For citation purposes: Cerezo-Manchado JJ, Romera M, Gallego P, Rold?n V. Are biomarkers useful in thrombotic risk assessment in oncologic patients? OA Molecular Oncology 2013 Mar 01;1(1):4.

Critical Review

 
Biomarkers

Are biomarkers useful in thrombotic risk assessment in oncologic patients?

JJ Cerezo-Manchado1, M Romera1, P Gallego1,2*, V Roldán1
 

Authors affiliations

(1) Department of Haematology and Clinical Oncology, Hospital Universitario Morales Meseguer, Murcia, Spain

(2) University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom

* Corresponding author: E-mail: pilargallegoh@yahoo.es

Abstract

Introduction

Primary and recurrent venous thromboembolism–persists as a source of major morbidity and mortality. Although frequent in general population, the incidence of venous thromboembolism among oncologic patients is roughly higher, and expected to keep rising not only due to prevalence of cancer and the ageing of occidental population, but also due to an enhanced detection of incidental thrombosis during follow-up and the thrombogenecity of some chemotherapeutic regimens.

Because of the potential life-threatening nature of venous thromboembolism, oncologic patients might benefit from thromboprophylaxis. Therefore, in the last years, efforts have been made to help clinicians in the prevention and management of thrombotic events in cancer patients. In this way, some biomarkers have been used to create stratification risk scores, joined with clinical characteristics, and in this review we pursue to demonstrate the main thrombotic risk biomarkers related to cancer.

Conclusion

The widely used Khorana risk assessment model has been expanded by adding sP-selectin and D-dimer. Other biomarkers showing some improvement in thrombotic risk assessment as factor VIII (with a dose-related increased risk), elevated peak thrombin (defined as thrombin values = 611 nM), tissue factor or C-reactive protein have yielded promising results.

However, the absence of widespread clinical availability of tests measuring these biomarkers, the lack of standardisation and their cost make their implementation in daily practice difficult.

Introduction

Primary and recurrent venous thromboembolism (VTE) persists as a source of major morbidity and mortality in hospitalised patients with >900,000 events per year[1]. Although frequent in general population, the incidence of VTE among oncologic patients is roughly higher, and expected to keep rising not only due to prevalence of cancer and the ageing of occidental population, but also due to an enhanced detection of incidental thrombosis during follow-up and the thrombogenecity of some chemotherapeutic regimens[2]. Even if deep vein thrombosis (DVT) and pulmonary embolism (PE) are the main thrombotic complications, other vascular territories, such as the splanchnic veins and upper extremity venous system, can also be affected.

Several conditions might initiate thrombus formation, as blood stream slowing down, vascular wall injuries or blood thickening, according to Virchow’s triad[3]. Clot formation is a physiological stepwise process, launched by activation of coagulation cascade. After the exposure of cell-derived tissue factor (TF), the factor VIIa/TF complex is formed, leading to the conversion of factor X to factor Xa. Thrombin generation is subsequently augmented by intrinsic activities (factors XI, IX and VIII dependent). Both the extrinsic (factor VIIa/TF) and intrinsic (factors IXa/VIIIa) tenase complexes produce factor Xa. Then prothrombinase complex (factors Xa, Va and prothrombin) are assembled, leading to thrombin production. Most current antithrombotic agents target one or more of the active enzymes generated during the clotting cascade, including vitamin K-dependent factors (such as factors II, VII, IX and X), factors Xa, IXa and thrombin.

Proteolytic conversion of circulating, soluble fibrinogen to an insoluble fibrin meshwork involves thrombin-mediated cleavage of N-terminal peptides from fibrinogen, end-to-end polymerisation of fibrin monomers to protofibrils and lateral aggregation of protofibrils to fibres. This sequence of events has been extensively studied and reviewed[4,5,6,7].

