Clinical symptoms for DVT are nonspecific and can consist of swelling, erythema, warmth, pain, tenderness, and cramping of affected extremities which may slowly progress over several days and then suddenly accelerate [35]. Some individuals may not have any clinical signs or symptoms of DVT until after development of PE. Though most DVTs are distal, presenting in the calf and popliteal vein, iliac and common femoral vein DVT represent a specific subgroup of patients with highest risk of post-thrombotic morbidity [36].

Clinical diagnosis is based on a high index of suspicion leading to further lab and diagnostic imaging tests. Differential diagnosis for DVT include cellulitis, edema secondary to lymphedema, varicose veins, Baker’s cysts, congestive heart failure, and malignancy. Individual clinical signs and symptoms such as Homans’ sign have been used to guide physicians when to consider further diagnostic tests in patients; however, when used individually, these clinical signs have limited specificity and sensitivity given that they appear in only a fraction of patients. When clinical symptoms and signs are used in combination, they do have a high negative predictive value (90–95%), but positive predictive values are only in the range of 30–50%. Various scoring systems based off of clinical symptoms, signs, and risk factors have been developed to guide clinicians to determine pretest probability of VTE. The most commonly used scoring system for DVT, first proposed in 1995, is the Wells decision rule which incorporates whether or not a patient has a history of cancer , has a history of recent immobility, has localized tenderness, has leg enlargement, has collateral veins, and has a history of prior DVT and whether any other diagnosis is as likely to be the cause of patient’s symptoms [37, 38]. One point is given for each factor, and the score is then stratified into low (0), moderate (1, 2), or high risk (≥3). If a patient has a low score, the likelihood of a DVT is <5%, and testing is geared toward other more likely diagnoses. If score is moderate or high, further diagnostic imaging with duplex ultrasound should be undertaken. D-dimer, a fibrin degradation product, is also utilized in clinical workup of DVT; however, high D-dimer alone is not diagnostic of a VTE given that D-dimer elevation can occur secondary to other causes, including DIC/ICF, recent surgery, active or recent bleeding, hematomas, trauma, pregnancy, liver disease, inflammation, or malignancy [39, 40]. D-dimer, however, does have a high negative predictive value, and a normal D-dimer by ELISA in conjunction with low clinical probability can be satisfactory to rule out DVT [38]. A review of 15 studies in which the Wells score was tested demonstrated that in patients in the low pretest probability category, negative predictive value for DVT of the Wells score was 72–99% and was improved to 96–100% with the presence of a negative D-dimer [41].

PE is a result of a deep venous thrombus embolizing and lodging into the pulmonary circulation. Proximal lower extremity DVT, particularly those in the iliofemoral region, are at highest risk to lead to PE. Acute consequences from PE include death, pulmonary infarction, and right ventricular strain and failure.

Similar to DVT, clinical presentation of PE is quite variable and can manifest as many other diseases and thus is often known as “The Great Masquerader” [42]. Symptoms include combinations of dyspnea, chest pain, coughing, hemoptysis, and/or syncope. A patient’s manifestation of symptoms from PE is dependent on their pulmonary and cardiovascular reserve as well as location and extent of clot burden. Syncope is more likely to occur in patients who have a PE that is causing a sudden obstruction of the most proximal pulmonary arteries. Similarly, patients with a more central PE are at a higher risk for hemodynamic compromise. Patients with more distal PE who have developed pulmonary infarction may present with pleuritic chest pain and hemoptysis. Patients with poor clinical baseline health status may have more severe symptoms with lower thrombus burden than those who have a high cardiovascular and pulmonary reserve. It has been estimated that in patients without a history of heart or pulmonary disease, 30–50% of pulmonary bed obstruction is necessary to develop pulmonary hypertension [43].

Characteristic signs of PE include decreased oxygen saturation, tachycardia and tachypnea. Similar to DVT, clinical signs of PE are variable but still have diagnostic utility. For example, auscultation of a pleural friction rub and decreased breath sounds may be a sign of pleural infarction. Similarly, a patient developing pulmonary hypertension as a sequela of PE may be found to have a loud P2, right sided gallop, and increased central venous pressure.

Chest X-ray, arterial blood gas (ABG) , and electrocardiography (EKG) may or may not reveal abnormalities. Possible abnormal chest X-ray findings include pleural effusion, elevated hemidiaphragm, wedge-shaped atelectasis, and pulmonary consolidation [44]. EKG may indicate a right bundle branch block (complete or incomplete) and/or right ventricular strain pattern (QR in lead V1, T wave inversion in lead V1–V4, S1Q3T3 (prominent S wave in lead I, prominent Q wave, and an inverted T wave in lead III)). Classical EKG pattern is found only in about 2–15% of individuals with pulmonary embolism [45]. ABG analysis can demonstrate hypoxia (PaO2 < 80 mmHg), hypocapnia, and respiratory alkalosis; however it can also be normal.

