The relationship between malignancy and thromboembolic disease was first studied more than a century ago, when Armand Trousseau reported in 1865 that thrombosis in cancer patients was a specific change in the blood system secondary to spontaneous intravascular coagulation. 1878 Billroth found the presence of tumor cells in such thrombi, leading to the belief that there was an association with tumor metastasis. Evidence of thromboembolism can be seen in more than half of the patients with tumors at autopsy. However, not all malignancies are associated with thrombosis, with adenocarcinoma being the most prominent and lung, pancreatic, and gastrointestinal tumors being more likely to be hypercoagulable than breast or renal tumors. In this paper, we review the recent studies on malignant tumors and thrombosis to improve the understanding of related thrombotic diseases. Many patients with malignant tumors develop thrombotic disease during the course of their disease, and many patients develop thromboembolism first and then discover the primary tumor. Tumor is found in 25% of patients with primary deep vein thrombosis (DVT) and 4% of patients with secondary DVT are tumor patients. Therefore, the chance of DVT combined with tumor is significantly higher. In patients older than 50 years, multiple venous thrombosis, arterio-venous thrombosis, thromboembolism in patients resistant to warfarin, recurrent DVT, migratory thrombosis, cases of thrombosis in superficial veins or relatively uncommon sites, and embolism in patients with disorders of the coagulation mechanism itself, such as antithrombin deficiency, protein C/S deficiency, resistance to activated protein C, and antiphospholipid syndrome. In particular, the possibility of malignancy should be highly suspected. Thrombotic lesions in tumor patients often have specific clinical manifestations: venous thrombosis/pulmonary embolism: The incidence of venous thrombosis in tumor patients has been reported to be as high as 15%, with a higher incidence at autopsy. Lower extremity deep vein thrombosis is the most common embolic comorbidity. The incidence varies among tumors and is particularly likely to be combined in mucin-producing adenocarcinomas of the gastrointestinal tract. Other tumors that are prone to thromboembolism are lung cancer, breast cancer, ovarian cancer, primary brain tumors, prostate cancer, pancreatic cancer, and bladder cancer. Because of the high incidence of lung cancer, it is clinically the most common tumor to develop thromboembolism. There is also a high incidence of venous thrombosis in the upper extremities, often due to blockage of venous blood flow, such as seen with compression of large masses or enlarged lymph nodes. However, many times it is associated with intravenous cannulation therapy. Therefore, choosing the right cannula, appropriate puncture site, and the use of heparin and glucocorticoids during intravenous infusion can reduce the incidence of phlebitis and embolism. Non-invasive tests are preferred for the diagnosis of DVT in oncology patients. Doppler ultrasound and B-mode ultrasound are highly sensitive methods for the diagnosis of proximal DVT, and magnetic resonance scanning is also accurate and effective. Pulmonary embolism (PE) is nonspecific on chest radiograph, ECG, and arterial blood gas changes. Pulmonary arteriography is sensitive but risky and inappropriate in patients with severe cardiopulmonary disorders, so pulmonary ventilation and perfusion imaging is recommended. Pulmonary ventilation and perfusion mismatch is seen in only 25-40% of patients with PE, so the presence of pulmonary ventilation and perfusion mismatch should not be used to deny the presence of PE. The presence of PE in 70% of patients with proximal DVT at angiography indicates that PE is very common. If neither PE nor DVT can be clarified by noninvasive testing, pulmonary angiography should be considered to clarify the diagnosis. Hepatic/portal/splenic/mesenteric vein embolism: Hepatic vein thrombosis (Bou-ga syndrome) is commonly seen in patients with myeloproliferative disorders (MPD), especially true erythrocytosis (PV) and some nocturnal paroxysmal sleep hemoglobinuria (PNH), but also in hepatocellular carcinoma, adrenal and renal tumors. Local factors such as splenomegaly, increased portal blood flow, and hepatosplenic extramedullary hematopoiesis can lead to the formation of the aforementioned venous embolism. Systemic factors, especially abnormal platelet function, also play an important role. Non-bacterial embolic endocarditis, diffuse intravascular coagulation, small artery embolism: Non-bacterial embolic endocarditis occurs in association with mucin produced by adenocarcinoma and can lead to acute organ failure, such as brain, heart, kidney, spleen, and skeletal muscle. The possibility of this comorbidity should be considered in tumor patients presenting with embolic shock. early stages of DIC often present with organ failure due to multiple microthrombi. Embolism of small arteries in the brain or limbs is mostly seen in MPD, often presenting with dizziness, headache, TIA, blurred vision, limb ischemic necrosis, erythema, erythema, and erythematous limb pain disease. Hyperviscosity syndrome: Hyperviscosity syndrome occurs