In the 1970s, the role of inflammation in thrombogenesis was suspected, and further studies have supported this idea[7]: C-reactive protein (CRP) and interleukin 6 (IL-6) stimulate TF production from monocytes[8], and IL-6 increases the production of platelets and sensitivity to thrombin[9], stimulates transcription of fibrinogen[10] and is linked to both endothelial activation and damage[11].

Since 1865 when the Parisian physician Armand Trousseau described the combination of phlegmasia alba dolens and cancer cachexia[12], many studies have enhanced our understanding of cancer-associated thrombosis, which is a main cause of morbidity and mortality in patients with cancer. The risk of developing VTE in this population is increased up to seven-fold compared with the general population[13], and these thrombotic events are related to poor prognosis (shorter survival) of cancer patients, as well as to a more aggressive disease[14]. Therefore, in the last years, efforts have been made to help clinicians in the prevention and management of thrombotic events in cancer patients[15], and some guidelines have been released on behalf of a few international societies[16]. In this way, some biomarkers (listed in Table 1) have been used to improve the stratification risk scores based on clinical characteristics, and in this review we pursue to demonstrate the main thrombotic risk biomarkers related to cancer.

Table 1

Thrombotic risk factors in cancer patients

Discussion

Predictive risk models

Some characteristics, present at baseline, are well-known risk factors for thrombotic events (Table 1). Thrombocytosis is a frequent finding in cancer patients (10%–57%), and as expected, an elevated platelet count (>350 × 109/L) at the time of hospital admission is repeatedly found to be an independent predictor of thrombotic events in different settings of medical inpatients[17,18,19] and subsequent meta-analysis[20]. In fact, activated platelets may act as procoagulant surfaces amplifying the coagulation reactions[21].

However, leukocytes have some procoagulant activity as well, initiating the extrinsic pathway of blood clotting[22]. In fact, an elevated white blood cell (WBC) count was shown to be prognostic and associated with increased mortality among patients with cancer, mainly because of a higher risk of VTE[23]. Different studies among cancer patients initiating chemotherapy have shown that elevated WBC counts remain an independent predictor of VTE after adjusting for malignancy type, stage, thrombocytosis, haemoglobin levels, body mass index and use of erythropoietin-stimulating agents[24,25].

Because of the potential life-threatening nature of VTE, primary prevention is recommended by all guidelines in at-risk hospitalised patients, unless they are bleeding[26]. Indeed, Kutcher et al. in a randomised study showed higher rates of VTE among hospitalised patient who were not receiving thromboprophylaxis according to their thrombotic risk (Table 2)[15]. To identify which patients were more likely to benefit from thromboprophylaxis, Khorana et al. developed and validated a risk assessment model for ambulatory cancer patients, in which five predictive variables were identified in a stage-adjusted multivariate model: site of cancer, platelet count ≥350 × 109/L, haemoglobin <10 g/dL and/or use of erythropoietin, leukocyte count >11 × 109/L and body mass index ≥35 (Table 3). Rates of VTE in the development and validation cohorts, respectively, were 0.8% and 0.3% in the low-risk category (score = 0), 1.8% and 2% in the intermediate-risk category (score = 1–2), and 7.1% and 6.7% in the high-risk category (score ≥3) over a median period of 2.5 months (C-statistic = 0.7 for both cohorts)[27]. Furthermore, the Khorana model has demonstrated predictive power in later studies including more than 10,000 cancer patients[28]. Since then, the Khorana model is used to assess thrombotic risk among oncologic patients in further clinical trials (SAVE-ONCO[29] and SENDO[30] among others).

Table 2

Kutcher et al. thrombosis score

Table 3

Khorana et al. cancer-related thrombosis score

However, the initial Khorana model presented some limitations, and after performing additional analyses in the Vienna Cancer and Thrombosis Study (CATS) cohort, the Khorana score was expanded by adding two predictive biomarkers, soluble P-selectin and D-dimer, with an improvement of risk assessment (Table 4). Indeed, the stepwise cumulative probabilities of developing VTE within 6 months for a score of 0 to >5 were 1.0%, 4.4%, 3.5%, 10.3%, 20.3% and 35%, respectively (p < 0.001). Furthermore, using a cut-off score of 5, the expanded model had an negative predictive value of 94.4%, a PPV of 42.9%, and sensitivity and specificity of 19.1% and 98.2%, respectively[30,31].

