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The contribution of prothrombotic states to cancer-related stroke
Seminars in Cerebrovascular Diseasesand Stroke Vol. 2 No. 2 2002
The Contribution of Prothrombotic States to Cancer-Related Stroke DAVID E. JOYCE Indianapolis, Indiana
ABSTRACT Risk factors for cancer-related ischemic stroke are difficult to discern from the traditional risk factors for atheroembolic disorders. Certain hematologic and oncologic malignancies predispose to ischemic stroke. However, contributing pathophysiologic mechanisms are complex, and they cannot often be directly identified as specific causes of a thrombotic event. Generally speaking, interactions between the cellular phase and the plasma phase of coagulation are heightened in malignancy patients. Tissue factor and other procoagulant initiators of thrombosis predominate in certain solid tumor subtypes. Specific malignant hematologic disorders, such as polycythemia vera, essential thrombocythemia, Waldenstrom macroglobulinemia, and subtypes of acute leukemia, are perhaps best characterized as causes of a hypercoagulable state. Solid tumor treatments entail effects of radiation and specific chemotherapy agents that may pose a prothrombotic risk. This review focuses on the pathophysiology of ischemic stroke in malignancy with emphasis on underlying prothrombotic states and the management of these patients. Key words: cancer, malignancy, stroke, thrombosis, procoagulant, prothrombotic, brain rumor, cerebrovascular, polycythemia, leukemia, promyelocytic leukemia, cysteine protease, cancer procoagulant, mucin, marantic endocarditis.
Thrombosis and Stroke
matory mediators. The generation of thrombin and activation of platelets precede the formation of a thrombus. Capillaries and small and large vessels rely on these basic hemostatic mechanisms of protection to protect against hemorrhage. In this process, endothelial responses to generated thrombin can also directly modulate vessel wall function. 1 Although arterial and venous thromboses rely on different mechanisms, both may lead to vessel occlusion and ischemic compromise. The balance between procoagulant factors and natural anticoagulant pathways is important. Deficiencies of the procoagulant mechanism (genetic or acquired) can lead to hemorrhagic stroke. This would include a factor deficiency, as in the rare factor VII deficiency associated with hemorrhagic stroke. Conversely, deficiencies involving the vascular anticoagulant pathways (eg, protein C, protein S, antithrombin III, or factor V Leiden) may lead to embolic or ischemic stroke. Embolic paradoxical stroke would be included in these predominantly venous, aberrant circulatory pathways. Beyond the soluble regulation of coagulation, abnormal platelet activation or
The interface shared by the vascular endothelium and flowing blood is the defined platform for hemostatic regulation and thrombus formation. Prothrombotic mechanisms respond to hemostatic stress at the specific site of vascular injury to form a thrombus. Preeminent among these mechanisms is tissue factor, normally expressed in the subendothelial compartment of extracellular matrix and expressed in several types of tumors. The normal and pathological hemostatic responses are complex and involve the interplay of several components, including plasma proteins, platelets, and inftam-
From the Department of Hematology and Oncology, Indiana University School of Medicine, and Eli Lilly and Company, Indianapolis, IN.
Address reprint requests to David E. Joyce, MD, Eli Lilly and Company, DC 6072, Lilly CorporateCenter, Indianapolis,IN 46285. Copyright 2002, Elsevier Science (USA). All rights reserved.
1528-9931/02/0202-0008535.00/0 doi: 10.1053/scds.2002.123670
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adhesion can disturb the hemostatic balance in forming or maintaining the intact thrombus. 2 The importance of the endothelium in thrombotic, antithrombotic, fibrinolytic, and inflammatory pathways (thrombin receptor, adhesion, and cytokine pathways) cannot be overemphasized. Differences in these intricate mechanisms exist between different vascular beds. Alteration of endothelium, monocytes, or cytokine responses systemically or in specific capillary beds can bring about inflammatory changes that may predispose to thrombosis. Cancer-associated stroke may be linked to prothrombotic risks (mostly acquired) that are characteristic of the deranged mechanisms of hemostasis in malignancy. 3'4 The release of inflammatory mediators in malignancy can produce tissue factor expression on monocytes and probably also on the endothelium. Moreover, elevated fibrinogen as an acute-phase reactant results from cancerrelated inflammation. Cytokines such as tumor necrosis factor and interleukin 1 can elicit tissue factor expression. Tissue factor initiates clotting by binding factor VIIa. The tissue factor pathway is. now considered the primary physiological initiator of coagulation. Some tumors may express other similar serine proteases such as hepsin. 5 Other related cancer-specific mechanisms, such as cysteine protease cleavage of factor X or mucin-secreting tumors that express cancer procoagulant (mucin sialic acid [cleaving FX]), may initiate abnormal thrombosis in specific cancers (Fig 1 and Table 1). 6,7 The fibrinolysis inhibitor plasminogen activator inhibitor 1 (PAI-1) is elevated in cancer and inflammation contrib-
. . ~ , ~ ~ ---~
Cytokines (minornecrosisfactor, Interleukin-1)
Endothelittm (TF) "1
W
FactorX Tissue Factor(TF) 1 ~overexpression Cancer:TumorCell '\ Inflammation:Monocyte~Tissue factor:FVIIa ,
Mucin/sialicacid CysteineProtease FactorIX/VIII
FXa Fig. 1. Mechanisms of aberrant coagulation specific to cancer and inflammation. Cytokines can activate monocytes and tumor cells inducing tissue factor (TF) expression. This initiates the coagulation cascade. Coagulation initiation may also occur at the level of factor X (common pathway) by cancerspecific cysteine proteases and mucin sialic acid/cancer procoagulant. Specific tumors expressing these cancer procoagulant factors may overlap. Endothelium TF expression is suspected.
uting to the prothrombotic state of cancer. Maintaining the balance of thrombin generation, clot formation, and fibrinolysis can be delicate (Fig 2). Dysregulation of this balance in cancer may lead to both bleeding and thrombosis. This condition, termed disseminated intravascular coagulation (DIC), is usually chronic when found in the cancer patient (approximately 7% incidence), and treating the underlying cause might help improve this condition. More aggressive DIC with clinical signs, termed overt DIC, in cancer is rare, and as yet, screening recommendations have not been formalized. 8 In general, a screening prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer, or fibrin degradation product (FDP) are sensitive enough to discern most DIC. Fibrinogen levels less than 100 mg/dL can be associated with spontaneous bleeding in DIC, and consideration for fibrinogen replacement in acute DIC is warranted. Epidemiologically, venous thrombosis is more common than stroke as the presenting symptom in the diagnosis of cancer. 9'1~ Categories of malignancy contributing to abnormal thrombosis discussed above are listed in Table 2.
Ischemic Stroke Overall, there are 700,000 new cases of ischemic stroke each year in the United States. The most common predisposing factors include prior ischemic stroke, recent transient ischemic attack (TIA), and internal carotid artery stenosis. Marantic endocarditis is a well-known condition occasionally encountered in malignancy. In Table 2, cancer-related prothrombotic risk factors are listed and compared to the broader group of risk factors segregated as cellular disorders, plasma protein disorders, and secondary conditions predisposing to thrombosis. The malignancy-related prothrombotic risks will be discussed below.
