Thrombolytic Therapy

Thrombolytic agents are proteins that activate a plasma proenzyme, plasminogen, to the
active enzyme plasmin. Plasmin then solubilizes fibrin and degrades a number of other
plasma proteins, most notably fibrogen.
Agents Available And Indications
Agents

Streptokinase (SK)- Derived from group C, -hemolytic streptococci. Not fibrin specific.
Activates adjacent plasminogen by forming a non-covalent SK-plasminogen activator
complex. Plasma half-life 30 min. Stimulates antibody production making retreatment
difficult.
Urokinase (UK)- Derived from cultured human cells. Not fibrin specific. Activates
plasminogen directly by enzymatic action. Plasma half-life 20 min.
Tissue Plasminogen Activator- Derived by recombinant genetics from human DNA. Fibrin
specific. Activates plasminogen associated with fibrin directly by enzymatic action. Short
plasma half-life. Two preparations of tPA are available.

Alteplase (tPA) is the glycosylated protein of 527 amino acids produced by

recombinant DNA technology.

Reteplase (sometimes called rPA) is the 39,571 molecular weight non-glycosylated

deletion mutein of tPA. It contains 355 of the 527 amino acids of native tPA and
includes the kringle 2 and the protease domains of the parent molecule.

Tenecteplase is the 527 amino acid protein produced by recombinant DNA

technology. It differs from alteplase by 6 amino acids

Indications

Acute myocardial infarction- streptokinase, tPA (Alteplase, Reteplase &

Tenecteplase)

Acute ischemic stroke - tPA (Alteplase)

Acute pulmonary embolism - SK, UK, tPA (Alteplase)

Acute deep venous thrombosis - SK

Clotted AV fistula and shunts - UK

Precautions

Bleeding is the major complication of thrombolytic therapy. Consequently, absolute

contraindications include dissecting aortic aneurysm, pericarditis, stroke, or
neurosurgical procedures within 6 months or known intracranial neoplasm. Relative
contraindications include major surgery or bleeding within 6 weeks, known bleeding
diathesis, and severe uncontrolled hypertension.

Allergic reactions: SK and anistreplase are potentially allerogenic. Patients are usually
pretreated with intravenous hydrocortisone 100 mg.

Antibody production: SK and anistreplase induce antibody production, which makes

retreatment with either of these agents less effective.

Thrombolytic Therapy In Myocardial Infarction

Intravenous Dosing Of Thrombolytic Agents In Acute MI

(All patients with acute MI should receive one chewable aspirin 160-325 mg as soon as the
diagnosis is suspected)
Loading
Duration Of Concurrent
Drug
Maintenance Dose
Dose
Infusion
Heparin
Streptokinase No
1.5 million IU (45 mL NaCl)
1 hr
No
50 mg over 30 min** and 35 mg
tPA (Alteplase) 15 mg
over next hr*** (100 mL sterile 90 min
Yes
H2O)
Given by 10 + 10 U double bolus, 10 U bolus
tPA (Reteplase) over 2 min, wait 30 min and repeat 10 U over 34 min
Yes
2 min.
tPA
30-50 mg by single bolus body weight
5-10 sec
Yes
(Tenecteplase) (see package insert for precise dosing)
** 0.75 mg/Kg, not to exceed 50 mg over 30 min. *** 0.50 mg/Kg, not to exceed 35 mg over
the next hour.
Other Regimens For Thrombolytic Agents
Peripheral Intra-arterial Infusion

SK: 20,000 IU bolus followed by 2,000 IU/min for 60 min.

UK: 6,000 IU/min for 1-2 hrs. (Both SK and UK should be given with concurrent systemic
heparin.)
Clotted IV Catheter Clearance with UK

Inject UK 5,000 IU in 1 mL into catheter. For central venous catheter inject 5,000 IU/mL in
volume equal to volume of the catheter. Allow 30-60 min for thrombolysis.
Clotted AV Cannula Clearance with SK

Inject SK 250,000 in 2 mL in each end of cannula. Clamp ends and allow 30-60 min for
thrombolysis.
Rapid Evaluation Of Patients With Suspected Acute Myocardial Infarction
Chest pain or other symptoms suggestive of acute myocardial ischemia
ECG shows one of these:

ST-segment elevation >0.1 mV in at least 2 contiguous leads

New or presumed new left bundle branch block

ST depression with prominent R wave in V2-V3, if thought to represent posterior MI

Give one chewable aspirin 160 mg - 325 mg

Confirm absence of contraindications to thrombolytic agents*
Symptoms present less
than 6 hrs.

Symptoms present between 6 &

12 hrs.

Symptoms present more than

12 hrs.

