ANTICOAGULANTS AND THROMBOLYTIC AGENTS

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ANTICOAGULANTS AND THROMBOLYTIC AGENTS

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ANTICOAGULANTS AND THROMBOLYTIC AGENTS
Oral Anticoagulants Heparin Thrombolytic Agents
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Oral Anticoagulants- Actions

• Factors II, VII, IX, X, as well as protein C and
  S required vitamin K1
• Vitamin K1 must be reduced to be the active form
• Warfarin antagonized vitamin K1 epoxide reductase
• May be thrombogenic by inhibiting naturally
  occurring protein C and S

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Oral Anticoagulants- Dosing and Monitoring

• Peak plasma levels in 3 h
• Peak effect not occur until 36 to 72 h
• Half-life of warfarin is about 35 h
• Factor VII levels fall most rapidly, prolonging
  the prothrombin time (PT)
• Overlapping heparin and warfarin for at least 5
  days

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Oral Anticoagulants- Dosing and Monitoring

• Typically begun at 10 mg/day for 3 days, with a
  reduction of the dose after desired PT
• PT 1.3 to 1.5 times control (INR 2.0 to 3.0) is
  the desired effect

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Oral Anticoagulants- Complications

• Bleeding
• In contrast to heparin, hemorrhagic diathesis can
  be reversed immediately by FFP transfusion (2 to
  4 U)
• The action of vitamin K1 is delayed for 3 to 6
  hours, should be given 10 mg sc or iv and every 6
  h when no long-term anticoagulant effect is
  desired

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Oral Anticoagulants- Complications

• Warfarin Skin Necrosis
• Warfarin impairs protein C function
• The half-life of protein C is very short (similar
  to factor VII)
• A paradoxical hypercoagulable state results in
  thrombosis in skin, causing necrosis

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Oral Anticoagulants- Complications

• Teratogenesis
• During the 6th to14th weeks of gestation, a
  variety of skeletal abnormalities
• Later in pregnancy, CNS abnormalities and optic
  atrophy in the fetus
• Heparin is the anticoagulant of choice

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ANTICOAGULANTS AND THROMBOLYTIC AGENTS
Oral Anticoagulants Heparin Thrombolytic Agents
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Heparin

• Unfractionated heparin a mixture of heparins of
  differing molecular weights (average MW 15,000 to
  18,000)
• Low-molecular-weight-heparin mean MW 4,000 to
  5,000

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Heparin- Actions

• Bind to antithrombin III, facilitating the
  inhibition of clotting factors IIa, IXa, Xa, XIa,
  and XIIa
• Thrombin and Factor Xa are the most sensitive to
  heparin-antithrombin III
• Higher levels of heparin (20 times) are necessary
  to inhibit fibrin-bound thrombin

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Heparin
AT III
Heparin binds to antithrombin and increases the
rate of thrombin inactivation
Fibrin
Heparin
When thrombin binds to fibrin, it becomes
resistant to inactivation by heparin.
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Characteristics of Unfractionated Heparin and LMW
Heparin
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Unfractionated Heparin
AT III
LMWH
AT III
Fewer than half the chains of LMWH are of
sufficient length to bind factor IIa, therefore
has decreased anti-IIa activity.
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Characteristics of Unfractionated Heparin and LMW
Heparin
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Characteristics of Unfractionated Heparin and LMW
Heparin
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Heparin- Indications

• Critically ill patients who do not have a
  contraindication should be placed on prophylactic
  minidose heparin to prevent deep vein thrombosis
• Minidose heparin should also be given
  preoperatively to most patients

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Heparin- Indications

• Full-dose heparin is indicate in the treatment of
  deep vein thrombosis, arterial thrombosis,
  pulmonary embolism, acute myocardial infarction,
  unstable angina, and progressing nonhemorrhagic
  stroke
• Lower doses are sometimes used to treat DIC

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Heparin- Dosing and Monitoring

• Subcutaneous use peak effect at 4h and duration
  of 12 h
• Intermittent intravenous bolus increased
  hemorrhagic risk
• Intravenous infusion immediate effect and a
  half-life approximately 90 min