Hematologic Malignancy Polycythemia vera is a clonal stem cell condition causing panhyperplasia of erythrocyte, leukocyte, and megakaryocyte cell lines within the bone marrow. 11 The thrombotic risk in this malignant, myeloproliferative disorder correlates with elevation of hematocrit, age, and frequency of phlebotomy. In polycythemia vera, the most common neurological symptoms include headache, lethargy, and dizziness) Moreover, clinical concerns for the risk of stroke arise at a hematocrit of greater than 50%. 12'13 Elevated blood viscosity at the higher hematocrit will retard cerebral blood flow and produce symptoms. Regarding stroke or transient ischemic attack, the incidence is 4% to 5% per year in a middle-aged, phlebotomy-treated population. 3 High hemoglobin levels in untreated polycythemia vera portend a high risk of
Prothrombotic States and Cancer-RelatedStroke
*
David E. Joyce 153
Table 1. Suspected Prothrombotic Coagulation Mechanisms Specific to Tumor Type Tissue Factor VIIa
Cysteine Protease (FX)
Acute Leukemias Stomach Ovary Kidney
Lung Prostate Colon Breast Kidney Leukemia
Mucin/Sialic Acid (FX) Lung Pancreas Gastrointestinal Ovary Prostate Renal Celt
NOTES. Activation of coagulation can occur at factor VII (extrinsic path) or factor X (common path). Overlap may occur among tumor types and mechanisms. Abbreviation: FX, factor X.
stroke, hemorrhage, or infarction. Ischemic stroke appears to occur less frequently with associated secondary polycythemias than with polycythemia vera. Platelet qualitative abnormalities and elevated platelet numbers in polycythemia vera may add to the more concerning hyperviscosity hazard seen in this condition. Other causes of polycythemia related to malignancy, such as renal cell carcinoma or a cerebellar hemangioblastoma producing erythropoietin, could be considered malignancy-related prothrombotic risk factors for stroke. Polycythemia or secondary erythrocytosis without a malignant clone or reactive thrombocytosis would not be considered malignancies, but could pose a thrombotic
Tissue Factor FVIIa
Extrinsic
Cancer/Inflammation Mucin CysteinePr.
~ F Fxa /
VaI
ELEVATED:
Tissue Factor(TF) Hepsin
platelets Fibrinogen
Cytokiue~(TNF, IL-I ) Enhanced adhesion Apoptosis, 2hrombosis Thrombin receptors
PAI-I ESR Acute phase Pr, WBC proteases
C h e m o t h e r a p y , D1C, V i s c o s i t y Thrombin II a Antithrombotic pathways:
~
D-dimer
2. Prothrombotic mechanisms in malignancy. The coagulation cascade is initiated by tissue factor (TF). Factors X, V, and II form the common pathway to activate thrombin (IIa). The platelet-fibrin clot is broken down by plasmin (fibrinolysis) to form fibrin split products (FSP) including D-dimer. Antithrombotic pathways relieve the effects of thrombin generation. Cancer-related aberrations and elevated inflammation mediators are prothrombotic in general and cancer-specific mechanisms (eg, mucin sialic acid and cysteine proteases) promote a thrombotic tendency. Other factors including chemotherapy, disseminated intravascular coagulation (DIC), and increased viscosity predispose to thrombosis by various mechanisms. Fig.
risk. Therapies for polycythemia are few, but effective. Acute treatment of polycythemia vera is phlebotomy. Subsequent periodic removal of approximately 500 mL of whole blood with the long-term goal to reduce the hematocrit to 40% is the standard initial therapy. Chemotherapy with hydroxyurea is commonly used in the elderly. Despite a small probable risk of treatmentrelated, late-onset leukemia with hydroxyurea, it has found a favorable risk-benefit profile in this population. Phlebotomy in patients with underlying comorbid conditions requires caution. Leukocytosis and thrombocytosis respond to oral hydroxyurea therapy. A sustained elevated platelet count of >600 • 109/L characterizes essential thrombocythemia. Splenomegaly, bone marrow megakaryocyte hyperplasia, and the preponderance of both hemorrhagic and thrombotic events also characterize this clonal malignancy. When platelet counts rise more than 1,000 • 109]L in this myeloproliferative disorder, the possibility of cerebral ischemia is more of a concern. Ischemic stroke as a presenting sign of essential thrombocythemia is less often reported at platelet counts <1,000 • 109/L. 12 With clarification of the thrombotic risk in this myeloproliferative disorder, lower platelet counts than the above extreme are now being treated more judiciously (threshold <600 • 109/L).t4 For example, the first manifestation of essential thrombocythemia presenting as ischemic stroke investigated over a 7-year period found 6 of 1,099 patients (0.54%) with an event at a mean platelet count of 597 • 109/L. Looking for essential thrombocytosis in stroke patients at lower platelet levels and using megakarocyte culture to define the malignant clone earlier is one possible strategy to prevent further thrombotic events. 15 Treating thrombotic strokes or other thrombotic events with aspirin to prevent recurrence is acceptable. However, essential thrombocytosis with qualitative platelet dysfunction and without a declared bleeding or thrombotic event should not be considered an indication for aspirin as an initial, empiric therapy. Hydroxyurea, with its risk-benefit concerns, has been considered more in the elderly population, but it is used also in the acute setting. Anagrelide, as an acute treatment to reduce platelet
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Seminars in Cerebrovascular Diseases and Stroke Vol. 2 No. 2 June 2002 Table 2. Prothrombotic Risk Factors and Their Relation to Malignancy
Cellular Disorders Polycythemia Anemia Sickle cell disease Thrombocytosis Hemolytic uremic syndrome Thrombotic thrombocytopenicpurpura Heparin-induced/PF4 Leukemia
Plasma Proteins Protein C deficiency Protein S deficiency Antithrombin III deficiency Factor V Leiden mutation APC resistance Prothrombin 20210A mutation Heparin cofactor II deficiency Plasminogen deficiency Fibrinogen increase Thalassemia Glycoprotein deficiency Waldenstrom's (IgM) Antiphospholipid antibodies Lupus anticoagulant
Secondary Conditions Pregnancy Pnerperium Oral contraceptives Cancer Chemotherapy Dehydration Inflammatory bowel disease PNH Nephrotic syndrome Sepsis and inflammation Sticky platelets Other conditions
Malignancy-related Polycythemia vera Essential thrombocytosis Leukemia
Waldenstrom's (IgM) Antiphospholipid antibodies Mostly acquired factors
Tamoxifen, others Cancer/inflammation Mucinous adenocarcinoma Marantic endocarditis Myxoma Radiation Chemotherapy Nephrotic syndrome Sepsis and inflammation Left ventricular failure
Abbreviations: APC, Activated protein C; IgM, immunoglobulinM; PF4, platelet factor 4; PNH, paroxysmal nocturnal hemoglobinuria.