Give thrombolytic agent,

therapy most beneficial

Strongly consider thrombolytic

agent, therapy moderately
beneficial

Therapy less effective, but

consider if pain continues or
recurs

* See section on indications. Thrombolytic agents seem to offer less benefits in patients over
75 although age is not a contraindication.
Thrombolytic Therapy In Ischemic Stroke
Dosing tPA (Alteplase) In Acute Ischemic Stroke

Inclusion Criteria

Duration of symptoms and findings less than 3 hours

CT scan of head shows no intracranial bleeding

Blood pressure not higher than 185/100 mm Hg (BP must be kept below 185/110 mm
Hg during and after therapy)

tPA (Alteplase) Dose

0.9 mg/kg IV over one hour (no concurrent heparin or aspirin)

Note: Patients must be carefully selected and treated within 3 hours. Other thrombolytic
agents cannot be substituted for tPA. Please refer to the reference given below before using
tPA in ischemic stroke.
Clinical debate: should thrombolytic therapy be the first-line treatment of acute ischemic
stroke? New England Journal Of Medicine 1997; 337:1309-13

Thrombolytic Therapy In Pulmonary Embolism and Deep Venous Thrombosis

Dosing Thrombolytic Agents In PE/DVT
Loading
Maintenance
Drug
Indication
Dose
Dose
250,000 IU
PE
100,000 IU/hr
over 30
Streptokinase
min,
DVT or arterial
250,000 IU 100,000 IU/hr
thromboembolism
over 30 min
tPA
PE
None
100 mg
(Alteplase)
2,000 IU/lb
Urokinase
PE
2,000 IU/lb/hr
over 10 min

Duration Concurrent
Of Infusion Heparin
24 hrs.

NO

24-72 hrs

NO

2hrs.

Optional

12 hrs.

NO

Interfacing Heparin And Thrombolytic Agents

Drug First Step Second Step
Third Step
SK,
UK
tPA

Last Step
Restart heparin Infusion with or
Stop
Infuse thrombolytic Stop
without a loading dose when APTT
heparin
agent in prescribed thrombolytic
or thrombin time returns to less than
Infusion fashion
agent infusion twice normal (usually after 3-4
hours)
If it is elected to discontinue heparin during tPA Infusion for PE, follow directions for
the other thrombolytic agents given above.

Heparin
Heparin acts immediately to inhibit thrombin (factor IIa), and factors Xa and IXa. The drug
can be given either subcutaneously or intravenously but must achieve a plasma level >
0.2U/ml to have its optimum effect in treating active thrombosis. Lower doses of heparin are

used to prevent thrombosis. Heparin is used to treat unstable angina and to prevent and treat
venous thromboembolism (VTE).
Body Weight-Based Dosing Of Intravenous Heparin In VTE
Initial Dosing
Loading: 80 U/kg
Maintenance infusion*:18 U/kg/hr(APTT in 6 hrs.)
Subsequent Dose Adjustments
APTT (sec)
<35 (<1.2 x mean normal)
35-45 (1.2-1.5 x mean normal)
46-70** (1.5-2.3 x mean normal)
71-90 (2.3-3.0 x mean normal)
>90 (>3 x mean normal)

Dose Change
+4 U/kg/hr
+2 U/kg/hr
0
-2 U/kg/hr
-3 U/kg/hr

Additional Action
Rebolus with 80 U/kg
Rebolus with 40 U/kg
0
0
Stop infusion 1 hr

Next APTT
6 hrs
6 hrs
6 hrs***
6 hrs
6 hrs

* Heparin 25,000 u in 250 mL D5W. Infuse at rate dictated by body weight through an
infusion apparatus calibrated for low flow rates.
** The therapeutic range in seconds should correspond to a plasma heparin level of 0.2- 0.4
U/ml by protamine sulfate titration. When APTT is checked at 6 hrs or longer, steady state
kinetics can be assumed.
*** During the first 24 hrs, repeat APTT every 6 hrs. Thereafter, obtain APTT once every
a.m. unless it is outside the therapeutic range.
Overlapping Heparin And Warfarin During Acute Anticoagulation
Disease Suspected

Give heparin bolus IV

Obtain diagnostic study

Disease Confirmed

Heparin 80 u/kg IV bolus followed by 18u/kg/hr IV infusion

Obtain APTT at 4-6 hrs and keep APTT in a range that corresponds to a plasma
heparin level of 0.2-0.4 u/ml.

Start warfarin on day one at 5 mg and dose daily with the estimated daily maintenance
dose or start the estimated daily maintenance dose (2-5 mg.)

Obtain platelet count every 3-5 days of heparin therapy up to 21 days.

