Hematology in palliative medicine
Identifieur interne : 005F66 ( Istex/Corpus ); précédent : 005F65; suivant : 005F67Hematology in palliative medicine
Auteurs : Mellar P. DavisSource :
- American Journal of Hospice and Palliative Medicine [ 1049-9091 ] ; 2004-11.
Abstract
Advanced cancer and life-limiting chronic nonmalignant diseases are associated with a number of hematological problems. Anemia and coagulation disorders, principally venous thrombosis and thrombocytopenia, are most commonly observed. Patients undergoing chemotherapy and bone marrow transplant have unique problems that include neutropenias and chemotherapy-induced drug toxicities, which will not be covered in this article.
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DOI: 10.1177/104990910402100610
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Horvitz Center for Palliative Medicine, Cleveland Taussig Cancer Center, Cleveland, Ohio</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">American Journal of Hospice and Palliative Medicine</title><idno type="ISSN">1049-9091</idno><idno type="eISSN">1938-2715</idno><imprint><publisher>Sage Publications</publisher><pubPlace>Sage CA: Thousand Oaks, CA</pubPlace><date type="published" when="2004-11">2004-11</date><biblScope unit="volume">21</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="445">445</biblScope><biblScope unit="page" to="454">454</biblScope></imprint><idno type="ISSN">1049-9091</idno></series><idno type="istex">CBFC90D93595AA290F8873FF38C7F1EF6EAE9E0F</idno><idno type="DOI">10.1177/104990910402100610</idno><idno type="ArticleID">10.1177_104990910402100610</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1049-9091</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Advanced cancer and life-limiting chronic nonmalignant diseases are associated with a number of hematological problems. Anemia and coagulation disorders, principally venous thrombosis and thrombocytopenia, are most commonly observed. Patients undergoing chemotherapy and bone marrow transplant have unique problems that include neutropenias and chemotherapy-induced drug toxicities, which will not be covered in this article.</div></front></TEI><istex><corpusName>sage</corpusName><keywords><teeft><json:string>platelet</json:string><json:string>erythropoietin</json:string><json:string>venous</json:string><json:string>transfusion</json:string><json:string>thrombocytopenia</json:string><json:string>heparin</json:string><json:string>coagulation</json:string><json:string>thromboembolism</json:string><json:string>thrombosis</json:string><json:string>cancer patients</json:string><json:string>chemotherapy</json:string><json:string>embolism</json:string><json:string>warfarin</json:string><json:string>medicine volume</json:string><json:string>hematol</json:string><json:string>venous thromboembolism</json:string><json:string>platelet transfusions</json:string><json:string>pulmonary embolism</json:string><json:string>oncol</json:string><json:string>clin</json:string><json:string>american journal</json:string><json:string>oncology</json:string><json:string>lmwh</json:string><json:string>microangiopathic</json:string><json:string>hemolysis</json:string><json:string>anticoagulant</json:string><json:string>cancer patient</json:string><json:string>venous thrombosis</json:string><json:string>multiple myeloma</json:string><json:string>platelet count</json:string><json:string>deep venous thrombosis</json:string><json:string>platelet counts</json:string><json:string>hospice</json:string><json:string>anemia</json:string><json:string>dos</json:string><json:string>iron deficiency</json:string><json:string>aminocaproic acid</json:string><json:string>hematol oncol clin</json:string><json:string>malignancy</json:string><json:string>lymphoma</json:string><json:string>anticoagulation</json:string><json:string>palliative</json:string><json:string>folate deficiency</json:string><json:string>tissue factor</json:string><json:string>cancer cells</json:string><json:string>hemolytic uremic syndrome</json:string><json:string>tranexamic acid</json:string><json:string>prothrombin time</json:string><json:string>antitumor therapy</json:string><json:string>microangiopathic anemia</json:string><json:string>erythropoietin levels</json:string><json:string>semin hematol</json:string><json:string>prostate cancer</json:string><json:string>venous ultrasonography</json:string><json:string>intravascular coagulation</json:string><json:string>syndrome</json:string><json:string>iron overload</json:string><json:string>chronic disease</json:string><json:string>hemoglobin levels</json:string><json:string>chronic illness</json:string><json:string>bone marrow infiltration</json:string><json:string>immature leukocytes</json:string><json:string>cancer type</json:string><json:string>hormone therapy</json:string><json:string>liver disease</json:string><json:string>inflammatory cytokines</json:string><json:string>platelet aggregation</json:string><json:string>complete blood count</json:string><json:string>high risk</json:string><json:string>partial thromboplastin time</json:string><json:string>thrombotic thrombocytopenic purpura</json:string><json:string>molecular weight heparin</json:string><json:string>percent hematocrit</json:string><json:string>poor response</json:string><json:string>exogenous erythropoietin</json:string><json:string>inferior vena cava filters</json:string><json:string>nonchemotherapy patients</json:string><json:string>imaging studies</json:string><json:string>warfarin therapy</json:string><json:string>palliative population</json:string><json:string>bone marrow necrosis</json:string><json:string>breast cancer</json:string><json:string>relative risk</json:string><json:string>prophylactic platelet transfusions</json:string><json:string>neck cancer</json:string><json:string>nutritional deficiencies</json:string><json:string>natl cancer inst</json:string><json:string>lung cancer</json:string><json:string>chronic anemia</json:string><json:string>dependent areas</json:string><json:string>deep vein thrombosis</json:string><json:string>unfractionated heparin</json:string><json:string>semin thromb hemost</json:string><json:string>occult cancers</json:string><json:string>thrombophilic state</json:string><json:string>heparin therapy</json:string><json:string>cancer</json:string><json:string>marrow</json:string></teeft></keywords><author><json:item><name>Mellar P. 