Table 4

Ay et al. cancer-related thrombosis score.

In fact, numerous studies had previously linked D-dimer, a marker of fibrin formation, with VTE. Thrombin hydrolyses fibrinogen into soluble fibrin monomers, which then spontaneously polymerise in soluble fibrin polymer, entrapping circulating blood cells to set up the fibrin clot[32,33,34,35,36]. With the presence of calcium, covalent cross-linking by the thrombin-activated enzyme factor XIIIa increases the resistance of the clot to fibrinolysis and finally the fibrin network is established[36]. After that, the fibrinolysis cleavage of the cons-linked fibrin produces D-dimer, which is the most consolidated biomarker in VTE, and has been proposed as a predictive marker of recurrence [Le Gal[37], White[38]] that can help in the assessment of treatment length. Among oncologic patients, a larger study of 223 patients with solid tumours diagnosed with a first episode of VTE, showed that elevated D-dimer levels were predictive of recurrent VTE (p = 0.001)[39]. These preliminary data were also corroborated in the CAT Study where high fibrin D-dimer level (hazard ratio (HR), 1.8; 95% confidence interval (CI): 1.0–3.2; p = 0.048) and elevated prothrombin split products (HR, 2.0; 95% CI: 1.2–3.6; p = 0.015) were shown to be associated with increased risk of VTE in a large prospective study, even after adjusting for age, sex, surgery, chemotherapy and radiotherapy[40].

Besides, P-selectin—cell adhesion molecule—is stored in platelets (α-granules) and endothelial cells (Weibel-Palade bodies) and is responsible for the initiation of leukocyte rolling. Its main ligand is P-selectin glycoprotein ligand 1 (PSGL-1), which is expressed on the majority of leukocytes but also found in platelets[41]. It mediates the interaction of leukocytes expressing PSGL-1 with stimulated platelets and endothelial cells [42]. Different studies corroborate that elevated levels of P-selectin are correlated with a highest risk of DVT, both for initial event (Ramacciotti et al. found a cut-off of soluble P-selectin = 90 ng/mL, which was 28% sensitive and 96% specific, with a receiver-operating characteristic (ROC) curve area of 0.76 (p < 0.0001) for newly diagnosed DVT[43]) and for recurrent VTE[44]. These results have been confirmed in the CAT Study, where each 10 ng/mL increase in soluble P-selectin was associated with an HR of 1.2 (95% CI: 1.1–1.4; p = 0.005) for VTE. This was more pronounced when using stratified quartiles of soluble P-selectin: cut-off level of 53.1 ng/mL (75th percentile) was a statistically significant risk factor for VTE (HR = 2.6; 95%CI: 1.4–4.9; p = 0.003), even after adjustment for age, sex, surgery, chemotherapy and radiotherapy. The cumulative probability of VTE after 6 months was 11.9% in patients with soluble P-selectin above the 75th percentile and 3.7% in those below (p = 0.002)[45].

Nevertheless, this expanded Khorana risk score, while promising, requires further validation in other studies, and the wide use of the expanded score is roughly limited by the lack of wide availability of the soluble P-selectin assay[31].

To improve the accuracy of the Khorana score, other molecules are being studied, such as factor VIII, thrombin generation, TF and CRP.

Factor VIII

Factor VIII (FVIII), a glycoprotein cofactor, serves as a critical component in the intrinsic blood coagulation pathway: mainly bound to von Willebrand factor (vWF), upon activation by thrombin, it dissociates from the complex to interact with Factor IX, activating the coagulation cascade[46].