Give heparin and warfarin jointly for 5-7 days. Stop heparin thereafter when PT gives
an INR of 2.0-3.0.

Continue warfarin at an INR of 2.0-3.0

Managing Bleeding In Patients Receiving Heparin

Minor Bleeding

Discontinue heparin.

Monitor vital signs, APTT, Hgb, Hct, platelet count.

Major Bleeding

Discontinue heparin.

Monitor vital signs, APTT, Hgb, Hct, platelet count.

Give blood transfusions as necessary.

Consider protamine reversal of heparin.

Protamine reversal for patients receiving constant intravenous heparin:

Give protamine sulfate (1% solution) at 25 mg by slow IV infusion over 15 min.

Repeat APTT in 20 min. and 1 hr.

In patients receiving subcutaneous heparin, it may be necessary to repeat the

protamine sulfate infusion after 1 hr. because of variable heparin absorption.

Remember

Protamine sulfate can cause severe, anaphylactoid reactions. Use this agent only when severe
bleeding warrants it. Have resuscitation equipment nearby.
Heparin Induced Thrombocytopenia, Lepirudin & Argatroban
Standard unfractionated heparin can cause an antibody-mediated (Type II) thrombocytopenia
in 2-3% of individuals who receive this drug for longer than 7 days. When the platelet count
falls precipitously, STOP heparin. Do not start low-molecular-weight heparin because it will
cross-react with the antibody 90% of the time. If a rapidly acting drug is needed, substitute a
direct thrombin inhibitor, either lepirudin (Refludan) or agatroban.
Dosing Lepirudin in Acute Heparin-Induced Thrombocytopenia

Stop unfractionated heparin

Do not substitute LMW-heparin

Hold warfarin

IV infusion (for rapid therapeutic anticoagulation).

Loading dose: 0.4 mg/kg bolus i.v..

Maintenance: 0.15 mg/kg/hr i.v. (up to 110 kg body weight

Adjust maintenance dose to maintain activated partial thromboplastin time (APTT) at

1.5 to 2.5 times the laboratory's mean normal value.

Dosing Argatroban in Acute Heparin-Induced Thrombocytopenia

Stop unfractionated heparin

Do not substitute LMW-heparin

Hold warfarin

IV infusion (for rapid therapeutic anticoagulation)

Loading dose: no loading dose

Maintenance: 2 ug/kg/min

Adjust mainenance dose to maintain APTT at 1.5 to 2.5 times laboratory's mean
normal value

Give lepirudin or argatrobn for at least 3 days while holding warfarin. When the platelet
count has recovered above 100,000/uL, give warfarin at 5 mg/day and adjust dose by INR.
Clearance of these drugs can be reduced in patients with hepatic or renal insufficiency.
Contact the manufacturer of lepirudin (Aventis) or argatroban (SmithKline Beecham) for
details of usage in HIT.
* This outline is intended only for initiating therapy in an emergent situation. Contact
the manufacturer of danaparoid (Organon) for details of usage in HIT.

Low Molecular Weight Heparins

Low molecular weight heparins are smaller pieces of the heparin molecule that inhibit
clotting factor Xa more than factor IIa (thrombin). These drugs are given subcutaneously and
can usually be administered in a weight-based dose without subsequent monitoring or doseadjustment. At a higher dose these drugs are used to treat active thrombotic disease and at
lower dose to prevent thrombosis. Three LMW-heparins are widely used in the United States
and Canada. They are dalteparin, enoxaparin, and tinzaparin.
Use Of Low Molecular Weight Heparin To Prevent Thrombotic Disease
LMW-HEPARIN

INDICATION

Abdominal Surgery
Dalteparin(Fragmin) Higher-risk Abdominal Surgery, Hip
Replacement
Hip, Knee Replacement
Enoxaparin(Lovenox) Abdominal Surgery, Higher-risk
Medical Patients
Tinzaparin(Innohep) No prophylactic approval in U.S.

SUBCUTANEOUS
DOSE
2500 anti-Xa U q 24 h
5000 anti-Xa U q 24 h
30 mg* q 12 h
40 mg q 24 h
75 anti-Xa U/kg q24h

For enoxaparin 1 mg = 100 antiXa units. Enoxaparin also is used at 40 mg q 24h for longer
term outpatient proplylaxis in outpatients after hip or knee replacement.
Use Of Low Molecular Weight Heparin To Treat Unstable Angina
LMW-heparins have proven to be at least as effective as intravenous unfractionated heparin
in the treatment of unstable angina. Cost-analysis of LMW-heparin treatment of unstable
angina indicate that when total costs are considered, LMW-heparin incurs no more expense
than unfractionated-heparin. Dalteparin and enoxaparin are both approved for treatment of
unstable angina. Enoxaparin or dalteparin can be given safely to any patient who is a
candidate for unfractionated heparin. The major contraindications are active internal bleeding
and heparin-induced thrombocytopenia (HIT).