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Horvitz Center for Palliative Medicine, Cleveland Taussig Cancer Center, Cleveland, Ohio</affiliation></author></analytic><monogr><title level="j">American Journal of Hospice and Palliative Medicine</title><idno type="pISSN">1049-9091</idno><idno type="eISSN">1938-2715</idno><imprint><publisher>Sage Publications</publisher><pubPlace>Sage CA: Thousand Oaks, CA</pubPlace><date type="published" when="2004-11"></date><biblScope unit="volume">21</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="445">445</biblScope><biblScope unit="page" to="454">454</biblScope></imprint></monogr><idno type="istex">CBFC90D93595AA290F8873FF38C7F1EF6EAE9E0F</idno><idno type="DOI">10.1177/104990910402100610</idno><idno type="ArticleID">10.1177_104990910402100610</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2004</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Advanced cancer and life-limiting chronic nonmalignant diseases are associated with a number of hematological problems. Anemia and coagulation disorders, principally venous thrombosis and thrombocytopenia, are most commonly observed. Patients undergoing chemotherapy and bone marrow transplant have unique problems that include neutropenias and chemotherapy-induced drug toxicities, which will not be covered in this article.</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>palliative care</term></item><item><term>hematology</term></item><item><term>cancer</term></item><item><term>anemia</term></item><item><term>thrombocytopenia</term></item><item><term>deep vein thrombosis</term></item><item><term>pulmonary embolism</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2004-11">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/CBFC90D93595AA290F8873FF38C7F1EF6EAE9E0F/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus sage not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article" dtd-version="2.3" xml:lang="EN"><front><journal-meta><journal-id journal-id-type="hwp">spajh</journal-id><journal-id journal-id-type="publisher-id">AJH</journal-id><journal-title>American Journal of Hospice and Palliative Medicine</journal-title><issn pub-type="ppub">1049-9091</issn><publisher><publisher-name>Sage Publications</publisher-name><publisher-loc>Sage CA: Thousand Oaks, CA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1177/104990910402100610</article-id><article-id pub-id-type="publisher-id">10.1177_104990910402100610</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Hematology in palliative medicine</article-title></title-group>
<contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Davis</surname><given-names>Mellar P.</given-names></name><degrees>MD, FCCP</degrees><aff>The Harry R. Horvitz Center for Palliative Medicine, Cleveland Taussig Cancer Center, Cleveland, Ohio</aff></contrib></contrib-group>
<pub-date pub-type="ppub"><month>11</month><year>2004</year></pub-date><volume>21</volume><issue>6</issue><fpage>445</fpage><lpage>454</lpage><abstract>
<p><italic>Advanced cancer and life-limiting chronic nonmalignant diseases are associated with a number of hematological problems. Anemia and coagulation disorders, principally venous thrombosis and thrombocytopenia, are most commonly observed. Patients undergoing chemotherapy and bone marrow transplant have unique problems that include neutropenias and chemotherapy-induced drug toxicities, which will not be covered in this article.</italic></p>
</abstract><kwd-group><kwd>palliative care</kwd><kwd>hematology</kwd><kwd>cancer</kwd><kwd>anemia</kwd><kwd>thrombocytopenia</kwd><kwd>deep vein thrombosis</kwd><kwd>pulmonary embolism</kwd></kwd-group><custom-meta-wrap><custom-meta xlink:type="simple"><meta-name>sagemeta-type</meta-name><meta-value>Journal Article</meta-value></custom-meta><custom-meta xlink:type="simple"><meta-name>cover-date</meta-name><meta-value>November/December 2004</meta-value></custom-meta><custom-meta xlink:type="simple"><meta-name>search-text</meta-name><meta-value> Abstract Advanced cancer and life-limiting chronic nonmalignant diseases are associated with a number of hemato- logical problems. Anemia and coagu- lation disorders, principally venous thrombosis and thrombocytopenia, are most commonly observed. Pa- tients undergoing chemotherapy and bone marrow transplant have unique problems that include neutropenias and chemotherapy-induced drug toxi- cities, which will not be covered in this article. Key words: palliative care, hema- tology, cancer, anemia, thrombocy- topenia, deep vein thrombosis, pul- monary embolism Introduction Both anemia and deep venous thrombosis are associated with specific symptoms such as dyspnea, fatigue, and reduced quality of life, and both can cause sudden death as a result of myocardial ischemia and pulmonary embolization, respectively. Bleeding, as a result of thrombocytopenia, will pro- duce petechiae in dependent areas and mucosal hematomas, where coagulopa- thy associated with factor deficiencies presents with large ecchymosis. Both will cause intracranial hemorrhage if persistent and severe. Anemia Nearly half of cancer patients develop anemia.1 Anemia is defined as a hemoglobin of less than 12 grams per deciliter. Anemia is more common with leukemia, lymphoma, lung can- cer, gynecological, and gastrointesti- nal cancers.2 Severe anemia will cause debilitating symptoms, including cold skin, dizziness, palpitations, dyspnea with pulmonary edema and conges- tive heart failure, chest pains related to coronary insufficiency and cardiac ischemia, as well as depression and cognitive failure.3 Fatigue and asthe- nia related to cancer are commonly associated with anemia although in- fections, hormone and nutritional deficiencies, depression, sleep distur- bances, and medications also con- tribute to fatigue in advanced cancer.4 The elderly with multiple comorbidities will experience symptoms related to anemia at higher hemoglobin levels than younger patients. Small decre- ments in hemoglobin may produce profound symptoms in these patients. Anemia influences the survival of patients with carcinoma of the lung, cervix, and prostate; head and neck cancer; lymphoma, and multiple myeloma. The relative