number, is a consideration without the leukemogenic concerns of hydroxyurea, t4 However, anagrelide may have some effects that could worsen edema states (eg, cardiac/congestive heart failure). Platelet pheresis in an acute symptomatic stroke setting warrants some consideration, given the acuity, feasibility, and potential benefits for each individual case. As' mentioned above, hyperviscosity fi'om polycythemia is a prothrombotic risk factor from this clonal stem cell malignancy. Hyperviscosity is not seen in other myeloproliferative diseases. However, hyperviscosity develops in multiple myeloma (incidence: immunoglobulin G [IgG] 4%, immunoglobulin A [IgA] 5%-10%), Waldenstrom macroglobulinemia (immunoglobulin M [IgM] 10%-30%), and less often in POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin lesions). The M protein, if elevated greatly, may predispose to stroke, t6'17 For example, 25% of patients with Waldenstrom macroglobulinemia have neurological abnormalities such as peripheral neuropathy, hyperviscosity, encephalopathy, and subarachnoid hemorrhage. Rarely, there is a bleeding diathesis, hemolytic anemia, or type I cryoglobulinemia. is Plasmapheresis for acutely symptomatic IgM hyperviscosity is considered, followed by maintenance chemotherapy (eg, fludarabine or chlorambucil), or in some cases, anti-CD20 monoclonal antibody therapy has shown a response. ~9
Acute myelogenous leukemia (AML) with blast cell counts > 100,000/pL is considered a risk for hyperviscosity and stroke. In contrast to the blast cells of acute lymphocytic leukemia, myeloblasts have a greater propensity for adhesion. Approximately 20% to 30% of leukemia patients present with DIC, compared to 7% of solid tumor patients. 2~ With elevated blast counts or associated hyperviscosity syndromes (chest pain, vascular ischemic, neurologic symptoms), leukapheresis may be indicated. The most treatable of the myeloid leukemias is promyelocytic leukemia. Promyelocytic leukemia (M3) typically presents with severe disseminated intravascular coagulation. The malignant promyelocytic leukemia granules contain potent thromboplastin and proteases. 2a Bleeding and hemorrhagic stroke are commonly seen in promyelocytic leukemia. Characteristically, hyperfibrinolysis predominates over thrombosis in promyelocytic leukemia. With elevated blast counts or associated hyperviscosity syndromes, leukapheresis may be indicated. All-trans-retinoic acid (ATRA), a molecularly targeted therapy, given acutely will differentiate the promyelocytic blast cell, thus reducing leukemic blast cell number and the resultant DIC; but this does not often occur immediately (>1-3 days). 22 Lower doses of intravenous heparin have been approved for treatment of this specific DIC, although with some risk of bleeding. Myelomonocytic and monocytic leukemia (FrenchAmerican-British classifications M4 and M5) may also
Prothrombotic States and Cancer-Related Stroke 9 present with DIC and possible risk of subdural hematoma. 23 Controlling blast counts immediately with induction chemotherapy is essential. Low platelet counts in both leukemia and bone marrow transplant patients after induction chemotherapy regimens have been associated with subdural hematoma. Although controversial, thrombocytopenia less than 20 • 109/L requires routine transfusion. 24'25 Thrombocytopenia may become problematic, with subdural hematoma occurring in up to 44% of platelet refractory transplant patients versus 2.5% of others studied receiving platelet transfusion. 26 Immunocompromised patient's, particularly those receiving chemotherapy, run the risk of bacteremia and sepsis. The background rates of intracranial hemorrhage or infarction in the condition of sepsis are lacking. From some recent large studies, in severe sepsis the background rates of patients experiencing sepsis and intracranial hemorrhage primarily treated in the intensive care unit were from 0.1% in a large controlled study to 0.4%. 27,28 Another retrospective study reported similar rates. 29 This risk may be highel: in the thrombocytopenic, immunocompromised patient, but further studies are needed. Invasive infections such as endocarditis or Aspergillus in the immunocompromised patient are a risk for ischemic stroke or hemorrhage.
Solid Organ Tumors The diagnosis of cancer-associated hypercoagulable state first appeared in 1865, and now this Trousseau syndrome includes both arterial accelerated atherosclerosis and venous thrombosis. 3~ Hypercoagulability in cancer manifested as a venous thrombotic event most often requires long-term anticoagulation with heparin or low molecular weight heparin. The renewed interest in thromboembolic disease in the at-risk cancer patient has confirmed the evolving concerns for heparin prophylaxis and revisited consideration of the anti-inflammatory and anticancer effects of these drugs. 31 Thrombocytosis from cancer-related inflammation, hyperfibrinogenemia, endothelial apoptosis, tissue factor expression on tumor, and mucin-producing adenocarcinoma are all examples of hypercoagulability mechanisms in cancer. 7 Disseminated intravascular coagulation, nonbacterial thrombotic endocarditis (NTBE), and septic emboli were found to be the primary etiologies of cerebral infarction (7 strokes / 3,426 cancer patients) in a large autopsy series.l~ Cancerassociated NTBE in earlier series supported lung and other adenocarcinomas as major sources and an overall rate of 2% in cancer patients at autopsy. 32-34 Atrial myxoma by virtue of its location and thrombogenicity is a risk factor for embolic strokeY Cerebrovascular disease is second only to metastases as a cause of central nervous system pathology in the cancer patient. 36 Presenting symptoms of subacute or acute encephalopathy are common, given the diffuse or embolic nature of most
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cancer-related stroke. Most studies in cancer and stroke are retrospective. A retrospective study identified 33 patients (3.5% of all stroke consultations over approximately 4 years) looking at the incidence of cerebral ischemic events and TIA. This study found gynecologic cancer to be the most common cancer consulted upon for stroke (20.6%). Others included renal/genitourinary (10.5%), gastrointestinal (10.5%), lymphoma (8.0%), prostate (7.5%), lung (5.1%), and breast cancer (1.9%). The conclusion of this small study was that the ischemic cerebral events in adult cancer should not be termed Trousseau syndrome, but that the importance of and incidence of hypercoagulability-related stroke requires more study. Treatment of stroke with antiplatelet agents was felt to be appropriate by these authors. 37
Chemotherapy and Vascular Toxicity Chemotherapy has been shown to cause cerebral and extremity thrombotic events without evidence of active, demonstrable cancer. Varied vascular complications include pulmonary and hepatic veno-occlusive disease, Budd-Chiari syndrome, Raynaud syndrome, myocardial infarction, venous thromboembolic events, thrombotic microangiopathy, vasculitis, retinal toxicity, acral erythema, and alterations in blood pressure. 38 Combination chemotherapy regimens for head and neck cancer, germ cell tumors, lymphoma, and breast cancer have been recognized) 9 Combination chemotherapy regimens for stage II and III breast cancer with or without estrogen-like modulators (eg, tamoxifen) have been associated with venous thrombosis (5%-7%) and arterial thrombotic e v e n t s (3.1%). 40'41 Stroke in this population was approximately 8 to 9 events per 1,000 patients. Tamoxifen used alone may be associated with a slight lowering of antithrombin III, protein S, and fibrinogen, and a slight increase of ischemic stroke. 42 Doxorubicin as treatment for breast or other cancers can induce congestive heart failure at high cumulative doses (>550 mg total exposure). Thrombotic stroke in the setting of chemotherapy-induced heart failure may be considered a prothrombotic risk factor for cancer-related stroke. Chemotherapy for breast cancer can be linked to endothelial damage) However, its mechanisms are incompletely understood. Other chemotherapy agents can induce arterial ischemia or thrombosis. Vascular beds of the heart and brain are commonly involved, and older patients with underlying vascular disease who are receiving chemotherapy may be at risk. However, stroke in young patients receiving cisplatin and bleomycin and having no underlying vascular disease risk factors contrasts the above. Cisplatin and bleomycin for testicular cancer patients have been found to cause the chronic toxicity of Raynaud syndrome (40% of young men exposed, beginning months after therapy). Smoking compounds this risk. Bleomycin is the likely agent causing these