Guidelines for Enoxaparin Treatment of Unstable Angina

Obtain baseline ECG, cardiac enzymes, troponin, APTT, PT, and CBC

Determine need for thrombolytic therapy

Start aspirin, -adrenergic blocker and nitrates

Check for contraindications to LMW-heparin

Start enoxaparin* or dalteparin* subcutaneously q 12 hr without monitoring or doseadjustment

Determine need for long-term anticoagulants (warfarin)

*Dalteparin: 120 anti-Xa U/kg subcutaneously q 12 hr. Enoxaparin 1 mg/kg subcutaneously q

12 hr
Thrombolytic Therapy and LMW-Heparins

LMW-heparin is used in place of unfractionated heparin in unstable angina (UA). If a patient

with unstable angina requires thrombolytic therapy because of ST-segment elevation or new
LBBB, follow these recommendations:

TPA (Activase, Retavase or TNKase ): If the last LMW-heparin injection

occurred within 6 hrs, the patient can be assumed to be anticoagulated and no
concurrent heparin is necessary. If the last LMW-heparin injection occurred more than
6-8 hrs. previously, give concurrent IV unfractionated heparin with the TPA.

Streptokinase- Hold the LMW-heparin during the SK infusion and give the next
injection as scheduled after the APTT or TT has returned to less than 1 times mean
normal.

Invasive Procedures and LMW-Heparins- If cardiac catheterization or coronary

artery bypass surgery is to occur within 6 hrs. of a LMW-heparin dose, the patient can
be assumed to be fully anticoagulated. If the procedure is to be done more than 6 hrs.
after a LMW-heparin dose, IV unfractionated heparin can be given and followed with
an activated clotting time (ACT). LMW-heparins have very little effect on the ACT.

Reversing the effect of LMW-heparin- Although it is rarely necessary, LMWheparin can be partially neutralized with protamine sulfate. This is rarely necessary.
Please see the package insert or PDR for details.

Dalteparin has been studied in the treatment of deep venous thrombosis (DVT) and
unstable angina (UA).
Treatment of DVT

Dalteparin Dose: 120 anti-Xa U/kg q 12 h

Dalteparin Dose: 200 anti-Xa U/kg q 24 h
Treatment of UA

Dose: 120 anti-Xa U/kg q 12 h

Tinzaparin has been studied in both DVT and PE. The drug is approved for treatment
of DVT with or without PE. The effective treatment dose is 175 anti-Xa U/kg q24h.
Algorithm For DVT Care Path
Initial Assessment of Patient
Evidence of DVT. Stool guaiac and

NO

F.U. Telephone call from

weight in office

Call Case Manager. Send for duplex

sonography

office

NEG

Symptomatic Rx

Positive Sonogram

Evaluate inpatient vs. outpatient criteria-

In-Pt. Crit. Admit; initiate inpatient

Care Path

Eligible for outpt. Rx.

Day 1
>>>

1. Pt. to lab in Wc from Ultrasound.

2. Call Case Mgr. with orders.
3. Patient Education.
4. Administer 1st doses of LMWH & Warfarin
after normal lab results back.

Day 2
>>>

RN Telephone Assessment

Day 3
>>>

PT/INR/Plt Ct.
Warfarin Protocol
RN Assessment

Warfarin

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.
Test your knowledge in a real life case simulation of patient J.B., scheduled to under go left
hip replacement surgery.
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

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.).

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.

Frequency of Dosing

Daily
Monitoring

Warfarin is monitored by the one stage prothrombin time. Prothrombin times are reported in
seconds, as a ratio of the prothrombin time in seconds to the mean normal prothrombin time
of the laboratory, and as the international normalized ratio (INR). The INR is the most
reliable way to monitor the prothrombin time.
Some Drug Interactions With Warfarin

Drugs That May Lengthen PT

(higher INR; increased warfarin effect)
Antibiotics

Drugs That May Shorten PT

(lower INR; decreased warfarin effect)

Anti-inflammatories Alcohol

Penicillin

Carbenicillin

Allopurinol

Antacids

Rifampin

Erythromycin

Fenoprofen

Antihistamines

Spironolactone

Fluconazole

Ibuprofen

Barbiturates

Sucralfate

Isoniazid

Indomethacin

Carbamazepine

Trazodone

Ketoconazole

Naproxen

Cholestyramine

Vitamin C
(large doses)

