Pathogenesis/classification

Thrombus formation preferentially starts in the valve pockets of the veins of the calf and extends proximally. This is especially true for those that occur following surgery.16 Though most thrombi begin intraoperatively, some start a few days, weeks, or months after surgery. Lending its support to the origin of thrombus in valve pockets is a recent hypothesis of an increased expression of endothelial protein C receptor (EPCR) and thrombomodulin (TM) and a decreased expression of Von Willebrand factor (vWF) noted in valve sinus endothelium compared with vein luminal endothelium. This means an upregulation of anticoagulants (EPCR, TM) and a downregulation of procoagulant (vWF) properties of the valvular sinus endothelium.17

Thrombus is composed predominantly of fibrin and red cells (red or static thrombus). Venous thrombus must be differentiated from postmortem clot at autopsy. Postmortem clots are gelatinous and have a dark red dependent portion (formed by red cells that have settled by gravity and a yellow chicken fat supernatant resembling melted and clotted chicken fat). They are usually not attached to the underlying wall. This is in contrast to the venous thrombi which are firmer. They almost always have a point of attachment to the wall and transection reveals vague strands of pale gray fibrin.18

DVT in the lower limb can be classified as a) proximal, when the popliteal vein or thigh veins are involved or b) distal, when the calf veins are involved. Clinically, 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.19 Post-thrombotic syndrome, a chronic, potentially disabling condition characterized by leg swelling, pain, venous ectasia, and skin induration, is established by 1 year after DVT in 17% to 50% of cases.20

Uncommon presentations of VTE are forms of acute massive venous thrombosis with obstruction of venous drainage to the extremity.Deep Vein Thrombosis after Open-Heart Surgery Essay.  These include phlegmasia alba dolens, phlegmasia cerulea dolens, and venous gangrene. In phlegmasia alba dolens, the thrombosis involves only the major deep venous channels of the extremity, sparing collateral veins. However, in phlegmasia cerulea dolens, the thrombosis extends to the collateral vein, resulting in massive fluid sequestration and more significant edema.

Clinical features

History and clinical examination are not reliable ways of diagnosing DVT.21 Lower extremity DVT can be symptomatic or asymptomatic. Patients with lower extremity DVT often do not present with erythema, pain, warmth, swelling, or tenderness. Symptomatic patients with proximal DVT may present with lower extremity pain, calf tenderness, and lower extremity swelling.22,23 Homans’ sign may be demonstrable in DVT. Most of these features lack specificity; hence clinical evaluation usually implies the need for further evaluation. The left leg is the commonest site for venous thrombosis in pregnancy11 and in acute massive venous thrombosis. This may be due to compression of the left iliac vein by the right iliac artery (May–Thurner syndrome).24

Phlegmasia alba dolens is characterized by edema, pain, and blanching without cyanosis while phlegmasia cerulea dolens is characterized by these features in addition to cyanosis, which characteristically progresses from distal to proximal areas and bleb/bulla formation.

Risk factors

Rudolph Virchow described three conditions that predispose to thrombus, the so-called Virchow’s triad. This triad includes endothelial injury, stasis or turbulence of blood flow, and blood hypercoagulability.

Stasis and endothelial injury are important in DVT following trauma or surgery while hypercoagulability is responsible for most cases of spontaneous DVT. At least 96% of patients treated for VTE have been shown to have at least one risk factor.25

Risk can be classified as acquired or genetic. When genetic defects are combined with one or more acquired risk factors, or in combined genetic defects or combination of two acquired defects, it results in a risk of VTE that exceeds the separate effects of a single factor.26

In adults, the clinical conditions that predispose to VTE are increasing age, cancer and its treatment, prolonged immobility, stroke or paralysis, previous VTE, congestive heart failure, acute infection, pregnancy or puerperium, dehydration, hormonal treatment, varicose veins, long air travel, acute inflammatory bowel disease, rheumatological disease, and nephrotic syndrome. Deep Vein Thrombosis after Open-Heart Surgery Essay.Other acquired factors that have recently been associated with increased risk of VTE disorders include persistent elevation of D-dimer and atherosclerotic disease.27

