Thrombosis and Antithrombotic Therapy

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Thrombosis and Antithrombotic Therapy

• Greg Marchand, MD
• Gyn Onc Rotation

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Acute Presentation and Treatment of DVT and PE

• Mortality rate for these disorders is 15
• Death is often linked with missed or delayed
  diagnosis, which points to the importance of
  clinical suspicion in successful management.

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Clinical Presentation

• DVT
• Unilateral leg swelling
• Leg pain/tenderness
• - may increase with walking, standing, or
  exertion.
• warmth in the leg
• Bluish or reddish skin discoloration

• PE
• Dyspnea/tachypnea
• Tachycardia
• Fever
• Cough/hemoptysis
• Hypotension
• Syncope

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Virchows Triad

• Hypercoagulability
• Endothelial injury
• Venous flow disturbance (stasis or turbulence)

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Who is at Risk?

• Trauma
• History of DVT
• Age gt 40
• Prolonged Immobility
• CVA
• CHF
• Surgery (especially orthopedic or pelvic)
• Fracture of LE or pelvis
• Venous catheters

• Pregnancy or recent delivery
• Obesity
• Estrogen Therapy
• Inflammatory disorders (vasculitis, IBD, SLE)
• Cancer
• Genetic/acquired thrombophilia

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Who is at risk for a DVT?

• Incidence 5 per 10 000 general pop
• 30 surgical patients
• 1/4 patients after MI
• 1/2 patients after ischaemic stroke

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Venous Thrombosis After Long-haul Flights

• Long-haul flights of 8 hours and longer double
  the risk for isolated calf muscle venous
  thrombosis in patients with other risk factors.
• Schwarz et. Al., Arch Intern Med. 20031632759-27
  64.

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Predictive value of clinical criteria for the
diagnosis of deep vein thrombosis.

• The combination of
• calf circumference discrepancy of less than 2 cm
• absence of risk factors (recent operation,
  trauma, malignancy, previous history of DVT, or
  hypercoagulable state).
• predicted the absence of DVT in 92 of inpatients
  and 97 of outpatients.
• Clinical symptoms, risk factors, and physical
  findings are poor predictors of the presence of
  acute DVT.
• Criado E, Burnham CB. Surgery. 1997
  Sep122(3)578-83.

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PREDICTING THE PROBABILITY OF PE

• S/S of DVT 3 PTS
• Alternative dx deemed less likely than PE 3 PTS
• Immobility or surgery in the previous 4wks 1.5
  PT
• HR gt100 1.5 PT
• Prev. DVT/PE 1.5 PT
• Hemoptysis 1.0 PT
• Cancer 1.0 PT
• Low Probability lt 2.0
• Intermediate 2.0-6.0
• High gt 6.0
• Frost Mayo Clin Proc, Volume 78(11).November
  2003.1385-1391

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A 47 y.o. woman presents with acute dyspnea. She
has no h/o travel, trauma, or medications. She is
otherwise healthy, does not smoke, and has never
used oral contraceptives. She had a DVT with her
1st pregnancy at age 23, and a PE after a
hysterectomy at age 38. Her mother died suddenly
at 57 y.o. of unknown causes. She is found to
have a recurrent P.E. What is the most likely
contributing factor?

• (A) Factor V Leiden mutation
• (B) Protein C deficiency
• (C) Occult malignant tumor
• (D) Antiphospholipid antibody

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(A) Factor V Leiden mutation

• Most common form of hereditary thrombophilia
• 3-11 prevalence in the general population
• Identified in 20 of 1st VTE, and 50 of
  recurrent VTE

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The work-up

• Venous Duplex US
• Chest X-Ray
• Electrocardiogram
• Arterial Blood Gas
• D-dimer
• V-Q Scan
• High-resolution CT

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ULTRASOUND (Compression, Duplex, or Doppler)

• Pros
• Quick, cheap, and non-invasive
• Cons
• highly operator dependent
• cannot be used to rule out VTE
• negative in 10-20 of random patients
• pos in 50 of patients with proven VTE

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Chest X-Ray

• Common radiographic findings - nonspecific
• atelectasis
• pleural effusion
• pulmonary infiltrates
• elevation of a hemidiaphragm
• Classic findings - suggestive but infrequent.
• Hampton's hump (pulmonary infarction)
• Westermark's sign (decreased vascularity)

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Chest X-Ray

• The majority of patients with PE have an abnormal
  but nonspecific chest radiograph.
• A normal chest X-Ray in the setting of severe
  dyspnea and hypoxemia without evidence of
  bronchospasm or anatomic cardiac shunt is
  strongly suggestive of PE.

