Peggy Choye, Pharm.D.
Spring 1998

Pulmonary Embolism

  1. Objectives and Goals
  2. General Principles of Thromboembolic Disease
    1. Heparin
    2. Warfarin
  3. Heparin dosing in pregnancy (as coumadin is a teratogen)
  4. Pulmonary Embolism Recitation Case
  5. Answers to PE case

Objectives

Upon completion of this section on pulmonary embolism, the student should be able to:

  1. Understand the basic pathophysiology of thrombus formation and risk factors to formation
  2. Describe the rationale behind the use of anticoagulants as well as the mechanisms of action of heparin and warfarin and how the two are used together for clot resolution
  3. Initiate a patient on heparin/warfarin and to be familiar with monitoring parameters in order to adjust the doses of each

I. General Principles of Thromboembolic Disease

A. Definitions
  1. Thrombus
    A solid mass (clot) formed in the blood vessels from constituents of blood
  2. Embolus
    A venous thrombi dislodged from the site of formation which then flows through the venous circulation to become lodged elsewhere
    Ex/ deep venous thrombosis (DVT) of lower extremity embolizing to lung--pulmonary embolus (PE)
B. Pathophysiology
  1. Three fundamental mechanisms:
    a. Venous stasis--can cause hypoxia and endothelial damage to venous valves
    b. Vascular injury
    c. Hypercoaguability
  2. Risk factors
    • obesity -- immobility
    • heart disease -- CHF
    • prolonged immobility
    • malignancy
    • surgery -- vascular injury
    • estrogen use
    • pregnancy
    • blood dyscrasias
      Ex/
      antithrombin III deficiency
      protein C deficiency
      protein S deficiency
C. Sites of thrombus formation
  1. Majority of venous thrombi form in the deep veins of the lower extremities (see diagram)
  2. Approximately 15-20% of venous thrombi in the legs embolize to the lung
  3. These often originate from the veins above the knee
  4. Calf vein thrombi embolize less often and are of minor consequence; however, up to 30% propagate to sites above the knee where they are more likely to embolize.
  5. Why treat DVT/PE?
    Major consequence of DVT include:
    a. Compromised blood flow to the lower extremity
    b. Destruction of venous architecture
    c. Embolization -- embolization to lung -- potentially life-threatening


D. Clot formation
  1. Platelet plug formation
    (exposure of collagen and other subendothelial cell surfaces)
    vessel wall damage -- platelet adhesion -- adenosine diphosphate (ADP) -- platelet aggregation
  2. Transformation of platelet plug to fibrin clot
    a. Imbalance between procoagulant and anticoagulant factors
    b. Again, tissue injury or exposure of collagen initiates clotting process
  3. Coagulation cascade
    a. Consists of the intrinsic, extrinsic and common pathways
    b. Point of interest -- Factor X activation
    c. Extrinsic pathway mediates Factor X activation through Factor VIIa
    d. Intrinsic pathway mediates Factor X activation via a chain of events initiated by Factor XI
    e. Both the intrinsic and extrinsic pathway then activate the common pathway via Factor X






E. Clinical presentation
  1. DVT
    • pain and tenderness of calf
    • swelling (unilateral)
    • positive Homan's sign (non-specific)
    • warmth
  2. PE
    • sudden onset SOB, tachycardia
    • pleuritic chest pain
    • cough, hemoptysis (not always)
F. Diagnosis
  1. DVT
    a. Venous doppler--noninvasive, depends on soundwaves being reflected from moving cells, the trained ear should recognize abnormal flow patterns produced by a clot (obstruction) in the underlying vein
    b. Impedence plethysmography (IPG)
    c. Iodine-labeled-fibrinogen scanning
    d. Venography--gold standard, invasive
  2. PE
    a. V/Q scan
    b. Arterial blood gas (ABG)
    c. EKG
    d. Chest x-ray
    e. Pulmonary angiography
G. Treatment
  1. Goals
    a. Prevent embolism of thrombus to lungs
    b. Prevent extension of thrombus
    c. Restore patency to venous circulation
  2. General management
    a. Bed rest with heels elevated above heart
    b. Analgesics for pain
    c. For PE, oxygen, mechanical ventilation if necessary
    Anticoagulation
    *Indications:
    • Proximal DVT--thrombus extending above the popliteal vein; high risk of PE
    • Symptomatic calf vein thrombosis

