questions 5

Anticoagulants

Topic updated on 10/18/17 2:26pm

Overview

  • Anticoagulants decrease the formation of fibrin clots
    • heparin
    • warfarin (coumadin)
    • bivalirudin
Heparin
  • Mechanism
    • catalyzes the binding of antithrombin III to multiple clotting factors  
    • inactivates several factor
      • IIa (thrombin)
      • Xa
      • IXa
      • XIa
      • XIIa
  • Clinical use
    • immediate anticoagulation
      • pulmonary embolism
      • acute coronary syndrome
      • stroke
      • MI
      • DVT
      • DIC
    • during pregnancy
      • does not cross placenta
  • Toxicity
    • bleeding
    • osteoporosis
    • heparin-induced thrombocytopenia (HIT)
      • heparin binds to platelet factor IV
      • antibodies bind to and activate platelets
      • leads to hypercoagulable state and thrombocytopenia
    • hypersensitivity
  • Pharmacology
    • IV delivery only for theurapeutic anticoagulation
    • short half-life (2h)
    • large, water-soluble polysaccharide
    • low-molecular-weight heparins (e.g. enoxaparin) have advantages of
      • longer half-lives (2-4x)
      • less thrombocytopenia
      • enhanced activity against factor Xa
      • administered subcutaneously without laboratory (PTT) monitoring
      • not easily reversible
  • Monitoring
    • partial thromboplastin time (PTT
  • Antagonist
    • protamine sulfate 
      • positively charged to bind negatively charged heparin
Warfarin (coumadin)
  • Mechanism
    • ↓ hepatic synthesis of vitamin K-dependent clotting factors
      • prevents the reduction of vitamin K, a necessary step in the synthesis of clotting factors
        • vitamin K epoxide reductase is inhibited
        • γ-carboxylation of clotting factors cannot occur 
      • affected clotting factors include
        • II
        • VII
        • IX
        • X
        • protein C
        • protein S
    • no effect on clotting factors already present
    • affects the extrinsic pathway
  • Clinical use
    • chronic anticoagulation
      • DVT prophylaxis
      • post-STEMI
      • heart valve damage
      • atrial arrhythmias
  • Toxicity
    • transient hypercoagulability
      • transient protein C deficiency when beginning warfarin treatment
        • due to short half life of protein C
      • can lead to skin necrosis and dermal vascular thrombosis
        • pain, bullae formation, and skin necrosis following initiation of warfarin likely has warfarin-induced skin necrosis
        • often occurs in women who have protein C deficiency
        • treatment includes administration of vitamin K and discontinuation of warfarin 
      • give heparin as you begin warfarin treatment
    • bleeding
      •  retroperitoneal hematoma - back/abdominal pain and hemodynamic compromise 
        • CT scan to identify and guide treatment
    • teratogenic
      • bone dysmorphogenesis
      • not used in pregnancy
    • drug interactions
      • P450 metabolism 
        • inducers → ↓ PT
          • increase in P450 degrades more warfarin and levels fall
          • carbamazepine, barbiturates, rifampin
        • inhibitors → ↑ PT
          • decrease in P450 degrades less warfarin and levels rise
          • macrolides, cimetidine, imidazoles
      • ASA, sulfonamides, phenytoin
        • displace warfarin from plasma proteins, leading to increased free fraction → ↑ PT
      • cholestyramine
        • ↓ oral absorption
          • due to low pKa
  • Pharmacology
    • oral
    • long half life (>30 hr)
    • small, lipid-soluble
  • Monitoring
    • prothrombin time (PT)
    • INR
      • (tested PT / reference PT)^(calibration value)
  • Antagonist
    • vitamin K (slow onset)
    • fresh frozen plasma (fast onset)  
Lepirudin, bivalirudin
  • Mechanism
    • direct inihibtors of thrombin (IIa)
  • Clinical use
    • alternative to heparin
      • e.g. during HIT
    • unstable angina during percutaneous transluminal coronary angioplasty


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Qbank (2 Questions)

TAG
(M2.HE.16) A 50-year-old patient with a longstanding history of hypertension presents to the hospital with back pain. His only medication is warfarin for intermittent atrial fibrillation. His heart rate is 110 bpm and regular, blood pressure is 90/60 mmHg, and respiratory rate is 12 rpm. On exam he is found to have significant bruising over his flanks. CT imaging demonstrates a large retroperitoneal hematoma, and subsequent lab testing is normal except for an INR of 3.5 and a low hemoglobin. Which of the following is the next best treatment to halt further bleeding? Topic Review Topic

1. Infusion of fresh frozen plasma
2. Infusion of protamine sulfate
3. Infusion of vitamin K
4. Stop warfarin
5. Stop warfarin, oral vitamin K tablets

PREFERRED RESPONSE ▶
TAG
(M2.HE.24) A 55-year-old obese female with a past medical history of a deep vein thrombosis following a transatlantic flight several years ago presents with shortness of breath and chest pain. A CT PE protocol is positive for a pulmonary embolism. For chronic DVT prophylaxis, she is started on warfarin in the hospital. Three days later, she has excruciating leg pain and her leg is found to resemble Figure A. Which of the following is most likely responsible for this condition? Topic Review Topic
FIGURES: A          

1. Heart valve vegetations
2. A methicillin-resistant S. aureus infection
3. A recurrent deep vein thrombosis
4. A genetic enzyme deficiency
5. A drug allergy

PREFERRED RESPONSE ▶
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Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators.
N Engl J Med. 2003 Jul 10;349(2):146-53. PMID: 12853587 (Link to Pubmed)
6/4/2013
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