Characterization of blood coagulation in cancer patients for the development of an algorithm to predict the risk of thrombosis.

Cancer associated thrombosis (CAT) is the second leading cause of death in
cancer patients (1). Patient and cancer or cancer-therapy specific risk factors
are associated with a 4-7 fold increased risk of venous thromboembolism (VTE)
in cancer patients. VTE is reported to occur in 4-20% of cancers patients, and
an additional 2-5% of cancer patients develop arterial thrombosis. From
epidemiological studies it is known that brain cancer, haematological
malignancies and adenocarcinomas of the pancreas, stomach, ovary, uterus,
lungs, and kidneys are associated with the highest risk of VTE development.

Three classes of risk factors for VTE are distinguished in the cancer
population (Table 1): patient related, treatment related and cancer related
risk factors (1). Patients with advanced-stage cancer tend to be less mobile,
which can lead to venous stasis and VTE, and are more prone to infection
because of immunosuppression (2). In addition, there are several mechanisms
through which chemotherapy can induce a hypercoagulable state: direct tissue
toxicity, increase in coagulation factor levels, induction of tumor and
endothelial cell apoptosis causing increased tissue factor expression,
induction of platelet activation, and induction of monocyte tissue factor
expression (2). Hormonal agents such as Tamoxifen and Raloxifen increase the
risk of VTE (3), and antiangiogenic agents such as thalidomide and Lenalidomide
are associated with a VTE rate of 12-28%, when given in combination with
dexamethasone or chemotherapy (4-6).

Cancer cells themselves can cause intravascular coagulation via multiple
mechanisms, such as tissue factor expression, inflammatory cytokine release and
cancer procoagulant expression (1), but also by compression of large blood
vessels by the tumor.

Treatment of VTE in the cancer population
Effective treatment of VTE reduces morbidity and mortality. Low molecular
weight heparin (LMWH) is the first line treatment for VTE (1). Vitamin K
antagonists (VKA) are given if LMWH treatment is not available, but its use is
associated with higher VTE recurrence rates. Direct oral anticoagulants (DOACs)
that directly inhibit thrombin (FIIa) or Factor Xa (FXa) are promising for the
prophylaxis and long-term treatment of VTE in cancer. However, there is
insufficient evidence to support the use of DOACs in cancer patients with
thrombosis until the results of ongoing clinical trials comparing LMWH to DOACs
become available (10, 11).

Primary Objective:
The primary objective of this study is to measure a broad panel of coagulation
tests in a cohort of cancer patients to determine whether one or a combination
of these tests is able to predict the risk of thrombotic events in the cancer
population. To study this objective, we will compare the outcome of each
coagulation assay in the group of patients that did not suffer from a
thrombotic event in the 2-year follow-up and patients that did suffer from
thrombosis. In addition, we will determine the predictive power of each
coagulation test for the risk of thrombosis in cancer.

Secondary Objectives
The secondary objective of this study is to determine the effect of the cancer
type and stage and the effect of treatment on the probability to develop
thrombosis. Another secondary objective is to assess the effectiveness of
anticoagulant therapy in the patients who have suffered from a thrombotic
event. In addition, we aim to study the changes in coagulation parameters in a
cancer patient at baseline and after a thrombotic event.

Brief description of the study design:
* Prospective observational cohort study.
* Patients will be enrolled in the inpatient hospital setting of the Gelre
Hospitals.
* We aim to include patients with cancer without prior venous thrombosis and
patients with cancer with prior venous thrombosis, to obtain a blood sample
from each patient at inclusion and perform baseline coagulation tests. We will
follow the patients up to 2 years to document whether they experience a
thrombotic event. If a patient is admitted to the hospital because of
thrombosis, a second blood sample will be taken. Treatment of a thrombotic
event usually requires anticoagulation. We will take another blood sample two
weeks after the start of anticoagulation to determine the effectiveness of the
anticoagulant.

* Rationale for design features: In this study we aim to study the differences
in the coagulation parameters between the patients who develop a thrombotic
event and those who do not. Ideally, we would like to be able to predict the
risk of thrombosis in a patient as soon as possible, in order to treat patients
at risk with prophylactic anticoagulation. In this study our goal is to
identify (a panel of) coagulation tests that can discriminate between patients
that will or will not develop thrombosis in the future. Therefore, we want to
study coagulation tests in a cohort of cancer patients prospectively to see
which patients develop a thrombosis in the future and whether or not
coagulation tests could have predicted this risk.

* We expect the study to last for 2.5 years in total, from the inclusion of the
first patient in August 2017 until the last day of the 2-year follow-up of
patient in February 2020.

* In this study we perform 4 main types of coagulation assays: thrombin
generation assays, platelet function tests, coagulation factor determinations,
and assessment of clot lysis. In addition, we aim to characterize the disease
state of the patients through the use of a cancer biomarker panel, and by
having access to patient information including age, sex, type of cancer, tumor
histology results, PET/MRI/CT scan results, and autopsy if conducted.

* The purpose of the study is to cover the whole spectrum of the coagulation
system and identify abnormalities in cancer patients that could explain their
increased incidence of thrombotic events

Potential risks: Blood samples will be obtained by venepuncture, which is a
standard procedure with minimal risks. During the process of obtaining a blood
sample from the patient*s vein, it is possible to develop a bruise. Application
of pressure on the site of blood drawing for several minutes minimizes the risk
of bruising. The patient might feel minor pain or be light-headed from this or
may experience some temporary discomfort and short-term swelling at the site of
a needle stick. Importantly, the patient would also experience this minor
burden from the blood drawal without this study; blood will be drawn for
routine patient care, for this study only extra tubes will be drawn.

Potential Benefits: As this is an observational study, the participating
patients will not benefit directly from the results. However, the obtained
knowledge may help predict what cancer patients may benefit from
thromboprophylaxis in the future.