Anticoagulation 101

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