Lab control of anticoagulant and therapy

Dr. Kashmiri Lal Sharma

Hemostasis
Hemostasis blood in fluid state Blood vessel wall Platelets Coagulation cascade

Antithrombotic Agents
Anticoagulants: prevent clot formation and extension Antiplatelet drugs: interfere with platelet activity Thrombolytic agents: dissolve existing thrombi

The Chemical Process of Clotting

HMWK
XII XIIa XIa IXa VIIIa Xa V IIa VIIa TF VII
Desai, U. R., VCU (2005)

XI IX X

Note: IXa and VIIIa work together to convert X into Xa. Xa and Va work together to convert II into IIa. IIa works on a number of steps. HMWK and TF are initiation points CLOT is the end point

VIII

IIa

II Va Xa IIa X Fibrin monomers XIIIa CLOT

Fibrinogen IIa

XIII

Warfarin: Indications
Prophylaxis and/or treatment of Venous thrombosis and its extension Pulmonary embolism

Post MI To reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization Prevention and treatment of cardiac embolism

Warfarin
Major Adverse effect is Hemorrhage Factors that may influence bleeding risk Intensity of anticoagulation Concomitant clinical disorders Concomitant use of other medications Quality of management

Special Considerations in the elderly

Increased age associated with increased sensitivity at usual doses Comorbidity Increased drug interactions

 Elderly patients need less warfarin Age 20 needs 10-15 mg Age 40 needs 5-10 mg Age 70 needs 2.5 mg Always begin warfarin at the expected maintenance dose ( 2-5 mg), avoid large loading doses

Prothrombin Time (PT)

Proliferation of thromboplastin reagents with widely varying sensitivities to reduced levels of vitamin K dependent clotting factors has occurred Problem addressed by use of INR (International Normalized Ratio)

International Normalized Ratio

A mathematical correction (of the PT ratio) for differences in the sensitivity of thromboplastin reagents Relies upon reference thromboplastins with known sensitivity to antithrombotic effects of oral anticoagulants INR is the PT ratio one would have obtained if the reference thromboplastin had been used Allows for comparison of results between labs and standardizes reporting of the prothrombin time
J Clin Path 1985; 38:133-134; WHO Tech Rep Ser. 7. 983.

INR Equation
Patients PT in Seconds ISI INR = Mean Normal PT in Seconds
INR = International Normalized Ratio ISI = International Sensitivity Index

Blood from a single patient

How Different Thromboplastins Influence the PT Ratio and INR

Thromboplastin Reagent

Patients Mean PT Normal

(Seconds)

(Seconds)

PTR 1.3

ISI

INR

16 18 21 24 38

12

B C D
E

12 13 11
14.5

1.5 1.6 2.2

2.6

Blood from a single patient

How Different Thromboplastins Influence the PT Ratio and INR

Thromboplastin reagent

Patients Mean PT Normal

(Seconds)

(Seconds)

PTR 1.3

ISI 3.2

INR 2.6

16 18 21 24 38

12

B C D
E

12 13 11
14.5

1.5 1.6 2.2

2.6

2.4 2.0 1.2

1.0

2.6 2.6 2.6

2.6

Potential Problems with the INR

Limitations Unreliable during induction
Loss of accuracy with high ISI thromboplastins Solutions Use thromboplastin reagents with low ISI values (less than 1.5) Use thromboplastin reagents with low ISI values

Warfarin: Dosing Information

Individualize dose according to patient response (as indicated by INR) Use of large loading dose not recommended May increase hemorrhagic complications Does not offer more rapid protection Low initiation doses are recommended for elderly/frail/liver-diseased/malnourished patients

Conversion from Heparin to Warfarin

May begin concomitantly with heparin therapy Heparin should be continued for a minimum of four days Time to peak antithrombotic effect of warfarin is delayed 96 hours When INR reaches desired therapeutic range, discontinue heparin (after a minimum of four days)

Warfarin: Dosing & Monitoring

Start low Initiate 5 mg daily Educate patient Stabilize Titrate to appropriate INR Monitor INR frequently (daily then weekly) Adjust as necessary Monitor INR regularly (every 14 weeks) and adjust

