Updated: 3/17/2021

Anticoagulants

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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
      • prosthetic valves (requiring an INR of 2.5-3.5) 
      • atrial arrhythmias
  • Toxicity
    • transient hypercoagulability
      • transient protein C deficiency when beginning warfarin treatment
        • due to short half life of protein C
        • DVTs and warfarin skin necrosis in protein C deficiency 
      • 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, protein C concentrate 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, chronic alcohol use
        • inhibitors → ↑ PT
          • decrease in P450 degrades less warfarin and levels rise
          • macrolides, cimetidine, imidazoles, binge drinking alcohol, grapefruit juice, sodium valproate 
      • ASA, sulfonamides
        • displace warfarin from plasma proteins, leading to increased free fraction → ↑ PT
      • cholestyramine
        • ↓ oral absorption
          • due to low pKa
      • acetaminophen
        • mechanism is unclear, but metabolites thought to interfere with vitamin K cycle
        • leads to supratherapeutic INR and increased risk of bleeding
  • Pharmacology
    • oral
    • long half life (>30 hr)
    • small, lipid-soluble
  • Monitoring
    • prothrombin time (PT)
    • INR
      • (tested PT / reference PT)^(calibration value)
  • Antagonist
    • 4-factor prothrombin complex concentrate (PCC) 
      • first-line agent
      • contains the 4 vitamin K-dependent clotting factors
    • vitamin K (slow onset)
      • can be subtherapeutic from increased vitamin K consumption 
    • 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
Factor Xa Inhibitors
  • Mechanism
    • factor Xa inhibitor
  • Clinical use
    • anticoagulation requiring single daily dosing - ideal for a simple medication regimen 

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(M2.HE.17.4686) A 65-year-old veteran with a history of hypertension, diabetes, and end-stage renal disease presents with nausea, vomiting, and abdominal pain. The patient was found to have a small bowel obstruction on CT imaging. He is managed conservatively with a nasogastric tube placed for decompression. After several days in the hospital, the patient’s symptoms are gradually improving. Today, he complains of left leg swelling. On physical exam, the patient has a swollen left lower extremity with calf tenderness on forced dorsiflexion of the ankle. An ultrasound confirms a deep vein thrombus. An unfractionated heparin drip is started. What should be monitored to adjust heparin dosing? Tested Concept

QID: 107401
1

Prothrombin time

38%

(3/8)

2

Activated partial thromboplastin time

50%

(4/8)

3

Internationalized Normal Ratio (INR)

12%

(1/8)

4

Creatinine level

0%

(0/8)

5

Liver transaminase levels

0%

(0/8)

M 7 B

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(M2.HE.15.93) A 65-year-old male presents to the emergency department with a 2-day onset of right-lower quadrant and right flank pain. He also states that over this period of time he has felt dizzy, light-headed, and short of breath. He denies any recent trauma or potential inciting event. His vital signs are as follows: T 37.1 C, HR 118, BP 74/46, RR 18, SpO2 96%. Physical examination is significant for an irregularly irregular heart rhythm as well as bruising over the right flank. The patient's medical history is significant for atrial fibrillation, hypertension, and hyperlipidemia. His medication list includes atorvastatin, losartan, and coumadin. IV fluids are administered in the emergency department, resulting in an increase in blood pressure to 100/60 and decrease in heart rate to 98. Which of the following would be most useful to confirm this patient's diagnosis and guide future management? Tested Concept

QID: 104635
1

Ultrasound of the right flank

6%

(2/32)

2

Radiographs of the abdomen and pelvis

0%

(0/32)

3

Magnetic resonance angiography

34%

(11/32)

4

MRI abdomen/pelvis

3%

(1/32)

5

CT abdomen/pelvis

41%

(13/32)

M 6 E

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(M2.HE.14.24) A 55-year-old obese woman with a past medical history of a pulmonary embolism presents with shortness of breath and chest pain. It started this morning, and she can't recall any preceding symptoms. She feels short of breath and has chest pain with deep breaths. Her temperature is 97.6°F (36.4°C), blood pressure is 117/77 mmHg, pulse is 120/min, respirations are 22/min, and oxygen saturation is 92% on room air. A CTA is performed and the patient is subsequently treated with warfarin and admitted to the hospital. On hospital day 2, the patient complains of leg pain and demonstrates the finding in Figure A. Which of the following is the most likely etiology for this patient's presentation? Tested Concept

QID: 104235
FIGURES:
1

Allergic medication reaction

0%

(0/63)

2

Hereditary disorder

6%

(4/63)

3

Neisseria meningitidis

6%

(4/63)

4

Septic emboli

70%

(44/63)

5

Superficial vein thrombosis

16%

(10/63)

M 6 E

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Evidence (5)
EXPERT COMMENTS (13)
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