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Heparin- Dosing and Monitoring

• Subcutaneous use peak effect at 4h and duration
  of 12 h
• Intermittent intravenous bolus increased
  hemorrhagic risk
• Intravenous infusion immediate effect and a
  half-life approximately 90 min

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Heparin- Dosing and Monitoring

• Effect measured by APTT or heparin level
• Titrate to maintain a APTT of 1.5 to 2 times
  control
• Minidose heparin (5000 U sc, bid) does not affect
  the APTT
• APTT is insensitive to LMWH, should measure
  heparin level (anti- Xa assay)

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Initial Dose 60 U/kg bolus and 12 U/kg/hr
infusion Check APTT 6, 12, 24 hrs after bolus,
daily thereafter, and 4 to 6 hours after
adjustment
- Am Heart J 13759-71, 1999
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Heparin- Complications

• Bleeding
• Higher risk if APTT gt 3 times control
• Typically from the GI or urinary tract or
  surgical incisions
• Transfusion of FFP usually ineffective
• Protamine as antidote 1 mg per 100 U heparin,
  base on the half-life of heparin (90 min)

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Heparin- Complications

• Heparin-Induced Thrombocytopenia
• Usually on the third day to fifteenth day
• Platelet count commonly to 50,000 but can be
  severe to less than 5,000
• Prudent to measure platelet count daily
• Even trivial heparin can perpetuate it
• Platelet transfusion may precipitate arterial
  thrombosis

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ANTICOAGULANTS AND THROMBOLYTIC AGENTS
Oral Anticoagulants Heparin Thrombolytic Agents
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Thrombolytic Agents

• Streptokinase
• Anisoylated plasminogen-streptokinase activator
  complex (APSAC)
• Urokinase
• Single-chain urokinase plasminogen activator
  (scu-PA)
• Recombinant tissue-type plasminogen activator
  (rt-PA)

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Thrombolytic Agents- Indications and
Contraindications

• Indications
• Acute myocardial infarction
• Pulmonary embolism
• Acute ischemic stroke
• Clear long-term intravenous catheters

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Absolute Contraindications to Thrombolytic Therapy
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Relative Contraindications to Thrombolytic Therapy
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Thrombolytic Agents- Actions and Administration

• Thrombolytic agents convert plasminogen to the
  active plasmin
• Plasmin proteolyzes fibrin, fibrinogen, factor V,
  factor VIII, and vWF.
• Half-life of t-PA is only about 5 min in plasma
• Fibrinogen repletion requires greater than 24 h

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Thrombolytic Agents- Actions and Administration

• t-PA
• Acute myocardial infarction
• 15 mg bolus
• 35 mg over the next 30 min
• 50 mg over the subsequent 60 min
• Pulmonary embolism
• 100 mg over 2 h

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Thrombolytic Agents- Actions and Administration

• t-PA
• Acute Ischemic Stroke
• 0.9 mg/kg (maximum 90 mg)
• 10 bolus over 1 min
• 90 over 60 min

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Thrombolytic Agents- Actions and Administration

• Streptokinase (250,000 U/vial)
• Clearing Occluded Catheters
• 10,000 U per 2 mL into catheter
• Attempt to aspirate every 10 min for
• an hour

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Thrombolytic Agents- Monitoring and Heparinization

• Routine monitoring is not indicated (Thrombin
  time for SK)
• Clinical monitoring includes CNS hemorrhage, GI
  or retroperitoneal hemorrhage, and thigh girth
• With t-PA, heparin is given 5000 U bolus,
  followed by continuous infusion titrated to a
  APTT 1.5 to 2 times control

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Thrombolytic Agents- Complications

• Bleeding
• In AMI, the risk of bleeding is reduced to 0.6 to
  5.9 percent, particularly by avoiding vascular
  puncture
• In pulmonary embolism, the risk of hemorrhage is
  over 20 percent
• Cryoprecipitate, contains fibrinogen and factor
  VIII, is the preferred blood product, initial
  dose 10 U

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