    *** Remember, anticoagulation with heparin/warfarin prevents propagation (growth) of clot, prevents new clots from forming, but does not act to dissolve or break up clot

  3. Heparin

    Heterogeneous mixture of mucopolysaccharides
    Large, negatively charged molecule
    A. Mechanism of action
    1. Accelerates normal rate at which antithrombin III neutralizes the activity of thrombin
    2. Primarily affects the intrinsic pathway of the coagulation cascade
    3. Prevents thrombus from growing larger but does not act to dissolve or break up clot
    B. Pharmacokinetic properties
    1. Not absorbed orally, must be given by injection
    2. Half-life
      • dose-dependent, prolonged w/ higher doses
      • approximately 60-90 minutes (short)
      • Due to short t1/2, anticoagulant of choice when rapid anticoagulant effect is required, i.e. DVT/PE treatment
      • primarily metabolized via hepatic pathways
    C. Contraindications to heparin
    • hypersensitivity
    • active bleeding
    • intracranial hemorrhage
    • thrombocytopenia
    • severe HTN
    • post-surgery of eye, brain, spinal cord
    • others
    D. Dosage regimens
    1. Bolus
      70-100 units/kg -- 5000-7000 units (based on a 70kg person)
    2. Continuous infusion
      Immediately following the bolus, start infusion of 15-25 units/kg -- 1000 units/hr

    Subsequent adjustments based on laboratory monitoring--**May use the following table for dosing although other methods also acceptable. From Ann Intern Med. 1993;119:874-881.

    ADJUST heparin inlusion based on sliding scale below:

    PTT < 35 80 units/kg bolus = _____ units
    increase drip 4 units/kg.h = _____ units/h
    PTT 35 to 45 40 units/kg bolus = _____ units
    increase drip 2units/kg.h = _____ units/h
    PTT 46 to 70 No charge
    PTT 71 to 96 reduce drip 2 units/kg.h = _____ units/h
    PTT > 90 hold heparin for 1h
    reduce drip 3 units/kg.h = _____ units/h


    E. Laboratory monitoring
    1. Activated partial thromboplastin time (aPTT)
    2. Check baseline aPTT prior to therapy
    3. Therapeutic endpoint: 1.5-2.5 times control (control value at UIH = 24-39 sec)
    4. Again, t1/2 ~60-90min; takes 4-5 t1/2's to reach steady state; therefore, draw blood sample for aPTT 6hrs after start of infusion or after any changes in infusion rate
    F. Complications
    1. Hemorrhage
      a. Stop heparin
      b. Blood transfusion (for correction of blood loss)
      c. Protamine sulfate--in the event of a major bleed
      Mechanism: positively charged protamine binds with negatively charged heparin molecule--neutralizes
    2. Thrombocytopenia--Early vs. Late
      a. Early
      • Mild and transient
      • Occurs w/in first few days of therapy
      • Plts rarely drop below 100,000/mm3
      • Direct effect of heparin on plt function
      • Resolves without intervention
      b. Late
      • Can occur 5-14 days after start of therapy
      • Most likely immunologic
      • Dose independent
      • Usually resolves 3-5 days after stopping heparin