risk for death increases in anemic patients with lung cancer by 19 percent, with head and neck cancer by 75 percent, with prostate cancer by 47 percent, and with lymphoma by 65 percent com- pared to nonanemic patients.5 Anemia predicts a poor outlook for Hodgkin's disease. Anemia during radiation ther- apy for cervical cancer predicts a poor tumor response and, as a result, poor prognosis.6-8 The causes of anemia in patients with cancer are usually multiple and divided between those related to treat- ment and those related to the cancer. Hemodilution contributes to anemia at least in hospitalized patients who receive intravenous hydration. Bone marrow replacement displaces normal marrow stem cells with cancer cells and destroys the bone marrow microenvironment, leading to the development of bone 445American Journal of Hospice & Palliative Medicine Volume 21, Number 6, November/December 2004 Hematology in palliative medicine Mellar P. Davis, MD, FCCP Mellar P. Davis, MD, FCCP, Medical Director, The Harry R. Horvitz Center for Palliative Medicine, ClevelandTaussigCancerCenter,Cleveland,Ohio. Palliative oncology update marrow necrosis.1 A desmoplastic bone marrow reaction due to cancer cells and/or as a result of radiation leads to myelofibrosis and a leukoery- throblastic differential. Breast cancer and prostate cancer are the most com- mon adult malignancies to invade the bone marrow. However, the most common cause of anemia is inflam- matory cytokine-induced suppression of erythropoietin production and ery- thropoiesis.9 This condition is due to the cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL6), and interleukin-1 (IL1).10 It can be reversed by exogenous erythro- poietin, but other treatable causes need to be excluded prior to using erythropoietin. Iron, B12, and folate deficiencies are relatively common in cancer patients. Failure of anemia to respond to erythropoietin is a poor prognostic factor.11 The development of microangio- pathic anemia with schistocytes, reduced platelets, reduced serum haptoglobin, and elevated lactate dehydrogenase (LDH) is also a poor prognostic sign and suggests pul- monary metastases and poor response to erythropoietin.9 Immuno- hemolytic anemia and red-cell apla- sia can occur in nonhematological malignancies, non-Hodgkin's lym- phoma, and Hodgkin's lymphoma.9 Anticancer drugs, particularly mito- mycin C and the immunosuppressant cyclosporine, will cause a hemolytic uremic syndrome (HUS). In this dis- order, which resembles thrombotic thrombocytopenic purpura (TTP), platelets are low and schistocytes are present, but coagulation (i.e., the pro- thrombin time and partial thrombo- plastin time as well as fibrinogen) is normal. Cisplatin, melphalan, and methotrexate will also cause hemoly- sis and renal damage associated with HUS. Doxorubicin can cause a non- hemolytic acute hemolysis in indi- viduals deficient in glucose-6 dehy- drogenase.9 Assessment of anemia Prognosis and therapeutic options guide the evaluation of anemia. Patients who have advanced disease and short survival expectancy should not be extensively evaluated with multiple tests, endoscopy, or bone marrow biopsy. Transfusion should be provided for symptom support. Laboratory studies should include a complete blood count (CBC) and, of particular importance, a review of the peripheral smear. Macrocytosis, if oval in appearance, suggests B12 and folate deficiency or chemotherapy- induced red cell changes. Round macrocytes suggests liver disease, particularly when associated with acanthocytes. This also can occur with hyposplenism. Associated red cell abnormalities include schistocytes and fragmented red cells with microangiopathic hemolytic anemia, hemolytic uremic syndrome, or TTP. Spherocytes are found with immune (antibody mediated)-induced hemoly- sis. Polychromasia will be found with reticulocytes and marrow regenera- tion. Rouleaux will occur in dyspro- teinemias or inflammatory states. Thrombocytosis and microcytosis are common with iron deficiency. Immature leukocytes and nucleated red cells are seen as part of a leukoerythroblastic differential and associated bone mar- row infiltration with tumors. Hyperbi- lirubinemia, if uncongugated, is due to hemolysis and a mixed hyperbili- rubenemia with liver or biliary dis- ease. Haptoglobin levels are low with hemolysis. The LDH is increased in B12, folate deficiency, hemolysis, and neoplastic bone marrow infiltration. Iron levels are low with anemia of chronicillnessandirondeficiencywhere transferrin levels are low with chronic disease and elevated with iron deficien- cy.11,12 Ferritin, a storage protein for iron, is elevated in liver disease, iron overload states, and anemia of chronic illness but low with iron deficiency. Prothrombin time (PT), partial thromboplastin (PTT) and fibrinogen are abnormal with dis- seminated intravascular coagulation (DIC) but normal with HUS and TTP. Methylmalonic acid and homocysteine are increased in B12 and folate deficien- cy and are helpful ancillary tests in assessing macrocytic anemia. Bone marrow examination pro- vides valuable information about the cellularity, marrow function, and iron stores. This should not be done if it is only to satisfy one's curiosity. Measuring serum erythropoietin may be a useful indicator in anemia. Elevated erythropoietin levels and bone marrow infiltration by tumors are indicators of a poor response to exogenous erythropoietin due to criti- cal loss of erythroid stem cells where low erythropoietin levels or a low ratio of erythropoietin to reticulcyte count is associated with response and erythropoietin deficiency.1,13-16 Pa- tients with erythropoietin levels greater than 1,000 µ/ml are unlikely to respond to erythropoietin.1 In addi- tion, elevated serum transferrin recep- tors and low platelet counts suggest resistances to erythropoietin. Treatment Reversible causes for anemia should besoughtbecausetheyareeasilytreated. Iron deficiency, nutritional deficiencies, and immune mediated hemolysis should be treated first, and transfusions given sparingly. Iron is given orally as ferrous sulfate 324 mg three times a day or, if the patient is unable to take oral iron, as iron dextran 1 gm given intravenously over eight hours for two days. Anaphylaxis can occur with intravenous iron dextran. Oral