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ABG

• Hypoxemia and elevated A-a gradient may be
  present, but PaO2 and A-a gradient may be normal,
  especially in young patients with normal
  pulmonary function. In proven PE
• PaO2 gt 80mmHg in 29 under 40 y.o.
• A-a gradient increase lt 20mmHg in 14 under 40
  y.o.

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EKG

• Nonspecific
• per UPET, 87 sens/ 32 specific
• S1 Q3 T3 pattern
• right bundle branch block
• P-wave pulmonale
• right axis deviation
• TWI in V1-V4
• Urokinase in PE Trial

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D-DIMER

• Fibrin Degradation Product
• Highly sensitive, but a nonspecific screening
  test for DVT
• Can be elevated in pregnancy, inflammation,
  advanced age, trauma,
• post-op period, and cancer
• D-Dimer is only specific if it is negative
• 95-99 neg predictive value (ELISA)

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V/Q SCAN

• Diagnosis based on pre-test probability
• Rarely diagnostic (i.e. high or intermediate
  probability)
• Unreliable in the setting of concomitant lung
  disease (e.g. pneumonia, cancer, surgery, COPD)
  or significant cardiac disease.

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V/Q SCAN
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Ventilation-Perfusion Scan ventilation
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Ventilation-Perfusion Scan perfusion
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SPECIAL CIRCUMSTANCES

• Pre-existing lung disease V/Q scan is of
  limited usefulness, initially using a CT scan
  would be appropriate
• History of PE it is uncertain whether
  abnormalities detected by V/Q scan and CT scan
  represent residual of the initial event or
  recurrent thromboembolism Angiogram would be
  the test of choice in this instance
• Pregnancy Venous Dopplers should be the initial
  test of choice. If the probablity of an embolism
  is high even though dopplers are negative, V/Q
  Scan or CT Scan would follow.

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High-Res CT SCAN

• Quick, accurate, available, and relatively
  non-invasive.
• Sensitivity ranges from 57-100 (79 ave.)
• Specificity ranges from 78-100 (91 ave.)
• Helpful with other elements of the Ddx
• Valid only for main, lobar, or segmental artery
  occlusions.
• Not an option in renal insufficiency.

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ANGIOGRAPHY

• Gold Standard for the diagnosis of VTE
• It is invasive and has associated risks
• Reserved for the small sub-set of patients in
  whom the diagnosis of VTE cannot be established
  by less invasive tests

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• A 65 y.o. diabetic woman develops acute dyspnea
  and chest tightness on day 2 s/p TAH/BSO. She has
  a h/o angina, but this is different. She also has
  moderate COPD. A pre-op echo was normal. Her P.E.
  is unchanged except for tachycardia. BP is stable
  in the 110s/60s, and she is currently afebrile.

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ABG on 2L nc pCO2 53, pO2 40. CXR is normal. ECG
is unchanged except for sinus tachycardia. Chest
pain persists after SL nitro. A LE doppler US is
negative. A V-Q scan shows 2 matched defects and
one unmatched. Heparin is started. What is your
next step?

• (A) High-resolution CT of the chest
• (B) MRI of the chest
• (C) Pulmonary angiography
• (D) Continue heparin and start warfarin

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(C) Pulmonary angiography

• In the setting of an indeterminate V-Q scan,
  further testing must be done to justify long-term
  anticoagulation
• While promising, CT and MRI do not have enough
  evidence in their favor
• If in doubt, go with the Gold Standard

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Thrombosis
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Inherited Prothrombotic State
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Inherited Hypercoagulable States

• Mutations Rare
• Antithrombin III deficiency.
• Protein C deficiency.
• Protein S deficiency.
• Polymorphisms Common
• Factor V Leiden.
• Prothrombin gene polymorphism.
• Thermolabile MTHFR variant.

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Who should get athrombophilia (Inherited
Hypercoagulable State) workup?

• Single episode of idiopathic venous
  thrombo-embolism and one or more of the
  following
• Positive family history.
• Young age (less than 50 years).
• Thrombosis at an unusual site.
• Massive thrombosis.
• Recurrent episodes of venous thromboembolism.