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Raynaud symptoms. Impairment of arteriole smooth muscle function is the presumed mechanism. The folic acid antagonist 5-fluorouracil (5-FU) when given as a continuous infusion (eg, colon cancer) had an approximate 10% cardiac toxicity in o n e study. 43 During infusion, waalaing symptoms of angina can be relieved by discontinuation of therapy. Coronary vasospasm is the possible mechanism in 5-FU vascular toxicity. 5-FU in patients with underlying vascular disease needs to be used with caution, especially in regimens requiring continuous infusion. Other agents associated with vascular, endothelial toxicity include (1) direct acting ('carmustine, vincristine, and bleomycin), (2) delayed acting (doxorubicin), and (3) combined acting (5-fluorouracil). Irinotecan may also cause vascular damage. L-asparaginase causes thrombosis by depleting plasma coagulation inhibitors, primarily antithrombin III. Sinus venous thrombosis and cerebral hemorrhage have been seen with L-asparaginase in acute lymphocytic leukemia patients. Some chemotherapy agents associated with thrombosis or endothelial dysfunction are listed in Table 3. Other regimens related to thrombosis are reviewed elsewhere. 44 Special Situations This section addresses other situations related to hematologic or oncologic malignancies and their treatment. Some of the information will consider inferences to prothrombotic risk factors in stroke. Anatomical considerations of location of brain tumorhnalignancy are obvious: vessel invasion, extrinsic compression, surgical injury to vessels, or neck mass predisposing to embolic stroke. 45 One study of brain hemorrhages from intracranial tumors revealed histology consistent with patterns of both primary and metastatic cancer. Over 4 years, a total of 13 patients had histologies of glioblastoma multiforme (7), oligodendroglioma (1), metastatic carcinoma (4) (lung, melanoma, hypernephroma, and adrenal carci-
Table 3. Examples of Some Chemotherapy Agents and Their Suspected Vascular or Coagulation Effects Chemotherapy Agent Tamoxifen Carmustine (BCNU) Vincristine Cytoxarff5-FU/MTX Cisplatin/Bleomycin Cisplatin/5-FU Iridotecan/5-FU Mitomycin C Gemcitabine L-asparaginase Doxombicin
Vascular Toxicity Cardiac/stroke Endothelial integrity Endothelial integrity Decreased protein C and S Raynaud syndrome Cardiac/stroke Cardiac/VTE/stroke HUS-TTP/stroke HUS/TTP VTE/stroke Endothelial integrity
Abbreviations: 5-FU, 5-fluorouracil; HUS, hemolytic uremic syndrome; MTX, methotrexate; TTR thrombotic thrombocytopenic purpura; VTE, venous thromboembolic disease.
noma), and hemangiopericytoma (1). High-grade malignancy and extensive abnormal vascularity seemed to be predisposing factors. Vessel invasion of tumor is a major cause of hemorrhage in brain malignancies. Primary brain malignancies express increased tissue factor (thromboplastin). Although this series is small, it affords a picture of the varied histologies that metastasize more commonly to the brain. Metastatic brain tumors are 10-fold more common than primary tumors. 46 Malignancies that commonly metastasize to the brain are listed in Table 4. Abnormal microvasculature within tumors allows us to mention the role of growth factors such as vascular endothelial growth factor (VEGF), which has become a target for upcoming tumor therapies. On the endothelium, the VEGF functions to increase permeability and to promote neovascularization. Both small molecules and monoclonal antibodies against receptors for VEGF are being studied in cancer and other disorders of the endothelium. 4v Another treatment modality risk factor is radiation therapy. Most patients who receive whole brain irradiation never return to the radiation oncologist. This reflects the mortality of both metastatic and primary brain malignancies. However, prior higher dose radiation to any vascular bed could be considered a prothrombotic risk factor. Tumors secreting erythropoietin (renal cell, hemangiopericytoma) induce a polycythemia related to malignancy that could be considered a prothrombotic risk of stroke. Sinus venous thromboses do not appear to have any different cancer-specific risk than arterial thromboses. Congestive heart failure from doxorubicin (>550 mg total dose), embolization from myxoma, endocarditis (bacterial and nonbacterial), and puhnonary embolus traversing a patent foramen ovale are cardiac-specific causes of cancer-related stroke. 35 Antiphospholipid antibodies have been associated with cancer. The presence of antibodies to phospholipid B2-glycoprotein I is found in certain infectious (human immunodeficiency virus), inflammatory, and other conditions. Detected in cancer and hematologic malignancy, these rare, transient antibodies usually do not cause thrombosis. In comparison, defned syndromes of lupus
Table 4. Differences of Brain Metastases by Tumor Type Common Primary Tumor Site Lung Breast Gastrointestinal Renal cell Melanoma
Uncommon Primary Tumor Site Ovarian Prostate Cervical Hodgkin Lymphoma Sarcomas (some)
Prothrombotic States and Cancer-Related Stroke 9 erythematosus, Snedden syndrome, NTBE, or the primary antiphospholipid syndrome may present with high titer antibodies and recurrent thrombotic events. Searching for anticardiolipin antibodies and screening with a dilute Russell's viper venom time (DRVVT) should be considered in cancer patients with an event. Treatment decisions may be aided by knowing these results. 4s Reduction of antithrombin III levels from paraneoplastic nephrotic syndromes may predispose to arterial thrombosis. Hodgkin disease has been associated with minimal change disease and lung carcinoma with nephrotic range proteinuria. These conditions may improve with treatment of the malignancy. 49
Summary This review evaluating prothrombotic risk of stroke in the cancer patient presents a broad view of coagulationrelated mechanisms suspected to contribute to the complexity of thrombosis in cancer. Specific disease states, their mechanisms of prothrombotic risk, presenting signs and symptoms, and some treatment strategies are presented. The contribution of cellular and soluble components of coagulation, chemotherapy, radiation, infection and related inflammation, and underlying atherosclerotic risk make stroke etiology complex in the individual patient evaluation. Using prophylactic anticoagulants for cancer-related venous thrombosis is under investigation. Discerning stroke risk in the cancer patient remains difficult. Future information from venous thrombosis trials is pending and further evaluation of the risk of stroke in cancer is warranted.
Acknowledgment A gracious thanks to Dr Jacques LeClerc for his thoughtful review and suggestions in preparing this manuscript.