  4. Warfarin

    A. Mechanism of action
    1. Interferes with the hepatic synthesis of the vitamin K dependent clotting factors (factors II, VII, IX and X) by interfering with carboxylation of glutamic acid residues
    2. Delayed onset of action due to effect on synthesis of the decarboxylated vitamin K dependent clotting factors to replace the normal clotting factors
      Factor t1/2 (hrs)
      VII 6
      IX 20
      X 40
      II 60
    B. Pharmacokinetic properties
    1. Half-life:
    36-42 hours
  5. Protein binding:
97% protein bound (source of certain drug-interactions)
  • Hepatically metabolized by microsomal mixed-function oxidase enzymes
    • C. Laboratory monitoring
    1. Prothrombin time (PT)
      a. Responsive to depressions of 3 of the 4 vit. K dependent clotting factors (II, VII, X)
      b. During first few days of warfarin therapy, the PT reflects primarily the depression of Factor VII, which has the shortest t1/2 of only 6 hrs. It does not necessarily reflect overall picture of anticoagulation
      c. Values for prothrombin times have not been interchangeable between laboratories due to variable response to thromboplastin and different ways of reporting values.
      d. PT values are now standardized to an International Normalized Ratio, or INR
    2. International Normalized Ratio (INR) INR = patient PT c control PT c represents the international sensitivity index (ISI) which is unique to each batch of thromboplastin used
    3. Patient not on coumadin would expect to have an INR of 1.
    4. Optimal therapeutic range for the control of oral anticoagulant therapy
      a. For DVT/PE, desired INR usually 2.0-3.0
      b. Although INR is the accepted standard for monitoring of therapy, PT can also be useful as well, used in conjunction with INR
    D. Warfarin dosing
    1. Delayed anticoagulant effect--usually 2-3 days
      • Due to the long half-lives of the vit K dependent clotting factors
      • Early anticoagulant effect is caused by replacement of Factor VII which has a very short t1/2 of 6hrs
      • Full anticoagulant effect delayed 72-96 hrs (maybe longer) as the other 3 clotting factors (II, IX and X) are considerably longer.
    2. Choosing a dose
      • Although there is not a specific mg/kg dosing recommendation, should consider patient weight when choosing dose
      • Serum albumin may affect sensitivity to warfarin as it is highly protein bound
      • Generally, warfarin can be initiated at 7.5mg-10mg daily for the first 2 days and then decreased to an average maintenance dose of 2.5-5.0mg daily, depending on PT/INR values
      • Dosing may be more conservative if patient is hypoalbuminemic or low in wt (i.e. start w/5mg)
    E. Length of treatment
    1. Again, due to delayed onset of warfarin, patient should be heparinized first to achieve rapid anticoagulation.
    2. When should warfarin be initiated?
      May begin warfarin on day #1 along with heparin--best if pt on stable heparin regimen first
    3. Should overlap IV heparin with warfarin (about 5 days) to allow warfarin to approach steady state as well as allow the body to begin to endothelialize the clot--Remember, heparin/coumadin prevent further propagation of the clot but do not dissolve it.
    4. Treatment with warfarin is indicated for at least 3 months.
    F. Adverse effects
    1. Hemorrhage--GI tract, GU tract, mucous membranes (essentially anywhere)
      • Treatment--w/drawal of coumadin, vitamin k, fresh frozen plasma (FFP)
      • Be conservative with vitamin k especially if intend to resume anticoagulation with warfarin once bleed resolved
    2. Skin necrosis/"purple toe" syndrome--RARE
      • Thought to be secondary to decreased protein C and S since both are vit K dependent anticoagulants
      • Shorter half-life than coagulation factors; inhibited before the anticoagulant effect of warfarin is therapeutic
      • Theoretically, may cause a hypercoagualble state
    G. Drug interactions (Know common ones)
    H. Patient Education

    II. Heparin dosing in pregnancy (as coumadin is a teratogen)

    A. Administer dose-adjusted subcutaneous heparin
    1. If initiated in hospital on full-dose iv heparin:
      a. Calculate total daily dose of 24hr infusion i.e. 1000u/hr--24,000u/day
      b. Add 1000-2000u to adjust for decrease in absorption per SQ route vs. iv--26,000u/day
      c. Divide into q12hr dose--13,000u SQ q12hr
    2. If not on previous iv infusion, may initiate at 15,000-17,500u or 250u/kg total body wt. divided into q12hr dosing interval.
    B. Monitoring
    1. Baseline aPTT
    2. Should check a midinterval PTT (i.e. 6hr post-dose) after the first dose
    3. Adjustment of dose--May refer to Table 12.6 in Applied Therapeutics

    Pulmonary Embolism Case

    S.D. is a 33 y.o. male with no significant PMH who was admitted with sudden onset SOB. Also c/o right calf tenderness, especially with walking. S.D. recently returned from a trip to India 2 days prior to the onset of symptoms. Upon Physical exam, the right calf is markedly larger than the left, +warmth and +erythema.

