Page 125 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

104 PART I The Biology and Pathogenesis of Cancer

As with anemia, decreased platelet production can result from clinical signs of organ dysfunction caused by microthrombo-
myelophthisis and hyperestrogenism (see earlier). Cancer-asso- sis and/or hemorrhage. The compensated chronic phase, where
time exists for replenishment of coagulation factors, anticoagu-
ciated immune-mediated thrombocytopenia is most commonly
VetBooks.ir associated with lymphoma, multiple myeloma, and HS, but also lation proteins, and platelets, is more difficult to diagnose and
likely even more prevalent.
has been reported with mammary adenocarcinoma, MCT, HSA,
83
nasal adenocarcinoma, and fibrosarcoma. 148–151 Non–immune- The pathogenesis of thromboembolic disease in cancer patients
mediated platelet destruction in cancer patients most commonly is complex and multifactorial. One of the major causes for hemo-
occurs secondary to microangiopathy. The spleen normally stores dynamic derangement is the inherent abnormalities of tumor
about one third of the body’s platelets, and tumors causing dif- microvasculature, including absent or incomplete endothelial cov-
fuse splenomegaly can increase platelet sequestration. This occurs erage, vessel tortuosity, variations in vascular caliber, and blood
most commonly with splenic lymphoma and feline splenic flow turbulence. 83,105 Hyperviscosity or tumor invasion into
83
MCT, but also can occur with highly vascularized tumors such blood vessels can further contribute. There also is considerable
as hemangioma and HSA. 83,151 Increased consumption can occur “cross talk” between the inflammatory and coagulation pathways.
secondary to hemorrhage. Severe, acute hemorrhage frequently Tissue factor, expressed on monocytes and endothelial cells dur-
causes thrombocytopenia. Chronic low-grade hemorrhage is ing inflammation and on some cancer cells, complexes with factor
98
more likely to cause thrombocytosis; thrombocytopenia results VIIa to activate the extrinsic clotting cascade. 161 This is the major
only when the regenerative capacity of the bone marrow has been stimulus for thrombin production in DIC. In addition, TNF-α,
exhausted. 151 More importantly, increased platelet consump- IL-1, and IL-6 can directly activate certain clotting factors and
tion can result from the hypercoagulable state that is common in downregulate protein C-thrombomodulin expression on endothe-
cancer patients (see later). 83,151 Platelet counts and kinetics were lial cells. 83,161
evaluated in 52 tumor-bearing and 24 normal dogs. 152 Tumor- Thrombosis initially was thought to be merely a consequence
bearing dogs had significantly lower platelet counts and shorter of cancer, but more recent evidence supports that it might be a
mean survival time of circulating platelets. In addition, mean necessary intrinsic step in cancer progression. Fibrin deposition
platelet survival time was the shortest for dogs with metastatic around neoplastic foci forms a provisional extracellular matrix
cancers. for angiogenesis. 83,162 In addition, the formation of fibrin–
platelet–tumor cell complexes increases adhesion to endothe-
Coagulopathies and Disseminated Intravascular lium and enhances metastatic efficiency. 83,162
Coagulation
Hypocoagulability can result from thrombocytopenia and altera- Cutaneous Manifestations of Cancer
tions in platelet function secondary to paraproteinemia (see Nodular Dermatofibrosis
earlier). Hemorrhagic diathesis also can result from blood hyper-
viscosity (see earlier). The most common clotting factor dysfunc- Nodular dermatofibrosis (ND) is a well-recognized PNS char-
tion seen in veterinary cancer patients results from the release of acterized by multiple slowly growing cutaneous collagenous
heparin by MCT, which acts as a cofactor for antithrombin III to nodules in association with bilateral renal cystadenocarcinomas
inactivate clotting factors XII, XI, X, and IX. 139 or cystadenomas. 163–168 Almost all reported cases have been in
Hypercoagulability is much more common in cancer patients. German shepherd dogs, and pedigree analysis strongly indi-
In human cancer patients, thromboembolic disease can manifest cates autosomal dominant inheritance. 168 The ND-associated
as deep venous thrombosis, pulmonary thromboembolism (PE), mutation was mapped to the BHD gene on chromosome 5. 169
migratory superficial thrombophlebitis (Trousseau’s syndrome), This is the causative gene for the human renal cancer syndrome
83
nonbacterial thrombotic endocarditis, and DIC. In dogs with Birt–Hogg–Dubé syndrome, which bears some similarities to
various untreated cancers, platelet aggregation in response to ago- renal cystadenocarcinoma/nodular dermatofibrosis. The func-
nists (collagen, adenosine diphosphonate, or platelet-activating tion of folliculin, the protein encoded by the BHD gene, is
factor) was significantly greater compared with healthy control unknown.
dogs. 153,154 Thromboelastography documented hypercoagulabil- Most dogs present with multiple firm cutaneous nodules
ity in 56% of dogs with lymphoma and 50% of dogs with vari- ranging in size from 2 mm to 5 cm that are not painful or
ous other cancers. 83,155 Although many of these patients did pruritic (Fig. 5.1). Lesions are found predominately on the limbs,
not necessarily have clinical manifestations of hypercoagulabil- although the head and trunk may be affected in advanced cases.
ity, underlying cancer was identified in 27% of dogs with por- Histologically, the nodules consist of irregular bundles of dense,
tal vein thrombosis, 30% with PE, and 54% with splenic vein well-differentiated collagen fibers in the dermis or subcutis. 165,166
thrombosis. 156–158 ND almost always precedes systemic signs of illness related to
DIC is a syndrome of systemic activation of coagulation, tumor-induced renal failure or metastasis by months to years,
leading to widespread microthrombosis. Consumption of plate- although microscopically detectable renal changes can occur at a
lets and clotting factors can then lead to uncontrollable hem- young age. Affected females almost always have concurrent uter-
orrhage. Cancer is one of the most common causes of DIC. ine leiomyomas that carry little clinical significance. 163,164
One study estimated 10% of dogs with cancer to have DIC. 159 Currently, there is no effective therapy for the underlying
Tumors with the highest incidences include HSA (with up to cancer. Affected dogs develop multiple tumors bilaterally, pre-
50% of dogs affected at initial evaluation), mammary adeno- cluding surgery, and chemotherapy has not been evaluated.
carcinoma (particularly inflammatory mammary carcinoma), Palliative surgical removal of cutaneous nodules can be con-
and pulmonary adenocarcinoma. 105,159,160 It is worth noting, sidered when they are ulcerated or interfering with function.
though, that these studies focused primarily on acute phase Mean time from first observation of ND until death is about
DIC, characterized by obvious laboratory abnormalities and 2.5 years. 163,168