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36. Rogers LR: Cerebrovascular complications in cancer patients. Neurol Clin 9:889-899, 1991 37. Chaturvedi S, Ansell J, Recht L: Should cerebral ischemic events in cancer patients be considered a manifestation of hypercoagulability? Stroke 25:1215-1218, 1994 38. Doll DC, Yarbro JW: Vascular toxicity associated with antineoplastic agents. Semin Oncol 19:580-596, 1992 39. Doll DC, Yarbro JW: Vascular toxicity, in Perry MC (ed): The Chemotherapy Source Book (ed 2). Baltimore, MD, Williams and Wilkins, 1997, pp 767-784 40. Wall JG, Weiss RB, Norton L: Arterial thrombosis associated with adjuvant chemotherapy for breast carcinoma: A Cancer and Leukemia Group B Study. Am J Med 87:501-504, 1989 41. Levine MN, Gent M, Hirsh J: The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med 318:404-407, 1988 42. Shapiro CL, Recht A: Side effects of adjuvant treatment of breast cancer. N Engl J Med 344:1997-2008, 2001 43. Robben NC, Pippas AW, Moore JO: The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiomyopathy. Cancer 71:493-509, 1993 44. MacDonald DR: Neurotoxicity of chemotherapeutic agents, in Perry MC (ed): The Chemotherapy Source Book (ed 2). Baltimore, MD, Williams and Wilkins, 1997, pp 745-765 45. Newton H: Neurologic complications of systemic cancer. Am Fam Physician 59:878-886, 1999 46. Newton HB: Primary brain tumors: Review of etiology, diagnosis and treatment. Am Fam Physician 49:787-797, 1994 47. Miller KD, Sweeney CJ, Sledge GW Jr: Redefining the target: Chemotherapeutics as antiangiogenics. J Clin Oncol 19:1195- 1206, 2001 48. Khamashta MA, Cudrado MJ, Mujic F: The management of thrombosis in the antiphospholipid antibody syndrome. N Engl J Med 332:993-997, 1995 49. Weiss RB: Miscellaneous toxicities, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer (ed 5). Philadelphia, PA, Lippincott-Raven, 1997, pp 2796-2806.
The Contribution of Prothrombotic States to Cancer-Related Stroke DAVID E. JOYCE Indianapolis, Indiana
ABSTRACT Risk factors for cancer-related ischemic stroke are difficult to discern from the traditional risk factors for atheroembolic disorders. Certain hematologic and oncologic malignancies predispose to ischemic stroke. However, contributing pathophysiologic mechanisms are complex, and they cannot often be directly identified as specific causes of a thrombotic event. Generally speaking, interactions between the cellular phase and the plasma phase of coagulation are heightened in malignancy patients. Tissue factor and other procoagulant initiators of thrombosis predominate in certain solid tumor subtypes. Specific malignant hematologic disorders, such as polycythemia vera, essential thrombocythemia, Waldenstrom macroglobulinemia, and subtypes of acute leukemia, are perhaps best characterized as causes of a hypercoagulable state. Solid tumor treatments entail effects of radiation and specific chemotherapy agents that may pose a prothrombotic risk. This review focuses on the pathophysiology of ischemic stroke in malignancy with emphasis on underlying prothrombotic states and the management of these patients. Key words: cancer, malignancy, stroke, thrombosis, procoagulant, prothrombotic, brain rumor, cerebrovascular, polycythemia, leukemia, promyelocytic leukemia, cysteine protease, cancer procoagulant, mucin, marantic endocarditis.
Thrombosis and Stroke
matory mediators. The generation of thrombin and activation of platelets precede the formation of a thrombus. Capillaries and small and large vessels rely on these basic hemostatic mechanisms of protection to protect against hemorrhage. In this process, endothelial responses to generated thrombin can also directly modulate vessel wall function. 1 Although arterial and venous thromboses rely on different mechanisms, both may lead to vessel occlusion and ischemic compromise. The balance between procoagulant factors and natural anticoagulant pathways is important. Deficiencies of the procoagulant mechanism (genetic or acquired) can lead to hemorrhagic stroke. This would include a factor deficiency, as in the rare factor VII deficiency associated with hemorrhagic stroke. Conversely, deficiencies involving the vascular anticoagulant pathways (eg, protein C, protein S, antithrombin III, or factor V Leiden) may lead to embolic or ischemic stroke. Embolic paradoxical stroke would be included in these predominantly venous, aberrant circulatory pathways. Beyond the soluble regulation of coagulation, abnormal platelet activation or
The interface shared by the vascular endothelium and flowing blood is the defined platform for hemostatic regulation and thrombus formation. Prothrombotic mechanisms respond to hemostatic stress at the specific site of vascular injury to form a thrombus. Preeminent among these mechanisms is tissue factor, normally expressed in the subendothelial compartment of extracellular matrix and expressed in several types of tumors. The normal and pathological hemostatic responses are complex and involve the interplay of several components, including plasma proteins, platelets, and inftam-
From the Department of Hematology and Oncology, Indiana University School of Medicine, and Eli Lilly and Company, Indianapolis, IN.
Address reprint requests to David E. Joyce, MD, Eli Lilly and Company, DC 6072, Lilly CorporateCenter, Indianapolis,IN 46285. Copyright 2002, Elsevier Science (USA). All rights reserved.
1528-9931/02/0202-0008535.00/0 doi: 10.1053/scds.2002.123670
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adhesion can disturb the hemostatic balance in forming or maintaining the intact thrombus. 2 The importance of the endothelium in thrombotic, antithrombotic, fibrinolytic, and inflammatory pathways (thrombin receptor, adhesion, and cytokine pathways) cannot be overemphasized. Differences in these intricate mechanisms exist between different vascular beds. Alteration of endothelium, monocytes, or cytokine responses systemically or in specific capillary beds can bring about inflammatory changes that may predispose to thrombosis. Cancer-associated stroke may be linked to prothrombotic risks (mostly acquired) that are characteristic of the deranged mechanisms of hemostasis in malignancy. 3'4 The release of inflammatory mediators in malignancy can produce tissue factor expression on monocytes and probably also on the endothelium. Moreover, elevated fibrinogen as an acute-phase reactant results from cancerrelated inflammation. Cytokines such as tumor necrosis factor and interleukin 1 can elicit tissue factor expression. Tissue factor initiates clotting by binding factor VIIa. The tissue factor pathway is. now considered the primary physiological initiator of coagulation. Some tumors may express other similar serine proteases such as hepsin. 5 Other related cancer-specific mechanisms, such as cysteine protease cleavage of factor X or mucin-secreting tumors that express cancer procoagulant (mucin sialic acid [cleaving FX]), may initiate abnormal thrombosis in specific cancers (Fig 1 and Table 1). 6,7 The fibrinolysis inhibitor plasminogen activator inhibitor 1 (PAI-1) is elevated in cancer and inflammation contrib-
. . ~ , ~ ~ ---~
Cytokines (minornecrosisfactor, Interleukin-1)
Endothelittm (TF) "1
W
FactorX Tissue Factor(TF) 1 ~overexpression Cancer:TumorCell '\ Inflammation:Monocyte~Tissue factor:FVIIa ,
Mucin/sialicacid CysteineProtease FactorIX/VIII
FXa Fig. 1. Mechanisms of aberrant coagulation specific to cancer and inflammation. Cytokines can activate monocytes and tumor cells inducing tissue factor (TF) expression. This initiates the coagulation cascade. Coagulation initiation may also occur at the level of factor X (common pathway) by cancerspecific cysteine proteases and mucin sialic acid/cancer procoagulant. Specific tumors expressing these cancer procoagulant factors may overlap. Endothelium TF expression is suspected.
uting to the prothrombotic state of cancer. Maintaining the balance of thrombin generation, clot formation, and fibrinolysis can be delicate (Fig 2). Dysregulation of this balance in cancer may lead to both bleeding and thrombosis. This condition, termed disseminated intravascular coagulation (DIC), is usually chronic when found in the cancer patient (approximately 7% incidence), and treating the underlying cause might help improve this condition. More aggressive DIC with clinical signs, termed overt DIC, in cancer is rare, and as yet, screening recommendations have not been formalized. 8 In general, a screening prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer, or fibrin degradation product (FDP) are sensitive enough to discern most DIC. Fibrinogen levels less than 100 mg/dL can be associated with spontaneous bleeding in DIC, and consideration for fibrinogen replacement in acute DIC is warranted. Epidemiologically, venous thrombosis is more common than stroke as the presenting symptom in the diagnosis of cancer. 9'1~ Categories of malignancy contributing to abnormal thrombosis discussed above are listed in Table 2.