folate 5 mg or intramuscular B12 100 mcg daily for two weeks then 1 mg daily and 1000 mcg intramuscularly monthly,respectively,areusualdosesfor replacement. Replacing endocrine defi- ciencies related to thyroid or pituitary insufficiency will secondarily improve anemia.17 Gastrointestinal bleeding 446 American Journal of Hospice & Palliative Medicine Volume 21, Number 6, November/December 2004 should be treated if possible with proton pump inhibitors for peptic ulcer disease, sclerotherapy, and ß-blockers (such as propranolol) for esophageal and gastric varices associated with cirrhosis and colonoscopy with photocoagulation, or with polyp snare for colon polyps. Blood transfusions Arbitrary decisions that trigger trans- fusion often fail to take into account the particulars regarding the patient. The young may tolerate hemoglobins of 7 gm/dl, while the elderly with comorbid diseases may develop anemia-associated symptoms at just below 10 gm/dl hemo- globin. When anemia is gradual, chronic compensatory mechanisms such as an increase in 2, 3-diphosphoglycerate, car- diac output, respiratory rate, and reduced systemic vascular resistance may decrease symptoms by improving oxy- genation.18 Anemia as a direct cause of death occurs with 10 percent hematocrit (if the plasma volume is maintained and there is no comorbid vascular disease). Adequate oxygen delivery occurs between 30 to 40 percent hematocrit. Transfusions of one to two units of packed red cells should be given with each unit infused over three hours and symptoms assessed within one to two days. If fatigue, dyspnea, or other associ- ated symptoms are not improved within 24 hours, further transfusions are unlike- ly to be helpful. Whether a transfusion benefits quality of life is controversial in nonchemotherapy patients. Compli- cations of transfusions include immedi- ateanddelayedhemolyticreactions,iron overload, febrile reactions to white cells, alloimmunization to platelets, immuno- suppression, fluid overload, and infec- tions--particularly viral--which would include cytomegalovirus (CMV), HIV, and hepatitis with associatedmorbidity and mortality.1,19 Desferrioxamine 500 mg to 1 gm can be given with each trans- fusion in patients who are heavily trans- fused in order to prevent or delay iron overload. Alternatively, 1 to 2 g can be infused subcutaneously by portable pump in individuals with iron over- load and ongoing transfusion require- ments in order to avoid the morbidity of hemoriderosis. Erythropoietin in doses of 100 IU/kg threetimesaweekor40to60,000IUper week as a single dose reduces the need for transfusions, improves hemoglobin, and improves quality of life in patients who receive chemotherapy and radia- tion.20,21 Responses are usually seen within eight weeks. The use of erythro- poietin in patients not receiving antitu- mor therapy is controversial but is com- monly used in patients with multiple myeloma and chronic lymphocytic leukemia who are not on therapy. In gen- eral, transfusions are preferred because of the cost of erythropoietin and lack of randomized studies in nonchemotherapy patients. Erythropoietin is rarely associ- ated with hypertension or polycythemia in the advanced cancer population.1 Sialic acid containing erythropoietin is commercially available. Recommendations for erythropoietin Guidelines generated from the Federation of the French Cancer Centers22 are as follows: · erythropoietin is an alternative to transfusions when patients are receiving platin chemotherapy; · cancer-induced anemia reduces quality of life; · treatment with erythropoietin may improve quality of life; · hemoglobin levels should be followed during radiation, and erythropoietin should be used if anemia should develop; · erythropoietin is effective treat- ment for anemia associated with multiple myeloma, non-Hodgkin's lymphoma, and the use of non- platinum-based chemotherapy and pediatric patients, but the risk and benefit ratio--including the cost-- needs to be individualized; and · economic analysis needs to be done. Recommendations for the use of erythropoietin in multiple myeloma and chronic lymphocytic leukemia23 · erythropoietin should be admin- istered to anyone with a hemo- globin of less than 10 gm/dl; · erythropoietin should be used for patients with a hemoglobin level of 10 to 12 gm/dl if they are symptomatic; · doses are initially 10,000 IU three times a week or 40,000 IU once a week and titrated to maintain a hemoglobin of 12 gm/dl, alterna- tively, 200 to 300 µg of darbepoi- etin is given every other week; · patients with less than 1 gm/dl increase in hemoglobin over four weeks should have erythro- poietin doses increased to 20,000 IU three times a week or 60,000 IU once a week; · erythropoietin is discontinued if there is no response or if hemo- globin exceeds 14 gm/dl in those who do respond; and · treatment should be resumed if hemoglobin falls below 12 gm in responders. Deep venous thrombosis and cancer Idopathic thrombosis Unexplained deep venous thrombo- sis (DVT) is a significant indicator of 447American Journal of Hospice & Palliative Medicine Volume 21, Number 6, November/December 2004 448 American Journal of Hospice & Palliative Medicine Volume 21, Number 6, November/December 2004 Unexplained pleuritic chest pain Unexplained shortness of breath Hemoptysis Hypoxemia Palpitations Chest Radiography Electrocardiogram Diagnostic of congestive heart failure Nondiagnostic Normal Pneumonia Pneumothorax Lymphangitic carcinomatosis Treat appropriately Doppler ultrasound of lower extremity Abnormal Normal Heparinize Spiral computer tomography Normal Abnormal Repeat ultrasound in Heparinize two weeks Figure 1. Diagnosing pulmonary embolism. an underlying malignancy. The rela- tive risk is 4.6 for an underlying malignancy. Age, gender, and location of DVT have no bearing on the inci- dence for a malignancy. The majority of patients with a cancer and a DVT will have clinical abnormalities at the time of presentation, which suggests the underlying cancer. Medical histo- ry, physical examination, routine lab- oratory tests--a CBC and chemistries, including liver function tests--and a chest x-ray should be done. Extensive testing otherwise is not justified.24-26 Recurrent idiopathic DVT has an even greater risk for an underlying malignancy compared