Anticoagulation 101Neil A. Lachant, MD
Chief, Section of Hematology
Director, Thrombosis Program
Cooper Cancer Institute
Professor of Medicine
UMDNJ Robert Wood Johnson Medical School
Venous ThrombosisMagnitude of the Problem
• No national data• Incidence
– 1- 2/1,000– 300,000 - 600,000 new cases per year– increasing as population ages
• life expectancy 78 years
Incidence of VTE
Age Incidence
<10 1:100,000
20 1:10,000
50 1:1,000
80 1:100
Manifestations
• 2/3 DVT– 50- 80% post-phlebitic syndrome
• 1/3 pulmonary emboli– 30% mortality– 30,000 – 60,000 deaths per year
A 22 yo female presents with an iliofemoral DVT. Her aPTT is 37 sec (nl <32) and she is found to have a lupus anticoagulant. She weighs 55 kg and her creatinine is 0.5 mg/dl. She is started on weight -based UFH. Her aPTT at 4 hrs is 123 s. She could be anticoagulated by all of the following EXCEPT:
1. Decrease UFH with aPTT goal of 1.5-2.5 x her baseline
2. UFH monitoring heparin level
3. UFH correlating heparin level with the aPTT
4. LMWH without monitoring
5. Fondaparinux without monitoring
A 22 yo female presents with an iliofemoral DVT. Her aPTT is 37 sec (nl <32) and she is found to have a lupus anticoagulant. She weighs 55 kg and her creatinine is 0.5 mg/dl. She is started on weight -based UFH. Her aPTT at 4 hrs is 123 s. She could be anticoagulated by all of the following EXCEPT:
1. Decrease UFH with aPTT goal of 1.5-2.5 x her baseline
2. UFH monitoring heparin level
3. UFH correlating heparin level with the aPTT
4. LMWH without monitoring
5. Fondaparinux without monitoring
Heparin Therapy in APLS
• Lupus anticoagulant with prolonged baseline aPTT
– use LMWH– use standard weight-based unfractionated heparin
dosing
1. correlate aPTT with heparin level (3-4 points)
use aPTT range that corresponds to therapeutic heparin level (0.3 –
0.7 iu/ml)
2. follow thrombin time if standardized in your lab
0
20
40
60
80
100
120
140
0 0.2 0.4 0.6 0.8
Heparin Level (u/ml)
aPT
T
Normal
Patient
• A 34 year old African American male presents with a femoral DVT. He is given a 5000 u bolus of UFH and is started on a heparin drip at 1000 u/hr. The aPTT remains subtheraputic despite an increase to 1800 u/hr. A hematology consult is obtained on the 3rd hospital day for “inability to be anticoagulated”.
• What is the most appropriate goal for UFH:
1. aPTT ratio 1.5 - 2.5 x baseline
2. aPTT that correlates with heparin level of 0.3 - 0.7 u/ml
3. Whatever the lab computer says the therapeutic range is
• What is the most appropriate goal for UFH:
1. aPTT ratio 1.5 - 2.5
2. aPTT that correlates with heparin level of 0.3 - 0.7 u/ml
3. Whatever the lab computer says the therapeutic range is
aPTT
20 40 60 80 100 120 140 160 180 200
aP
TT
Ra
tio
1
2
3
4
5
6
Effect of Thromboplastin on aPTT Ranges
(Anti-Xa 0.3 - 0.7 IU/ml)
aPTT
20 40 60 80 100 120 140 160 180 200
aP
TT
Ra
tio
1
2
3
4
5
6
Effect of Thromboplastin on aPTT Ranges
(Anti-Xa 0.3 - 0.7 IU/ml)
• Review of the patients records shows that he weighs 150 kg. His current aPTT is 38 sec (normal < 37.1) with an infusion rate of 1800 u/hr. The most appropriate rate for the UFH infusion is:
1. 2700 u/hr (18 u/kg/hr)
2. 2000 u/hr (18 u/kg/hr capped for patient size)
3. Continue at 1800 u/hr
4. Switch to LMWH because UFH doses above 2000 u/hr are too dangerous to use
• Review of the patients records shows that he weighs 150 kg. His current aPTT is 38 sec (normal < 37.1) with an infusion rate of 1800 u/hr. The most appropriate rate for the UFH infusion is:
1. 2700 u/hr (18 u/kg/hr)
2. 2000 u/hr (18 u/kg/hr capped for patient size)