Ischemic Stroke Overall, there are 700,000 new cases of ischemic stroke each year in the United States. The most common predisposing factors include prior ischemic stroke, recent transient ischemic attack (TIA), and internal carotid artery stenosis. Marantic endocarditis is a well-known condition occasionally encountered in malignancy. In Table 2, cancer-related prothrombotic risk factors are listed and compared to the broader group of risk factors segregated as cellular disorders, plasma protein disorders, and secondary conditions predisposing to thrombosis. The malignancy-related prothrombotic risks will be discussed below.
Hematologic Malignancy Polycythemia vera is a clonal stem cell condition causing panhyperplasia of erythrocyte, leukocyte, and megakaryocyte cell lines within the bone marrow. 11 The thrombotic risk in this malignant, myeloproliferative disorder correlates with elevation of hematocrit, age, and frequency of phlebotomy. In polycythemia vera, the most common neurological symptoms include headache, lethargy, and dizziness) Moreover, clinical concerns for the risk of stroke arise at a hematocrit of greater than 50%. 12'13 Elevated blood viscosity at the higher hematocrit will retard cerebral blood flow and produce symptoms. Regarding stroke or transient ischemic attack, the incidence is 4% to 5% per year in a middle-aged, phlebotomy-treated population. 3 High hemoglobin levels in untreated polycythemia vera portend a high risk of
Prothrombotic States and Cancer-RelatedStroke
*
David E. Joyce 153
Table 1. Suspected Prothrombotic Coagulation Mechanisms Specific to Tumor Type Tissue Factor VIIa
Cysteine Protease (FX)
Acute Leukemias Stomach Ovary Kidney
Lung Prostate Colon Breast Kidney Leukemia
Mucin/Sialic Acid (FX) Lung Pancreas Gastrointestinal Ovary Prostate Renal Celt
NOTES. Activation of coagulation can occur at factor VII (extrinsic path) or factor X (common path). Overlap may occur among tumor types and mechanisms. Abbreviation: FX, factor X.
stroke, hemorrhage, or infarction. Ischemic stroke appears to occur less frequently with associated secondary polycythemias than with polycythemia vera. Platelet qualitative abnormalities and elevated platelet numbers in polycythemia vera may add to the more concerning hyperviscosity hazard seen in this condition. Other causes of polycythemia related to malignancy, such as renal cell carcinoma or a cerebellar hemangioblastoma producing erythropoietin, could be considered malignancy-related prothrombotic risk factors for stroke. Polycythemia or secondary erythrocytosis without a malignant clone or reactive thrombocytosis would not be considered malignancies, but could pose a thrombotic
Tissue Factor FVIIa
Extrinsic
Cancer/Inflammation Mucin CysteinePr.
~ F Fxa /
VaI
ELEVATED:
Tissue Factor(TF) Hepsin
platelets Fibrinogen
Cytokiue~(TNF, IL-I ) Enhanced adhesion Apoptosis, 2hrombosis Thrombin receptors
PAI-I ESR Acute phase Pr, WBC proteases
C h e m o t h e r a p y , D1C, V i s c o s i t y Thrombin II a Antithrombotic pathways:
~
D-dimer
2. Prothrombotic mechanisms in malignancy. The coagulation cascade is initiated by tissue factor (TF). Factors X, V, and II form the common pathway to activate thrombin (IIa). The platelet-fibrin clot is broken down by plasmin (fibrinolysis) to form fibrin split products (FSP) including D-dimer. Antithrombotic pathways relieve the effects of thrombin generation. Cancer-related aberrations and elevated inflammation mediators are prothrombotic in general and cancer-specific mechanisms (eg, mucin sialic acid and cysteine proteases) promote a thrombotic tendency. Other factors including chemotherapy, disseminated intravascular coagulation (DIC), and increased viscosity predispose to thrombosis by various mechanisms. Fig.
risk. Therapies for polycythemia are few, but effective. Acute treatment of polycythemia vera is phlebotomy. Subsequent periodic removal of approximately 500 mL of whole blood with the long-term goal to reduce the hematocrit to 40% is the standard initial therapy. Chemotherapy with hydroxyurea is commonly used in the elderly. Despite a small probable risk of treatmentrelated, late-onset leukemia with hydroxyurea, it has found a favorable risk-benefit profile in this population. Phlebotomy in patients with underlying comorbid conditions requires caution. Leukocytosis and thrombocytosis respond to oral hydroxyurea therapy. A sustained elevated platelet count of >600 • 109/L characterizes essential thrombocythemia. Splenomegaly, bone marrow megakaryocyte hyperplasia, and the preponderance of both hemorrhagic and thrombotic events also characterize this clonal malignancy. When platelet counts rise more than 1,000 • 109]L in this myeloproliferative disorder, the possibility of cerebral ischemia is more of a concern. Ischemic stroke as a presenting sign of essential thrombocythemia is less often reported at platelet counts <1,000 • 109/L. 12 With clarification of the thrombotic risk in this myeloproliferative disorder, lower platelet counts than the above extreme are now being treated more judiciously (threshold <600 • 109/L).t4 For example, the first manifestation of essential thrombocythemia presenting as ischemic stroke investigated over a 7-year period found 6 of 1,099 patients (0.54%) with an event at a mean platelet count of 597 • 109/L. Looking for essential thrombocytosis in stroke patients at lower platelet levels and using megakarocyte culture to define the malignant clone earlier is one possible strategy to prevent further thrombotic events. 15 Treating thrombotic strokes or other thrombotic events with aspirin to prevent recurrence is acceptable. However, essential thrombocytosis with qualitative platelet dysfunction and without a declared bleeding or thrombotic event should not be considered an indication for aspirin as an initial, empiric therapy. Hydroxyurea, with its risk-benefit concerns, has been considered more in the elderly population, but it is used also in the acute setting. Anagrelide, as an acute treatment to reduce platelet
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Seminars in Cerebrovascular Diseases and Stroke Vol. 2 No. 2 June 2002 Table 2. Prothrombotic Risk Factors and Their Relation to Malignancy
Cellular Disorders Polycythemia Anemia Sickle cell disease Thrombocytosis Hemolytic uremic syndrome Thrombotic thrombocytopenicpurpura Heparin-induced/PF4 Leukemia
Plasma Proteins Protein C deficiency Protein S deficiency Antithrombin III deficiency Factor V Leiden mutation APC resistance Prothrombin 20210A mutation Heparin cofactor II deficiency Plasminogen deficiency Fibrinogen increase Thalassemia Glycoprotein deficiency Waldenstrom's (IgM) Antiphospholipid antibodies Lupus anticoagulant
Secondary Conditions Pregnancy Pnerperium Oral contraceptives Cancer Chemotherapy Dehydration Inflammatory bowel disease PNH Nephrotic syndrome Sepsis and inflammation Sticky platelets Other conditions
Malignancy-related Polycythemia vera Essential thrombocytosis Leukemia
Waldenstrom's (IgM) Antiphospholipid antibodies Mostly acquired factors
Tamoxifen, others Cancer/inflammation Mucinous adenocarcinoma Marantic endocarditis Myxoma Radiation Chemotherapy Nephrotic syndrome Sepsis and inflammation Left ventricular failure
Abbreviations: APC, Activated protein C; IgM, immunoglobulinM; PF4, platelet factor 4; PNH, paroxysmal nocturnal hemoglobinuria.
