Decision Making in Venous Thromboembolism

Pathogenesis

Abnormalities in both coagulation factors and the vascular bed are at the core of the pathogenesis of VTE. The multifaceted etiology of thrombosis was first described in 1856 by Virchow, who defined a triad of defects in the vessel wall, platelets, and coagulation proteins [24].Usually the vessel wall is lined with endothelial cells that provide a nonthrombotic surface and limit platelet aggregation through release of prostacyclins and nitric oxide. When the endothelial lining is compromised, the homeostatic surveillance system is disturbed and platelet activation and the coagulation system are initiated. Tissue factor exposure in the damaged area of the vessel leads to activation of the coagulation cascade. Collagen that is present in the area of the wound is also exposed and can activate platelets, which provide the phospholipid surface upon which the coagulation cascade occurs. Platelets initially tether to the exposed collagen through binding of glycoprotein Ib-V-IX in association with von Willebrand factor [25].The thrombus is initiated as more platelets are recruited to exposed collagen of the injured endothelium through aggregation in response to the binding of GPIIIb/IIa with fibrinogen. This process is self-perpetuating as these activated platelets release additional proteins such as adenosine diphosphate (ADP), serotonin, and thromboxane A2, all of which fuel the recruitment and activation of additional platelets [26].

Diagnosis

The key to decreasing the morbidity and mortality associated with VTE is timely diagnosis and early initiation of therapy. Various imaging modalities can be employed to support a diagnosis of a VTE and are used based on clinical suspicion arising from the presence of signs and symptoms. DVT is usually associated with pain in calf or thigh, unilateral swelling, tenderness, and redness. PE can present as chest pain, shortness of breath, syncope, hemoptysis, and/or cardiac palpitations.

Decision Rules

Clinical decision rules based on signs, symptoms, and risk factors have been developed to estimate the pretest probability of PE or DVT and to help determine which patients warrant further testing. These clinical decision rules include the Wells criteria (separate rules for DVT and PE) [27,28],as well as the Geneva score [29],which is focused on identifying patients with a likelihood of having a PE. In general, these clinical rules are applied at presentation to predict the risk of VTE, and patients who score high are evaluated by imaging modalities, while those with lower scores should be considered for further stratification based on D-dimer testing. The goal of clinical assessment and use of a decision rule is to identify patients at low risk of VTE to reduce the number of imaging studies performed. Most of the decision rules focus on the use of noninvasive evaluations that are easily implemented, including clinical history and presentation, abnormalities in oxygen saturation, chest radiography findings, and electro-cardiography.

D-Dimer Testing

D-dimer testing is at the core of all predictive models for VTE. D-dimer is a fibrin degradation product that is detectable in the blood during active fibrinolysis and occurs after clot formation. The concentration of D-dimer increases in patients with active clot. D-dimer testing is usually performed as a quantitative ELISA or automated turbidometric assay and is highly sensitive (> 95%) in excluding a diagnosis of VTE if results are in the normal range [30].The presence of a normal D-dimer and a low probability based on clinical assessment criteria can be integrated to determine which patients have a low (generally < 99%) likelihood of having VTE [31].It should be noted that other factors can lead to an increased D-dimer, including malignancy, trauma, critical illness, disseminated intravascular coagulation, pregnancy, infection, and postoperative status, which can produce false-positive results and cloud the utility of the test in excluding those at low risk of VTE from undergoing imaging [32–34].Additionally, D-dimer values naturally increase with age and recent work has shown utility of an age-adjusted D-dimer threshold, though this method is not yet widespread in clinical practice [35,36].