to those with only one episode. Patients who have one episode have a 6.1 percent preva- lence of having an underlying cancer, while patients with two events will have a 17.1 percent prevalence.24 Thrombosis in cancer patients Up to 15 percent of patients with an advanced cancer will have a clinically detected venous thromboembolism. Postmortem examinations reveal a prevalence of 30 to 50 percent. Cancer patients represent 30 percent of patients who develop a DVT.27,28 The incidence of venous thromboembolism is particu- larly high among patients with mucin- producing adenocarcinomas, pancreat- ic, gastrointestinal, lung, and ovarian cancer. Untreated breast cancer has a low incidence, although the risk increas- es when patients are placed on hormone therapy or receives chemotherapy. Renal cancer, melanoma, prostate can- cer, and carcinomas of unknown prima- ry have a low incidence. Treatment for cancer,includingsurgery,hormonether- apy, chemotherapy, and the placement of central venous catheters increases the risk of venous thromboembolism in solid tumor patients.28-31 Arterial throm- bosis is much less common and is most often the result of nonbacterial thrombotic endocarditis or dissem- inated intravascular coagulation.32 Patients with cancer at the time of a venous thromboembolism have a one- year survival of 12 percent as com- pared to 36 percent for cancer patients without thromboembolism. The mor- tality ratio is 2.20 for cancer associat- ed thromboembolism when compared to patients who are matched for age and cancer type but no thromboem- bolism.33 Unusual presentations include upper extremity thrombosis due to axillary metastases, mediastinal tumor, or cen- tral venous catheters. Full-blown pre- sentations of superior vena cava syn- drome may follow. The Trousseau syndrome is migratory superficial thrombophlebitis usually in uncom- mon sites. Hepatic venous thrombosis with a rapid development of ascites and hepatic failure will occur with hepatocelluar carcinomas and myelo- proliferative syndromes. Pathophysiology A variety of hemostatic laboratory abnormalities have been reported in cancer patients. These abnormalities include a shortened prothrombin and partial thromboplastin time, elevated D-dimers, increased fibrinogen levels, circulating prothrombin fragments 1 and 2, and thrombin-antithrombin complexes. These can be found in 50 to 70 percent of cancer patients.34 Some patients will have elevated platelet counts and elevated platelet activity as demonstrated by increased expression of platelet factor 4, CD-62, and CD-63. Cancer cells contain tissue factor, which forms a complex with the coag- ulation factor VIIa, which in turn acti- vates factors IX and X. In addition, mucin-producing tumors contain a cysteine protease that directly acti- vates factor X.35-37 Endothelial cells and monocytes found within tumors can be induced to express tissue factor under the influ- ence of inflammatory cytokines such as TNF-alpha and IL1. Inflammatory cytokines also will increase directly the expression of tissue factor in tumor cells.30 Circulating tumor cells and tumor membrane fragments induce platelet aggregation and platelet adhesion.36 Aggregation is induced by thrombin generated on tumor cell membranes.36,37 High levels of the coagulation inhibitor tissue factor protein inhibitor (TFPI) are found in 50 percent of patients solid tumors.38 Cytokines, IL1, and TNF stimulates endothelial production of TFPI. The levels of TFPI do not correlate with activation of coagulation.38 Activation of protein C, an inhibitor to coagulation impor- tant in hemostasis, fails to occur (resistance to activated protein C), which leads to thrombosis and is com- monly acquired with advanced cancer. The prevalence of acquired activated protein C resistance is 54 percent in patients with cancer and thromboem- bolism and 17 percent in those with- out thromboembolism.39 Extrinsic factors also contribute to thrombosis, most importantly venous stasis and direct trauma to the vessel walls by intravascular catheters. Im- mobilization due to surgery, infections, or as a result of cancer will lead to slug- gish blood flow and poor clearance of activated coagulation factors. Chemo- therapy directly reduces protein C and S and damages endothelial cells.40 Diagnosis In general, the diagnosis of throm- bosis and pulmonary embolism is made by the same diagnostics test used in patients without cancer. Cancer patients often present with typical symptoms, but the clinical pre- sentation is less specific than in patients without cancer because of the development of cancer related lym- phedema.41 Contrast venography has been the reference standard, but due to limited availability of venography and 449American Journal of Hospice & Palliative Medicine Volume 21, Number 6, November/December 2004 the noninvasive nature of compres- sion or duplex ultrasonography (US), ultrasound is used initially with a high degree of accuracy. Noninvasive me- thods for symptomatic proximal thrombosis of the leg are 95 percent sensitive and 96 percent specific. Patients can frequently be managed based upon ultrasonography alone.41 The negative predictive value for patients with suspected deep venous thrombosis is less than 2 percent if the ultrasonography of proximal veins remains normal in the course of one week.41 Venous ultrasonography is much less reliable in asymptomatic, isolated, distal, and recurrent deep venous thrombosis.41 Making a diagnosis of pulmonary embolism requires clinical assessment and a battery of investigations such as venous perfusion lung scans, venous ultrasonography, and D-dimer testing.42 If there is a clinical suspicion of pul- monary embolism, a nondiagnostic ven- tilation-profusion lung scan and a nor- mal lower extremity ultrasound for venous clot, 80 percent will not have a pulmonary embolism. Twenty percent would have a pulmonary embolism, but if the lower extremity ultrasound remains normal, recurrence is unlikely (i.e., less than 2 percent).41 Spiral com- puter tomography (CT) is specific, reli- able, and not subject to alterations in ventilation perfusion scans caused by chronic obstructive lung disease. Spiral CT scans will visualize central pul- monary vasculature but not subsegmen- tal arteries.42 Pulmonary arteriography may be necessary