number, is a consideration without the leukemogenic concerns of hydroxyurea, t4 However, anagrelide may have some effects that could worsen edema states (eg, cardiac/congestive heart failure). Platelet pheresis in an acute symptomatic stroke setting warrants some consideration, given the acuity, feasibility, and potential benefits for each individual case. As' mentioned above, hyperviscosity fi'om polycythemia is a prothrombotic risk factor from this clonal stem cell malignancy. Hyperviscosity is not seen in other myeloproliferative diseases. However, hyperviscosity develops in multiple myeloma (incidence: immunoglobulin G [IgG] 4%, immunoglobulin A [IgA] 5%-10%), Waldenstrom macroglobulinemia (immunoglobulin M [IgM] 10%-30%), and less often in POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin lesions). The M protein, if elevated greatly, may predispose to stroke, t6'17 For example, 25% of patients with Waldenstrom macroglobulinemia have neurological abnormalities such as peripheral neuropathy, hyperviscosity, encephalopathy, and subarachnoid hemorrhage. Rarely, there is a bleeding diathesis, hemolytic anemia, or type I cryoglobulinemia. is Plasmapheresis for acutely symptomatic IgM hyperviscosity is considered, followed by maintenance chemotherapy (eg, fludarabine or chlorambucil), or in some cases, anti-CD20 monoclonal antibody therapy has shown a response. ~9
Acute myelogenous leukemia (AML) with blast cell counts > 100,000/pL is considered a risk for hyperviscosity and stroke. In contrast to the blast cells of acute lymphocytic leukemia, myeloblasts have a greater propensity for adhesion. Approximately 20% to 30% of leukemia patients present with DIC, compared to 7% of solid tumor patients. 2~ With elevated blast counts or associated hyperviscosity syndromes (chest pain, vascular ischemic, neurologic symptoms), leukapheresis may be indicated. The most treatable of the myeloid leukemias is promyelocytic leukemia. Promyelocytic leukemia (M3) typically presents with severe disseminated intravascular coagulation. The malignant promyelocytic leukemia granules contain potent thromboplastin and proteases. 2a Bleeding and hemorrhagic stroke are commonly seen in promyelocytic leukemia. Characteristically, hyperfibrinolysis predominates over thrombosis in promyelocytic leukemia. With elevated blast counts or associated hyperviscosity syndromes, leukapheresis may be indicated. All-trans-retinoic acid (ATRA), a molecularly targeted therapy, given acutely will differentiate the promyelocytic blast cell, thus reducing leukemic blast cell number and the resultant DIC; but this does not often occur immediately (>1-3 days). 22 Lower doses of intravenous heparin have been approved for treatment of this specific DIC, although with some risk of bleeding. Myelomonocytic and monocytic leukemia (FrenchAmerican-British classifications M4 and M5) may also
Prothrombotic States and Cancer-Related Stroke 9 present with DIC and possible risk of subdural hematoma. 23 Controlling blast counts immediately with induction chemotherapy is essential. Low platelet counts in both leukemia and bone marrow transplant patients after induction chemotherapy regimens have been associated with subdural hematoma. Although controversial, thrombocytopenia less than 20 • 109/L requires routine transfusion. 24'25 Thrombocytopenia may become problematic, with subdural hematoma occurring in up to 44% of platelet refractory transplant patients versus 2.5% of others studied receiving platelet transfusion. 26 Immunocompromised patient's, particularly those receiving chemotherapy, run the risk of bacteremia and sepsis. The background rates of intracranial hemorrhage or infarction in the condition of sepsis are lacking. From some recent large studies, in severe sepsis the background rates of patients experiencing sepsis and intracranial hemorrhage primarily treated in the intensive care unit were from 0.1% in a large controlled study to 0.4%. 27,28 Another retrospective study reported similar rates. 29 This risk may be highel: in the thrombocytopenic, immunocompromised patient, but further studies are needed. Invasive infections such as endocarditis or Aspergillus in the immunocompromised patient are a risk for ischemic stroke or hemorrhage.
Solid Organ Tumors The diagnosis of cancer-associated hypercoagulable state first appeared in 1865, and now this Trousseau syndrome includes both arterial accelerated atherosclerosis and venous thrombosis. 3~ Hypercoagulability in cancer manifested as a venous thrombotic event most often requires long-term anticoagulation with heparin or low molecular weight heparin. The renewed interest in thromboembolic disease in the at-risk cancer patient has confirmed the evolving concerns for heparin prophylaxis and revisited consideration of the anti-inflammatory and anticancer effects of these drugs. 31 Thrombocytosis from cancer-related inflammation, hyperfibrinogenemia, endothelial apoptosis, tissue factor expression on tumor, and mucin-producing adenocarcinoma are all examples of hypercoagulability mechanisms in cancer. 7 Disseminated intravascular coagulation, nonbacterial thrombotic endocarditis (NTBE), and septic emboli were found to be the primary etiologies of cerebral infarction (7 strokes / 3,426 cancer patients) in a large autopsy series.l~ Cancerassociated NTBE in earlier series supported lung and other adenocarcinomas as major sources and an overall rate of 2% in cancer patients at autopsy. 32-34 Atrial myxoma by virtue of its location and thrombogenicity is a risk factor for embolic strokeY Cerebrovascular disease is second only to metastases as a cause of central nervous system pathology in the cancer patient. 36 Presenting symptoms of subacute or acute encephalopathy are common, given the diffuse or embolic nature of most
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cancer-related stroke. Most studies in cancer and stroke are retrospective. A retrospective study identified 33 patients (3.5% of all stroke consultations over approximately 4 years) looking at the incidence of cerebral ischemic events and TIA. This study found gynecologic cancer to be the most common cancer consulted upon for stroke (20.6%). Others included renal/genitourinary (10.5%), gastrointestinal (10.5%), lymphoma (8.0%), prostate (7.5%), lung (5.1%), and breast cancer (1.9%). The conclusion of this small study was that the ischemic cerebral events in adult cancer should not be termed Trousseau syndrome, but that the importance of and incidence of hypercoagulability-related stroke requires more study. Treatment of stroke with antiplatelet agents was felt to be appropriate by these authors. 37
Chemotherapy and Vascular Toxicity Chemotherapy has been shown to cause cerebral and extremity thrombotic events without evidence of active, demonstrable cancer. Varied vascular complications include pulmonary and hepatic veno-occlusive disease, Budd-Chiari syndrome, Raynaud syndrome, myocardial infarction, venous thromboembolic events, thrombotic microangiopathy, vasculitis, retinal toxicity, acral erythema, and alterations in blood pressure. 38 Combination chemotherapy regimens for head and neck cancer, germ cell tumors, lymphoma, and breast cancer have been recognized) 9 Combination chemotherapy regimens for stage II and III breast cancer with or without estrogen-like modulators (eg, tamoxifen) have been associated with venous thrombosis (5%-7%) and arterial thrombotic e v e n t s (3.1%). 40'41 Stroke in this population was approximately 8 to 9 events per 1,000 patients. Tamoxifen used alone may be associated with a slight lowering of antithrombin III, protein S, and fibrinogen, and a slight increase of ischemic stroke. 42 Doxorubicin as treatment for breast or other cancers can induce congestive heart failure at high cumulative doses (>550 mg total exposure). Thrombotic stroke in the setting of chemotherapy-induced heart failure may be considered a prothrombotic risk factor for cancer-related stroke. Chemotherapy for breast cancer can be linked to endothelial damage) However, its mechanisms are incompletely understood. Other chemotherapy agents can induce arterial ischemia or thrombosis. Vascular beds of the heart and brain are commonly involved, and older patients with underlying vascular disease who are receiving chemotherapy may be at risk. However, stroke in young patients receiving cisplatin and bleomycin and having no underlying vascular disease risk factors contrasts the above. Cisplatin and bleomycin for testicular cancer patients have been found to cause the chronic toxicity of Raynaud syndrome (40% of young men exposed, beginning months after therapy). Smoking compounds this risk. Bleomycin is the likely agent causing these
