Transcript Coagulation Studies - Lock Haven University of Pennsylvania

Coagulation Studies
Walter Eisenhauer
Basic Physiology
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Homeostasis
Hemostasis
 All bleeding eventually stops !
 Complex mechanism with various pathways and steps
 Defect at any step can cause problems:
 Two major issues
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Bleed to much
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Platelet disorders
Calcium Disorders
Vitamin K dependent Factor Disorders (intrinsic pathway)
Factor deficiencies- Von Willibrands, Factor 8 hemophilia etc
Clot to easily
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Protein C or S deficiency
Antithrombin III
Clotting Physiology
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Pathways used to be thought of a separate
and distinct-now recognized as
interdependent
Clotting Cascade
Physiologic Effects of Vitamin K
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Vitamin K serves as an essential cofactor for
a carboxylase that catalyzes carboxylation of
glutamic acid residues on vitamin Kdependent proteins. The key vitamin Kdependent 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
Clotting time
Whole blood
4-8 min
Whole blood + EDTA or citrate
infinite
Citrated platelet-poor plasma + Ca
2-4 min
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Citrated platelet-poor plasma + PL + Ca
60-85 sec
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Citrated platelet-poor plasma + kaolin + PL + Ca
21-32 sec (aPTT)
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Citrated platelet-poor plasma + thromboplastin + Ca
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11-12 sec (PT)
Tests used to assess clotting
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Bleeding Time
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Assess entire cascade from platelet aggregation
to Fibrin Formation
Platelet Count
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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
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Prothrombin Time
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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
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Activated Partial Thromboplastin Time
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Used to evaluate intrinsic Pathway
Used to monitor Heparin Dosage
Normal 21-32 seconds
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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
Heparin Dosage
Used to monitor
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
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The prothrombin time (PT) and its derived
measures of prothrombin ratio (PR) and
international normalized ratio (INR) are measures
of the extrinsic pathway 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
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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
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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
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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
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Use ~32,000 units per 24 hours to achieve PTT of
1.5-2.5 times normal lab reference
Low Molecular Weight Heparin
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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
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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
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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
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Therapeutic recommendations for warfarin
Disease
INR Range
DVT/PE
2.0-3.0
Atrial Fibrillation
2.0-3.0
Myocardial Infarction
2.0-3.0
Mechanical Heart Valves
2.5-3.5
Coumadin
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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
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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
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Drugs That May
Lengthen PT
Antibiotics
Antiarrhythmics
Others
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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
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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
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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
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Are there any contra-indications?
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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
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In Patient
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5mg Day 1
5mg Day 2
2-5mg Day 3*
2-5 mg Day 4*