with the presence of abnormal proteins in peripheral blood or abnormal increases in blood-forming fractions, which can affect cerebral blood flow and lead to dizziness, vertigo, memory loss, and drowsiness. It is seen in Fahrenheit macroglobulinemia, myeloma, leukemia, PV, etc. II , laboratory tests The above tumor patients present with abnormalities in laboratory tests related to coagulation system, which is much higher than the chance of clinical symptoms. [6] It includes the activation of coagulation system and fibrinolytic system, damaged endothelial cells, activated monocytes, and corresponding manifestations of platelets. Abnormalities of the coagulation system are manifested by elevated prothrombin fragment 1+2 (F1+2), plasma fibrinopeptide A (FpA), and D-dimer; the fibrinolytic system is manifested by urokinase-type fibrinolytic activator (uPA), fibrin degradation products (FDP), fibrin β1-42 and/or 15-42, elevated D-dimer, prolonged euglobulin lysis time, fibrinogen activator inhibitor-1 (PAI-1) is elevated. Elevated vWF, thrombomodulin (TM), t-PA, and PAI-1 are most often seen during chemotherapy indicating the presence of endothelial damage. Hyperfibrinogenemia is seen in 50-80% of patients and is particularly pronounced in the end-stage of the tumor. Because of accelerated fibrinogen conversion, plasma fibrinogen survival time is often shortened. Levels of coagulation factors such as V, VIII, IX, and D, are elevated. Coagulation time and whole blood clotting level are significant. Plasma fibrinopeptide A (FpA) can reflect coagulation activity sensitively. The formation of fibrin at the tumor site can increase its level, so it can reflect tumor load. In patients with advanced tumors it continues to be significantly increased, suggesting tumor progression, poor treatment response and poor prognosis. The thrombin-antithrombin III (TAT) complex has the same significance as it. Fibrinolytic plasminogen levels decreased and fibrinolytic-anti-fibrinolytic enzyme complexes increased. Fibrinogen-α2-anti-fibrinolytic enzyme complex (PAP) can be used as a marker of active fibrinolysis in tumors, up to 50 times more than the normal range in active disease, and significantly decreases to normal levels after chemotherapy, which is useful for prognostic estimation of breast and lung cancer. The radioimmunoassay method is a sensitive and specific test that can be used for a variety of these factors. In-depth studies also include the detection of platelet function, such as platelet survival time, aggregation function, platelet factor 4 levels, expression of activated platelets CD62 and CD63. PT and APTT levels are of little significance for the diagnosis of hypercoagulable states. No markers have been found to predict the occurrence of thrombosis, especially for patients requiring surgery or chemotherapy, and it would be extremely helpful to decide when to start prophylactic anticoagulation therapy. 3. Pathogenesis Hypercoagulable state is the result of the interaction between malignant tumor cells and their products with host cells, causing the body’s defense against thrombosis to be reduced. Hypercoagulable state is commonly seen in patients with malignant tumors. The pathogenesis of the hypercoagulable state is complex and involves the interaction of multiple variables that disrupt the balance between pro- and anti-coagulation. Tumor cells can directly activate coagulation pathways, induce the production of procoagulant substances, and inhibit the anticoagulant activity of vascular endothelial cells, platelets, monocytes, and macrophages. et al. proposed that the causes of hypercoagulable state can be classified as: (i) abnormal blood flow, (ii) abnormal blood components, and (iii) abnormal blood vessel walls. The combination of these abnormalities in malignant tumors is described as follows: Blood flow abnormalities: prolonged bed rest, reduced activity or compression of blood vessels by large masses are very common in tumor patients, which lead to venous blood flow stagnation. Abnormalities of blood components: Tumor cell membranes can express procoagulant active substances that directly cause thrombin production. It can be divided into two major groups, namely tissue factor and cancer procoagulant substances. Other relevant procoagulant substances are detailed in Table 1. Tissue factor (TF) is a transmembrane protein that is expressed in most sarcomas, adenocarcinomas, melanomas, neuroblastomas, leukemias, and lymphomas. It can act as an agonist of VIIa and factor X. Mucin secreted by adenocarcinoma can turn factor X into Xa directly without the action of enzymes, so thromboembolism is common in adenocarcinoma. [2] Cancer procoagulant (CP) is a cysteine protease that directly activates factor X without relying on the catalysis of the TF/VIIa complex. It is found in the leachate of colon, breast, lung, kidney, and melanoma cancers. It is detected by ELISA and is elevated in approximately 85% of tumor patients. The presence of CP was found to be closely associated with disease activity. A concomitant decrease in CP activity was found during in vitro induction of promyelocyte maturation with all-trans retinoic acid (ATRA). et al. purified a sialic acid from mucin that directly activates