As with DVT, there are clinical scoring tools for predicting the likelihood of PE. The Wells score for PE (Table 19.3) takes into account whether patients have clinical signs of DVT, recent surgery or immobilization, patient’s heart rate, prior history of PE or DVT, presentation with hemoptysis, history of malignancy, and likelihood of alternative diagnosis other than PE. Patients are stratified into low (<2)-, intermediate (2-6)-, and high (≥6)-risk groups. The negative predictive value of a low (<2) Wells score is high (96.4%) and improves further when combined with a negative D-dimer (98.5%) [46, 47]. Patients who have an intermediate or high PE risk score should then undergo a computed tomography pulmonary angiogram (CTPA) to evaluate for PE.

Severity of PE can be grouped by clinical symptom presentation into acute massive, acute sub-massive, subacute massive, and acute small PE [48]. The most severe form of PE is an acute massive PE with mortality rates exceeding 20% regardless of treatment. Hemodynamic instability with persistent hypotension and cardiogenic shock that may require the use of inotropic and vasopressor support for adequate organ perfusion is associated with severe PE presenting acutely. Patients with acute sub-massive PE are hemodynamically stable but have tachycardia and tachypnea. Mortality rates for acute sub-massive PE range from 5 to 25%. Acute small PEs have a good prognosis with a 3-month morality rate of <1%. Some patients may be asymptomatic or have tachypnea and tachycardia. In subacute massive PE, numerous small emboli form within the pulmonary bed. Symptoms, including exertional dyspnea and fatigue, take longer to develop as it takes longer for pulmonary bed obstruction to develop [49].

Though the introduction of CTPA led to an increased diagnosis of PE, it has also increased detection of small defects within the subsegmental pulmonary arteries. These defects are of questionable clinical significance. In addition to CTPA, advances in imaging techniques have increased incidental discovery of PE in patients obtaining CT of the chest for other reasons as well [50]. The incidence of unsuspected PE (UPE) is 1–5%. In a systematic review of 609 patients with UPE, 48 were localized in the subsegmental branches [51]. In another study investigating morbidity and mortality in patients with UPE, patients with UPE limited to subsegmental arteries had a similar survival and recurrent PE rate when compared to a matched control group of symptomatic PE patients; however those with more proximal locations had increased mortality at 6 months [52]. UPE has been reported in patients with malignancy, trauma patients, and mechanically ventilated patients. In addition, UPE is reported in 50–60% of postmortem autopsy . The question still remains as to whether small subsegmental PE negatively impact patients to the point that they should be treated as having a PE . There has not been a significant decrease in PE-related mortality even though there has been an increase in the diagnosis of PE, suggesting that PE may be “overdiagnosed” [53], although this data should be interpreted with caution as it is based solely on indirect evidence.

Though DVTs are more likely to occur in lower extremities, they also occur in upper extremities, and acute upper extremity DVT (UEDVT) represents 1–4% of all DVTs [36, 54]. The lower incidence of UEDVT can be explained by considering the anatomy of the upper and lower extremities. Upper extremities are not as likely to be immobilized compared to legs, which results in less venous stasis. In addition, arm veins experience less gravitational stress and have fewer valves and therefore have fewer potential foci of thrombus [54].

UEDVT can be grouped into catheter-related and non-catheter-related UEDVT. With increasing use of central venous catheters, catheter-related UEDVT is the most common risk factor for UEDVT. Non-catheter-related UEDVT may be primary or associated with risk factors such as pregnancy, oral contraceptive use, and malignancy [55, 56].

Primary UEDVT, also known as Paget-Schroetter syndrome, differs from lower limb DVT in its pathophysiology and demographic profile and has a poor association with the usual risk factors of DVT. The etiology of primary UEDVT, which is triggered by repetitive exercise, is caused by subclavian vein compression in the narrow space of the thoracic inlet formed by the anterior aspect of the first rib, the medial clavicle, and its associated musculature. Primary UEDVT typically presents in young individuals.

UEDVT may be asymptomatic or can present with pain in the arm, neck, and shoulder regions, arm discoloration, swelling, and venous distention . It may also present with symptoms characteristic of a muscle strain [57]. Differential diagnosis includes cellulitis, lymphedema, hematoma, and superficial phlebitis. Patients could present with a complication of UEDVT including superior vena cava syndrome, PE, or gangrene of the arm [54].

The superior vena cava (SVC) is the major conduit for venous return to the heart from the upper body, and SVC syndrome which is caused by obstruction of blood flow within the SVC either by external compression or thrombosis leads to symptoms of facial, neck, and upper extremity swelling, dyspnea, and cough [58]. External compression from intrathoracic malignancies is the most common etiology of SVC syndrome, with other causes including infectious etiologies such as tuberculous mediastinitis or syphilitic aortic aneurysms [59]. Thrombosis within the SVC occurs most often in the setting of indwelling catheters or pacemakers. In addition to SVC syndrome, patients with UEDVT are also at risk for similar complications from DVT as seen with lower extremities, though patients with UEDVT, whether primary or idiopathic, are less likely to present with symptomatic PE when compared with LE DVT [60].