in the few patients with negative CT scans but highly sug- gestive history and symptoms. High sensitivity D-dimer assays have a high negative predictive value for the diagnosis of deep venous thrombosis and pulmonary embolism (i.e., normal or negative assay essen- tially renders a diagnosis of venous thromboembolism unlikely). A nega- tive D-dimer in a patient with cancer is not as reliable compared to non- cancer patients as reported in a recent experience.43 Treatment Treatment of cancer patients with venous thrombosis and pulmonary embolism is similar to patients with- out cancer. However, two additional concerns are unique: 1) whether to anticoagulate someone with a poor prognosis and a short survival; and 2) when to insert an inferior vena cava filter. Thrombolytics are rarely used since cancer is a relative counterindi- cation. Patients with brain metastases can be anticoagulated except when metastases are from melanoma, which has a high risk of bleeding. Patients with recent (i.e., within the last 30 days) craniotomy should not be anti- coagulated. Oral anticoagulants are subject to dietary habits, drug interac- tions, and end organ failure (liver), and are precarious to use in poor per- formance status patients. The benefits of anticoagulants are the reduction of symptoms (e.g., dyspnea, leg pain, and postphlebitic symptoms), preven- tion of pulmonary hypertension, and reduced mortality but must be individ- ualized based on goals of care.42 Antithrombotic treatment of acute venous thrombosis consists of an ini- tial phase and a long-term phase. Standard heparin is used with a dose of 80 IU/kg and continued as an hourly infusion of 18 IU/kg but has been replaced recently by low molec- ular weight heparin (LMWH) given subcutaneously on a weight-adjusted dose. LMWH, unlike standard unfrac- tionated heparin (UFH), does not require laboratory monitoring (unless the patient is obese or in renal failure), is given subcutaneously twice daily and therefore can be given as an out- patient treatment, and has a reduced risk of heparin-induced thrombocy- topenia.44 LMWH gives a more con- sistent biologic effect due to less pro- tein binding and better bioavailability and thus provides more predictable pharmacokinetics.45,46 LMWHs do not lengthen partial thromboplastin times and cannot be monitored by usual coagulation tests. A modification of the PTT, which uses factor X (the "tenase" time), is necessary to mea- sure the biological activity of LMWH. This is usually neither required nor routine. Long-term anticoagulants Patients with acute thromboem- bolism who are treated with an initial course of heparin require continued anticoagulation to prevent recurrence. The vitamin K antagonist warfarin is started on the first or second day of a five-day heparin course to allow for overlap. Initial doses are 5 mg. An average dose of 4 mg is required in patients less than 65 years old and 3 mg in patients over the age of 65. High loading doses are associated with excessive anticoagulation.42,47 A tran- sient period of hypercoagulability will occur as a result of the rapid reduction of protein C and S with the initial dose of warfarin. This period can lead to coumadin tissue necrosis--hence the reason to overlap with heparin. The prothrombin time reported as an inter- national normalized ratio (INR) should be maintained between 2 to 3.47 Cancer patients can develop re- current thromboembolism while on therapeutic warfarin doses. Options in these circumstances include the fol- lowing: · maintaining warfarin but at a higher dose (i.e., an INR 3 to 4.5); · subcutaneous unfractionated heparin given twice daily with a PTT checked six hours after the morning dose to gauge the appropriate level; and · weight adjusted LMWH on an ongoing basis. 450 American Journal of Hospice & Palliative Medicine Volume 21, Number 6, November/December 2004 Inferior vena cava filters can be used for individuals at high risk for bleeding (gastrointestinal bleeding within two years, CNS metastases, particularly with melanoma and recent neurosurgery). Inferior vena cava filters reduce the risk of recurrent pulmonary embolism in the short term but at the expense of recurrent deep vein thrombosis.48,49 The duration of anticoagulation is usually greater than six months and probably lifetime in patients because of an ongoing risk of clotting with advanced cancer. Patients who are rapid- ly failing, develop anorexia, and have a significant risk for over anticoagulation (particularly when placed on antibi- otics) should have their warfarin dis- continued. When the care plan is for comfort only, anticoagulation should be discontinued. The following is an anticoagulation algorithm for venous thrombosis50 : · obtain a baseline APTT, PT and complete blood count; · check for contraindications to heparin therapy; · order appropriate imaging studies; · confirm venous thrombosis; · start LMWH (enoxaparin 1 mg/ kg q 12) or UFH (80 IV/kg and 18 IV/kg/h continuous infusion); · if suspicion is high, start heparin while obtaining imaging studies; · start warfarin 5 mg on day one, adjust dose based upon INR; · check platelet count on day three and five; · stop heparin after four to five days of combined warfarin therapy when the INR is greater than 2.0; and · continue anticoagulation with warfarin at doses that maintain INR between 2 and 3. Complications of anticoagulation Long-term complications of antico- agulants can be significant. Long-term heparin therapy is associated with hair loss and osteopenia (though perhaps less so with LMWH). Warfarin is terato- genic, particularly for first-trimester pregnancies but is rarely a concern in the palliative population. There is a strong relationship between the intensity of anticoagulants therapy and risk of bleed- ing.51 Patients on more intense warfarin therapy targeted to an INR > 3 will have twice the frequency of major hemor- rhagic complications. Intracranial hem- orrhage significantly increases with an INR > 4.0.51 Associated risk factors include ages over 75 years, past history of gastrointestinal bleeding, hyperten- sion, cerebral vascular disease, serious heart disease, and renal insufficiency.51 Older patients, a history of recent surgery and trauma, and the use of aspirin are additional risk factors for heparin-associated