Venous Thromboembolism

Clinical Pharmacy

Chapter Five: Venous Thromboembolism

Dr. Amani Abushanab

  

DEFINITION & PATHOPHYSIOLOGY

Venous thromboembolism (VTE) refers to the formation of a blood clot within the venous circulation and can manifest as either deep vein thrombosis (DVT) or pulmonary embolism (PE).

Risk Factors for VTE:

The risk factors for VTE include:

  • Increasing age: The likelihood of clot formation increases as individuals age.
  • History of VTE: Previously diagnosed venous thromboembolism heightens the risk for future occurrences.
  • Virchow’s triad: This triad summarizes three key contributors to thrombosis:
      1. Blood stasis: Conditions such as immobility (e.g., prolonged travel or hospitalization) and obesity lead to decreased blood flow.
      2. Vascular injury: Surgical procedures, trauma, or placement of venous catheters can disrupt vascular integrity, facilitating clot formation.
      3. Hypercoagulability: Factors such as malignancies, certain coagulation factor abnormalities, presence of antiphospholipid antibodies, and usage of specific drugs can increase clotting tendencies.

CLINICAL PRESENTATION

Many patients may remain asymptomatic despite having acute VTE. However, typical signs and symptoms include:

Symptoms of DVT:
  • Unilateral leg swelling
  • Pain and tenderness in the affected leg
  • Erythema (redness of the skin)
  • Increased warmth in the affected area
    Physical examination may reveal a palpable cord and a positive Homans’ sign (pain in the calf upon dorsiflexion of the foot).
Symptoms of PE:
  • Cough
  • Chest pain or tightness
  • Shortness of breath
  • Palpitations
  • Hemoptysis (coughing up blood)
  • Dizziness or lightheadedness
    Signs of PE can include:
  • Tachypnea (rapid breathing)
  • Tachycardia (rapid heart rate)
  • Diaphoresis (excessive sweating)
  • Cyanosis (bluish discoloration of the skin)
  • Hypotension (low blood pressure)
  • Shock and cardiovascular collapse

Postthrombotic syndrome may lead to chronic symptoms such as lower extremity swelling, pain, tenderness, skin discoloration, and possible ulcerations.

DIAGNOSIS

Diagnosis should focus on identifying risk factors. The following diagnostic modalities are commonly used:

  • Compression ultrasound (CUS): A primary tool for DVT evaluation.
  • Computed tomography pulmonary angiography (CTPA): Often used for the assessment of PE.
  • Radiographic contrast studies: Venography and pulmonary angiography are the most accurate but are expensive and invasive.
  • Ventilation-perfusion (V/Q) scan: An alternative diagnostic method for PE.
D-dimer Testing:

In patients with VTE, serum levels of d-dimer are typically elevated. Values less than 500 ng/mL (or mcg/L) in conjunction with clinical decision rules can help rule out VTE.

Clinical Assessment:

Utilize checklists such as the Wells score to stratify the probability of DVT or PE.

DESIRED OUTCOME

Goals of Treatment:
  • Prevention: Initial goals focus on preventing VTE in those at risk.
  • Management of VTE: The treatment aims to prevent thrombus extension, prevent embolization, reduce recurrence, and avert long-term complications, such as postthrombotic syndrome and chronic thromboembolic pulmonary hypertension.

PREVENTION OF VTE

Nonpharmacologic Methods:

Improve venous blood flow via mechanical strategies, including:

  • Early ambulation
  • Graduated compression stockings
  • Intermittent pneumatic compression (IPC) devices
  • Inferior vena cava filters for high-risk patients.
Pharmacologic Prophylaxis:
  • Low-dose unfractionated heparin (LDUH), low-molecular-weight heparin (LMWH), or fondaparinux are recommended for hospitalized patients with high VTE risk and low bleeding risk.
  • In nonorthopedic surgery patients, prophylactic measures with LDUH or LMWH, along with mechanical compression devices, should be employed.
  • For joint replacement surgeries, various agents, including aspirin, adjusted-dose warfarin, unfractionated heparin, LMWH, fondaparinux, dabigatran, apixaban, or rivaroxaban are recommended for at least 10 days post-surgery. Clinical trials advocate for prophylaxis extending up to 21-35 days post-surgery in total hip replacement and hip fracture repair procedures.

GENERAL APPROACH

Anticoagulation remains the primary treatment modality for both DVT and PE, as they are managed similarly. Upon confirmation of VTE, rapid initiation of anticoagulation should occur.

  • Most patients with DVT and selected hemodynamically stable PE cases can be treated as outpatients.
Duration of Anticoagulation Therapy:
  • Generally, an initial duration of treatment should be three months for a first episode of VTE, especially if linked to a transient or reversible risk factor (surgery, hospitalization).
  • For patients with unprovoked (idiopathic) VTE, extended therapy beyond three months should be considered given higher recurrence rates.
  • In patients with VTE and active cancer, anticoagulation is usually continued indefinitely due to elevated recurrence risks.