Signs of Warfarin Overdosage

Any unusual bleeding: Blood in stools or urine Excessive menstrual bleeding Bruising Excessive nose bleeds/bleeding gums Persistent oozing from superficial injuries Bleeding from tumor, ulcer, or other lesion

Warfarin: Current Indications/Intensity

Indication INR Range Target
2.03.0 2.5 Prophylaxis of venous thrombosis (high-risk surgery) Treatment of venous thrombosis Treatment of PE Prevention of systemic embolism Tissue heart valves AMI (to prevent systemic embolism) Valvular heart disease Atrial fibrillation

Mechanical prosthetic valves (high risk) 2.53.5 Certain patients with thrombosis and the antiphospholipid syndrome AMI (to prevent recurrent AMI) Bileaflet mechanical valve in aortic position 2.03.0

3.0

2.5

Patient education & information

Effective Patient Education

Teach basic concepts of safe, effective anticoagulation Discuss importance of regular INR monitoring Counsel on use of other medications, alcohol Develop creative strategies for improving compliance

PATIENT EDUCATION
Inform patients about the mechanism of action of warfarin and caution them about diet and drug interactions Advise patients to avoid alcohol Instruct patients to report any drug changes to the physician monitoring the INR Counsel women to avoid pregnancy while on warfarin

LAB MONITORING OF HEPARIN THERAPY

Essential because of complicated pharmacokinetics. Response is affected by body weight event of thrombosis heparin binding to plasma and endothelial cell proteins

 Monitoring is performed to achieve a targeted therapeutic range 1.5 to 2.5 times the mean lab control aPTT value Plasma heparin level of 0.2-0.4 u/m1 (Protamine titration) or 0.35 to 0.7 u/m1 (antifactor Xa methods) Low-does prophylactic therapy with either UFH or LMWH is given by subcutaneous injection and usually not monitored except in some circumstances like pregnancy and renal failure

Tests used
Test Advantages Whole blood Simple clotting inexpensive time No equipment needed APTT Simple many tests can be carried out in parallel Simple many test can be carried out in parallel Sensitive to all concentrations Sensitive to all concentrations and to LMWT heparin

TT

Protamine neutralization Anti-Xa assays

ACTIVATED PARTIAL THROMBOPLASTIN TIME

The test measures the clotting time of plasma after activation of contact factors but without added tissue thromboplastin indicates overall efficiency of intrinsic pathway Very sensitive to heparin but few short comings Different aPTT reagents have different sensitivities to heparin

HEPARIN MONITORING AT BEDSIDE

Whole blood activated clotting time (ACT) Determined by using clotting cascade activators such as kaolin and end - pt detection by optical or electromagnetic method. Not specific affected by factors like hypothermia, hemodilution and platelet dysfunction.

Indications for LMWH monitoring

Renal Dysfunction Body Wt < 60 Kg Body Wt > 100 Kg High Risk patients (Recent bleeding) Consider it in elderly patients above age 70 yrs Pregnancy

Failing Anticoagulants
Things to Consider Short duration of antithrombotic Rx Heparin induced thrombocytopenia Poor control of INR Drug interactions Non-compliance

Reversal of anticoagulants
Unfractionated heparin Protamine 1 mg per 100 units, risks bradycardia and hypotension Allergic reactions due to previous exposure to protamine containing insulin, vasectomy and fish allergies LMWH Protamine less effective due to shorter heparin chains Normal dosing acutely reverses 42% of factor Xa activity and 92% of anti-factor IIa actvity

Warfarin Oral vitamin K reduces INR in 24 hrs Low dose IV doses effective (0.5 to 2.5mg), higher doses (>10mg) associated with temporary warfarin resistance on reintroduction

Warfarin INR <5 and no bleeding => lowering or omitting a dose INR >5 and <9 and no bleeding => withhold 1 to 2 doses +/- 1 to 2.5mg of oral vitamin K INR >9 3 to 5mg of oral vitamin K For serious bleeding => FFP and slow IV administration of 10mg vitamin K In preparation for surgery, most patients require 4 days to reach an INR <1.5 after discontinuation of therapy

Thanks