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Hematological System

Deep vein thrombosis (DVT)

Subset of venous thromboembolism (VTE) in which blood clot forms in one of the larger, deeper veins that run through the muscles.

Subset of venous thromboembolism (VTE) in which blood clot forms in one of the larger, deeper veins that run through the muscles.

  • M/C cause of lost disability-adjusted life years (DALY) worldwide
  • #3 M/C cause of cardiovascular death worldwide

Etiology

Venous thrombosis refers to the formation, from constituents of blood, of an abnormal mass within the vascular system of a living animal. When this process occurs within the deep veins, it is referred to as deep vein thrombosis (DVT).

Virchow’s triad:

A combination of blood stasis, plasma hypercoagulability and endothelial dysfunction is thought to trigger thrombosis, which starts most often in the valve pockets of large veins.
Suspected deep vein thrombosis
The Calgary Guide | http://calgaryguide.ucalgary.ca/

Increased risk of coagulation:

  • Non-O blood groups
  • Factor V Leiden mutation
  • Oral contraceptive (OCP) use
  • Hormone replacement therapy (HRT)
  • Advanced age
  • Surgery, hospitalization and long-haul travel
Air Travel–Related Deep Vein Thrombosis and Pulmonary Embolism
Air Travel–Related Deep Vein Thrombosis and Pulmonary Embolism | HJ, S., BG, E., WD, T., AE, B. and EH, L. (2012) ‘Air travel–related deep vein thrombosis and pulmonary embolism’, JAMA, 308(23), p. 2531. Available at: http://dx.doi.org/10.1001/jama.2012.4098.

Classification

Proximal vein thrombosis is of greater importance and is associated with serious chronic diseases such as active cancer, congestive cardiac failure, respiratory insufficiency, or age above 75 years, whereas distal thrombosis is more often associated with risk factors such as recent surgery and immobilization. Fatal PE is far more likely to result from proximal DVT.

  • Proximal DVT: Popliteal vein or thigh veins involved
  • Distal DVT: Calf veins involved
Diagram of leg veins (anterior view of right leg)
Diagram of leg veins (anterior view of right leg) | Photo by: Lianne Friesen and Nicholas Woolridge

Presentation

Lower extremity DVT can be symptomatic or asymptomatic. Patients with lower extremity DVT often do not present with erythema, pain, warmth, swelling, or tenderness.

  • Lower extremity pain
  • Calf tenderness
  • Lower extremity swelling
Clinical presentation of deep-vein thrombosis
Clinical presentation of deep-vein thrombosis. These images show patients with extensive deep-vein thrombosis that included the proximal veins of the legs. Note the pronounced swelling in the calves and thighs (indicated by asterisks). Images courtesy of S. Moll, University of North Carolina, Chapel Hill, USA.

Uncommon presentations of VTE:

Forms of acute massive venous thrombosis with obstruction of venous drainage to the extremity
  • Phlegmasia alba dolens “white legs”: Thrombosis involves only major deep venous channels of extremity, sparing collateral veins characterized by edema, pain, and blanching without cyanosis
  • Phlegmasia cerulea dolens “milk legs”: Thrombosis extends to collateral veins, resulting in massive fluid sequestration and more significant edema, characterized by above features in addition to cyanosis, which characteristically progresses from distal to proximal areas and bleb/bulla formation.
  • Venous gangrene (both phlegmasia cerulea and alba dolens are complicated by venous gangrene)
Clinical examples of phlegmasia alba dolens (PAD) (A) and phlegmasia cerulea dolens (PCD) (B and C)
Clinical examples of phlegmasia alba dolens (PAD) (A) and phlegmasia cerulea dolens (PCD) (B and C): Most patients with iliofemoral DVT (IFDVT) present with swelling that involves the entire limb, causing varying degrees of discomfort. PAD (A) generally results from a more limited occlusion of the iliac veins, which causes leg discomfort and oedema. However, the venous return is efficient enough to clear the dermal and subdermal venous blood before cyanosis occurs. The difference between PAD and PCD (B and C) is the amount of deoxyhemoglobin in the venous plexus of the skin and subcutaneous tissue and the degree of discomfort produced by the associated venous hypertension and elevated compartment pressures. | (2020) Phlegmasia alba dolens and phlegmasia cerulea dolens | Surgical Focus. Retrieved December 30, 2020, from https://emorysurgicalfocus.com/2020/07/24/phlegmasia-alba-dolens-phlegmasia-cerulea-dolens/