3. Continue at 1800 u/hr
4. Switch to LMWH because UFH doses above 2000 u/hr are too dangerous to use.
UFH Dosing
Anti-Xa APTT
Initial dose 80 u/kg bolus, then 18 u/kg/hr
< 0.15 80 u/kg bolus, increase 4 u/kg/hr
0.15 – 0.29 40 u/kg bolus, increase 2 u/kg/hr
0.30 – 0.70 No change
0.71 – 0.85 Decrease infusion by 2 u/kg/hr
> 0.85 Hold 1 hr, decrease infusion by 3 u/kg/hr
Adopted from Raschke Arch Int Med 156:1645, 1996
Utilization management is pushing for discharge, but his INR is only 1.6. The most appropriate recommendation for the use of enoxaparin would be:
1. 150 mg (1 mg/kg) sc q 12 hr
2. 150 mg sc q 12 hr and check a heparin level immediately before the third dose
3. 150 mg sc q 12 hr and check a heparin level 3.5 - 4 hours after the third dose
4. 225 mg (1.5 mg/kg) sc q 24 hr
5. Enoxaparin contraindicated in a patient this large
Utilization management is pushing for discharge, but his INR is only 1.6. The most appropriate recommendation for the use of enoxaparin would be:
1. 150 mg (1 mg/kg) sc q 12 hr
2. 150 mg sc q 12 hr and check a heparin level immediately before the third dose
3. 150 mg sc q 12 hr and check a heparin level 3.5 - 4 hours after the third dose
4. 225 mg (1.5 mg/kg) sc q 24 hr
5. Enoxaparin contraindicated in a patient this large
Kinetics of LMWH
• Different for each LMH
• Doses not interchangable
Low Molecular Weight Heparin Dosing
Prophylactic
Therapeutic
Enoxaparin 40 mg q 24 h 1 mg/kg q12 h, or
1.5 mg/kg q 24 h Daltaparin 2,500 or 5,000 u
q 24 h
200 u/kg q 24 h
Tinzaparin 175u/kg q 24 h
LMWH in Obesity
• Relationship of intravascular volume and TBW is not linear– adipose tissue has a relative decrease in
plasma volume compared to muscle– could lead to overdosing
Weight in LMWH Studies
Enoxaparin <144 kg
Daltaparin <190 kg
Tinzaparin <165 kg
Actual weight dosed anti-Xa activity is not significantly increased in obesity
Recommendations For the Use of LMWH in Obesity
• Patient should receive LMWH dose based on actual body weight– if < 150 kg,
• monitoring not necessary on a routine basis
– if > 150 kg, • check heparin level 3.5 - 4 hrs after 3rd or
4th dose• dose reduce if > 1.0 IU/ml
• A 24 yo dialysis dependant female is paraplegic. She receives enoxaparin 1 mg/kg q 12h for an acute DVT. One week later in rehab, she develops pain in her right shoulder. She is brought to the emergency room during the night with a 20 cm hematoma in her right supraclavicular fossa. What is her correct enoxaparin dose?
A. 1 mg/kg q 12h
B. 1 mg/kg qd
C. Enoxaparin contraindicated with ESRD
• A 24 yo dialysis dependant female is paraplegic. She enoxaparin 1 mg/kg q 12h for an acute DVT. One week later in rehab, she develops pain in her right shoulder. She is brought to the emergency room during the night with a 20 cm hematoma in her right supraclavicular fossa. What is her correct enoxaparin dose?
A. 1 mg/kg q 12h
B. 1 mg/kg qd
C. Enoxaparin contraindicated with ESRD
LMWHDosing in Renal Dysfunction
• LMWH accumulates as Ccr decreases– cutoff point varies between different LMWHs
– Ccr 30 - 50
• monitor heparin level if concern about dosing or bleeding
– Ccr < 30
• dose reduce
• monitor heparin level
– Ccr < 10
• do not use LMWH under any circumstances
Enoxaparin Dosing with Renal Dysfunction
Indication
Ccr > 30 ml/min
Ccr 10 - 30 ml/min
Abdominal Surgery Prophylaxis
40 mg qd 30 mg qd
Medical Prophylaxis 40 mg qd 30 mg qd
Orthopedic Prophylaxis 30 mg q 12h 30 mg qd
DVT and/or PE 1 mg/kg q 12h 1 mg/kg qd
• A 24 year old Hispanic female presents to her local hospital with left calf pain. Duplex shows a popliteal DVT. Therapy with UFH is initiated on Saturday. She is discharged on Sunday. Her only anticoagulation is 12 mg warfarin which she is told to start at 6 PM that night. She presents to Cooper Hospital on Monday evening with a leg that is painful and swollen to the groin. Duplex shows a DVT extending to the iliac vein.
