Deep Vein Thrombosis - Pulmonary Embolism

Venous thromboembolism (VTE) is the presence of thrombus in a vein with accompanying inflammation. Clots in deep veins can cause significant morbidity or mortality. D-dimer is an initial laboratory test for clinical symptoms suggestive of clot; however, diagnosis of VTE relies heavily on imaging. Other laboratory testing may include CBC, evaluation for thrombophilia, and monitoring for heparin-induced thrombocytopenia (HIT) antibody. If treatment with warfarin is initiated, prothrombin time is used for monitoring. Pharmacogenetic testing for pathways associated with warfarin metabolism may be indicated.

Diagnosis

Indications for Testing

  • Evaluation for venous thromboembolism (VTE) should include assessment of deep vein thrombosis (DVT) and pulmonary embolism (PE), both of which present with nonspecific symptoms
    • PE symptoms
      • Shortness of breath, pleuritic chest pain, presyncope or syncope, and hemoptysis
    • DVT symptoms
      • Lower extremity – unilateral extremity swelling and pain in absence of trauma
      • Portal vein – symptoms of hepatic congestion
      • Mesenteric venous system – pain out of proportion to exam

Criteria for Diagnosis

Laboratory Testing

  • Initial testing
    • D-dimer test
      • For patients with intermediate or low pretest probability by CPR
      • Negative test rules out VTE
      • Cutoff >500 ng/mL fibrinogen equivalent units (FEUs) or age times 10 ng/mL if >50 years old (cutoffs in FEUs do not apply to results generated from assays in D-dimer units [DDUs])
      • Test is not specific – patients with positive test require imaging, usually Doppler or compression ultrasound
  • Concurrent testing
    • CBC
      • Low platelets suggest consumption by clotting cascade
      • Used for serial monitoring of patients on heparin to detect heparin-induced thrombocytopenia (HIT)
    • Prothrombin time and international normalized ratio (PT/INR)
      • Used to evaluate clotting status before starting anticoagulant therapy
    • Partial thromboplastin time (PTT)
      • Used to evaluate clotting status before starting anticoagulant therapy
    • HIT antibody – in high pretest probability scenario (refer to clinical probability charts); strong positive enzyme-linked immunosorbent assay (ELISA) confirms diagnosis of HIT
    • Testing for acquired thrombophilia should be considered for high-risk patients
    • Testing for inherited thrombophilia is not warranted in first DVT but may be indicated in select patients (see Thrombophilia topic)
    • Laboratory cardiac biomarker tests may be helpful for patients with right ventricular dilatation being considered for outpatient management – normal values indicate low-risk patients (see Acute Coronary Syndrome) (Luke, 2018)
      • B-type natriuretic peptide (BNP)
      • N-terminal pro B-type natriuretic peptide (NT-proBNP)
      • High-sensitivity troponin I or T (hsTnI or hsTnT)

Imaging Studies

  • Computed tomography angiography (CTA) – initial imaging for patients with high pretest probability (D-dimer is not necessary)
  • Venous duplex ultrasound (DUS) – initial imaging for patients with positive D-dimer
    • Positive scan confirms diagnosis; negative scan requires further imaging with CTA or ventilation/perfusion (V/Q) scan
  • V/Q scan
    • Imaging of choice to avoid radiation or contrast exposure in young patients (especially female) or those with
      • Pregnancy
      • History of contrast medium-induced anaphylaxis
      • Severe kidney disease
      • Myeloma
      • Paraproteinemia
    • Also indicated for patients with low clinical probability of PE and normal chest x-ray
  • Contrast venography and magnetic resonance imaging (MRI) are not recommended imaging, although MRI is being investigated for clinical use
  • Pulmonary angiography is rarely performed

Prognosis

  • Undetected clot carries a 30% risk of mortality, whereas the mortality for treated clot may be as low as 3%
  • Two-to six-fold increase in mortality in patients with cancer (National Comprehensive Cancer Network [NCCN], 2017)

Differential Diagnosis

  • Shortness of breath
  • Swollen leg
    • Cellulitis
    • Lymphedema
    • Venous stasis/venous insufficiency
    • Ruptured Baker cyst
    • Postphlebitic syndrome
  • Chest pain
    • Acute coronary syndrome
    • Pleurisy
    • Musculoskeletal chest pain
    • Malignancy
    • Pneumonia
    • Aortic dissection
  • Elevated D-dimer
    • Cancer
    • Inflammation
    • Bleeding
    • Trauma
    • Surgery
    • Necrosis

Monitoring

  • Prothrombin time and international normalized ratio (PT/INR) – standard monitoring for warfarin therapy
  • Partial thromboplastin time (PTT) – standard monitoring for unfractionated heparin therapy
  • Heparin antifactor Xa assay – monitoring for low molecular weight heparin therapy when indicated
  • CBC – monitoring of platelets in patients receiving heparin for heparin-induced thrombocytopenia (HIT)

Pharmacogenetics

  • Warfarin (Coumadin) – metabolized in the liver by cytochrome P450 enzymes
    • Therapy
      • Response to warfarin therapy is routinely assessed through prothrombin time and international normalized ratio (PT/INR) testing
      • Cautions
        • Consider warfarin/drug interactions

Cytochrome P450 drug interactions – Flockhart table  (Flockhart, 2007)