bleeding and compli- cations.51 Prevalence of major bleeding is 3 percent when heparin is followed by warfarin maintained at an INR of 2 to 3 for a duration of three months.51 The rate of major bleeding with unfractionated heparin range between 0 and 7 percent and fatal bleeding between 0 and 2 per- cent.Therateofmajorbleedingwithlow molecular weight heparin is 0 to 3 per- cent and fatal hemorrhage 0 to 0.8 per- cent.51 There is a suggestion that bleed- ing is more frequent with excessive heparin doses but is by no means defi- nite. There is no difference whether heparin is given intravenously or subcu- taneously. Thrombocytopenia Among the treatment- and tumor- related coagulation complications are thrombocytopenia, acquired platelet abnormalities, disseminated intravas- cular coagulation (DIC), microang- iopathic hemolytic anemia, paraneo- plastic thrombocytopenic purpura (TTP), acquired circulating inhibitors (antiphospholipid antibodies), and pri- mary fibrinolysis.52-54 Bone marrow invasion with marrow necrosis caused by cancer results in thrombocy- topenia.55 Drug- and radiation- induced thrombocytopenia are common risks. Drugs and chemotherapy can produce thrombocytopenia through an immune mechanism. Sepsis, a common event in advanced cancer, can initially present with a sudden reduction in platelet counts. Clinical presentation Patients with critically low platelet counts generally present with multifo- cal mucocutaneous bleeding. Pete- chiae will appear in dependent areas. Oral hematomas indicate severe thrombocytopenia and are a sign of an increased risk for cerebral hemor- rhage. Coagulation factor deficiencies mimic hemophilia by producing large joint bleeds and ecchymosis. Laboratory Machine counted platelet deter- minations can be misleading. Pseudo- thrombrocytopenia is seen with an ethyl- ene diamine tetra acetate (EDTA) artifact, a failure of this anticoagulant to prevent aggregation in vitro. The blood smear has clumped platelet aggregates. Microangiopathic hemolytic anemia, TTP, and DIC will be associated with schistocytes as previously mentioned, and bone marrow necrosis due to tumor infiltration will produce immature leukocytes and nucleated red cells along with thrombocytopenia. Coagulation tests PT, PTT, and fib- rinogen will be abnormal in DIC and microangiopathic anemia but will be normal in the HUS-TTP syndrome.56 451American Journal of Hospice & Palliative Medicine Volume 21, Number 6, November/December 2004 Thrombocytopenia with marrow fail- ure is associated with elevated throm- bopoietin levels where consumptive platelet disorders (i.e., immune throm- bocytopenia, DIC, and TTP) are asso- ciated with low to normal throm- bopoietin levels due to absorption onto megakaryocytes.57 Drug-induced thrombocytopenia Chemotherapy has predictable myelosuppression with an expected recovery time. Immunothrombo- cytopenia related to medications most commonly occurs with quinine, quini- dine, and trimethoprim-sulfamethoxa- zole.58 Mitomycin-C, bleomycin, cis- platin, and gemcitabine are reported to cause a TTP-HUS syndrome.56 Microangiopathic hemolytic anemia and treatment Paraneoplastic TTP-HUS, sepsis with DIC, and disseminated malig- nancy will produce a microangiopath- ic anemia. Sepsis requires antibiotics and supportive care. TTP is treated with plasma exchange and plasma- pheresis. Platelet transfusions should be avoided with TTP. Paraneoplastic TTP-HUS is usually seen with gastric cancer, breast cancer, and small cell cancer.59 Disseminated cancer with DIC requires coagulation (cyroprecip- itate) factor replacement platelet sup- port and chemotherapy.56 Immunothrombocytopenia Immunothrombocytopenia (ITP) is associated with a normal differential, a normal white cell morphology, and an isolated reduced platelet count. Coagulation is normal. Secondary thrombocytopenia occurs with the antiphospholipid syndrome, immunod- eficiency states such as AIDS, chronic lymphocytic leukemia or lymphoma, and hepatitis C.60 A major differential diagnosis is hypersplenism. The patient with ITP will not have an enlarged spleen, hence any patient whose spleen is enlarged does not have ITP. Patients with platelet counts above 50,000 per cubic ml are usually found incidentally. Bruising and bleeding with mild trauma will occur with a platelet count between 30,000 and 50,000. Spontaneous bruising or petechiae occur between 10,000 and 30,000, and internal bleeding risks increase once the platelet count is below 10,000. Initial treatment of immunothrombocytopenia is pred- nisone at a dose of 1 to 1.5 mg/kg per day. Prednisone should be tapered over three to four months. Responses occur in 50 to 70 percent and are usually seen within the first three weeks.60 Patients with a platelet count of greater than 50,000 usually do not require therapy. Patients with AIDS and immunothrom- bocytopenia will respond to antiretrovi- ral therapy and intravenous gamma globulin at a dose of 1 gm/kg for two days. Treatment of the underlying lym- phoproliferative disorder will frequent- ly produce a remission in patients with chronic lymphocytic leukemia or lym- phoma. Splenectomy may be required if more than 10 to 20 mg of prednisone is required per day to maintain a platelet count above 30,000.60 Sepsis-induced thrombocytopenia Isolated thrombocytopenia is the most common coagulapathy associated with sepsis. Qualitative platelet abnor- malities and antithrombin-III deficiency may also occur. In rare circumstances, DIC and multiple organ failure occur. Replacement of platelets by transfusion may be necessary if platelets are less than 10,000 to 20,000 per cubic ml. Coagulation factor replacement using either fresh frozen plasma or cyroprecip- itate will be necessary if fibrinogen is less than 100 mg/dl. Antibiotics should be started immediately.61,62 Platelet transfusions Platelet transfusions should be withheld in the case of TTP-HUS, heparin-induced thrombocytopenia, and posttransfusional thrombocytope- nia purpura due to alloimmunization to PLA-1 antigen. Platelet transfusions are given prophylactically at 10,000 per cubic ml for stable oncohematol- ogy patients, 20,000 to 50,000 per cubic ml for disseminated intra- vascular coagulation, and 50,000 per cubic ml if thrombocytopenia occurs in the face of massive transfusions.63 In