Complications

Acute complications:

  • Pulmonary embolism (PE) (15% cases) (potentially fatal)
  • Recurrent DVT (30%)
  • Proximal propagation of thrombus (20-30%)
Mechanisms of PE
Mechanisms of PE: After travelling to the pulmonary arteries, emboli may either break down and lodge in the peripheral pulmonary arteries or, alternatively, if very large, remain at the main pulmonary artery bifurcation, which then gives rise to a saddle embolism; this latter event causes severe haemodynamic compromise, collapse and severe dyspnoea. | PE, pulmonary embolism | Huisman, M., Barco, S., Cannegieter, S. et al. Pulmonary embolism. Nat Rev Dis Primers 4, 18028 (2018). https://doi.org/10.1038/nrdp.2018.28

Long-term complications:

  • Post-phlebitis/thrombotic syndrome (17-50% cases): Chronic, potentially disabling condition characterized by leg swelling, pain, venous ectasia, and skin induration, established by 1 year after DVT
  • Pulmonary hypertension
Long-term consequences of venous thromboembolism
Long-term consequences of venous thromboembolism | PTS: Post-thrombotic syndrome | Wolberg, A., Rosendaal, F., Weitz, J. et al. Venous thrombosis. Nat Rev Dis Primers 1, 15006 (2015). https://doi.org/10.1038/nrdp.2015.6

Diagnosis

Diagnosis of VTE requires testing and exclusion of other pathologies, and typically involves laboratory measures (such as D-dimer) and diagnostic imaging.

Clinical examination:

Most of these features lack specificity; hence clinical evaluation usually implies the need for further evaluation.
  • Homan’s test/dorsiflexion sign: Calf pain at dorsiflexion of the foot
  • Bancroft’s sign aka. Moses’ sign: Pain is elicited when the calf muscle is compressed forwards against the tibia, but not when the calf muscle is compressed from side to side
  • Neuhoff’s sign: Tender fullness of the calf on palpation
  • Perthes manoeuvre: Limb is elevated and an elastic bandage is applied firmly from the toes to the upper 1/3 of the thigh to obliterate the superficial veins only. With the bandage applied the patient is asked to walk for 5 minutes.
    • If deep system is competent, the blood will go through and back to the heart
    • If the deep system is incompetent, the patient will feel pain in the leg
  • Linton test (verification of Perthes manoeuvre): Patient is then placed supine, and the leg is then elevated
    • If varices distal to the tourniquet fail to drain after a few seconds, again deep venous obstruction must be considered.

Clinical prediction rules:

Takes into account signs, symptoms and risk factors can be accurately applied to categorize patients as having low, moderate or high probability of DVT. Alternatively, the same rule can be used to categorize cases as “DVT likely” or “DVT unlikely.”
Clinical model predicting pretest probability of DVT
Scarvelis, D., & Wells, P. S. (2006). Diagnosis and treatment of deep-vein thrombosis. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne, 175(9), 1087–1092. https://doi.org/10.1503/cmaj.060366

D-dimer assay:

D-dimer is a degradation product of cross-linked fibrin that is formed immediately after thrombin-generated fibrin clots are degraded by plasmin. It reflects a global activation of blood coagulation and fibrinolysis. It is the best recognized biomarker for the initial assessment of suspected VTE.
  • Enzyme linked immunosorbent assay (ELISA)
  • Latex agglutination assay
  • Red blood cell whole blood agglutination assay (simpliRED)
Management algorithm for suspected venous thromboembolism
Management algorithm for suspected venous thromboembolism. | Wolberg, A., Rosendaal, F., Weitz, J. et al. Venous thrombosis. Nat Rev Dis Primers 1, 15006 (2015). https://doi.org/10.1038/nrdp.2015.6