Elevated plasmatic levels of FVIII are an independent risk factor for VTE[47,48,49], showing a dose-related relation: Kaaijenhagen et al. [48] observed a 10% increased risk of VTE for each 10 UI/dL increased in FVIII. This is supported by a sub-analysis of the Vienna CAT Study, where the cumulative probability of VTE after 6 months was 14% in patients with elevated FVIII levels, while 4% in those with normal levels (p = 0.001)[49]. Baseline factor VIII levels were significantly higher among the 7.4% of patients who experienced thromboembolic events than among event-free individuals (p < 0.001), independent of gender, previous treatment and blood type (although patients with blood type O had significantly lower factor VIII activity than did those with other blood types). However, these results remain controversial as another prospective trial showed no relation between baseline factor VIII levels and the incidence of VTE or survival although elevated levels were found among cancer patients with VTE[50].

Thrombin generation

Thrombin combines pro- and anticoagulant functions and serves as an activator for platelets, factor V and FVIII. Because of its central position, the formation of thrombin is considered one of the most important steps in coagulation[51]. Therefore, commercial methods for studying thrombin generation (TG) in plasma have been developed, giving information about the lag time, the peak of TG and the endogenous thrombin potential (ETP). Clinical research has focused on the measurement of TG and its predictive value for VTE[52,53], with an elevated ETP present in patients at risk of VTE[54], and an elevated basal peak TG associated with the risk of recurrent VTE, independent of other confirmed VTE risk factors[55].

This hypothesis has been recently confirmed in a study with one 1033 patients with different malignancies, followed for a median observation period of 517 days. VTE occurred in 77 patients (7.5%). Patients with elevated peak thrombin (defined as thrombin values = 611 nM, representing the 75th percentile of the total study population) had an increased risk of VTE with an HR of 2.1 (95% CI: 1.3–3.3; p < 0.05) on multivariable analysis including age, sex, surgery, chemotherapy and radiotherapy. The cumulative probability of developing VTE after 6 months was significantly higher in patients with elevated peak thrombin than in those with lower peak thrombin (11% vs. 4%; log-rank test: p < 0.05)[56].

Tissue Factor

Tissue factor, an intrinsic membrane protein, acts as a cofactor to factor VIII in the intrinsic system, and to factor V in the final common pathway of the coagulation cascade[57]. The synthesis of TF by macrophages and endothelial cells is induced by endotoxin and by such cytokines as IL-1 and tumour necrosis factor[58,59]. A study among pancreatic cancer patients showed that high TF expression was related to VTE rates (26.3% compared with 4.5% in patients with low TF expression; p = 0.04)[60]. However, a preponderance of data involving patients with pancreatic cancer needs to be highlighted. Therefore, it remains unclear, whether TF is a valid biomarker for all cancers or just for those particularly associated with high TF-expressing, such as pancreatic cancer[61]. Besides, the lack of consensus on a ‘standard’ assay to evaluate TF[62] compels us considering it as an investigational biomarker, awaiting standardisation before clinical use[28]. In addition, some studies on TF and associated microparticles have yielded mixed results, although discrepancies might be due to the lack of standard assay for measuring TF or microparticle expression or activity, and novel assays are under development[63].

C-reactive protein

Increasing evidence suggests a role for inflammatory markers such as CRP and different interleukins in VTE. Inflammatory markers may influence the expression of TF, initiating this way the coagulation cascade[64].

Although CRP levels have been studied in correlation with VTE—showing a significant effect of increased CRP levels on VTE[65,66]—nowadays, plasma CRP levels, used alone, does not appear to be useful on DVT diagnosis, in non-oncologic patients[67].

Some preliminary investigations on CRP as a biomarker for cancer-associated VTE have yielded promising results. Kroger et al. led a prospective observational study in 507 patients (predominantly with lung and gastrointestinal malignancies) to assess risk factors present within 30 days preceding a diagnosis of acute VTE. They found elevated CRP levels (above 5 mg/L) to be linked to the occurrence of VTE on multivariate analysis[67,68]. Indeed, in the CAT Study elevated CRP levels at baseline were associated with an increased risk of developing VTE. However, after additional adjustment for stage, tumour type and soluble P-selectin, CRP was then no longer a statistically significant and independent parameter for the prediction of VTE[69].