  • Incorrect dosing can result in potentially severe hemorrhagic or thrombotic consequences
  • Narrow therapeutic index influenced by many medications and illnesses
  • Inhibits production of vitamin K-dependent coagulation factors through inhibition of vitamin K epoxide reductase
    • Intake of vitamin K (eg, green leafy vegetables) must be carefully regulated during treatment
    • Dosing
      • Consider CYP2C8, CYP2C9, CYP4F2, and VKORC1 genotyping in warfarin-naive patients and those with a history of previous difficulty in anticoagulation
      • CYP2C9 genotype accounts for up to 18% of the variability in warfarin dosing
      • CYP2C8 and CYP2C9 variant alleles reduce warfarin clearance, which affects the time required to reach steady state warfarin concentrations
      • VKORC1 genotype accounts for up to 29% of the variability in warfarin dosing
      • Combining genotypes with clinical factors may account for 50-70% of variability in warfarin dosing
      • Many algorithms and models for dosing are available to assist with clinical/genotype-based dosing of warfarin
        • Algorithms predict maintenance dose but do not necessarily consider pharmacokinetic differences that may influence the time required to achieve a steady state
        • Algorithms typically do not offer guidance regarding dosing intervals or indicate when interpretation of an INR result is appropriate
        • Dose revision algorithms after INR response are also available (Lenzini, 2010)
        • See 2010 labeling revision for Coumadin or one of many warfarin dosing calculators for therapeutic dose estimates

Background

Epidemiology

  • Incidence (CDC, 2015)
    • 1-2/1,000 affected by deep vein thrombosis (DVT)/pulmonary embolism (PE) per year in U.S.
    • Mortality up to 100,000 per year in U.S. from blood clots
  • Sex – M>F (minimal)
    • M<F during childbearing years

Risk Factors

  • Surgery – highest risk with orthopedic operations
  • Cancer – highest risk with cancers of pancreas, gynecologic, lung, urinary tract, brain, stomach, bladder, kidney, lymphoma, myeloproliferative neoplasms, and metastatic cancers (National Comprehensive Cancer Network [NCCN], 2017)
    • Neutropenia associated with even higher risks
  • Trauma – highest risk with fractures of the spine and lower extremities
  • Pregnancy – highest risk in first and third trimesters
  • Hormone use – postmenopausal replacement, oral contraceptives, tamoxifen citrate
  • Immobilization – highest risk with acute myocardial infarction, congestive heart failure, and stroke
  • Hypercoagulable statesantiphospholipid antibodies; activated protein C resistance/factor V Leiden mutation; prothrombin G20210A mutation; deficiencies of protein C, protein S, or antithrombin; elevated homocysteine
  • Previous DVT or PE
  • Indwelling catheters – most common source of upper-extremity DVT
  • Age – risk increases incrementally with age
  • Hereditary thrombophilia – higher risk for recurrence of VTE/PE (Konstantinides, European Society of Cardiology, 2014)

Pathophysiology

  • Factors that predispose to VTE were first described by Virchow in 1856
    • Virchow triad – stasis, vascular damage, and hypercoagulability
    • Individual risk – complex interaction of acquired risk factors and congenital (inherited) factors

Clinical Presentation

  • DVT
    • Extremity pain and swelling, warmth and erythema, pain in calf with foot dorsiflexion (Homans sign); usually unilateral
  • PE
    • Dyspnea, pleuritic chest pain, hemoptysis, low-grade fever, tachycardia, split S2 heart sound on cardiac auscultation, syncope, decreased oxygen saturation
  • Mesenteric/portal vein clot
    • Abdominal pain more severe than indicated by physical exam (Bala, World Society of Emergency Surgery, 2017)

ARUP Laboratory Tests

Use to rule out venous thromboembolism

Utilizes age-stratified reference intervals

D-Dimer for Venous Thromboembolism

Initial test for suspected bleeding disorder

Monitor heparin therapy

Initial test for evaluating bleeding disorders and monitoring oral anticoagulation therapy (warfarin/Coumadin)

Related Tests

Monitor patients on heparin for heparin-induced thrombocytopenia (HIT)

Recommended initial screening test for heparin-PF4 antibodies that cause HIT

Confirmation with serotonin release assay unfractionated heparin may be necessary based on clinical presentation

Monitor low molecular weight heparin therapy

Acceptable screening panel for common inherited thrombophilias

Acceptable panel to screen for uncommon inherited thrombophilias

Acceptable panel to detect the 2 most common inherited thrombophilias (prothrombin related and FVL related)

Panel includes FVL (F5) R506Q mutation, MTHFR 2 variants (c.665C>T and c.1286A>C), and prothrombin (F2) G20210A variant

Aid in diagnosing and following disseminated intravascular coagulation (DIC)

Identify individuals with inherited variants that affect metabolism and/or sensitivity to warfarin

Detect factor V Leiden variant

Diagnostic errors can occur due to rare sequence variations

F5 gene mutations, other than c.1601G>A; p.Arg534Gln (R506Q), will not be detected

Medical Experts

Contributor

Lehman

Christopher M. Lehman, MD
Associate Professor of Clinical Pathology, University of Utah
Medical Director, University of Utah Health Hospital Clinical Laboratory, ARUP Laboratories
Contributor
Contributor

Smock

Kristi J. Smock, MD
Professor of Clinical Pathology, University of Utah
Medical Director, Hemostasis/Thrombosis, ARUP Laboratories

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®