as rodenticide
but research continued
In 1955 :USA president Eisenhower suffered MI ----
given Warfarin---started commercial promotion.
Action: Vitamin K- Antagonist (VKA) :
Inhibits Vit K reduction no formation of Vit K
dependant factors (II, VII, IX & X + protein C&S.)

22. Anticoagulation in Orthopedics (Oral)
1-Warfarin: (the father of oral AC):
Disadvantages : Slow action -Multiple interactions & Side effects.
-3 days to reach target ( target INR= 2.5)
-Numerous drug interaction strict monitoring ( about 800 drugs
including aspirin, diuretics, rifampicin , ------).
-Food interactions: e.g.: food rich in Vit K ( spinach) + alcohol.
-Genetic variation : (two types); so affect response.
- Side effects: Haemorrhage ( 3-5 %) and Many others.
However: reduces total DVT by 60-70% and Oral.

23. Anticoagulation in Orthopedics (Oral)
1-Warfarin: (the father of oral AC):
Monitoring: Prothrombin time (PT) + International Normalized Ratio --
INR=(PT patient/PT normal)ISI ratio(without unit) to allow comparison
from lab. to another
-N= 0.8-1.2 Target= 2-3 (2.5)
Antidote: Vit. K : IV slow action (3 days for reversal),
Fresh Frozen Plasma: immediate action
Route of administration: oral 5 mg night before surgery---3 days---
INR--- adjust dose 2-10 mg once oral
Stratification: highest risk groups.( dose adjustment and many
interactions)
Duration: up to 35 d.

24. Anticoagulation in Orthopedics (Oral)
2- NOVEL ORAL Anti-Coagulants : (NOACs):
No frequent monitoring- less inter and intra-patient variability.
1- Direct Thrombin inhibitor: Dabigatran (Pradaxa) (year 2010)
Action: inhibit thrombin action directly (IIa).
T ½ : 16 h.
Metabolism: 80 % renal ( +liver) so not in Renal ptn
Efficacy: similar to enoxaparin.
Disadvantage: GIT upsets, bleeding (similar to enoxaparin 1.7%) and
Not in renal patient ( not if CrCl < 30ml/min .
Monitoring: no
Antidote: Idarucizumab (Praxbind)(2015)
Route of Administration: Oral : ½ dose (110mg) 4h post-operative
then 220mg (two cap) once daily ( lower dose if CrCl 30 -60ml/min).

25. Anticoagulation in Orthopedics
Risk Stratification: high and highest risk groups
Duration: up to 35 days ( TKR --- 2 weeks)
(THR--- 5 weeks)

26. Anticoagulation in Orthopedics (Oral)
2- Direct factor Xa inhibitors:
1-Rivaroxaban (Year 2011)(Xarelto , Andorivaban, Vaxato)
2-Apixaban(Year 2012) (Eliquis)
• Mechanism: direct Xa inhibitor
• Metabolism: Rivaroxaban 1/3 by renal
Apixaban ¼ by renal
• Disadvantage: bleeding ( Rivaroxaban similar to enoxaparin, Apixaban less).
• Antidote :no current antidote (Prothrombin Complex Concentrates (PCCs),
trilas

27. Anticoagulation in Orthopedics (Oral)
Route of administration: Oral Rivaroxaban 10 mg / once. 8 h post-
operative.
Apixaban: 2.5 mg / twice . 12 h post-operative
Risk Stratification: High and highest risk groups.
Duration: up to 35 days ( TKeeR --- 2 weeks) (THipR--- 5 weeks)
The evolution of anticoagulant therapy.
Year Anticoagulant drug
1940s Unfractionated heparin
1950s Warfarin
1980s Low molecular weight heparins
1990s Parenteral thrombin inh(Hirudin)
2002 Fondaparinux
2010 Dabigatran
2011 Rivaroxaban
2012 Apixaban
2014 Edoxaban

28. Anticoagulation in Orthopedics
When to start Anticoagulation:
Wait till primary haemostasis (surgical site) developed
then start AC;

