Cancer-associated venous thromboembolism: unfolding the role of the intrinsic coagulation pathway

Patients with cancer have a 9- to 20-fold higher risk of venous thromboembolism
(VTE) compared with patients without cancer. Despite adequate anticoagulant
therapy (e.g. with direct oral anticoagulants [DOACs] and low-molecular-weight
heparin [LMWH]), the risk of recurrent VTE and bleeding is much higher in these
patients than in VTE patients without cancer. Recent trials comparing DOACs
with LMWH in cancer patients have reported a 6-month risk of about 8% for
recurrent VTE, and 6% for major bleeding.

The extrinsic coagulation pathway was long thought to be the main driver of VTE
in cancer patients. However, recent evidence suggests that the intrinsic
coagulation pathway may play an important role as well. The extrinsic pathway
is initiated by the complex of tissue factor (TF) and plasma factor VII/VIIa
(TF-FVIIa), which subsequently activates FIX and finally way the common
pathway. The intrinsic pathway is initiated through activation of FXII. FXIIa
will subsequently activate FIX and FX, through FXIa and kallikrein (KAL), which
will ultimately lead to thrombin generation. Increasing data suggest that the
intrinsic pathway is activated in patients with cancer. Campello et al.
compared the coagulation profile of 104 patients with cancer-associated VTE and
555 patients with VTE not related to cancer. Factor XI levels were found to be
higher in patients with cancer-associated VTE (127 ± 33% vs. 119 ± 32%, p =
0.042), suggesting a potential role of the intrinsic pathway in
cancer-associated VTE. Previous small case-control studies have reported
similar findings on higher intrinsic pathway activation in cancer patients
without VTE compared with healthy controls. However, these studies were limited
by a lack of standardized measures to assess intrinsic pathway activation.
Assessing activation of intrinsic coagulation is limited to quantification of
enzyme:inhibitor complexes due to the lack of assays for free coagulation
enzymes. Furthermore, there are currently no data on the difference of
intrinsic pathway activation between cancer patients with and those without
VTE, which renders the role of the intrinsic pathway in cancer-associated VTE
uncertain. Several studies have reported on potential mechanisms that can lead
to intrinsic pathway activation in cancer patients specifically. For example,
neutrophil extracellular traps (NETs), cell-free DNA (cfDNA), and
polyphosphate-bearing extracellular vesicles were shown to induce VTE in cancer
patients in an intrinsic pathway-dependent manner.

Low-molecular weight heparins and DOACs mainly target the common coagulation
pathway (factor Xa and IIa). In the past few years, several drugs have been
developed that target the intrinsic pathway. An open-label phase II study in
patients undergoing knee arthroplasty demonstrated that FXI antisense
oligonucleotide (hepatic FXI synthesis inhibitor) 300 mg dosed once was more
effective than standard-of-care enoxaparin (LMWH) once daily (VTE risk 4% vs.
30%) with less bleeding (3% vs. 8%). We hypothesize that the intrinsic pathway
plays a prominent role in cancer-associated VTE, and that novel intrinsic
pathway inhibitor might be especially efficacious in cancer patients, while
mitigating their high risk of bleeding. Before using such agents in this
high-risk population, it is crucial to get better understanding of the
underlying role of the intrinsic pathway in development of VTE in cancer
patients.

The primary aim of this study is to compare intrinsic pathway activation
between cancer patients with acute VTE and those without VTE. Intrinsic pathway
activation will be assessed by measuring coagulation factor complexes with
their natural inhibitor and by means of a factor XIa-dependent thrombin
generation test, providing the most robust measurement of intrinsic coagulation
pathway activation. Secondary objectives include evaluation and comparison of
intrinsic pathway activation between cancer patients with VTE, cancer patients
with no history of VTE, non-cancer patients with VTE a healthy individuals and
evaluation of cancer-related activators of the intrinsic pathway, as well as
evaluation of activation of the extrinsic pathway.

Investigator-initiated prospective multicenter cohort study

At baseline blood will be drawn from all patients for laboratory analysis (in
total 22 ml). A telephone or clinic visit will be scheduled at day 30±10. All
patients will be assessed for symptoms of (recurrent) VTE, bleeding, and (newly
diagnosed) cancer. A second blood withdrawal will be performed in those
patients who had VTE at baseline (both with and without cancer; in total 22
ml). There are no risks or benefits for patients given the observational nature
of the study.