Duplex ultrasound (B-mode imaging and Doppler waveform analysis)

GOLD STANDARD investigation in patients stratified as DVT likely.
  • Normal vein:
    • Spontaneous blood flow, phasic with respiration, and can be augmented by manual pressure
    • Mickey mouse sign: Normal anatomy at saphenofemoral junction (SFJ):
      • Common femoral artery (CFA)
      • Common femoral vein (CFV)
      • Great saphenous vein (GSV)
  • DVT findings:
    • Failure to compress the vein lumen under gentle probe pressure
    • Loss of phasic pattern in which flow is defined as continuous
    • Response to valsalva or augmentation
Sonographic landmark of superficial femoral veins
Sonographic landmark of superficial femoral veins. (A) The ‘Egyptian eye’: a transverse ultrasound image of the great saphenous vein in the thigh with/without compression showing the fascial components that constitute the saphenous compartment. (B) Transverse view of the common femoral vein (CFV) and artery in the right groin: ‘Mickey mouse’ view. GSV, great saphenous vein; CFA, common femoral artery; SFJ, saphenofemoral junction. | Youn, Y. J., & Lee, J. (2019). Chronic venous insufficiency and varicose veins of the lower extremities. The Korean journal of internal medicine, 34(2), 269–283. https://doi.org/10.3904/kjim.2018.230

Color Doppler imaging:

Pulsed Doppler signal used to produce images
  • Complete absence of spectral or color Doppler signals from the vein lumen
Venous color-flow Doppler. US Doppler imaging of the left femoral vein showing complete occlusion by a heterogeneous thrombus with dilatation of the vein at the site of thrombosis
Venous color-flow Doppler. US Doppler imaging of the left femoral vein showing complete occlusion by a heterogeneous thrombus with dilatation of the vein at the site of thrombosis. No significant waveform is present. The adjacent artery is also shown for reference. | US, ultrasound. | Stone, J., Hangge, P., Albadawi, H., Wallace, A., Shamoun, F., Knuttien, M. G., Naidu, S., & Oklu, R. (2017). Deep vein thrombosis: pathogenesis, diagnosis, and medical management. Cardiovascular diagnosis and therapy, 7(Suppl 3), S276–S284. https://doi.org/10.21037/cdt.2017.09.01

Contrast venography

Definitive diagnostic test for DVT, but it is rarely done because noninvasive tests (D-dimer and venous ultrasound) are more appropriate and accurate to perform in acute DVT episodes. It involves cannulation of a pedal vein with injection of a contrast medium, usually noniodinated, eg, Omnipaque. It is highly sensitive especially in identifying the location, extent and attachment of a clot and also highly specific.
  • Constant intraluminal filling defect evident in two or more views (cardinal sign)
  • Abrupt cutoff of a deep vein
Contrast venography. Angiogram imaging of the left popliteal vein demonstrating a partially occlusive thrombus with irregular margins and diminished contrast flow
Contrast venography. Angiogram imaging of the left popliteal vein demonstrating a partially occlusive thrombus with irregular margins and diminished contrast flow. This thrombus was subsequently treated with catheter directed therapy. | Stone, J., Hangge, P., Albadawi, H., Wallace, A., Shamoun, F., Knuttien, M. G., Naidu, S., & Oklu, R. (2017). Deep vein thrombosis: pathogenesis, diagnosis, and medical management. Cardiovascular diagnosis and therapy, 7(Suppl 3), S276–S284. https://doi.org/10.21037/cdt.2017.09.01

Impedance plethysmography:

Technique is based on measurement of the rate of change in impedance between two electrodes on the calf when a venous occlusion cuff is deflated. It is portable, safe, and noninvasive but its main drawback remains an apparent insensitivity to calf thrombi and small, nonobstructing proximal vein thrombi.
  • Free outflow of venous blood produces a rapid change in impedance while delay in outflow, in the presence of a DVT, leads to a more gradual change.
Normal digital photoplethysmography curve together with an abnormal curve implying deep vein thrombosis
Normal digital photoplethysmography curve together with an abnormal curve implying deep vein thrombosis | Tovey, C., & Wyatt, S. (2003). Diagnosis, investigation, and management of deep vein thrombosis. BMJ (Clinical research ed.), 326(7400), 1180–1184. https://doi.org/10.1136/bmj.326.7400.1180

