Virchow’s triad delineates the three most commonly cited pathogenic mechanisms for the development of VTE: venous stasis, a hyper-coaguable state, and endothelial damage. Most patients who develop VTE have at least one of these typical risk factors, and many have two or more.

Beyond Virchow’s triad, recent literature has suggested that a wide range of additional factors are related to the development of VTE in cancer patients [30]. Data on VTE development in brain tumor patients, however, are limited. When discussing the pathogenesis of VTE in brain tumor patients, it is convenient to categorize the risk factors for VTE development by dividing them into patient-related, tumor-related, and host tissue-related mechanisms [5, 31, 32].

VTE is far more common during the post-operative period than it is in the general population [33–41]. Proposed explanations for this phenomenon include limited post-operative mobility, which can promote venous stasis, and damage to endothelial tissue. So from one stand point, brain tumor patients are at risk for VTE simply by undergoing an operation. Additionally, certain procedures confer more VTE risk than others. Orthopedic procedures, for example, increase the risk of VTE development: Day et al. recently reported a VTE rate of 1.2 % for lower extremity arthroplasties, and 0.53 % for shoulder arthroplasties [42]. Craniotomy, the most common operation for brain tumor resection, has also been implicated in increasing VTE risk compared to other operations [43]. Several studies have also shown that patients harboring brain tumors develop DVT at a higher rate than patients with cancer at other sites or patients undergoing procedures for diseases other than cancer (Table 1) [10, 29].

Patient with brain tumors are also more commonly afflicted with motor deficiencies that can render them bed ridden or immobile [44]. This limited mobility can result in relatively slower venous blood flow, one of the chief risk factors for VTE development [32, 45]. The use of indwelling central venous catheters for delivery of chemotherapeutic agents involved in the treatment of brain tumors can also contribute to the development of DVTs and PEs [46]. Patient specific genetic factors, such as factor V Leiden or an excess of pro-thrombotic factors can also be implicated in VTE development in brain tumor patients [24].

Many other risk factors have been reported as potential contributors to the development of VTE [44] (Table 2). Incidence of DVT and PE almost double when comparing those aged 65–69 to those above 85 years of age [47]. A similar trend is seen in a study comparing those aged 30–39 to younger patients with a twofold increase in the risk of VTE [48]. Traditionally, patients above the age of 40 are considered at a higher risk of VTE development [49]. A BMI >25–35 has also been implicated as a risk factor for VTE in other studies, along with increased operative duration, increased post-operative complications (all-types), and increased hospital stay [50, 51]. Gender, post-operative ICU days, anti-coagulation state, and blood type have also been studied as potential factors related to VTE in cancer patients [24, 42, 49]. Steroids and some chemotherapy protocols, often prescribed after cranial surgeries for brain tumors, have also been reported to contribute to VTE formation [44, 51].

Beyond these general risk factors for patients harboring brain tumors, there are many mechanisms specific to brain tumors that increase the risk of VTE development, most notably increased production of tissue factor (TF) and other pro-coagulants [21, 24, 52]. A study by Bastida et al. demonstrated that micro-vesicles from the cell-free supernatant of U-87 MG (a cell line of human glioblastoma cells) results in platelet aggregation and coagulation [52]. This is clinically correlated with a higher rate of VTE in patients with gliomas, one of the most common types of brain tumor [21, 24]. Khorana et al., in a series of pancreatic cancer patients, demonstrated that increased plasma TF correlates with the formation of VTE [53]. This has been suggested as a possible mechanism through which malignancies increase the risk of VTE [54].

Other studies have investigated this, but found negative immuno-histochemical staining for TF in a glioma specimen. Thus the models supporting this hypothesis (linking the increase of TF in brain tumors to VTE) remain limited to cell cultures, and are not in-vivo models [52, 55].

Another brain tumor-specific risk factor for VTE development are TF-bearing micro-particles (TFMP). In a group of 96 patients with advanced malignancies including glioblastoma, increased levels of TFMP tissue factor antigens were found to be 3.72 times more likely to result in VTE [56]. In 2011, Sartori et al. studied the pro-coagulant activity of circulating MPs in patients harboring glioblastoma multiforme (GBM). They found that MP activity levels increased in 63.6 % of 61 patients who underwent resection of GBM, a statistically significant association (chi² = 4.93, p = 0.026) [57] (Table 3).

Host tissues also contribute to the formation of VTE in patients with brain tumors. Collagen-rich endothelial membranes stimulate platelet aggregation, and thus the collection of white blood cells and ultimately VTE formation [31, 58]. Animal models also demonstrate that tumor interaction with platelets can lead to aggregation [59]. Both local and systemic tissue inflammation are also thought to take part in development of VTE through inflammatory markers, such as C-reactive protein (CRP), which is considered a potential indicator of the presence of VTE [60]. Evidence also suggests the involvement of tumor necrosis factor (TNF), a known inflammatory mediator, in the process of VTE development [61]. In addition to inflammation, disruption of the endothelium during operations leads to a pro-thrombotic state via the release of pro-thrombotic factors [31]. Cell adhesion molecules like P-selectin and E-selectin also promote leukocyte margination and adhesion [31]. P-selectins found in alpha granules of platelets and Weibel-Palade bodies of endothelial cells increase tissue factor expression and were found to be pro-thrombotic in animal models [62]. This has been clinically correlated by a study that displayed their increased presence in patients with cancer who developed VTE [63].