Oral contraceptive pills, especially those that contain third-generation progestins increase the risk of VTE.28 Risk of DVT associated with long-duration air travel is called economy class syndrome.29 It is 3% to 12% in a long-haul flight with stasis, hypoxia, and dehydration being pathophysiological changes that increase the risk.30 van Aken et al demonstrated that subjects with elevated levels of interleukin-8 have increased risk of venous thrombosis, supporting an important role of inflammation in etiopathogenesis of venous thrombosis.31

Clayton et al have described a strong association between recent respiratory infection and VTE. They demonstrated an increased risk of DVT in the month following infection and PE in 3 months following infection, both persisting up to a year.32

In the pediatric age group, the most important triggering risk factors for development of thromboembolism are the presence of central venous lines, cancer, and chemotherapy. Severe infection, sickle cell disease, trauma, and antiphospholipid syndromes are clinical conditions associated with hypercoagulability states.33

Genetic risk factors can be divided into strong, moderate, and weak factors.34 Strong factors are deficiencies of anti-thrombin, protein C and protein S. Moderately strong factors include factor V Leiden, prothrombin 20210A, non-O blood group, and fibrinogen 10034T. Weak genetic risk factors include fibrinogen, factor XIII and factor XI variants. Deep Vein Thrombosis after Open-Heart Surgery Essay.

Clinical prediction rules

A commonly accepted evidence-based approach to diagnosis of VTE is the use of a clinical model that standardizes the clinical assessment (combining risk factors, signs and symptoms) and subsequently stratifies patients suspected of DVT.

Though this model has been used for both primary care patients and secondary settings, there is no doubt that it does not guarantee accurate estimation of risk in primary care patients in whom DVT is suspected.35

The most commonly recommended model is that developed by Wells and colleagues. Based on clinical presentation and risk factors, an initial model was developed to group patients into low-, moderate-, and high-probability groups. The high-probability group has an 85% risk of DVT, the moderate-probability group a 33% risk, and the low-probability group a 5% risk.36 However, in a later study, Wells and colleagues further streamlined the diagnostic process by stratifying patients into two risk categories: “DVT unlikely” if the clinical score is ≤1 and “DVT likely” if the clinical score is >1 (Table 1).37

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.Deep Vein Thrombosis after Open-Heart Surgery Essay. It reflects a global activation of blood coagulation and fibrinolysis.38 It is the best recognized biomarker for the initial assessment of suspected VTE. The combination of clinical risk stratification and a D-dimer test can exclude VTE in more than 25% of patients presenting with symptoms suggestive of VTE without the need for additional investigations.39 Even in patients with clinically suspected recurrent DVT, this combination (clinical evaluation and D-dimer) has proved to be useful for excluding DVT, especially in patients included in the lower clinical pretest probability group.40

Levels of D-dimer can be popularly measured using three types of assay:

• Enzyme linked immunosorbent assay (ELISA).

• Latex agglutination assay.

• Red blood cell whole blood agglutination assay (simpliRED).

These assays differ in sensitivity, specificity, likelihood ratio, and variability among patients with suspected VTE. ELISAs dominate the comparative ranking among D-dimer assays for sensitivity and negative likelihood ratio.

D-dimer assays are highly sensitive (values up to 95%), but have poor specificity to prove VTE. The negative predictive value for patients with a negative D-dimer blood test is nearly 100%. Hence a negative value of D-dimer may safely rule out both DVT and PE. False positive D-dimer results have been noted in inflammation,41 pregnancy,42 malignancy,43 and the elderly.44 Clinical usefulness of the measurement of D-dimer has been shown to decrease with age.45 The use of age-dependent cut-off values of D-dimer assays is still a matter of controversy. Several studies have shown that the levels of D-dimer assays increase with gestational age and in complicated pregnancies as observed in preterm labor, abruptio placenta, and gestational hypertension.46–48 Elevated D-dimer was found to be predictive of poor outcome (persistent thrombosis, recurrence or post-thrombotic syndrome) in children with an acute thrombotic event.49 False negative D-dimer results have been noted after heparin use; hence it has been recommended that D-dimer assay should be done prior to administering heparin to a patient.43 Other causes of false negative D-dimer results are late presentation (symptoms longer than 2 weeks) and small below-knee DVT.