29. Anticoagulation in Orthopedics
Risk Stratifications:
-Inclusion of the patient in a specific risk group that identifies the AC method and for
how long.
-Guidelines of AAOS (American academy of Orthopaedic surgeons) 2008 & ACCP
(American College of Chest Physicians) 2012.
-Scoring system:

30. Anticoagulation in Orthopedics
Risk Stratifications:
Risk Factor Score 0-1 2 3-4 5+
DVT Incidence 2% 10-20% 20-40% 40-80%
RISK LEVEL LOW MODERATE HIGH HIGHEST

31. Anticoagulation in Orthopedics
DVT prophylaxis according Risk Stratifications: (AAOS)
Low Risk: (e.g.: knee arthroscopy)
No, early ambulation,
only if other risk (previous DVT) LMWH .
Moderate Risk( e.g. distal LL fractures as tibia).
No, early ambulation,
only if other risk (as previous DVT) LMWH & IPC.
High Risk( major trauma e.g. long bone femur, multiple trauma &
spine).
LMWH 12 h after operation ( 40 mg once daily) &IPC.
Other ACs as highest risk group (no VKA).
Bleeding risk: IPC & VFoot Pump then switch to LMWH

32. Anticoagulation in Orthopedics
DVT prophylaxis according Risk Stratifications:
4-Highest risk: (THR, TKR, HFS, Pelvic fracture, spine fracture with
paralysis)
1-LMWH: 40mg once, 12 h post-operative. S.C. OR
2-Fondaparinux: 2.5mg once 8h post-operative.(not in renal) S.C.
OR
3-VKA (warfarin): adjusted- dose, pre-operatively , 2-10 mg once
oral target INR 2.5. OR
4-Direct oral Thrombin Inhibitor: Dabigatran: ½ dose (110) 4 h post-
operative then 220 once oral ( not in renal). OR
5-Direct oral Xa inhibitors: Rivaroxaban: 10mg once / 8 h post-
operative OR Apixaban: 2.5mg twice/ 12 h post-
operative.
IPC / GCS can be used.

33. Anticoagulation in Orthopedics
Duration of DVT prophylaxis:
THR: 35 days (5 weeks) TKR 14 days (2 weeks)
Rest of groups : 14 d
If trauma patients + delayed surgery : start pre-operative
anticoagulation –stop night of surgery– continue 12 h post-op.)
Inferior Vena Caval Filter.
-Not recommended as
primary DVT prophylaxis.
-In complex fractures (pelvis) to prevent PE if:
1-Contraindication to AC OR
2-Emergency situations that needs surgery with possible DVT presence.
- Retrievable (removable) filters then continue AC.

34. Anticoagulation in Orthopedics
Anti-platelets: (e.g. Aspirin):
. Recent AAOS and ACCP guidelines added support in
patients without significant risk of VTE (as previous DVT)
• The SIGN guidelines (2010, updated 2015) other agents
are more effective than aspirin - not recommended as
the sole agent for VTE prophylaxis in orthopaedic
patients
• J. of Arthroplasty 2016: the evidence for Aspirin use is
limited by the low quality of studies and variations in
dose.
J Arthroplasty. 2016 Nov;31(11):2608-2616. doi: 10.1016/j.arth.2016.04.004. Epub 2016 Apr 13.
Aspirin as Thromboprophylaxis in Hip and Knee Arthroplasty: A Systematic Review and Meta-Analysis.
An VV1, Phan K1, Levy YD2, Bruce WJ3.

35. Take Home Message
-Anticoagulation prophylaxis after orthopaedic surgery is of
utmost importance to prevent Fatal PE.
-Historic Fatal PE was 1-2 % and current PE is 0.1-0.2 %.
-Evolution of AC therapy is a continuous process to take
more benefits with less complications and a wide range.
-Appropriate drug, timing and duration of AC should be
considered for each case according to the Risk Stratification.
-LMWHs are appropriate for All risk groups while antiplatelet and
UFH are Not recommended.
Thank you.