Coagulation Studies

Walter Eisenhauer

Basic Physiology

  Homeostasis Hemostasis     All bleeding eventually stops !

Complex mechanism with various pathways and steps Defect at any step can cause problems: Two major issues  Bleed to much     Platelet disorders Calcium Disorders Vitamin K dependent Factor Disorders (intrinsic pathway) Factor deficiencies- Von Willibrands, Factor 8 hemophilia etc  Clot to easily   Protein C or S deficiency Antithrombin III

Clotting Physiology

 Pathways used to be thought of a separate and distinct-now recognized as interdependent  Clotting Cascade

Physiologic Effects of Vitamin K

 Vitamin K serves as an essential cofactor for a carboxylase that catalyzes carboxylation of glutamic acid residues on vitamin K dependent proteins. The key vitamin K dependent proteins include: 

Coagulation proteins

: factors II (prothrombin), VII, IX and X 

Anticoagulation proteins

: proteins C, S and Z

Clotting Times

Table 1 Coagulation

in vitro

Whole blood Whole blood + EDTA or citrate Citrated platelet-poor plasma + Ca ++ Citrated platelet-poor plasma + PL + Ca ++ Citrated platelet-poor plasma + kaolin + PL + Ca ++ Citrated platelet-poor plasma + thromboplastin + Ca ++

Clotting time

4-8 min infinite 2-4 min 60-85 sec 21-32 sec (aPTT) 11-12 sec (PT)

Tests used to assess clotting

  Bleeding Time  Assess entire cascade from platelet aggregation to Fibrin Formation Platelet Count     Only measures number (Quantitative) not function (Qualitative) < 5,000 risk for spontaneous intracranial Hemorrhage < 30,000 risk for bleeding with minor trauma < 50,000 risk for hemorrhage perioperatively

Tests used to assess clotting

 Prothrombin Time  Used to assess Extrinsic Pathway  Used to monitor Coumadin Dosage  Normal range 12-15 seconds  Must be used with INR for Coumadin Dosing to “Standardize Test”

Tests used to assess clotting

 Activated Partial Thromboplastin Time  Used to evaluate intrinsic Pathway  Used to monitor Heparin Dosage  Normal 21-32 seconds

    

aPTT

Add 2 parts patient’s platelet-poor plasma, 1 part of combination of phospholipids & negatively charged surface active agent; then add calcium & measure time to clot.

Measures intrinsic pathway Used to monitor

Heparin Dosage

Sensitive to upper factors (XII, XI,) more than lower factors Unlike bleeding time, these tests are sensitive to bleeding problems in the haemostatic range

PT/INR

     The

prothrombin time

(

PT

) and its derived measures of

prothrombin ratio

(

PR

) and

international normalized ratio

of the

extrinsic pathway

(

INR

) are measures of coagulation They are used to determine the clotting tendency of blood, in the measure of

warfarin (Coumadin)

dosage, liver damage and vitamin K status. The reference range for prothrombin time is usually around 12-15 seconds The normal range for the INR is 0.8-1.2. PT measures factors II, V, VII, X and fibrinogen.

Anticoagulation Therapy

   

Heparin

Mechanism of action

Heparin is a naturally occurring anticoagulant produced by basophils and mast cells.

Heparin binds to the enzyme inhibitor antithrombin III (AT-III) causing a conformational change which results in its active site being exposed. The activated AT-III then inactivates thrombin and other proteases involved in blood clotting, most notably factor Xa. The rate of inactivation of these proteases by AT-III increases 1000-fold due to the binding of heparin

Heparin Indications

         Venous thrombosis Pulmonary embolism Mural thrombus after myocardial infarction Post thrombolytic coronary rethrombosis Unstable angina Acute myocardial infarction Additive effectiveness when heparin is combined with aspirin is uncertain. Additive effectiveness when heparin is used with streptokinase has not been demonstrated.

Heparin is recommended for patients treated with PTA

Heparin

  Dosing ½ life very short (30 minutes)  Administered IV or Subcutaneously

NOT IM

 Administer 5,000 iu IV then titrate to desired effect via IV infusion  Use ~32,000 units per 24 hours to achieve PTT of 1.5-2.5 times normal lab reference

Low Molecular Weight Heparin

 Binds less avidly to heparin binding proteins  More free drug to achieve therapeutic effect  May be superior to unfractionated drugs in many circumstances  Longer half life allows for Q 12-24 hour dosing

Low Molecular Weight Heparin

 PTT not good for monitoring must monitor factor Xa level  100mg/kg/24 hours  No concurrent ASA use  Can accumulate in renal failure patients

Coumadin

 Warfarin is taken by mouth to inhibit vitamin K. This vitamin is essential for effective production of clotting factors II, VII, IX, X, and anticoagulant proteins C&S. Warfarin is given once daily. It is monitored by the prothrombin time and the international normalized ratio (INR).

 Warfarin is a narrow therapeutic index drug (NTI). When the INR falls below 2.0 thrombosis risk increases and when the INR rises above 4.0 serious bleeding risk increases.

Coumadin

 Therapeutic recommendations for warfarin

Disease INR Range



DVT/PE 2.0-3.0



Atrial Fibrillation Myocardial Infarction



Mechanical Heart Valves 2.0-3.0 2.0-3.0

2.5-3.5

Coumadin

   

Duration of Action

Warfarin takes 4-7 days to have its optimum effect. Large loading doses do not markedly shorten the time to achieve a full therapeutic effect but cause rapid falls in the level of protein C, which may precipitate paradoxical thrombosis in the first few days of warfarin therapy. The following general recommendations for warfarin use are made.

Initiate therapy with the estimated daily maintenance dose (2-5 mg.). Elderly or debilitated patients often require low daily doses of warfarin (2-4 mg.).

Coumadin

 Patients are confused by alternating daily doses (e.g. 7.5 and 5.0 mg).  Significant changes in INR can usually be achieved by small changes in dose (15% or less).  4-5 days are required after any dose change or any new diet or drug interaction to reach the new antithrombotic steady state.

Some Drug Interactions With Warfarin

  

Drugs That May Lengthen PT

Antibiotics Antiarrhythmics

Others

 Anabolic steroids Omeprazole Cimetidine Phenytoin Clofibrate Tamoxifen Disulfiram Thyroxine Lovastatin Vitamin E (large doses)

Drugs That May Shorten PT

 Alcohol Penicillin   Antacids Rifampin Antihistamines Spironolactone    Barbiturates Sucralfate Carbamazepine Trazodone others

Dietary And Other Interactions With Warfarin

 Patients taking warfarin should eat a diet that is constant in vitamin K.

 Minimize changes in intake of

green leafy vegetables

(spinach, greens, and broccoli),

green peas, and oriental green tea

Dietary And Other Interactions With Warfarin

     Expect a longer prothrombin time in patients with CHF, jaundice, hepatitis, liver failure, diarrhea, or extensive cancer or connective tissue disease. Expect a longer prothrombin time when patients receiving warfarin are hospitalized for any reason. Metabolic alterations can affect the prothrombin time.

Expect a longer prothrombin time in patients with hyperthyroidism or high fever. Expect a shorter prothrombin time in patients with hypothyroidism

Initiating Warfarin Therapy

  

Are there any contra-indications?

   Pregnancy History of warfarin-induced purpura Active Bleeding

Has the patient been instructed on drug interactions and a diet of constant vitamin K intake?

Has a baseline PT, APTT, and platelet count been obtained?

Initiating Warfarin Therapy



In Patient



5mg Day 1



5mg Day 2



2-5mg Day 3*



2-5 mg Day 4*