VTE presentation in afflicted patients can vary widely depending on the region involved. In some patients, VTE (especially DVT) can be asymptomatic. The most common presenting symptoms for DVT include pain and edema of the affected limb [64–66]. Symptoms can also include severe tenderness of the extremity, a palpable mass, blanching of the skin, and excessive warmth or redness in the extremity [23, 64, 67, 68]. PE, on the other hand, commonly present with signs and symptoms that include dyspnea, pleuritic pain, cough, hemoptysis, and palpitation [64, 69]. The location of these presenting symptoms can greatly aid in diagnosis and localization of the thrombus.

Definitive diagnosis of VTE often requires radio-graphical investigation. A low threshold of suspension should provoke the work up for DVT, which typically involves an upper/lower extremity ultrasound to locate the embolus [38, 69]. Well’s score is the most widely used tool for assessment of likelihood of VTE occurrence, despite the availability of other scoring systems [70]. A systematic review of 17 articles evaluating the use of such scores reported a median positive likelihood ratios of 6.62, 1, and 0.22 when patients had a high, moderate, and low pretest probability for the use of Well’s score, respectively [71]. Another study showed that the use of compression ultrasonography had a negative predictive value of 97–98 % after a normal result, which rose to 99 % after serial testing in an outpatient setting [72]. In a recent report, basing the choice of investigation on symptoms and clinical signs in such clinical scores was found to be less accurate than the use of biomarkers. For instance, clinical signs were found to be statistically less useful in aiding the diagnosis of DVT (Area under the curve (AUC): 0.69), as compared to serum protein S (AUC: 0.82) and albumin (AUC: 0.80) [73].

In the case of PE, however, workup is more complex and should include radiographic imaging techniques such as chest CT scans and V/Q scans, depending on the risk and the profile of the patient [21, 66, 67, 74]. The use of Well’s score was similarly useful for detection of PE as DVT, with median positive likelihood ratios of 6.75, 1.82, and 0.13 when patients had a high, moderate, and low pretest probability, correspondingly [71]. Helical spiral computed tomography (CT) has a negative prediction value of >99 % to diagnosing PE, and can thus safely replace the gold standard of angiography [72].

There are multiple modalities available for physicians to achieve thrombo-prophylaxis in their patients. The methods of achieving thrombo-prophylaxis can be broadly divided into two categories: pharmacological or mechanical. The ideal method depends on multiple factors, and physicians should always aim to achieve thrombo-prophylaxis without conferring additional health risks to patients. Viewing the patient holistically, physicians can determine how to tailor the ideal method of thrombo-prophylaxis based on several factors, including prior history of VTE, presence of a malignancy, pertinent contraindications to anti-coagulation, and the overall type of patient (e.g. medical vs. surgical; neurosurgical vs. general surgical).

These factors, in addition to the risk factors mentioned earlier, may guide physicians towards optimal prophylaxis. For general surgical patients, the Modified Caprini risk assessment model for VTE can be used to categorize patients by risk from very low to high [75, 76]. Patients with a high Modified Caprini risk (≥5) are estimated to have a six percent chance of developing VTE if left untreated. Based on this risk score, an appropriate method of prophylaxis is then prescribed.

A scoring system like the Modified Caprini scale has not been developed or validated specifically for neurosurgical patients. Based on evidence from observational studies, however, the nature of neurosurgical procedures and central nervous system malignancy are both significant contributors to risk of VTE [54]. Craniotomy patients are thus considered at high risk for acquiring VTE. Furthermore, brain tumor patients undergoing craniotomy have a higher risk for developing VTE compared to patients undergoing craniotomy for other pathologies (e.g., elective aneurysm surgery).

An important complicating factor in thromboprophylaxis for neurosurgical patients is the risk of intracranial hemorrhage (ICH). Patients undergoing transcranial operations for tumors or vascular lesions are already at an increased risk for hemorrhage. The addition of anti-coagulant medication has been proposed as a potential risk factor for higher rates of hemorrhage among neurosurgical patients. Data on this association have been mixed. Some studies have demonstrated an increased rate of intracranial hemorrhage when VTE chemoprophylaxis is initiated pre-operatively [77]. In contrast, other studies have failed to demonstrate any evidence of increased hemorrhage risk with VTE chemoprophylaxis [78–81]. One study estimated that craniotomy patients have approximately 1 % risk for developing ICH in the absence of thromboprophylaxis [82]. Other studies report even a lower risk [83]. Despite this relatively low risk, the consequences of ICH are great (e.g., disability, paresis or paralysis, speech impediment, diminished neurological function, or death), emphasizing the need to approach medical prophylaxis thoughtfully.