NON-PHARMACOLOGIC THERAPY

  • Walking and ambulating as much as symptoms allow is advised.
  • Combining ambulation with graduated compression stockings promotes faster symptom relief than complete bed rest without an elevated risk of embolization.
  • Inferior vena cava filters serve as an adjunct in case anticoagulants are contraindicated.
  • Thrombolysis or thrombectomy may be appropriate in cases of severe DVT posing risks to life or limb.

PHARMACOLOGIC THERAPY

Direct Oral Anticoagulants (DOACs):
  • Rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) inhibit factor Xa, while dabigatran (Pradaxa) targets factor IIa directly. DOACs require caution in renal impairment.
Comparisons with Warfarin:
  • Single-drug therapy with rivaroxaban or apixaban proves noninferior to warfarin with similar recurrence rates and potentially reduced bleeding incidents. These agents commence with a higher initial dosage transitioning to maintenance doses.
  • The use of DOACs is discouraged in patients with creatinine clearance (CrCl) less than 25 mL/min, active cancer, or those needing thrombolysis.
Initiation Protocols:
  • Administer edoxaban and dabigatran after a minimum of 5 days with parenteral anticoagulation (e.g., UFH, LMWH).
  • Monitoring for bleeding is paramount, as this is a common side effect of DOACs (Idarucizumab may reverse dabigatran effects during emergencies).
Low-Molecular-Weight Heparin (LMWH):
  • LMWH is derived from unfractionated heparin (UFH) to produce smaller sulfated glycosaminoglycan fragments.
  • It acts by amplifying antithrombin's effects, inhibiting thrombus growth and is administered subcutaneously in weight-based doses.
  • LMWH provides predictable responses and minimal routine laboratory monitoring; it has become the standard for initial VTE treatment and offers benefits over UFH, including reduced thrombocytopenia risk.
Fondaparinux:
  • A synthetic agent that inhibits factor Xa and is effective in treating acute VTE, typically upon transitioning to long-term warfarin therapy.
  • It is contraindicated with CrCl <30 mL/min and requires monitoring for bleeding.
Unfractionated Heparin (UFH):
  • UFH inhibits multiple factors (IXa, Xa, XIIa, and IIa) through direct interaction with antithrombin.
  • The need for monitoring via activated partial thromboplastin time (aPTT) persists, adjusting based on response to dosing.
Warfarin:
  • Warfarin acts by inhibiting vitamin K metabolism crucial for coagulation protein synthesis.
  • Timely initiation alongside parenteral anticoagulants is critical, with a recommended overlap of at least five days.

- Monitoring occurs through INR, ideally targeting 2.5 for VTE, necessitating dietary consideration relative to vitamin K.

THROMBOLYTICS

Thrombolytics are proteolytic enzymes that accelerate the conversion of plasminogen to plasmin, aiding fibrin degradation.

Clinical Indications:
  • Thrombolytic therapy should be reserved for select patients with extensive proximal DVT or massive PE and compromised hemodynamics (hypotension, shock).
Therapy Administration:
  • In cases of DVT, catheter-directed thrombolysis is preferred with careful monitoring.
  • For PE, initiate concurrent IV UFH and monitor coagulation status post-therapy.
Common Thrombolytic Agents:
  • Alteplase (Activase)
  • Streptokinase (Streptase)
  • Urokinase (Abbokinase)

EVALUATION OF THERAPEUTIC OUTCOMES

Patients must be monitored for symptom resolution, recurrence of thrombosis, and any side effects from anticoagulant therapy. Laboratory assessments are critical for:

  • Monitoring hemoglobin, hematocrit, and blood pressure to identify bleeding.
  • Pre-therapy coagulation tests (aPTT, PT, INR) for baseline values are essential.
  • Regular inquiries about medication adherence, additional medications, and dietary factors, particularly vitamin K intake, should be conducted.

OVERLAP AND SWITCHOVER THERAPY

The following guidelines illustrate the management of anticoagulant therapy during the acute and maintenance phases.

Example Protocols Include:
  • Apixaban 10 mg PO BID for first 7 days, then transition to 5 mg PO BID for maintenance.
  • Rivaroxaban 15 mg PO BID for first 21 days, followed by 20 mg PO daily.
  • LMWH or fondaparinux for the initial 5 days, subsequently overlapping with warfarin until INR target is reached.

ANTICOAGULANT SELECTION

A range of factors influences the choice of anticoagulant for initial and ongoing treatment of VTE. This includes considerations concerning cancer, renal function, adherence, and any history of gastrointestinal issues.
Options include:

  • LMWH as preferable when avoiding parenteral therapy in cancer patients.
  • Warfarin in liver dysfunction cases or other risk factors for compliance and potential interactions with other medications.
  • Each situation should be evaluated for specific patient needs, considering antagonist availability and the risk of bleeding.