the past 30 years, platelet trans- fusions have gradually increased and now exceed red cell transfusions. Most platelet transfusions are given to myelosuppressed patients receiving chemotherapy. Platelet transfusions are associated with bacterial and viral infections, as well as alloimmuniza- tion. Platelet transfusions are very expensive, particularly when using single donors and platelet pheresis. Therefore, prophylactic platelet trans- fusions in the palliative population not receiving chemotherapy are usually not warranted.64 Using growth factors such as interleukin-11, stem cell fac- tor, interleukin 3, and thrombopoietin would be inappropriate when patients are no longer candidates for antitumor therapy, and the goal of care is symp- tom management.65-67 Hemostatic drugs When bleeding is the consequence of a specific defect, replacement ther- apy is specific (e.g., factor VIII con- centrate infusions for hemophilia). Such treatments in advanced cancer may be impossible because bleeding is due to multiple defects, local tumor growth, or unknown causes. Patients may not be able to be transfused due to alloimmunization (in the case of plate- lets) or location (home). Nontrans- fusional hemostatic drugs are avail- able.68 Two synthetic derivatives, 452 American Journal of Hospice & Palliative Medicine Volume 21, Number 6, November/December 2004 aminocaproic acid and tranexamic acid (which is 10 times more potent than aminocaproic acid), reversibly bind to plasminogen and prevent transformation to plasmin, the enzyme that catabolizes fibrin. Both are effective when there is no evidence of fibrinolysis or DIC. Both agents will produce thrombotic complications in patients with low- grade DIC. Both agents should be avoided with upper urinary tract bleeding, as the development of clots in this situation will obstruct urinary flow. In cases of oral bleeding from tumors, administering either 50 to 60 mg/kg of aminocaproic acid every four hours or 20 to 25 mg/kg of tranexamic acid every eight hours by mouth can reduce bleeding. Mucosal bleeding due to thrombocytopenia will diminish with either agent.68 Side effects to aminocaproic acid and tranexamic acid include nausea, vom- iting, abdominal pain, and diarrhea. Desmopressin 0.3 mcg/ kg given sub- cutaneously or intravenously every 12 hours or 300 mcg given intranasal will reduce bleeding associated with quali- tative platelet defects related to cirrho- sis or uremia. Desmopressin reduces bleeding associated with aspirin as well. Benefits appear to be transient. Desmopressin is not effective in con- trolling acute gastrointestinal bleeding with cirrhosis. Bleeding from eso- phageal gastric varices will be dimin- ished by the use of the ß-blocker propanolol. Octreotide also reduces varice bleeding. The mechanism of action is reduced portal blood flow. Conclusion Anemia, venous thromboembolism, and thrombocytopenia are the most common hematological problems in advanced cancer. Management will require an accurate diagnosis and should be guided by the plan of care. Transfusions are appropriate for pa- tients undergoing antitumor therapy or who have an excellent performance status but are inappropriate for patients who are bed bound, have a limited sur- vival, or are not symptomatically improved by previous transfusions. Hemostatic medications are useful alternatives to platelet transfusions in some patients. Prophylactic platelet transfusions are generally not done in palliative patients. Individualization of therapy based on clinical circumstances is important when considering guide- lines related to hematological support. References 1. Mercadante S, Gebbia V, Marrazzo A, et al.: Anaemia in cancer: Pathophysiology and treat- ment. Cancer Treat Rev. 2000; 26(4): 303-311. 2. Groopman JE, Itri LM: Chemotherapy- induced anemia in adults: Incidence and treatment. J Natl Cancer Inst. 1999; 91(19): 1616-1634. 3. Ludwig H, Strasser K: Symptomatology of anemia. 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</ref-list></back></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Hematology in palliative medicine</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Hematology in palliative medicine</title></titleInfo><name type="personal"><namePart type="given">Mellar P.</namePart><namePart type="family">Davis</namePart><namePart type="termsOfAddress">MD, FCCP</namePart><affiliation>The Harry R. Horvitz Center for Palliative Medicine, Cleveland Taussig Cancer Center, Cleveland, Ohio</affiliation></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Sage Publications</publisher><place><placeTerm type="text">Sage CA: Thousand Oaks, CA</placeTerm></place><dateIssued encoding="w3cdtf">2004-11</dateIssued><copyrightDate encoding="w3cdtf">2004</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Advanced cancer and life-limiting chronic nonmalignant diseases are associated with a number of hematological problems. Anemia and coagulation disorders, principally venous thrombosis and thrombocytopenia, are most commonly observed. Patients undergoing chemotherapy and bone marrow transplant have unique problems that include neutropenias and chemotherapy-induced drug toxicities, which will not be covered in this article.</abstract><subject><genre>keywords</genre><topic>palliative care</topic><topic>hematology</topic><topic>cancer</topic><topic>anemia</topic><topic>thrombocytopenia</topic><topic>deep vein thrombosis</topic><topic>pulmonary embolism</topic></subject><relatedItem type="host"><titleInfo><title>American Journal of Hospice and Palliative Medicine</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">1049-9091</identifier><identifier type="eISSN">1938-2715</identifier><identifier type="PublisherID">AJH</identifier><identifier type="PublisherID-hwp">spajh</identifier><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>21</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>445</start><end>454</end></extent></part></relatedItem><identifier type="istex">CBFC90D93595AA290F8873FF38C7F1EF6EAE9E0F</identifier><identifier type="DOI">10.1177/104990910402100610</identifier><identifier type="ArticleID">10.1177_104990910402100610</identifier><recordInfo><recordContentSource>SAGE</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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