• Which of the following statements about anticoagulation after VTE is/are true?1. Warfarin should only be given simultaneously
with a heparin, DTI or other rapid acting anticoagulant
2. Warfarin should be started at a dose of 5 - 7.5 mg 3. Warfarin should be overlapped with heparin for a
minimum of 5 days (no matter what the INR is)4. Heparin should be stopped when the INR > 2.0
for 2 days or INR > 2.5 5. All of the above
• Which of the following statements about anticoagulation after VTE is/are true?1. Warfarin should only be given simultaneously
with a heparin, DTI or other rapid acting anticoagulant
2. Warfarin should be started at a dose of 5 - 7.5 mg3. Warfarin should be overlapped with heparin for a
minimum of 5 days (no matter what the INR is)4. Heparin should be stopped when the INR > 2.0
for 2 days or INR > 2.5 5. All of the above
A 60 year old female is taking a stable dose of coumadin as prophylaxis for atrial fibrillation (INR 2.6). She develops a UTI and is treated with bactrim. Two weeks later her INR is 6.9. She has no clinical bleeding. Her coumadin is held. The most appropriate adjunctive therapy would be:
A. Transfuse 4-6 units FFP
B. Transfuse 15 bags cryoprecipitate
C. Vitamin K 0.5 mg sc x 1
D. Vitamin K 10 mg sc x 1
E. Vitamin K 10 mg sc x 3d
F. Vitamin K 2.5 mg po x 1
G. No additional therapy is needed
A 60 year old female is taking a stable dose of coumadin as prophylaxis for atrial fibrillation (INR 2.6). She develops a UTI and is treated with bactrim. Two weeks later her INR is 6.9. She has no clinical bleeding. Her coumadin is held. The most appropriate adjunctive therapy would be:
A. Transfuse 4-6 units FFP
B. Transfuse 15 bags cryoprecipitate
C. Vitamin K 0.5 mg sc x 1
D. Vitamin K 10 mg sc x 1
E. Vitamin K 10 mg sc x 3d
F. Vitamin K 2.5 mg po x 1
G. No additional therapy is needed
Reversal of Warfarin
• INR < 5.0, no bleeding– lower dose or – omit dose, restart at lower dose
Chest June, 2008
Reversal of Warfarin
• INR > 5.0 but < 9.0, no significant bleeding– omit 1 or 2 doses and restart at lower dose, or– omit dose, give vitamin k 1-2.5 mg po, or– for rapid reversal (i.e., surgery) 3 - 5 mg po
(INR should decrease in 24 hr)• can repeat vitamin k 1-2 mg po if goal not
reached
Reversal of Warfarin
• INR > 9.0, no significant bleeding– hold warfarin– give vitamin K 2.5 - 5 mg po (INR should be
significantly reduced in 24 - 48 hrs)– additional vitamin k po if needed– resume warfarin when INR therapeutic
Reversal of Warfarin
• Any INR > 3.0, serious bleeding– hold warfarin– vitamin k 10 mg slow iv infusion– repeat every 12 hours as needed– FFP, r-VIIa or prothrombin complex depending
upon urgency of the situation
Reversal of Warfarin
• Any INR > 3.0, life threatening bleeding– hold warfarin– fresh frozen plasma, r-VIIa or prothrombin
complex– vitamin k 10 mg slow iv infusion
Warfarin Pearls
• Coumadin if possible– If generic, keep track of brands
• Dose adjustment– Think in terms of a week– New warfarin dose = current dose x goal INR
current INR– New dose = 35 mg x 2.5/5.0– New dose = 17.5 mg/week = 2.5 mg/day
IVC FilterIndications
• Recent proximal DVT, and– Contraindication to anticoagulation
• current or recent active GI bleed • intracranial bleed in last 5 days• recent neurologic or ophthalmologic surgery• cerebral metasteses at risk for bleeding
– seminoma, melanoma, renal cell, choriocarcinoma
• planned major surgery in next 4 weeks• severe, prolonged thrombocytopenia
• Recurrent pulmonary emboli while fully anticoagulated
New Anticoagulants
• Pentasaccharide– Fondaprinux (Arixtra)
• Oral IIa inhibitors– ximelagatran
• Oral Xa-inhibitors
Fondaparinux (Arixtra)
Theoretical Models for Differential Effects of Heparin and LMWH on Thrombin and
Factor Xa
Fondaparinux: 5 Saccharide Units
Fondaparinux
XaATIIaAT55
Binds to AT but not to Thrombin
Binds to AT
New Anticoagulants
• Fondaparinux (Arixtra)– Synthetic pentasaccharide– Selective anti-Xa inhibitor
• no anti-IIa activity• PT or PTT are insensitive
– Renal excretion– T1/2 17 – 20 hrs– Does not bind PF4
• One reported case of HIT
• FDA Approved– hip and knee surgery prophylaxis– treatment of DVT– treatment of PE when started in hospital– surgical DVT prophylaxis
• Fondaparinux dosing for DVT or PE– < 50 kg 5 mg qd sc– 50 – 100 kg 7.5 mg qd sc– >100 kg 10 mg qd sc
• Dose modification– Ccr 30 – 50, use with caution– Ccr < 30, contraindicated
• Because of long half-life, anticoagulant effect may last for 2 – 4 days after stopping fondaparinux with normal renal function
• Anti-Xa activity can be measured– ? <0.3 u/ml safe
• R-VIIa if severe bleeding