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Oral anticoagulants

• Warfarin (Coumadin) Wisconsin Alumni Research
  Foundation.
• Antagonizes the vitamin K-dependent
  g-carboxylation of factors II, VII, IX, and X (as
  well as protein C and protein S).
• A narrow-therapeutic-index drug that must be
  monitored by the prothrombin time (PT).

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Factors Affecting Warfarin Effect

• Drug Interactions
• Hereditary Resitance and Hypersenstivity
• cytochrome P450 (CYP2C9 mutn)
• Altered liver function
• Hypermetabolic state (fever, thryoid)
• Co-morbid conditions (chemotherapy, albumin)

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Duration of Therapy

• First Episode DVT/PE
• Limited Risk factor identified 3-6 mths
• Lifelong Risk factor identified6mths/indefinate
• (APLA, homozygous FVL, ATIII)
• Risk factor not identified 6 12 mths
• Second Episode DVT/PE
• Limited Risk factor identified 3-6 mths
• Risk factor not identified indefinite (yearly
  eval)
• Chest, 11915S-21S

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Thrombolytic Therapy

• Not often indicated in venous thrombosis
• Useful in major PE
• Possible new indication in PE

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Therapeutic options for venous thromboembolism

• Anticoagulant therapy.
• Fibrinolytic therapy.
• Inferior vena caval interruption.

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Monitoring Levels

• Coumadin PT and INR (2.0-3.0 Therapeutic)
• Heparin (UFH) PTT (65-95 Therapeutic)
• (activated partial thromboplastin time)
• Lovenox (LMWH) Anti Xa Levels (0.7-1.1)
• CHEST 2004 126338S-400S, "Prevention of Venous
  Thromboembolism" Geents, William H. 2004

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Heparin Mechanism of ActionAccelerates
antithrombin III activity
Antithrombin III
(Heparin)
Factor X
Factor IXa
Ca2, PL
Factor VIIIa
Factor Xa
Prothrombin
Thrombin
Factor Va
Ca2, PL
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Low molecular weight heparinsPreferential
inactivation of factor Xa
Antithrombin III
(LMWH)
Factor X
Factor IXa
Ca2, PL
Factor VIIIa
Factor Xa
Prothrombin
Thrombin
Factor Va
Ca2, PL
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Heparin

• Natural anticoagulant
• Binds to AT III
• Inactivates factors IIa, Xa, IXa, XIIa.
• Binds to platelets
• Inhibits plt function (contributes to bleeding)
• Heterogenous Mw 3,000 30,000 ( 15,000 d)

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Heparin Side Effects

• Bleeding
• Osteoporosis
• (inhibits osteoblasts, activates osteoclasts)
• gt 3 mths, gt 20,000 units qd
• Thrombocytopenia
• Type I HIT
• Type II HIT (3-5)
• Skins lesions- urticaria, papules, necrosis
• Hypoaldosteronism, hyperkalemia

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Heparin and Bleeding

• Monitor aPTT carefully
• 6 hours after bolus
• 4 hours after dose adjustment
• Reversable with Protamine
• Short Half life.

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Heparin Weight Adjusted Normogram

• Number of published normograms
• Bolus 80 U/kg
• CI 15-18 U/kg
• Shorter time to therapeutic APTT
• No increase in bleeding
• Raschke et al, Arch Int Med 1561645,1996

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LMWH

• Increased bioavailability
• More predictable anticoagulant response
• Once daily, subcutaneous injection
• Outpatient management
• Not teratogenic
• Decresed incidence of HIT (but cross reacts with
  anitbody whne present)

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LMWH and Bleeding

• Bleeding
• Only partially reversible with protamine
• 30 -60
• Longer t1/2 then UFH
• Equivalent efficacy to UFH

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LMWH

• Anti-Xa activity greater than AT activity,
  purified from UFH, MWt 4500-6000
• Long duration of action, not reversible with
  protamine
• Included enoxaparin (Lovenox), dalteparin
  (Fragmin), tinzaparin (Innohep)

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LMWHClinical Applications

• Prevention of DVT/PE
• In patients undergoing hip replacement, during
  following hospitalization
• In patients undergoing knee replacement
• In patients undergoing abdominal surgery who are
  at risk of TE complications
• Treatment of DVT/PE
• Ischemic complications of unstable angina and
  non-Q wave MI