Conclusion

Broadly, the use of VTE prediction models is limited by the low availability of tests for these biomarkers, the lack of standardisation and their cost. However, cancer-associated VTE leads to increased healthcare expenditures. Primary prophylaxis might reduce the incidence of VTE, improve survival and overall quality of life, and reduce healthcare costs; however, further studies are needed to assess which patients are going to benefit more from thromboprophylaxis.

Abbreviations

CATS, Cancer and Thrombosis Study; CI, confidence interval; CRP, C-reactive protein; DVT, deep vein thrombosis; ETP, endogenous thrombin potential; HR, hazard ratio; IL-6, interleukin 6; PE, pulmonary embolism; PSGL-1, P-selectin glycoprotein ligand 1; ROC, receiver-operating characteristic; TF, tissue factor; TG, thrombin generation; VTE, venous thromboembolism; WBC, white blood cell.

Authors contribution

All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.

Competing interests

None declared.

Conflict of interests

None declared.

A.M.E

All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.

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Thrombotic risk factors in cancer patients

Patient associated risk factors Cancer associated risk factors Biomarkers
Age Chemotherapy Platelet count (≥350,000)
Gender Anit-angiogenic agents (lenalidomide, thalidomide) Leukocyte count (≥11,000)
History of thrombosis Kind of tumour Haemoglobin (<10 g/dL)
Medical co-morbidities Stage of tumour D-dimer
Surgery TF and related markers
Erythropoietin-stimulating agents Soluble P-selectin (>53 ng/mL)
Radiation Factor VIII
Prothrombin fragment F 1+2 (>358 pmol/L)
C-reactive protein

Kutcher et al. thrombosis score

Study Kutcher et al.15
Number of patients 2506
Thrombosis risk factors Prior venous thromboembolism 3 points
Hypercoagulability (any of Factor V Leiden, lupus anticoagulant, and anticardiolipin antibodies) 3 points
Major surgery (>>60 min of surgery) 2 points
Age (>70) 1 point
Obesity (BMI >29) 1 point
Bed rest 1 point
Use of hormone-replacement therapy or oral contraceptives 1 point
VTE rate Low ≤4: 5%High >4: 8%
Widely validated No

Khorana et al. cancer-related thrombosis score

Study Khorana et al.27
Number of patients 1365
Thrombosis risk factors Site of cancer
Very high risk: stomach, pancreas 2 points
High risk: lung, lymphoma, gynaecologic, bladder, testicular 1 point
Haemoglobin <10 g/dL and/or use of erythropoiesis-stimulating agents (ESAs) 1 point
Leukocyte count >11 × 109 /L 1 point
Body mass index ≥35 kg/m2 1 point
Platelet count ≥350 × 109/L 1 point
VTE rate Low (score 0): 0.3%Intermediate risk group (score 1–2): 2.0%High risk group (score ≥3): 6.7%
Widely validated Yes

Ay et al. cancer-related thrombosis score.

Study Ay et al.31
Number of patients 819
Thrombosis risk factors Site of cancer
Very high risk: stomach, pancreas 2 points
High risk: lung, lymphoma, gynaecologic, bladder, testicular 1 point
Haemoglobin <10 g/dL and/or use of erythropoiesis-stimulating agents (ESAs) 1 point
Leukocyte count >11 × 109/L 1 point
Body mass index ≥35 kg/m2 1 point
Platelet count ≥350 × 109/L 1 point
D-dimer ≥1.44 μg/mL
sP-selectin ≥53.1 mg/mL
VTE rate Score 3: 10%Score 4: 20%Score 5: 30%
Widely validated No
Keywords