factor X. Injection of this substance into rabbits caused hematological abnormalities consistent with DIC. This substance could be involved in the process of thromboembolism triggered by mucus production by adenocarcinoma. Other studies suggest that the MHC class II antigen DR also has procoagulant activity. The membrane vesicles of tumor cells also provide a favorable phospholipid surface for the assembly of coagulation factors. Some tumor cells can synthesize factor V or express factor V receptors or both, and also express binding sites for Xa. [1] Tumor cells can secrete peptides, vascular permeability factor (VPF), vascular endothelial growth factor (VEGF). vPF enhances microvascular permeability and leads to extravascular fibrinogen deposition. vEGF promotes angiogenesis. tF and VEGF synergize with each other and are beneficial for coagulation response, activation of inflammatory factors, tumor growth and metastasis. The host tissue also has procoagulant activity due to substances produced in response to the tumor. Monocytes themselves do not express procoagulant activity, but monocytes/macrophages can produce procoagulant activity through stimulation by tumor-specific antigens, tumor antigen immune complexes, tumor-associated proteases, or indirectly through the stimulation of cytokine secretion by immune cells by tumor-associated antigens. This plays an important role in the activation of intravascular coagulation. Although thrombocytosis is seen in 30-60% of tumor patients, the increased number does not increase the risk of thrombosis. Hypercoagulation can result secondary to MPD and PNH or due to tumor cell-platelet interactions. Tumor cell secretion of ADP and induction of thrombin production can cause platelet activation. Tumor cell membrane vesicles promote platelet aggregation and secretion. In addition, significant elevation of serum vWF in the acute phase of tumor also causes platelet hyperreactivity. Endothelial cells exhibit procoagulant activity under the influence of inflammatory factors or by the action of peptide substances produced by the host in response to the tumor. In particular, TNF and IL-1 production by activated monocytes, natural killer cells, and antigen-stimulated T cells can cause endothelial cells to produce leukocyte adhesion molecules, platelet-activating factor, TF, and PAI. TNF can promote IL-1 expression by endothelial cells and reduce thrombomodulin expression. The secretion of tumor cells can enhance the procoagulant activity of endothelial cells. Abnormalities of the vascular wall: The normal vascular endothelial defense against thrombosis is disrupted when the tumor invades the vascular wall. Tumor cells also secrete a vascular permeability factor that increases microvascular permeability leading to deposition of extravascular fibrinogen and plasma coagulation proteins, which can rapidly clot in the presence of tumor cell procoagulant substances. Studies have also shown that fibrin deposition or encirclement of tumor lesions can protect them from destruction by the immune system, that platelet microthrombi facilitate tumor cell growth, and that fibrin promotes angiogenesis, thereby facilitating tumor growth and spread. Animal models have found that anticoagulation therapy can affect tumor growth and metastasis. Prolonged bed rest during hospitalization, infection, central venous cannulation, and the use of arterial catheter chemotherapy in oncology patients all promote thromboembolism. Surgery activates the coagulation system and, combined with bedrest immobility, increases the risk of embolism 2-3 times over non-surgical cancer patients. The clinical presentation of chemotherapy-induced thromboembolism is highly variable, ranging from asymptomatic to fatal TTP, pulmonary vaso-occlusive disease (VOD), etc. Some chemotherapeutic agents used alone or in combination can exacerbate the hypercoagulable state triggering thrombosis, such as pulmonary VOD (bleomycin, mitomycin), Bu-plus syndrome (methylbenzylhydrazine, 6-TG + MTX/Ara-C), Raynaud’s phenomenon (bleomycin, vincristine + cisplatin), myocardial ischemia/myocardial infarction (VCR, 5-FU, cisplatin), stroke (cisplatin, levomeprase ), thrombotic microangiopathy (mitomycin, cisplatin), etc. More prominently, levomenadase can cause DVT, dural sinus venous thrombosis. A hypercoagulable state occurs after drug administration, and in the past it was thought that the tendency to hypercoagulation was due to a disproportionate decrease in antithrombin III resulting in an imbalance between procoagulation and anticoagulation. Recently, it has been found that a transient and significant increase in plasma vWF during treatment causes platelet aggregation and thrombosis. Chemotherapy plays an important role in thrombotic disease in combination with breast cancer. Tamoxifen is an estrogen antagonist, but has weak estrogenomimetic effects. Estrogen has long been implicated in embolism, and it decreases antithrombin III activity. Tamoxifen has procoagulant activity but is not clinically significant, and the ECOG study showed a much higher risk of thrombotic disease with chemotherapy + tamoxifen than with chemotherapy alone and tamoxifen alone. Of course the presence of embolism with chemotherapy is also related