Venous ultrasonography

Venous ultrasonography is the investigation of choice in patients stratified as DVT likely.50 It is noninvasive, safe, available, and relatively inexpensive. There are three types of venous ultrasonography: compression ultrasound (B-mode imaging only), duplex ultrasound (B-mode imaging and Doppler waveform analysis), and color Doppler imaging alone. In duplex ultrasonography, blood flow in normal vein is spontaneous, phasic with respiration, and can be augmented by manual pressure. In color flow sonography, pulsed Doppler signal is used to produce images.51 Compression ultrasound is typically performed on the proximal deep veins, specifically the common femoral, femoral, and popliteal veins, whereas a combination of duplex ultrasound and color duplex is more often used to investigate the calf and iliac veins.52

The major ultrasonographic criterion for detecting venous thrombosis is failure to compress the vein lumen under gentle probe pressure.  Deep Vein Thrombosis after Open-Heart Surgery Essay.Other criteria for ultrasonographic diagnosis of venous thrombosis include loss of phasic pattern in which flow is defined as continuous, response to valsava or augmentation (Duplex ultrasound), and complete absence of spectral or color Doppler signals from the vein lumen.53

The other advantages of venous ultrasound are its ability to diagnose other pathologies (Baker’s cysts, superficial or intramuscular hematomas, lymphadenopathy, femoral aneurysm, superficial thrombophlebitis, and abscess), and the fact that there is no risk of exposure to irradiation, while its major limitation is its reduced ability to diagnose distal thrombus.22 Venous compressibility may be limited by a patient’s characteristics such as obesity, edema, and tenderness as well as by casts or immobilization devices that limit access to the extremity. Compression B-mode ultrasonography with or without color Duplex imaging has a sensitivity of 95% and a specificity of 96% for diagnosing symptomatic, proximal DVT.54 For DVT in the calf vein, the sensitivity of venous ultrasound is only 73%.55

Repeat or serial venous ultrasound examination is indicated for initial negative examination in symptomatic patients who are highly suspicious for DVT and in whom an alternative form of imaging is contraindicated or not available. Serial testing has been found unnecessary for those in whom DVT is unlikely by Wells score and has a negative D-dimer test.

Contrast venography

Venography is the definitive diagnostic test for DVT, but it is rarely done because the 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. A large volume of Omnipaque diluted with normal saline results in better deep venous filling and improved image quality.56

The most reliable cardinal sign for the diagnosis of phlebothrombosis using venogram is a constant intraluminal filling defect evident in two or more views.56 Another reliable criterion is an abrupt cutoff of a deep vein, a sign difficult to interpret in patients with previous DVT.57 It is highly sensitive especially in identifying the location, extent and attachment of a clot and also highly specific.

Being invasive and painful remains its major setback. The patient is exposed to irradiation and there is also an additional risk of allergic reaction and renal dysfunction. Occasionally a new DVT may be induced by venography,58 probably due to venous wall irritation and endothelial damage. The use of nonionic contrast medium has reduced considerably risks of anaphylactic reaction and thrombogenecity or may have even eliminated them.59,60

Impedance plethysmography

The 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. 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.61 It is portable, safe, and noninvasive but its main drawback remains an apparent insensitivity to calf thrombi and small, nonobstructing proximal vein thrombi. Deep Vein Thrombosis after Open-Heart Surgery Essay.

Magnetic resonance imaging (MRI)

This investigative modality has high sensitivity in detecting calf and pelvic DVTs,62 and upper extremity venous thromboses.63 It is also relevant in ruling out differential diagnoses in patients suspected of DVT. MRI is 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.

Algorithm for the diagnosis of DVT

The first step is the pretest probability assessment using an established model such as the Wells score (Figure 1). If score is ≤1 (DVT unlikely), D-dimer assay is done. If assay is negative, DVT is excluded and the patient can be discharged without further investigations. If assay is positive, a venous ultrasound is indicated. Negative venous ultrasound scan excludes the diagnosis of DVT. Diagnosis of DVT is made if venous ultrasonography is positive.

If the DVT is likely (probability score ≥2), venous ultrasonography is indicated. DVT is diagnosed and treated if venous ultrasound is positive. If negative, D-dimer assay should be done. Negative D-dimer excludes the diagnosis of DVT while a positive result is an indication for follow-up studies; repeat ultrasound in 6 to 8 days or do venography. This algorithm is not used in pregnancy because D-dimer is falsely elevated.

Prophylaxis