Magnetic resonance imaging (MRI)

High sensitivity in detecting calf and pelvic DVTs, and upper extremity venous thromboses. and the diagnostic test of choice for suspected iliac vein or inferior vena caval thrombosis when computed tomography venography is contraindicated or technically inadequate. There is no risk of ionizing radiation but it is costly, scarce, and reader expertise is required.
MR venography. MR imaging demonstrating a focal thrombus in the left common iliac vein that was seen extending superiorly to the inferior vena cava. No thrombus is seen on the contralateral side. + MR, magnetic resonance.
MR venography. MR imaging demonstrating a focal thrombus in the left common iliac vein that was seen extending superiorly to the inferior vena cava. No thrombus is seen on the contralateral side. + MR, magnetic resonance. | Stone, J., Hangge, P., Albadawi, H., Wallace, A., Shamoun, F., Knuttien, M. G., Naidu, S., & Oklu, R. (2017). Deep vein thrombosis: pathogenesis, diagnosis, and medical management. Cardiovascular diagnosis and therapy, 7(Suppl 3), S276–S284. https://doi.org/10.21037/cdt.2017.09.01

Differential diagnosis:

  • Ruptured Baker’s cyst
  • Ruptured plantaris tendon
  • Calf muscle hematoma
  • Cellulitis leg
  • Superficial thrombophlebitis

Management

Mechanical prophylaxis:

Enhances blood flow in the deep veins of the leg, preventing venous stasis and hence preventing venous thrombosis. It is indicated in high risk of bleeding with anticoagulation prophylaxis. These includes patients with active or recent gastrointestinal bleeding, patients with hemorrhagic stroke, and those with hemostatic defects such as severe thrombocytopenia. It is contraindicated in patients with evidence of leg ischemia due to peripheral vascular disease. There is a theoretical risk of fibrinolysis and clot dislodgement.
  • Intermittent pneumatic compression (IPC) device
  • Graduated compression stocking (GCS)
  • Venous foot pump

Anticoagulant therapy:

mainstay of treatment. VTE is treated with anticoagulants and occasionally with thrombolytics to prevent thrombus extension and to reduce thrombus size. Anticoagulants are also used to reduce recurrence. New therapies with improved safety profiles are needed to prevent and treat venous thrombosis.
  • Unfractionated heparin (UFH)
  • Low-molecular-weight heparins (LMWH)
  • Vitamin K antagonists
  • Warfarin: Drug of choice for long-term therapy to prevent clot formation once acute anticoagulation is achieved.
  • Newer drugs:
    • Sselective indirect factor Xa inhibitor: Fondaparinux
    • Selective direct thrombin inhibitor: Dabigatran
    • Selective direct factor Xa inhibitors: Rivaroxaban and apixaban
The different phases of treatment with traditional and novel therapies in venous thromboembolism (VTE)
The different phases of treatment with traditional and novel therapies in venous thromboembolism (VTE) | Streiff, M. B., Agnelli, G., Connors, J. M., Crowther, M., Eichinger, S., Lopes, R., McBane, R. D., Moll, S., & Ansell, J. (2016). Guidance for the treatment of deep vein thrombosis and pulmonary embolism. Journal of thrombosis and thrombolysis, 41(1), 32–67. https://doi.org/10.1007/s11239-015-1317-0

Summary:

Activation of blood coagulation in veins leads to thrombosis
Activation of blood coagulation in veins leads to thrombosis. Deep-vein thrombosis is often asymptomatic and only becomes apparent when its consequences, such as pulmonary embolism and breathlessness, occur. | Venous thrombosis. Nat Rev Dis Primers 1, 15050 (2015). https://doi.org/10.1038/nrdp.2015.50

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