Thrombin Generation As a Predictive Biomarker for Venous Thromboembolism in Patients with Pancreatic and Lung Cancer Undergoing Systemic Therapy

Introduction:

Venous thromboembolism (VTE) is common in patients with active malignancy. While

thromboprophylaxis can mitigate this risk, current guidelines do not support routine use as the benefit is

modest and maybe negated by an increase in bleeding complications. However, there is significant

variation in VTE risk within the cancer population, thus prophylaxis can be considered in high-risk

patients. The Khorana score (KS) is validated to predict chemotherapy-associated VTE; however, it has

several limitations including variable performance based on tumor type as well as a static risk

categorization, based on pre-chemotherapy laboratory data, rather than a continuous assessment.

Thrombin generation (TG) is an emerging biomarker that assesses global coagulation activation and

predicted increased VTE risk in cancer patients in the Vienna Cancer and Thrombosis Study (PMID:

21464402). This study enrolled a heterogeneous cancer population, however, peak TG was not reported

by tumor type nor were the TG levels monitored over time in response to systemic therapy. The primary

aim of this study was to assess the relationship between TG (both peak TG and endogenous thrombin

potential, ETP) and KS. Secondary outcomes were to evaluate the impact of systemic therapy on peak

TG and ETP levels over time and to assess the relationship between TG and clinical outcomes.

Methods:

This was a prospective study that enrolled adults with newly diagnosed, locally advanced or metastatic

adenocarcinoma of the lung or pancreas. All patients received their care at Dartmouth Hitchcock

Medical Center. Those with a history of active VTE or use of full dose anticoagulant within 30 days prior

to enrollment were excluded. After informed consent, KS was calculated and blood was collected in

sodium citrate tubes at 3 different time points (at initiation of therapy, and at the beginning of the 2 nd

and 3 rd cycles of systemic therapy). Platelet-poor plasma was prepared by centrifugation and stored at -

80°C until analysis by calibrated automated thrombogram (CAT; Thrombinoscope BV, Maastricht,

Netherlands) using 1 pM tissue factor and 4 uM phospholipids to trigger coagulation reactions.

Measurements were performed in triplicate for each specimen, and raw data were converted to peak

TG and ETP. Information about VTE events, response to treatment and survival was obtained by chart

review. Mean and standard deviation were calculated for continuous variables and unpaired T test was

used for statistical analysis.

Results:

We report the results from 32 participants (17 lung, 15 pancreas). The majority of patients had

metastatic disease (94%) and all received systemic therapy. The median age was 67 and 56% of

participants were male. The KS breakdown for the cohort was: KS1, 25%; KS2, 53%; KS3, 19%; KS4, 3%.

Mean peak TG was 279, 352, 487 and 325 nmole and mean ETP was 1320, 1653, 2252, 1726 nmole/min

for KS 1, 2, 3 and 4, respectively. Initial peak TG and ETP levels were significantly higher in the KS ≥2

group compared to those with KS=1 (peak TG: 384 ±135 vs 279 ±82, p 0.047; Initial ETP: 1806 ±632 vs

1320 ±286, p 0.045). There were 8 VTE events (25%) with all but one occurring in the pancreatic cancercohort; all events occurred in KS 2 and 3 groups (75% and 25% respectively). No statistically significant difference was observed for initial peak TG or ETP in those with VTE vs those without (Peak TG: 342

±171 vs 363 ±119, p 0.701; ETP: 1736 ±720 vs 1667 ±571, p 0.783). Both peak TG and ETP decreased in

response to systemic therapy (initial peak TG vs final: 376 ±115 vs 225 ±125, p 0.0001; initial ETP vs final:

1799 ±498 vs 1254 ±423, p 0.0003). No significant difference in survival was noted based on initial ETP

level of <1500 nmole/min vs ≥1500 nmole/min (574 ±620 vs 287 ±227, p 0.069).

Conclusions:

There appears to be an association between KS and peak TG and ETP. In addition, both peak TG and ETP

declined in response to systemic therapy, suggesting that the degree of coagulation activation is related

to tumor burden. Our findings in this small study support further investigation of TG for VTE risk

assessment in cancer patients. Future strategies incorporating TG into risk stratification models may

allow oncologists to better identify the population that may benefit most from pharmacologic

thromboprophylaxis.

Funding: Northern New England Clinical Oncology