Lawrence LK Leung, MD
Stephen A Landaw, MD, PhD
INTRODUCTION — Many patients with cancer are in a hypercoagulable state. The spectrum of manifestations ranges from abnormal coagulation tests in the absence of thrombotic symptoms to massive thromboembolism. Thrombotic episodes may precede the diagnosis of malignancy by months or years (see “Overview of the causes of venous thrombosis”, section on ‘Malignancy’) and can present in one of the following ways :
- Migratory superficial thrombophlebitis (Trousseau’s syndrome)
- Idiopathic deep venous thrombosis and other sites of venous thrombosis
- Nonbacterial thrombotic endocarditis (marantic endocarditis)
- Disseminated intravascular coagulation (DIC)
- Thrombotic microangiopathy (eg, thrombotic thrombocytopenic purpura)
- Arterial thrombosis
This topic review will discuss the pathogenetic factors that might contribute to the hypercoagulable syndromes that can be associated with malignancy and its treatment . The incidence and clinical manifestations of these disorders are discussed separately. (See “Hypercoagulable disorders associated with malignancy”.)
PATHOGENESIS — The pathogenesis of the hypercoagulable state of malignancy involves the interplay of multiple variables. As an example, intact tumor cells may express procoagulant activity that can directly induce thrombin generation; in addition, normal host tissues may express procoagulant activity in response to the tumor. Comorbid factors such as bed rest, infection, surgery, and drugs, may play a contributory role and may determine whether an asymptomatic increase in coagulability becomes manifest clinically . (See “Drug-induced thrombosis and vascular disease in patients with malignancy” and “Overview of the causes of venous thrombosis”, section on ‘Virchow’s triad’ and “Overview of the causes of venous thrombosis”, section on ‘Malignancy’ and “Hypercoagulable disorders associated with malignancy”.)
Early reports noted that many tumors associated with thrombotic complications were mucin-secreting adenocarcinomas of the gastrointestinal tract [4,5]. However, many nonmucin-producing tumors are also associated with hypercoagulability and it has not been possible to purify a unique procoagulant moiety from mucin. The substances that have been isolated from animal and human tumors with procoagulant activity fall into two major categories: tissue factor-like procoagulant and cancer procoagulant . (See “Hypercoagulable disorders associated with malignancy”, section on ‘Mucin’.)
Tissue factor — Tissue factor (TF) forms a complex with factor VII to activate factor IX and factor X, thereby initiating blood coagulation. TF is a transmembrane protein expressed by some normal human parenchymal and connective tissue cells and many malignant counterparts such as sarcoma, melanoma, neuroblastoma, lymphoma, pancreatic and colorectal cancer, ovarian cancer (especially the clear cell variant), and acute promyelocytic leukemia (APL) [7-15]. Tissue factor expression may correlate inversely with the degree of differentiation of the tumor [16,17].
However, data indicating the importance of TF expressed on tumor cells as a procoagulant should be interpreted with caution, since the expression of TF antigen and activity depends heavily upon the source of malignant tissue . As an example, TF expression is frequently studied in cell culture, a milieu that may not be representative of that found in vivo [15,19].
Tissue factor has been implicated in the hypercoagulable state associated with APL and, less often, other subtypes of acute myeloid leukemia [7,20-22]. Myeloid precursor cells from normal bone marrow do not possess procoagulant activity . The induction of leukemia cell differentiation with all-trans-retinoic acid downregulates the expression of TF, cancer procoagulant, and annexin II and improves the hypercoagulable state [24-27].
In one series, for example, plasma fibrinogen began to increase and D-dimer and thrombin-antithrombin complex levels began to fall within two to four days after the onset of all-trans-retinoic acid therapy; the values were normal or near normal by eight days . (See “Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults”, section on ‘Disseminated intravascular coagulation’.)
Tissue factor-bearing microparticles — Tissue factor antigen is present in plasma . Some of the molecules are truncated, or result from alternative splicing of TF mRNA, and lack the transmembrane domain . There is considerable interest in assessing the physiologic importance of such blood-borne TF in microparticles [30-33], as well as their potential role in the pathogenesis of the hypercoagulable state accompanying cancer, sepsis, and sickle cell disease [34-36].
Using impedance-based flow cytometry, tissue factor-bearing microparticles (TFMP) were studied in patients with malignancy, leading to the following salient observations :
- TFMP were detected in patients with advanced malignancy, including two-thirds of patients with pancreatic carcinoma.
- Elevated levels of TFMP were associated with VTE in a cohort of 96 cancer patients of different histologies (adjusted OR 3.72; 95% CI 1.18-11.8).
- In a group of 60 cancer patients without VTE, a retrospective analysis revealed a cumulative incidence of VTE of 34.8 versus zero percent at one year in those with (4 of 16) or without (zero of 44) TFMP, respectively.
- Pancreatectomy with curative intent in three patients eliminated or nearly eliminated these microparticles. Microparticles in these patients coexpressed the epithelial tumor antigen MUC-1 found on pancreatic tumor cells, providing evidence that they were derived from the tumor cells rather than from platelets or other cells of hematologic origin.
Cancer procoagulant — Cancer procoagulant (CP) is a calcium-dependent cysteine protease that has been found in malignant and fetal tissue, but not normally differentiated tissue [38-40]. It activates factor X directly, independent of the tissue factor/factor VIIa complex . Cancer procoagulant has been reported to be present in extracts of cells obtained from patients with acute promyelocytic leukemia, malignant melanoma, and cancers of the colon, breast, lung, and kidney [7,42,43].
To date, only a small amount of sequence has been obtained and the cDNA of this procoagulant has not been cloned. CP is not currently felt to be important in the pathogenesis of the hypercoagulable state associated with malignancy.
