Thromboembolism in children with cancer: a retrospective multicenter study in Korea

Journal of Thrombosis and Thrombolysis - Thromboembolism (TE) is a major cause of morbidity and mortality in adult cancer patients; however, there is a lack of sufficient knowledge on TE in...     

Thromboembolism

Dr. Frederick K. Heath: The common denominator, prerequisite to an understanding of the mechanisms upon which present day therapy of thromboembolism is based, is the increased tendency of the blood to clot. This may be demonstrated by the Lee-White method of determining the clotting time by which, if lucite or paraffin coated tubes are used, an actual decrease in coagulation time below the normal may be noted. Why the blood tends to clot faster is not known but poor muscle tone, venous stasis and tissue damage seem to be predisposing factors.At any rate, clotting occurs and a thrombus is formed. In about 90 per cent of instances, this develops below the inguinal ligaments, most frequently in the deep veins of the calf. Early in its evolution no signs or symptoms are found. As the clot grows, inflammation of the vein wall, representing the reparative phase, may result in tenderness; obstruction of the vein may produce mild edema of the tissue drained. With growth of the ‘tail’ to involve larger veins, more venous obstruction and more edema may result until, with adherence of the ‘tail,’ definite venous obstruction is present and swelling of the calf ensues. At this juncture a considerable inflammatory reaction is present producing the common findings of pain, tenderness, fever, leukocytosis and elevation of the sedimentation rate. When these are marked, vasospasm may also occur. The typical picture is now one of acute thrombophlebitis as described by Ochsner. When the inflammatory process is less severe, or perhaps earlier in the course, the pattern resembles phlebothrombosis. Whether more profound differences exist between these clinical entities is not yet clear.The rate of healing is variable but takes place first by adherence of the clot and its ‘tail,’ which occurs about the fifth day, and then by endothelialization, completed by the tenth to twelfth day if growth can be prevented. These time factors are important not only because upon them is based the duration of anticoagulant therapy but also because they suggest when ligation is most needed.The breaking-off of the thrombus or its ‘tail’ before these are adherent, with consequent pulmonary embolization, is a major event, in the pathologic sequence and may produce a dramatic clinical picture. Again this aspect is variable, ranging from small emboli producing mild pleuritic pain with no signs to massive embolization causing sudden death. Between these extremes, deep constant pain, cyanosis, reflex dyspnea, cough and hemoptysis (rather infrequently), râles and, occasionally, pleural effusion may be encountered. Serious impairment of the pulmonary arterial flow and an accentuated pulmonic second sound may herald right heart failure and electrocardiographic evidence of acute cor pulmonale; nor should the presence of abdominal findings of pain and muscular spasm fail to suggest the possibility of a basal infarct with diaphragmatic irritation. The appearance of signs or symptoms referable to the lungs or pleura should always call to mind the possibility of thromboembolism.The aim of anticoagulant therapy is to prolong blood coagulation so as to prevent further growth of the thrombus in the vein of origin. If this can be done, the thrombus will become adherent and repair may take place before the ‘tail’ breaks off to become an embolus. When embolization has already occurred, the aim is not only to attain the same end at the original site so as to prevent further potential embolus formation but also to prevent proximal propagation of the thrombus which forms behind the embolus lodged in the lungs. This is carried out by the use of heparin and dicumarol with daily careful clotting and prothrombin time determinations. Statistics indicate that the results of anticoagulant therapy are excellent both in achieving a favorable local result as well as in preventing pulmonary embolization or its recurrence. Fatal pulmonary embolization, subsequent pulmonary embolization and venous thrombosis have each been reduced to about 1 per cent. Hemorrhage has been the only serious toxic manifestation of anticoagulant therapy. It is infrequent with adequate control and can be successfully combatted by the use of plasma and blood, and by vitamin K when dicumarol is the anticoagulant.Contraindications to anticoagulants exist: subacute bacterial endocarditis, hemorrhagic blood dyscrasias, recent threatened abortion, obstetrical cases near term and after a recent central nervous system operation. Anticoagulants obviously cannot be used prophylactically in the immediate preoperative period. They should be used with caution in liver disease or renal insufficiency and in patients with ulceration or malnutrition and in very old patients.At the present time, bilateral ligation of the femoral vein distal to the point of entry of the deep femoral vein is the surgical approach of choice. No obvious advantages can be expected from this mode of therapy which make it superior to anticoagulants. It is therefore usually reserved for situations in which anticoagulant therapy cannot be used.     