    Vitals: BP 120/80 HR 110 RR 32 afebrile
    ABG on RA: 7.48/30/70 (pH/pCO2/pO2)
    Labs: lytes WNL 14.5 PT 11.7 wt 84kg
    325 6.0 PTT 28.0 ht 6'2"
    42.0

    LE dopplers reveal a large DVT of the right leg extending from the posterior tibial to the popliteal vein. VQ scan done which showed high probability for PE. Pt to be started on anticoagulation.

    1. What risk factor(s) does S.D. have for development of DVT/PE?




    2. The resident asks for your advice regarding heparin dosing for S.D. What information would you like to know before dosing this patient and what are your recommendations?




    3. When would you check the PTT to assess efficacy of heparin dose chosen?




    4. The pt is started on the heparin dose that you recommended. The PTT is drawn at the appropriate time after the infusion is started. The medical student pages the resident to tell him that the PTT is >212 sec. The resident decides to repeat the PTT and draws it himself. The repeat PTT=45sec. What happened? (assume the heparin infusion was running at the same rate the entire time during these events)




    5. If the PTT=45 sec, what would your recommendations be regarding heparin dosing?




    6. Your recommendations are followed with a PTT after 6 hours of 70 seconds. When can you start coumadin? How much would you start?




    7. S.D. is started on 10mg. The next day after 1 dose of 10mg, the INR = 1.5. What would your recommendation be regarding the dose of coumadin?




    8. The morning of day #3 of heparin and coumadin, S.D.'s INR=2.5. The resident wants to D/C pt home. He enters orders to d/c the heparin drip. Do you agree?




    Answers to PE case

    1. Prolonged immobility secondary to S.D.'s long airline flight
    2. Baseline PT/INR, PTT, weight, check for occult blood--UA, rectal, CBC--platelet count

      Bolus heparin--70-100u/kg--5880-8400u (would probably give 6000u)

      I.V. drip--15-25u/kg/hr--1260u-2100u (would probably start at 1200u/hr)
    3. The t1/2 ~60-90min--4-5 t1/2's--~6hrs after infusion started
    4. The medical student probably drew the blood from the arm into which the heparin was infusing proximal to the infusion site which can give a falsely elevated reading of the PTT secondary to high conc. of heparin. The resident on the other hand knew to draw from the opposite arm and therefore got a more accurate reflection of the PTT.
    5. According to the table outlined in the handout, would give a partial bolus of 3000u and increase the drip by 100-200u/hr.
    6. May start coumadin the first day along with heparin. I prefer to have the pt on a stable dose of heparin first before starting coumadin but this theoretically could be on the first day of therapy, 6hrs after i.v. started.

      Dose--probably would give 7.5mg-10mg the first few days and then would decrease to 5mg
    7. Decrease the dose. Knowing that the full effect of coumadin may not be realized for 2-3 days (if not longer), if the INR by day #2 is already 1.5, will continue to rise and most likely if 10mg is continued, pt will become over anticoagulated.
    8. No. Heparin and coumadin have only been overlapped ~48hrs. Remember, early elevations in the INR usually reflect depression of Factor VII which has a very short t1/2 relative to the other clotting factors. This, however, does not necessarily reflect overall anticoagulation. It is recommended to overlap therapy for ~5 days to allow the other clotting factors with longer t1/2's to be cleared form the body as well as allowing the body to endothelialize the clot.
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