Page 2528 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 155 Hematologic Manifestations of Malignancy 2251

Coagulation and Tumor Progression symptomatic events were PEs. There was also a lower risk for recur-
rent thrombosis among those patients with an incidental thrombus
The activation of coagulation in cancer may also play a role in tumor compared with those with a symptomatic thrombus, and no differ-
progression. For example, TF expression levels often correlate with a ences in major bleeding and overall survival between groups. Taken
more aggressive tumor phenotype, and both clotting-dependent and together, these two studies support the routine anticoagulation treat-
clotting-independent signaling mechanisms of TF may be important ment of an incidentally found thrombosis, and do provide some
in regulating tumor metastasis. TF promotes angiogenesis and is insight into the risk of recurrent thrombosis according to the mecha-
coexpressed with VEGF on malignant cells. nism of presentation.
Thrombin is the key terminal enzyme of the coagulation cascade,
and results in fibrin deposition and platelet activation; it also serves
as a growth factor for a number of cell types including fibroblasts, Intravenous Catheter Thrombosis in Malignancy
endothelial cells, smooth muscle cells, and tumor cells. The cellular
effects of thrombin are mediated through seven transmembrane- Many patients with cancer undergo placement of a central venous
spanning G protein–coupled protease-activated receptors (PARs), catheter (CVC), commonly in the form of an implantable port, for
principally PAR1. PAR1 is activated by thrombin through cleavage chemotherapy infusion. Presence of an indwelling central line is a risk
of its N-terminus, which exposes a tethered ligand that then binds factor for thrombosis; this is augmented in patients with underlying
to the second transmembrane domain of the receptor. PARs are cancer. Nearly 15% of patients with cancer may develop a CVC-
expressed on platelets and other cells, as well as on tumor cells. associated thrombosis, and the risk of thrombosis is increased if there
Thrombin-activated tumor cells have PAR1-dependent enhanced is an exit site infection, among male patients, and in the presence of
expression of a number of cell surface integrins. Thrombin may metastatic disease; risk also varies according to the type of catheter,
enhance tumor progression via several mechanisms, including being higher with a peripherally inserted central catheter compared
enhancing tumor cell proliferation, activating tumor–platelet adhe- with an implanted portal catheter. Particular malignancies also con-
sion, tumor adhesion to the matrix or endothelium, tumor implanta- tribute to the risk of CVC-related thrombus; there is a significantly
tion, growth, and metastasis, and tumor angiogenesis. Thrombin higher rate of CVC thrombus in patients with acute promyelocytic
alters tumor cell gene expression with upregulation of angiogenesis- leukemia (32%) when compared with those with other types of acute
related genes such as VEGF, matrix metalloproteinase 2 (MMP-2), myelogenous leukemia (6%). Because of the high risk of bleeding in
angiopoietin 2 (ANG2), and other genes and microribonucleic acids cancer patients, routine VTE prophylaxis is not recommended among
affecting tumor cell proliferation and invasion. cancer patients with CVCs, in spite of the known thrombotic risk.
For those patients that develop CVC-associated thrombosis, general
treatment recommendations are for anticoagulation for 3 months.
Diagnosis of Coagulopathies in Cancer Patients Low-molecular-weight heparin (LMWH) is preferred over the
vitamin K antagonist, warfarin, in this population, and anticoagula-
Thrombotic events in patients with cancer are diagnosed in a similar tion is continued while the line is in place. These guidelines may
fashion to those in patients without cancer. However, several subtle- change as further studies reveal more information regarding newer
ties exist. For example, thrombosis may be confused with either anticoagulation agents.
intravascular disease progression and/or intravascular fungal infec-
tions. In many cases, the diagnosis of thrombosis, or an abnormality
in coagulation, may be made in an asymptomatic patient, leading to Management of Thrombosis in Patients With Cancer
a more complicated decision regarding the risks and benefits of
therapy. A process of fibrin formation and degradation is continuous Cancer patients with a VTE have a high rate of recurrent thrombosis
in the setting of many patients with malignancy, and may relate to and bleeding after anticoagulation when compared with the general
elevated thrombin–antithrombin complexes and fibrin degradation population, and merit a tailored treatment approach. One study
products. Thus cancer is thought by some to be a process of “chronic compared recurrent thrombosis and major bleeding rates in patients
DIC.” Of note, in two prospective studies of routine coagulation with VTE with and without an underlying malignancy, managed
parameters in cancer patients, elevated fibrinogen and platelet counts with dose-adjusted intravenous unfractionated heparin or weight-
were the most frequent alterations, not diminished as typically seen adjusted LMWH, followed by warfarin. The 12-month cumulative
in DIC. The clinical spectrum of coagulopathy in cancer ranges from incidence of recurrent thromboembolism among cancer patients was
asymptomatic to life-threatening thrombohemorrhagic disease. 20.7% versus 6.8% in patients without cancer, whereas the 12-month
Thrombotic manifestations of DIC include arterial and venous cumulative incidence of major bleeding was 12.4% in patients with
thromboembolism, migratory thrombophlebitis, marantic endocar- cancer and 4.9% in patients without cancer.
ditis, and microvascular thrombosis with organ failure or skin Warfarin can pose certain difficulties in cancer patients for several
necrosis. The consumptive phase of DIC may manifest as bleeding, reasons: there are numerous and often unpredictable drug interac-
treatment of which is supportive and patient specific. Some may tions, cancer patients have variable nutritional intake, with unpredict-
respond favorably to low-dose heparin, and/or plasma therapy, while able amounts of vitamin K in their diets, and the frequent use of
waiting for treatment of the underlying malignancy. In general, the antibiotics can result in altered bioavailability of dietary vitamin K.
treatment of cancer-associated DIC is centered on the treatment of Further, there is a frequent need to interrupt anticoagulation for
the underlying tumor. procedures, and there often is a coexisting thrombocytopenia, whose
With increased use of high-resolution computed tomographic impact on coagulation may be complicated by the long half-life of
imaging studies, pulmonary emboli (PEs) are increasingly being warfarin. The long-term use of LMWH in cancer patients has been
identified incidentally, in the absence of clinical suspicion. This has compared with warfarin, most notably in the CLOT trial. In this
led to the question of how to manage incidentally discovered throm- study, patients with cancer and VTE received dalteparin 200 IU/kg
bosis. A retrospective cohort study of the period from 2004 to 2010 subcutaneously once daily for 5 to 7 days, and were then randomized
compared the rate of recurrent VTE and overall survival between to either continued dalteparin 150 IU/kg subcutaneously once daily,
those patients whose PEs were detected incidentally on imaging or to dose-adjusted warfarin with a target international normalized
studies with those whose PEs were suspected by classic clinical criteria; ratio of 2 to 3. Patients treated with dalteparin had a lower hazard
there was no difference in recurrent VTE or overall survival when ratio for recurrent thromboembolism compared with the oral-
both groups were anticoagulated. A separate prospective observational anticoagulant group (0.48); rates of major (6% versus 4%) and all
study enrolled consecutive cancer patients newly diagnosed with bleeding (14% versus 19%) were similar. In this study, there was no
combined deep venous thrombosis and PE from 2006 to 2009; 60% difference in overall survival. A similar study that compared enoxa-
of the incidental thromboses were PEs, whereas only 26% of the parin with warfarin for treatment of venous thrombosis in cancer also