The correlation between malignancy and impaired hemostasis was established in 1865 when Trousseau observed a case of suspected malignancy with gastrointestinal symptoms associated with wandering thrombophlebitis, which was diagnosed as gastric cancer 6 months later. Hemostatic abnormalities that occur in tumors include thrombosis and disseminated intravascular coagulation (DIC). Unlike thrombosis from other causes, tumor-induced thrombosis usually affects the deep veins of the lower extremities and is isolated.
Venous thrombosis (VTE) is a major complication of cancer and can occur in 4% to 20% of patients; arterial thrombosis is less common and is seen in myeloproliferative disease. Venous thrombosis in tumors can be wandering and can involve superficial and deep veins and some rare sites, such as the upper arm and chest. In some patients, anticoagulation is ineffective; in others, venous thrombosis can be the first symptom, appearing when they do not have any other symptoms, and the tumor is not detected until months or even years later.
The incidence of thrombosis varies among cancer patients
Thromboembolism is frequently seen in autopsies of cancer patients, with up to 50% incidence of venous thrombosis found at autopsy. The incidence of venous thrombosis is highest in the presence of metastases in the pancreas, stomach, brain, ovaries, kidneys, and lungs. In recent years, a higher incidence of venous thrombosis has also been found in lymphomas. In addition, the incidence of venous thrombosis has been found to be 6.5 times higher in patients treated with chemotherapy and higher in those on anti-angiogenic drugs. The application of thalidomide for multiple myeloma can lead to lower extremity venous thrombosis (DVT) in 7-10% of patients. Patients with progressive cancer have a higher risk of thromboembolism. Statistics from the Japanese Society of Obstetrics and Gynecology Oncology showed a 6.5-fold increase in pulmonary embolism (PE) and a 3.5-fold increase in DVT in patients with hysterectomized uterine cancer between 1991 and 2007. The incidence of PE and DVT in patients with uterine malignancy was 16 times higher than that in patients with benign hysterectomy disease.
Pancreatic, pulmonary and gastric tumors predispose to thrombosis
In a retrospective study, Lieberman found that the most common tumors complicating thrombosis in men were lung and pancreatic cancer and in women were gynecologic tumors such as cervical and ovarian cancer. Colon and pancreatic cancers are prone to complicate thrombosis, suggesting that the distribution of tumors complicating thrombosis may correlate with the incidence of cancer in the general population.
Whether deep venous thrombosis is a sign of occult cancer is controversial
Trousseau reported thrombophlebitis as a precursor to malignancy, but there is no conclusive evidence as to whether patients with primary deep vein thrombosis are at risk for cancer.
It is generally accepted that older patients who present with primary DVT should be alerted to the presence of occult cancer, and screening should be performed for prostate, colon, and bladder cancers in male patients and colon, breast, and endometrial cancers in female patients.
Complex pathogenesis of hypercoagulable state in cancer patients
It has been reported that 50% of cancer patients and 90% of patients with metastatic tumors show one to several abnormal coagulation parameters. The most common coagulation parameter abnormalities include elevated levels of coagulation factors (e.g., fibrinogen, coagulation factors V, VIII, IX, and D), increased fibrinogen/fibrin degradation products (FDP), and thrombocytosis.
Tumor cell specific procoagulant mechanisms The hypercoagulable state in cancer patients is mainly due to the specific procoagulant mechanisms of tumor cells. Malignant tumor cells can interact with the hemostatic system in several ways: first, with the help of the tumor cells’ own activities, including procoagulant activity, fibrinolytic activity and release of cytokines; second, directly with other cells (e.g. endothelial cells, platelets and monocytes-macrophages).
External causes of hypercoagulation Antitumor therapy, including chemotherapy alone or in combination, hormonal therapy and hematocrit therapy are inevitably involved in venous and arterial thrombosis. Chemotherapy can alter the levels of coagulation factors and natural anticoagulants, reduce fibrinolytic activity and directly damage endothelial cells.
One study showed that fibrin A peptide (FPA) levels were increased after 5-fluorouracil (5-Fu) injection in 10 patients with head and neck cancer, while FPA returned to normal after completion of the injection. In stage II breast cancer patients treated with cyclophosphamide + methotrexate + 5 Fu (CMF regimen), the levels and activities of C- and S-protein antigens decreased by 70% to 90%, while the levels of fibrinogen activator inhibitor 1 (PAI-1) increased; 40 patients with stage III and IV lung cancer had a significant decrease in tissue-type fibrinogen activator (t-PA) and an increase in PAI-1 after chemotherapy. 1846 cases cancer patients treated with the blood cell growth factor GM-CSF or G-CSF had venous and arterial thrombosis rates of 4.2% and 1.2%, respectively, indicating a higher risk of thrombotic complications from GM-CSF, especially in gastrointestinal tumors, lung cancer, breast cancer, and lymphoma. The detailed mechanism is not known.
Clinical manifestations of hemostatic disorders in cancer are diverse
The clinical manifestations of hemostatic disorders are diverse and include DVT, DIC, thrombotic thrombocytopenia (TTP) and hemolytic uremic syndrome (HUS). Among them, DVT is more common in solid tumors and DIC is more common in malignant hematological diseases and extensive metastatic cancer. More DIC can be detected by coagulation tests. the incidence of severe DIC in cancer patients is 9%-15%. vte can also occur in less frequent sites such as kidney and mesentery, which should be noted clinically. Hepatic venous embolism disease (VOD), reported in recent years, is a lethal complication that occurs after cancer chemotherapy. Severe DIC with lethal bleeding can occur in acute leukemia and is a major cause of early death in patients with acute promyelocytic leukemia. In addition, DIC can cause multi-organ failure.