Metronidazole

Phenylbutazone

Griseofulvin

Moxalactam

Piroxicam

Haloperidol

and other
cephalosporins

Sulfinpyrazone

Oral contraceptives

Trimethoprimsulfa Zileuton
Antiarrhythmics
Amiodarone
Quinidine
Others
Anabolic steroids

Omeprazole

Cimetidine

Phenytoin

Clofibrate

Tamoxifen

Disulfiram

Thyroxine

Lovastatin

Vitamin E (large
doses)

Remember: Drug interactions with warfarin are not always known or predictable. Repeat an
INR 5-7 days after adding, subtracting or changing the dose of any drug in a patient receiving
warfarin.
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.

Conditions that interfere with vitamin K uptake or interfere with liver function will increase
the warfarin effect.

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?
1. Pregnancy
2. History of warfarin-induced purpura
3. 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?
Day 1 Day 2 Day 3
In-patient
Anticoagulation

Warfarin
Dose

5 mg 5 mg

Day 4 &
after

2-5
mg

2-5 mg

INR**

INR

* Should be overlapped for 3-5 days with heparin in cases with active thrombosis

Out-patient
Anticoagulation

Warfarin
Dose

Day 1 Day 2 Day 3

Day 4 &
after

2-5
mg

2-5 mg

2-5
mg

2-5
mg

INR** INR

** Starting on day 3, adjust subsequent doses as outlined below based on INR. Obtain INR 34 times in week 1; twice in 2nd week; then weekly until stable; then monthly. Elderly or
debilitated patients often require low daily doses of warfarin (2-3 mg).
Initiating Therapy: Dose Adjustment
Day

INR

Dosage

<1.5
1.5-1.9
2.0-3.0
>3.0

5.0 - 10.0 mg
2.5 - 5.0mg
0.0 - 5.0 mg
0.0

<1.5
1.5-1.9
2.0-3.0
>3.0

10.0 mg
5.0 - 7.5 mg
0.0 - 5.0 mg
0.0

<1.5
1.5-1.9
2.0-3.0
>3.0

10.0 mg
7.5 - 10.0 mg
0.0 - 5.0mg
0.0

<1.5
1.5-1.9
2.0-3.0
>3.0

7.5 - 12.5 mg
5.0 - 10.0 mg
0.0 - 7.5 mg
0.0

Stable Patients: Dosing Algorithm To Achieve INR Of 2.0 - 3.0

Warfarin Sodium: Monitoring and Dosage Adjustment in Stable Anticoagulated Patients

(based on a starting dose of 4 mg/d)
INR

Action

>10.0 Stop warfarin. Contact patient for examination.

7.010.0

Stop warfarin for 2 days; decrease weekly dosage by 25% or by 1 mg/d

for next week (7 mg total); repeat PT in 1 week.

4.57.0

Decrease weekly dosage by 15% or by 1 mg/d for 5 days of next week (5

mg total); repeat PT in 1 week.

3.04.5

Decrease weekly dosage by 10% or by 1 mg/d for 3 days of next week (3

mg total); repeat PT in 1 week.

2.03.0

No change.

1.52.0

Increase weekly dosage by 10% or by 1 mg/d for 3 days of next week (3

mg total); repeat PT in 1 week.

<1.50 Increase weekly dose by 15% or by 1 mg/d for 5 days of next week (5 mg

total); repeat PT in 1 week.

- Coumadin, 1mg tablet

- INR: International Normalized Ratio = (x/y)z , where:
x = Prothrombin Time of sample (sec)
y = Mean Normal Prothrombin Time (sec)
z = [ ISI of Thromboplastin]

Evaluation Of Atrial Fibrillation

Atrial fibrillation on ECG
(constant or intermittent)

Obtain history and physical exam

(valvular, ischemic or hypertensive
heart disease present? Diabetes
or thyrotoxicosis present?)

Obtain surface echocardiogram

(valvular heart disease, atrial or
appendegeal thrombus or
LV dysfunction present?)

Valvular, ischemic, or
hypertensive heart
disease present;
diabetes, previous
stroke or TIA present;
or patient 65 years or
older.

Anticoagulate with
Warfarin to
INR of 2.0-3.0

Thrombosis?
Consider TEE

No heart, or systemic
disease
detected and patient
less than 65
Years old.

No anticoagulation
("Lone atrial fibrillator")

If low intensity anticoagulation is contraindicated, aspirin at 325 mg daily may offer some
benefit, but warfarin has performed better in most comparisons to aspirin.
Test your knowledge in a real life case simulation of patient J.B., scheduled to under go left
hip replacement surgery.