to the stage of the tumor, the age of the patient, the presence or absence of surgery and bed rest with little movement. The reason for this is the activation of coagulation factors, reduction of anticoagulant proteins and vascular endothelial damage in chemotherapy. In addition radiotherapy, hormonal therapy, and bone marrow transplantation can lead to a hypercoagulable state. The use of stem cell growth factors increases the risk of embolism, which can occur with G-CSF and GM-CSF, but is more pronounced with GM-CSF. The reason may be that they enhance the expression of adhesion molecules by neutrophils, leading to the aggregation of neutrophils and their binding to the vessel wall causing embolism. Prevention and treatment The treatment of thromboembolic disease associated with malignancy is the same as that of other thrombotic diseases. Anticoagulants are the first choice of treatment. Due to the high incidence of embolism, it is believed that anticoagulation prophylaxis should be given to tumor patients as soon as it is detected, and elastic stockings can be considered for those who cannot be anticoagulated. For some cases such as post-surgery, in chemotherapy, central venous cannulation patients should be actively anticoagulated, applying small doses of low molecular heparin, if extensive abdominal and pelvic surgery requires higher doses. The effect of low molecular heparin is similar to that of oral enoxaparin in patients after elective tumor surgery, and glucosaminoglycan is an effective new anticoagulant. Low molecular heparin is recommended at 5000 U/dose, 2-3 times daily. Chemotherapy with warfarin 1 mg/day for 6 weeks to maintain INR 1.3-1.9 is guaranteed to be safe and effective. Intubated patients are treated with low-dose warfarin or heparin at 2500 U/dose once daily for 90 days to prevent venous thrombosis. The acute phase is treated with heparin to achieve an APTT of 1.5-2.5 times the control, or the dosage of low molecular heparin is adjusted according to body weight. Thrombolytic drugs are rarely applied, unless a large pulmonary embolism causes hemodynamic changes or a thrombus is still present after adequate anticoagulation therapy or a central venous cannula thrombus, then patience should be used to wait for anticoagulation therapy to take effect. Oral anticoagulants should be applied for maintenance after heparin, with attention to bleeding tendency. In case of rapid tumor progression, discontinuation of warfarin is very likely to result in thrombosis, so it is recommended that warfarin can be used continuously as long as the tumor exists to maintain INR 2.0-3.0. In case of thrombosis during the course of oral anticoagulation, consideration can be given to start with sufficient heparin followed by high-dose warfarin to maintain INR 3.0-4.5.[2] Patients who cannot tolerate high-dose warfarin can continue with low-molecular heparin therapy. If the patient has a poor prognosis, heparin therapy should be administered early, and if heparin therapy fails, the only option is implantation of an inferior vena cava filter. Comorbidity of bleeding in anticoagulation therapy is not seen to increase compared to non-oncology patients. The use of antiplatelet agents can affect fibrin deposition and lysis. The choice of aspirin, prostacyclin, and calcium antagonists such as nimodipine can inhibit tumor cell-platelet-endothelial interactions. Antifibrinolytic drugs tranexamic acid, urokinase-type fibrinogen activator can protect normal cells from tumor destruction and reduce tumor metastasis. By understanding the relationship between malignant tumor and thrombotic disease, we can see that primary DVT is often associated with the occurrence of malignant tumor, so we should pay great attention to these patients, and we need to take a detailed medical history, careful physical examination, routine blood test, biochemical examination, serum carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), fecal occult blood, breast scan, abdominopelvic CT and endoscopy if necessary. For thromboembolic disease of unknown cause, most tumors can be detected within 6-12 months, so the primary lesion should be actively searched for after excluding other causative factors such as prolonged bed rest, lower extremity trauma, and antithrombin III deficiency in order to make a clear diagnosis early. Small confined tumors can still activate the coagulation activity of the body, so some tumors are found at an early stage and may be curable. [3] New studies have shown that anticoagulation therapy can prolong life and reduce mortality, and therefore anticoagulation therapy may have anticancer activity, thus opening up new avenues for tumor treatment. Table Mediators of tumor hypercoagulable state Tumor cell procoagulant substances Tissue factor Direct factor X activator Cancer procoagulant substances Mucin Factor V, membrane-bound site of X Other: fibrin degradation products, cytokines Procoagulant activity induced by host response to tumor Monocytes Tissue factor Cytokines IL-1 and Coagulation factor membrane-bound site Platelets Aggregation Secretion Coagulation factor membrane-bound site Endothelial cells Platelets Activating factor Cell adhesion molecule Fibrinogen activation inhibitor Tissue factor