Page 2527 - Hematology_ Basic Principles and Practice ( PDFDrive )

2250 Part XIII Consultative Hematology

niche, which also render it resistant to therapy. Such tumor cell according to the timing of the VTE event. One study in patients with
evasion strategies could include changes in homing, adhesion, gastroesophageal malignancy undergoing chemotherapy failed to
immune escape, and angiogenic potential. Laboratory studies suggest show an association between VTE and overall survival. The risk of
that tumors that secrete more proangiogenic and proinflammatory mortality associated with VTE may therefore reflect the underlying
cytokines may be more likely to metastasize to the bone marrow. The cancer biology. Mucinous adenocarcinomas, for example, may
bone marrow niche itself may also play a role in promoting tumor directly release tissue factor (TF) and circulating mucin molecules
survival and in decreased immune surveillance. One example is the that activate the clotting cascade and platelets, thereby promoting
occurrence of bone marrow micrometastases in women with early- thrombosis.
stage breast cancer; approximately 30% of women with stage I to III
breast cancer may have bone marrow micrometastases, which is
associated with worse prognosis. Biologic Mechanisms Underlying
The pathophysiology by which marrow involvement by cancer Thrombosis in Cancer
causes cytopenias is not fully understood. Total marrow replacement
by tumor is rare, and only a small percentage of marrow may be The etiology of thrombosis is typically described in the context of
needed to support normal peripheral blood counts, as indicated by the classic Virchow triad: stasis or altered blood flow, injury to the
the observation that normal blood counts are often found in normal vessel wall, and hypercoagulability intrinsic to the blood and circulat-
older adults with hypocellular marrows. Cancer may disrupt normal ing plasma. Cancer contributes to thrombosis by mechanisms within
bone marrow interactions required for normal hematopoiesis, such all three of these categories. Mechanical compression and/or disrup-
as those that include osteoclast signaling and growth of specific bone tion of blood vessels by a tumor may cause disrupted flow or stasis.
marrow stromal cell populations. Upon interaction with cancer cells, monocytes or macrophages release
cytokines, including tumor necrosis factor, IL-1, and IL-6, which
damage vascular endothelial cells. The damaged vessel surface has
THROMBOSIS AND CANCER reduced expression of naturally occurring anticoagulants, such as
thrombomodulin, heparan sulfate, CD39/ecto-ADPase, nitric oxide,
The association of thrombosis and cancer is widely recognized, dating and prostacyclin. The damaged endothelium also has increased
to the middle of the 19th century, and can be considered the earliest expression of procoagulant proteins, particularly TF; circulating
recognized paraneoplastic syndrome. Armand Trousseau was the first blood is exposed to the procoagulant subendothelial matrix, which
to associate thrombosis and malignancy, the first to suggest screening contributes to a hypercoagulable state.
for malignancy in recurrent or idiopathic thromboembolic disease, Despite the contributions of stasis and vessel changes in cancer-
the first to suggest that the pathophysiology was not mechanical associated thrombosis, the best-documented contributing factor to
obstruction, but a change in the character in the coagulation system thrombosis in the cancer patient is elevated procoagulant plasma
itself, and the first to suggest that the association may be integral to factors, many of which are generated by the tumor itself. TF plays a
the cancer growth itself. Particularly poignant was the fact that Trous- critical role in the initiation of the coagulation cascade, particularly
seau predicted his own occult malignancy when he developed via the extrinsic pathway, by binding to and activating factor VII. TF
“phlebitis,” dying 6 months later of gastric cancer. More recently, is increased in a number of malignancies, including pancreatic cancer,
some of the biologic mechanisms underlying the increased risk for breast cancer, and non–small cell lung cancer, compared with the
thrombosis in patients with cancer have been better delineated. nontransformed epithelium. Low oxygen levels are often found in the
The incidence of cancer-associated thrombosis has steadily tumor microenvironment, which result in the activation and upregu-
increased in recent years, in part related to the increasing age of the lation of proteins encoded by oncogenes, such as RAS or MET, and
population, with an associated increase in cancer prevalence, longer inactivation of tumor suppressor genes such as TP53 or PTEN. The
survival with active malignancy, and better detection tools. Patients downstream effect of this is to directly induce TF expression, as well
with active malignancy have a higher risk for thrombosis than other as other genes involved in hemostasis. Targeting the human MET
medical patients: for instance, surgical oncology patients have a oncogene to mouse liver using a lentiviral vector results in hepato-
higher thrombosis rate than other surgical patients undergoing major carcinoma, associated with a coagulopathy similar to that in malig-
procedures. Although reports of thrombosis rates vary, in general nancy, with striking thrombotic events, similar to Trousseau
approximately 15% to 20% of cancer patients develop VTE at some syndrome, the migratory thrombophlebitis associated with malig-
point during their illness; conversely, approximately 20% of all VTE nancy. Elevated TF expression and activation of the coagulation
events occur in cancer patients. system appear to correlate with both thrombotic tendency and disease
Cancer is a potent risk factor for venous thrombosis, and increases progression.
the relative risk by roughly 6- to 10-fold. In comparison, the common In addition to TF expression in tumors, activated endothelium,
hereditary thrombophilia, homozygous factor V Leiden, increases the and tumor-associated macrophages, TF is also increased in platelets
risk for venous thrombosis by approximately fivefold. Virtually all and microparticles from cancer patients compared with healthy
solid tumor types, as well as hematologic malignancies, carry this controls. The generation of TF-expressing microparticles may be an
significantly increased risk for thrombosis. Certain tumor types, important mechanism of cancer hypercoagulability. Microparticles
particularly mucinous adenocarcinomas, appear to have particularly are vesicular structures released from cell membranes under a variety
high risk for thrombosis including lung, gastrointestinal cancers— of situations, including activation, malignant transformation, stress,
notably pancreatic adenocarcinoma—as well as primary brain tumors. or death. They can be detected in plasma in a wide range of disease
Development of thrombosis in the cancer patient generally carries states, including sepsis and cancer. Microparticles are generally con-
prognostic impact. In patients with advanced solid tumors, those who sidered to be between 100 nm and 1000 nm in diameter. Micropar-
have venous thromboembolic disease at the time of presentation have ticles have been reported to arise from platelets, monocytes,
a 1-year survival nearing only 10%, compared with 1-year survival endothelial cells, and tumor cells and carry on their surfaces a range
of closer to 40% among those without thrombosis at diagnosis. It is of proteins that are derived from the cell of origin, including TF.
less clear whether this thrombotic tendency is simply a marker of Cancer cells, directly and indirectly, lead to the generation and cir-
aggressive disease or whether the development of thrombosis itself is culation of TF-bearing microparticles, and the levels of circulating
the cause of the increased mortality. Thrombosis is second only to TF-bearing microparticles in pancreatic cancer patients appear to
disease progression as a cause of death among cancer patients, and correlate with the subsequent risk for venous thromboembolic disease.
accounts for nearly 10% of deaths among patients receiving outpa- In one study, approximately a third of patients with detectable
tient chemotherapy. This mortality risk appears to be independent of TF-bearing microparticles developed venous thrombosis, compared
cancer stage at the time of thrombus identification. The risk may, with no thrombotic events in those without detectable TF-bearing
however, vary depending on the underlying malignancy, and also microparticles.