There are criteria for the diagnosis and prevention of hemostatic disorders in cancer
The diagnosis of VTE is made by ultrasound Doppler and angiography. 125I-labeled fibrinogen is sometimes used to determine the location of the thrombus in VTE at special sites, etc. The diagnosis of DIC should refer to the diagnostic criteria for DIC established by the Chinese Medical Association Hematology Branch.
Drug treatment for patients with malignant tumor combined with VTE and pulmonary embolism can be applied with anticoagulants and thrombolytic drugs. Anticoagulants include warfarin, heparin and hirudin. It should be noted that anticoagulants mainly stop the development of thrombus, and thrombolytic drugs should be used for the formed thrombus. At present, the thrombolytic drugs used in China include urokinase, recombinant streptokinase and t-PA. Anti-platelet drugs such as anti-platelet glycoprotein IIb/IIIa Abciximab not only inhibit platelet aggregation, but also inhibit tumor growth and bloodstream metastasis. In addition, some anti-angiogenic drugs developed in recent years, such as Endostatin, Angioatatin and anti-VEGF antibodies all help to inhibit tumor growth and metastasis.
Guidelines for the prevention and treatment of venous thromboembolism in oncology patients were published by the American Society of Clinical Oncology in 2007, which are based on the analysis of a large body of literature and mainly include.
(1) For whether anticoagulants should be used to prevent venous thromboembolism in hospitalized oncology patients, the guidelines recommend that anticoagulant prophylaxis should be considered in the absence of bleeding and other contraindications to anticoagulants.
(2) For whether anticoagulants should be used to prevent venous thromboembolism in oncology patients receiving systemic chemotherapy on an outpatient basis, the guidelines do not recommend routine prophylaxis with anticoagulants; patients receiving thalidomide/lenalidomide in combination with chemotherapy or dexamethasone are at high risk for thrombosis and anticoagulant prophylaxis is recommended; patients with multiple myeloma receiving thalidomide/lenalidomide plus chemotherapy and/or dexamethasone require antithrombotic agents; there is an urgent need Discovery of multiple markers to predict venous thrombosis in patients with outpatient oncology.
(3) As to whether oncology patients undergoing surgery should receive perioperative venous thrombosis prophylaxis, the guidelines recommend that all patients with malignant disease undergoing major surgery should be considered for thrombosis prophylaxis; patients undergoing cesarean section, laparoscopy, or open-heart surgery lasting more than 30 minutes should be considered for thrombosis prophylaxis with low-dose plain heparin or low-molecular heparin (LMWH), unless contraindicated due to bleeding resulting in high-risk or active bleeding. It should be started preoperatively or as early as possible postoperatively.
(4) In patients with cancer who have been diagnosed with venous thrombosis, the best therapy to prevent recurrence of venous thrombosis includes: LMWH is preferred for the first 5-10 d of anticoagulation; LMWH is also preferred when given for at least 6 months as part of long-term anticoagulation; after 6 months, long-term anticoagulation should be considered for specific patients with progressive cancer, such as those with metastases and those receiving chemotherapy (this recommendation is based on expert panel After 6 months, anticoagulation should be considered for specific patients with progressive cancer, such as those with metastases and those receiving chemotherapy (this recommendation is based on the consensus of an expert panel, but clinical trials are lacking); venous filters should be inserted only in patients for whom anticoagulation is contraindicated and in those who have relapsed despite long-term LMWH therapy; anticoagulation should be recommended for patients with confirmed venous thrombosis in CNS malignant disease, carefully monitored to reduce the risk of bleeding complications, and avoided in those with active intracranial bleeding, recent surgery, and existing bleeding qualities such as thrombocytopenia or coagulation abnormalities; anticoagulation should be avoided in patients who have been diagnosed with a history of thrombosis. anticoagulants; anticoagulants are recommended for elderly patients with diagnosed venous thrombosis, but careful monitoring and dose adjustment are needed to avoid anticoagulant overdose and further increase the risk of bleeding.
(5) As to whether cancer patients with undiagnosed venous thrombosis should receive anticoagulants to improve survival, the guidelines recommend the use of anticoagulants for cancer patients without venous thrombosis; cancer patients should also be encouraged to participate in clinical trials in which anticoagulant therapy is used as an adjunct to standard anticancer treatment.
Summary
Hemostatic disorders have a high incidence in malignant tumors, mainly manifested as hypercoagulable or prone to thrombosis, which can appear clinically as thrombosis and DIC, and venous thrombosis can be considered a prodromal symptom of malignancy. Numerous studies have clarified that TF and procoagulant substances (PCA) expressed by tumor cells are the main causes of hypercoagulable state. In addition, the procoagulant activity of tumor cells plays an important role in the growth and metastasis of tumors. Treatment with anticoagulants, antiplatelet agents and thrombolytic agents not only improves the hypercoagulable state of patients, but also inhibits the growth and metastasis of tumor cells. The efficacy of pharmacological treatment of hemostatic disorders remains to be clarified in additional double-blind randomized studies.