Thromboembolism in women

Venous thromboembolism (VTE) occurs in one of every 1,000 individuals per year. The incidence is much lower in young persons. In persons younger than age 45, the incidence is one of every 10,000 individuals per year. VTE is a multifactorial disease due to the interaction of various risk factors that can be genetic (e.g., inherited thrombophilia), acquired (e.g., age, neoplastic or autoimmune diseases, antiphospholipid antibodies), or transient (e.g., surgical interventions, fractures, trauma, prolonged immobilization). VTE is found equally in the two sexes. There are other transient risk factors for VTE that are typical for females, and these render women more exposed than men to the risk of the disease during their lifetime. Such risk factors are encountered frequently in a woman's life; they are oral contraceptive (OC) use, hormone replacement therapy, and pregnancy/puerperium. Moreover, various obstetric complications have attributed at least in part to an impaired placental circulation, suggesting a thrombosis theory as their common basis. In this review, the relationship between VTE and risk factors specifically of women is discussed, also in relation to coagulation abnormalities causing inherited thrombophilia.     

Thromboembolism in brain tumors

Venous thromboembolism commonly affects patients receiving treatment for primary and secondary cerebral tumors. We review the recent literature on the molecular mechanisms underlying this hypercoagulable state and clinical studies of antithrombotic prophylaxis and therapy in this population. A computerized search of the MEDLINE database for articles from 1966 to the present day. Keywords/search terms used were glioma, astrocytoma, glioblastoma multiforme, cerebral tumor, primary brain tumour, secondary brain tumour, venous thromboembolism, thromboprophylaxis, heparin, warfarin, anticoagulants, and caval filters. Although neurological deficit has been identified as an independent risk factor for thrombosis it is also clear that malignant brain tumors induce changes in the makeup of circulating blood, making it more likely to clot. Concern for the perceived risk of perioperative intracranial bleeding with antithrombotic prophylaxis appears not to be justified by the available evidence. Prospective assessment of low molecular weight heparins for prophylaxis and treatment of established thrombosis is required. Antithrombotic therapy may also offer advantages over intracaval devices in prevention of secondary pulmonary embolism in patients with brain tumors.     

Thromboembolism in paediatric lupus patients

Paediatric patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL), specifically lupus anticoagulants (LAC) are at high risk of developing thromboembolic events (TE). Our objectives were to determine the prevalence of TE in paediatric SLE patients with LAC and to determine if anticoagulation was effective to decrease morbidity, and prevent recurrent TE. We reviewed data on 149 paediatric SLE patients treated over 10 years. In all, 24 patients (16%) were LAC positive, and 21 TE occurred in 13 of these LAC positive patients (54% incidence of TE in LAC positive patients). The events were cerebral venous thrombosis (9), arterial stroke (3), deep venous thrombosis (4), pulmonary embolism (2), other venous event (1) and other arterial events (2). The median duration between SLE diagnosis and first TE was 15.2 months (range 0-62), and the median age at first TE was 15.1 years (range 11.4-18.4). Long-term anticoagulation was prescribed, and eight patients (62%) were transferred to adult care on lifelong oral warfarin; four (31%) remain under our care on lifelong warfarin, and one patient died of causes unrelated to her TE. No patient has been identified with deficiencies of protein C, protein S or antithrombin III. One patient is heterozygous for Factor V Leiden, and one is heterozygous for both the Prothrombin 20210A mutation and the MTHFR (methylene tetrahydrofolate reductase) mutation. Four patients had recurrent TE (31%), and three were not anticoagulated at the time of their second event. One patient had two recurrences on therapeutic anticoagulation. Thromboembolic events are prevalent in the LAC positive paediatric SLE population, and consideration for lifelong anticoagulation must occur after an initial TE.     

Thromboembolism in lung cancer patients]

We reviewed 649 primary lung cancer patients with special reference to the occurrence of thromboembolism. Thirteen episodes of thromboembolism were detected in 12 (1.8%) of the 649. Eight of the 12 were men, and their mean age was 63. Adenocarcinoma was the predominant cell type. Most patients had an advanced stage of the disease, but in some in the cancer was at an early stage. In 5 cases, the finding of thromboembolisms led to diagnosis of the lung cancer (38.5%). Anticoagulant therapy was performed in 9 cases, of which 8 responded without serious complication. We emphasize the importance of anticoagulant therapy as a therapy indicated for thromboembolism in patients with lung cancer.     

Thromboembolism in inflammatory bowel disease.

Thromboembolism represents a severe complication of inflammatory bowel disease occurring in young patient, with active disease. Deep venous thrombosis and pulmonary embolism are the most frequent thromboembolism manifestations. Arterial complications and unusual sites for thromboembolism are more rare. Overall, inflammatory bowel disease is a real prothrombotic state as almost all parameters of coagulation are enhanced. Anticoagulation during the episode of thromboembolism is mandatory, and sometimes may ameliorate the course of inflammatory bowel disease.