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Biological Consequences of Reduced Binding of
LMWH to Proteins and Cells
Binding Target Biological Effects Clinical
Consequences Thrombin Reduced anti-IIa
to Unknown anti-Xa ratio Proteins More
predictable Monitoring of anticoagulant anticoagu
lant response effect unnecessary Macrophages Clear
ed through renal Longer plasma half-life mechani
sm once daily subcutaneous treatment
effective Platelets Reduced incidence of Reduced
incidence of heparin-dependent heparin-induced a
ntibody thrombocytopenia Osteoblasts Reduced
activation of Lower incidence of osteoclasts oste
openia
Dalen JE, Hirsh J. Fifth ACCP Consensus
Conference onAntithrombotic Therapy. Chest
1998114 501s
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Heparin/LMWHAdverse Effects

• LMWH
• Bleeding
• Thrombocytopenia
• Hypersensitivity

• Heparin
• Bleeding
• Thrombocytopenia
• Osteoporosis
• Hypersensitivity

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WarfarinMechanism of Action
Vitamin K
VII
Synthesis of Dysfunctional Coagulation Factors
IX
X
II
Warfarin
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Vitamin K Factors Warfarin Effect
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WarfarinIndications

• Prophylaxis and/or treatment of
• Venous thrombosis and its extension
• Pulmonary embolism
• Thromboembolic complications associated with AF
  and/or cardiac valve replacement
• CHEST 2004 126338S-400S, "Prevention of Venous
  Thromboembolism" Geents, William H. 2004

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Elimination Half-Lives of Vitamin K-Dependent
Proteins
Protein Half-Life Factor VII 46 hours Factor
IX 24 hours Factor II 60 hours Factor X 4872
hours Protein C 8 hours Protein S 30 hours
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What will increase the INR?

• Antibiotics (sulfonamides,cerythromycin and other
  macrolides, metronidazole) Antifungals
  (itraconazole, fluconazole, ketoconazole)
  Amiodarone Selective serotonin reuptake
  inhibitors (especially fluvoxamine, fluoxetine)
  Cimetidine Propylthiouracil Quinine and
  quinidine COX-2 inhibitors (celecoxib,
  rofecoxib)

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No change in INR, but will potentiate bleeding
risk because of the anti-platelet effect

• Aspirin Non-steroidal anti-inflammatory
  drugs
• (except COX-2 inhibitors!) Clopidogrel
  Dipyridamole Tirofiban

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Warfarin Contraindications

• Risk of hemorrhage is greater than benefits of
  therapy
• Pregnancy
• Hemorrhagic tendencies or blood dyscrasias
• Traumatic surgery with large open areas, recent
  or contemplated surgery of CNS or eye
• Bleeding tendencies with active ulceration or
  overt bleeding
• Senility, alcoholism, psychosis or other lack of
  patient cooperation
• Spinal puncture and procedures with potential for
  uncontrollable bleeding
• Inadequate laboratory facilities

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Heparin Contraindications

• All severe and endocranial bleedings.
  Hemorrhagic diathesis.
• Recent neurosurgical or ophthalmological
  interventions.
• CHEST 2004 126338S-400S, "Prevention of Venous
  Thromboembolism" Geents, William H. 2004

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WarfarinAdverse Effects

• Fatal or non-fatal hemorrhage from any tissue or
  organ
• Necrosis of skin and other tissues
• Other adverse reactions reported less frequently
  include
• cholesterol microembolization
• Alopecia
• Purple toes syndrome, urticaria, dermatitis
  including bullous eruptions

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Bridge Therapy

• When a patient who is at high risk of clotting
  needs the warfarin interrupted for a period of
  time. 
• This may be in preparation for a procedure, such
  as a surgery, endoscopy, colonoscopy, dental
  procedure, or other procedure where the treating
  physician feels that proceeding while the patient
  is on warfarin may be dangerous resulting in
  bleeding complications. 
• Normally the warfarin would be discontinued three
  days prior to the procedure and resumed at the
  discretion of the surgeon the day of or after the
  surgery. 
• Stopping the warfarin will lower the INR and also
  lower the risk of bleeding. 
• However, in patients at very high risk of
  clotting, these several days of being off
  anticoagulant therapy may result in a blood clot.

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Bridge Therapy

• In bridge therapy, the warfarin is discontinued
  and when the INR drops below the therapeutic
  level, heparin is instituted. 
• The heparin is discontinued on the day of the
  procedure (or the day before depending upon the
  timing and the planned procedure) and resumed
  later that day, or the next day.  This protects
  the patient from developing a blood clot while
  off anticoagulant therapy as the blood is thinned
  by the heparin until the warfarin is therapeutic
  in the body.