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Raynaud symptoms. Impairment of arteriole smooth muscle function is the presumed mechanism. The folic acid antagonist 5-fluorouracil (5-FU) when given as a continuous infusion (eg, colon cancer) had an approximate 10% cardiac toxicity in o n e study. 43 During infusion, waalaing symptoms of angina can be relieved by discontinuation of therapy. Coronary vasospasm is the possible mechanism in 5-FU vascular toxicity. 5-FU in patients with underlying vascular disease needs to be used with caution, especially in regimens requiring continuous infusion. Other agents associated with vascular, endothelial toxicity include (1) direct acting ('carmustine, vincristine, and bleomycin), (2) delayed acting (doxorubicin), and (3) combined acting (5-fluorouracil). Irinotecan may also cause vascular damage. L-asparaginase causes thrombosis by depleting plasma coagulation inhibitors, primarily antithrombin III. Sinus venous thrombosis and cerebral hemorrhage have been seen with L-asparaginase in acute lymphocytic leukemia patients. Some chemotherapy agents associated with thrombosis or endothelial dysfunction are listed in Table 3. Other regimens related to thrombosis are reviewed elsewhere. 44 Special Situations This section addresses other situations related to hematologic or oncologic malignancies and their treatment. Some of the information will consider inferences to prothrombotic risk factors in stroke. Anatomical considerations of location of brain tumorhnalignancy are obvious: vessel invasion, extrinsic compression, surgical injury to vessels, or neck mass predisposing to embolic stroke. 45 One study of brain hemorrhages from intracranial tumors revealed histology consistent with patterns of both primary and metastatic cancer. Over 4 years, a total of 13 patients had histologies of glioblastoma multiforme (7), oligodendroglioma (1), metastatic carcinoma (4) (lung, melanoma, hypernephroma, and adrenal carci-
Table 3. Examples of Some Chemotherapy Agents and Their Suspected Vascular or Coagulation Effects Chemotherapy Agent Tamoxifen Carmustine (BCNU) Vincristine Cytoxarff5-FU/MTX Cisplatin/Bleomycin Cisplatin/5-FU Iridotecan/5-FU Mitomycin C Gemcitabine L-asparaginase Doxombicin
Vascular Toxicity Cardiac/stroke Endothelial integrity Endothelial integrity Decreased protein C and S Raynaud syndrome Cardiac/stroke Cardiac/VTE/stroke HUS-TTP/stroke HUS/TTP VTE/stroke Endothelial integrity
Abbreviations: 5-FU, 5-fluorouracil; HUS, hemolytic uremic syndrome; MTX, methotrexate; TTR thrombotic thrombocytopenic purpura; VTE, venous thromboembolic disease.
noma), and hemangiopericytoma (1). High-grade malignancy and extensive abnormal vascularity seemed to be predisposing factors. Vessel invasion of tumor is a major cause of hemorrhage in brain malignancies. Primary brain malignancies express increased tissue factor (thromboplastin). Although this series is small, it affords a picture of the varied histologies that metastasize more commonly to the brain. Metastatic brain tumors are 10-fold more common than primary tumors. 46 Malignancies that commonly metastasize to the brain are listed in Table 4. Abnormal microvasculature within tumors allows us to mention the role of growth factors such as vascular endothelial growth factor (VEGF), which has become a target for upcoming tumor therapies. On the endothelium, the VEGF functions to increase permeability and to promote neovascularization. Both small molecules and monoclonal antibodies against receptors for VEGF are being studied in cancer and other disorders of the endothelium. 4v Another treatment modality risk factor is radiation therapy. Most patients who receive whole brain irradiation never return to the radiation oncologist. This reflects the mortality of both metastatic and primary brain malignancies. However, prior higher dose radiation to any vascular bed could be considered a prothrombotic risk factor. Tumors secreting erythropoietin (renal cell, hemangiopericytoma) induce a polycythemia related to malignancy that could be considered a prothrombotic risk of stroke. Sinus venous thromboses do not appear to have any different cancer-specific risk than arterial thromboses. Congestive heart failure from doxorubicin (>550 mg total dose), embolization from myxoma, endocarditis (bacterial and nonbacterial), and puhnonary embolus traversing a patent foramen ovale are cardiac-specific causes of cancer-related stroke. 35 Antiphospholipid antibodies have been associated with cancer. The presence of antibodies to phospholipid B2-glycoprotein I is found in certain infectious (human immunodeficiency virus), inflammatory, and other conditions. Detected in cancer and hematologic malignancy, these rare, transient antibodies usually do not cause thrombosis. In comparison, defned syndromes of lupus
Table 4. Differences of Brain Metastases by Tumor Type Common Primary Tumor Site Lung Breast Gastrointestinal Renal cell Melanoma
Uncommon Primary Tumor Site Ovarian Prostate Cervical Hodgkin Lymphoma Sarcomas (some)
Prothrombotic States and Cancer-Related Stroke 9 erythematosus, Snedden syndrome, NTBE, or the primary antiphospholipid syndrome may present with high titer antibodies and recurrent thrombotic events. Searching for anticardiolipin antibodies and screening with a dilute Russell's viper venom time (DRVVT) should be considered in cancer patients with an event. Treatment decisions may be aided by knowing these results. 4s Reduction of antithrombin III levels from paraneoplastic nephrotic syndromes may predispose to arterial thrombosis. Hodgkin disease has been associated with minimal change disease and lung carcinoma with nephrotic range proteinuria. These conditions may improve with treatment of the malignancy. 49
Summary This review evaluating prothrombotic risk of stroke in the cancer patient presents a broad view of coagulationrelated mechanisms suspected to contribute to the complexity of thrombosis in cancer. Specific disease states, their mechanisms of prothrombotic risk, presenting signs and symptoms, and some treatment strategies are presented. The contribution of cellular and soluble components of coagulation, chemotherapy, radiation, infection and related inflammation, and underlying atherosclerotic risk make stroke etiology complex in the individual patient evaluation. Using prophylactic anticoagulants for cancer-related venous thrombosis is under investigation. Discerning stroke risk in the cancer patient remains difficult. Future information from venous thrombosis trials is pending and further evaluation of the risk of stroke in cancer is warranted.
Acknowledgment A gracious thanks to Dr Jacques LeClerc for his thoughtful review and suggestions in preparing this manuscript.
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