Procoagulant activities expressed by host tissues — Normal cells can be stimulated to express procoagulant activity . In patients harboring a malignancy, these normal cells can play an important role in activating the hemostatic mechanism and ultimately in fibrin deposition.
P-selectin — Among these activators is the cell adhesion molecule P-selectin, found in the alpha granules of platelets and the Weibel-Palade bodies of endothelial cells. Among other functions, P-selectin increases the expression of tissue factor on monocytes and endothelial cells.
High plasma levels of P-selectin are prothrombotic in experimental animals , and have been associated with an increased risk of VTE in cancer patients . (See “Leukocyte-endothelial adhesion in the pathogenesis of inflammation”, section on ‘Selectins’.)
Monocytes — Monocytes constitutively express little if any procoagulant activity (PCA). However, they can be induced to produce tissue factor and other direct factor X activators  by T lymphocytes, antigens, cytokines, lipoproteins, immune complexes, endotoxin and complement [48-52].
Monocytes may also become activated by tumor-specific antigens, immune complexes involving tumor antigens, or indirectly by cytokines secreted by other immune cells in response to tumor related antigens. In a study of patients with lung cancer, for example, pulmonary alveolar macrophages close to the tumor expressed increased tissue factor activity in vitro compared with cells from normal controls or macrophages from the contralateral side of the neoplasm .
Platelets — Increased platelet reactivity secondary to either clonal abnormalities (eg, myeloproliferative disorders) or tumor-platelet interactions could contribute to hypercoagulability. Substances have been obtained from various animal and human tumors that can directly aggregate platelets [54,55]. However, efforts to recover and purify the active species from detergent-solubilized tumor cell membranes have thus far been unsuccessful.
Other mechanisms proposed for increased platelet activation in malignancy include tumor-induced thrombin generation, ADP production by tumor cells, and elevated levels of von Willebrand factor (vWF) [56-58]. It is postulated that platelet proaggregatory moieties may lead to clot formation on the vascular subendothelium, thereby stimulating hemostatic activation.
Endothelial cells — Endothelial cells may become procoagulant under the influence of inflammatory cytokines and other peptide products. In particular, both tumor necrosis factor (TNF) and interleukin (IL)-1 increase the expression of leukocyte adhesion molecules, platelet activating factor, and tissue factor. TNF also suppresses endothelial fibrinolytic activity, increases endothelial cell production of IL-1, and downregulates thrombomodulin expression, which diminishes the activation of the anticoagulant protein C.
By virtue of these effects, TNF is able to dramatically enhance the procoagulant and suppress the anticoagulant properties of cultured vascular endothelial cells [59,60]. In one study, infusion of TNF into patients with cancer produced a substantial net procoagulant stimulus to the hemostatic system .
Whether or not TNF levels are significantly and consistently elevated in patients with malignancy has not been determined. In one series, increased serum TNF concentrations were noted in as many as 50 percent of cancer patients with active disease . However, other reports have only infrequently observed elevated serum TNF in such patients [63,64].
Other mechanisms — Trousseau’s syndrome was mimicked in an animal model by targeting the activated human MET oncogene to the murine liver, causing slowly progressing hepatocarcinogenesis . This was preceded and accompanied by a hypercoagulable state (venous thromboses), evolving towards fatal internal haemorrhages. The syndrome was apparently driven by the transcriptional response to the oncogene, including upregulation of the plasminogen activator inhibitor type 1 and cyclooxygenase-2 genes.
Comorbid factors — A number of clinical factors may contribute to the thrombotic tendency in cancer patients. These include vascular stasis due to obstruction of blood flow by the tumor or patient immobility, hepatic involvement and dysfunction, sepsis, advanced age, other comorbid conditions, certain antineoplastic agents, and the presence of indwelling central venous catheters used for administration of chemotherapy. (See “Drug-induced thrombosis and vascular disease in patients with malignancy” and “Overview of the causes of venous thrombosis”, section on ‘Acquired thrombophilia’.)
Hypercoagulable manifestations of malignancy — The spectrum of hypercoagulable manifestations in cancer patients ranges from abnormal coagulation tests in the absence of thrombotic symptoms to massive thromboembolism. These can present in one or more of the following ways. (See “Hypercoagulable disorders associated with malignancy”.)
- Migratory superficial thrombophlebitis (Trousseau’s syndrome).
- Idiopathic deep venous thrombosis and other sites of venous thrombosis.
- Nonbacterial thrombotic endocarditis (marantic endocarditis).
- Disseminated intravascular coagulation (DIC).
- Thrombotic microangiopathy (eg, thrombotic thrombocytopenic purpura).
- Arterial thrombosis.
Causes of the hypercoagulable state — The pathogenesis of the hypercoagulable state of malignancy involves the interplay of multiple variables, including the following:
- Tissue factor — Tissue factor (TF) is a transmembrane protein expressed by some normal human parenchymal and connective tissue cells and many malignant counterparts such as sarcoma, melanoma, neuroblastoma, lymphoma, pancreatic and colorectal cancer, ovarian cancer (especially the clear cell variant), and acute promyelocytic leukemia. (See ‘Tissue factor’ above.)
- Reactions of host tissues — A number of normal host tissues can be stimulated to express procoagulant activity. These include platelets, endothelial cells, and monocytes. (See ‘Procoagulant activities expressed by host tissues’ above.)
- Other causes — A number of clinical factors may contribute to the thrombotic tendency in cancer patients. These include vascular stasis due to obstruction of blood flow by the tumor or patient immobility, hepatic involvement and dysfunction, sepsis, advanced age, use of certain antineoplastic agents, and the presence of indwelling central venous catheters. (See “Drug-induced thrombosis and vascular disease in patients with malignancy” and “Overview of the causes of venous thrombosis”, section on ‘Acquired thrombophilia’.)
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