IVC thrombosis is an underrecognized and underdiagnosed entity. It is estimated that 2.6–4.0% of patients with lower extremity DVT have an IVC thrombosis [61]. The etiology of IVC thrombosis can be divided into congenital versus acquired. Most congenital IVC abnormalities remain asymptomatic due to the development of collaterals. Acquired IVC thrombosis is associated with malignancy, endogenous intervention, placement of foreign bodies such as IVC filter, and abdominal trauma. IVC thrombosis is frequently associated with neoplastic disease, and Stein et al. reported carcinomas in 37.4% of patients diagnosed with IVC thrombosis compared to 11.4% in patients with lower extremity DVT [62]. Similar to lower extremity DVT, acquired thrombophilia and other environmental factors such as medications may also play a role in the development of thrombosis.

Clinical presentation of acute IVC thrombosis varies from an asymptomatic radiographic finding to severe hemodynamic compromise. Other symptoms, including low back or buttock pain, sciatica, and cauda equina-type symptoms, depend on the level of thrombosis and the degree of occlusion. Patients may also present with bilateral lower extremity swelling and dilation of the superficial abdominal vessels. Chronic IVC thrombosis can cause a dull aching pain in both lower limbs as well as symptoms of venous claudication. Most patients with congenital IVC anomalies have few symptoms because of collateral formation and subsequent venous compensation [63].

Unfortunately, if untreated, patients with IVC thrombosis will suffer from significant morbidity including post-thrombotic syndrome, venous claudication, and pulmonary embolism.

Renal vein thrombosis is used to describe the presence of thrombus in the major renal veins or their tributaries. Literature regarding presentation of RVT is limited, and RVT is extremely uncommon in patients without an underlying nephrotic syndrome or renal cancer. A prospective study of patients with nephrotic syndrome demonstrated the presence of RVT in 33% of 151 patients [64]. The largest study regarding RVT was an inception cohort analysis characterizing 218 patients at Mayo Clinic who had renal vein thrombosis (RVT) [65]. In this cohort, compared to DVT, RVT was more likely to be associated with local variables such as malignancy, nephrotic syndrome, infection, and surgery. The prevalence of malignancy was threefold higher in patients with renal vein thrombosis when compared to deep vein thrombosis, with the most common malignancy being renal cell carcinoma. Nephrotic syndrome, 87% of which was secondary to membranous nephropathy, was present in 19.7% of patients. Unlike DVT of the extremities, a personal or family history of VTE was less frequent in patients with RVT. The role of an underlying thrombotic diathesis in the pathophysiology of RVT is unclear, as thrombophilia evaluation was only carried out in a minority of patients with only 36 of 218 patients undergoing thrombophilia testing at time of diagnosis; 12 of these tested patients had a thrombotic diathesis [65].

RVT may occur unilaterally or bilaterally. In the previously discussed cohort of 218 patients, thrombosis of the left renal vein occurred in 94 patients, 73 had right renal vein involvement, and 47 patients had bilateral involvement. In addition to involvement of the renal vein, patients with RVT had involvement of the IVC, iliac vein, left gonadal vein, left adrenal vein, and extension into the right atrium in 94, 7, 1, 1, and 5 patients, respectively [65].

RVT may either present with acute symptoms or go unnoticed because of lack of symptoms. Those without symptoms may only present when they develop complications of RVT such as development of PE or renal failure. In the study by Wysokinski et al., presenting symptoms included flank pain in 73% of patients and gross hematuria in 36% of patients. Other symptoms included anorexia, nausea, and fever. On examination, asterixis was noted in nearly half of patients with RVT. Only 4% of patients had peritoneal signs. Over half of patients with RVT had laboratory evidence of renal function impairment at the time of diagnosis with 12 patients requiring dialysis therapy [65].

Reported recurrence rates are variable. In the study by Wysokinski et al., during 768 patient-years of follow-up, there were eight new lower extremity DVT and one paradoxical stroke for an event rate of 1.0/100 patient-years, although there were no recurrent renal vein thrombi [65]. Other studies, however, have reported rates ranging from 8.5 to 27%, though most of these studies occur in patients with nephrotic syndrome. Wysokinski et al. suggested that the variability regarding recurrent RVT could be due to the variability in the underlying etiology of RVT. It should be noted that patients with nephrotic syndrome are inherently more hypercoagulable given defects in the plasmatic coagulation and fibrinolysis system as well as platelet function combined with increased renal loss of the anticoagulant antithrombin [66]. Survival rates were poorer in patients with RVT than in patients with DVT; however, this was in the setting of malignancy. In the absence of malignancy, survival rates were similar to that observed in the general population [65].