Management of Bleeding Complications in Patients with Cancer

® HEMATOLOGY BOARD REVIEW MANUAL STATEMENT OF EDITORIAL PURPOSE Management of Bleeding The Hospital Physician Hematology Board Review Manual is a study guide for fellows Complications in Patients and practicing physicians preparing for board examinations in hematology. Each manual with Cancer reviews a topic essential to the current prac tice of hematology. Contributor: PUBLISHING STAFF Thomas G. DeLoughery, MD, FACP, FAWM Professor of Medicine, Pathology, and Pediatrics, Divisions of Hematology/ PRESIDENT, GROUP PUBLISHER Medical Oncology, Department of Medicine, and Division of Laboratory Bruce M. White Medicine, Department of Pathology, Oregon Health & Science University, Portland, OR SENIOR EDITOR Robert Litchkofski EXECUTIVE VICE PRESIDENT Barbara T. White EXECUTIVE DIRECtor Table of Contents OF OPERAtions Jean M. Gaul Introduction .............................1 Evaluation of the Bleeding Cancer Patient .....1 Merck is pleased to provide this Coagulation Defects .......................2 material as a professional service to the medical community. Disorders of Platelet Number and Function ....3 Hematologic Cancers Associated with Bleeding ..6 Therapy .................................8 Conclusion ..............................8 NOTE FROM THE PUBLISHER: This publication has been developed with Board Review Questions ....................8 out involvement of or review by the Amer ican Board of Internal Medicine. References ..............................8 Copyright 2014, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. All rights reserved. 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Information contained within this publication should not be used as a substitute for clinical judgment. HEMATOLOGY BOARD REVIEW MANUAL Management of Bleeding Complications in Patients with Cancer Thomas G. DeLoughery, MD, FACP, FAWM INTRODUCTION PT/INR out of proportion to the aPTT suggests vitamin K deficiency, perhaps due to poor oral intake. An Patients with cancer can have many hematologic isolated elevation of the aPTT has many causes, such complications. One of the most serious is bleeding, as the presence of a lupus inhibitor or specific factor which can range in severity from laboratory abnormali- deficiency. Prolongation of both the INR and aPTT ties to life-threatening hemorrhage. The bleeding can suggest multiple defects or deficiency of factors II, V, or be due to complications of the cancer, its therapy, or X, and marked prolongation of the INR and aPTT can treatment for complications of cancer such as throm- also be seen with low levels of fibrinogen. bosis. This manual discusses an approach to the cancer If the platelet count is low, examination of the blood patient with bleeding, with a specific focus on issues smear by the laboratory technician is essential to look such as coagulation defects, thrombocytopenia, and for platelet clumping, which will falsely lower the plate- platelet dysfunction. Bleeding complications of specific let count. The smear also should be reviewed for schis- cancers and their treatment will be discussed as well. tocytes, the presence of which is a marker for throm- botic microangiopathies. In the absence of recent chemotherapy, the differential diagnosis for isolated EVALUATION OF THE BLEEDING CANCER PATIENT profound thrombocytopenia (<10,000/µL) is generally limited to immune thrombocytopenia, drug-induced Bleeding problems in patients with cancer can thrombocytopenia, or posttransfusion purpura. result from the malignancy itself due to either direct Excessive bleeding has been reported with plasma fi- invasion of a vessel or as a paraneoplastic effect, as well brinogen levels lower than 100 mg/dL. The endpoints as from the effect of antineoplastic treatment or from of the PT/INR and aPTT are timed to the formation nonmalignancy–related factors. The first step in evalua- of the fibrin clot. When plasma levels of fibrinogen tion is to review the patient’s oncology history, especially fall below 80 mg/dL, the clot may be small and not for recent therapy they may have received. For patients detected by the machine, resulting in a very prolonged whose initial presentation of their cancer is a bleeding PT/INR and aPTT. Low fibrinogen levels reflect severe diathesis, attention should be directed to establishing liver disease or consumptive coagulopathy. the diagnosis (eg, abnormal forms on the blood smear Some bleeding disorders cannot be detected by rou- suggesting leukemia, abnormal lymph nodes). tine laboratory tests, such as platelet function defects or increases in fibrinolysis. Performing rapid tests to assess LABORATORY TESTING platelet function remains controversial. The PFA100 The next step in evaluation is to obtain a basic set is a rapid automatic test for platelet function that has of coagulation tests. The prothrombin time/interna- replaced the bleeding time, but may not reflect platelet tional normalized ratio (PT/INR), activated partial dysfunction due to patient use of drugs such as clopido- thromboplastin time (aPTT), platelet count, and fi- grel. Elevated values can be seen in patients with ane- brinogen level should be rapidly obtained. Three pat- mia, thrombocytopenia, and low fibrinogen level, and terns of defects can be seen in the PT/INR and aPTT it also can be difficult to assess for excessive fibrinolysis. (Table 1). Isolated elevations of the PT/INR are indic- The euglobulin clot lysis time is a screen for fibrinolysis, ative of a factor VII deficiency. In very sick patients, low but it is not standardized and can be difficult to obtain. factor VII levels are also common due to third-spacing Thromboelastography is a unique point-of-care labora- and increased consumption leading to an elevated tory test that examines whole blood thrombus forma- INR.1 High INR can also reflect hepatic synthesis de- tion and lysis, but it is not widely available and requires fects due to liver metastasis. A marked elevation of the experience in interpretation.2 www.hpboardreview.com Hematology Volume 9, Part 4 1 Management of Bleeding Complications in Patients with Cancer Table 1. Interpretation of Coagulation Test Results the high molecular weight multimers due to ab- Test Result Potential Cause sorption by the platelets, leading to the type 2 form of VWD. Elevated PT, Factor VII deficiency Patients with myeloproliferative neoplasms with normal aPTT Vitamin K deficiency platelet counts greater than 1,000,000/µL should be Warfarin screened for acquired VWD, especially before they Sepsis receive aspirin therapy or undergo major surgical pro- Normal PT, Isolated factor deficiency (VIII, IX, XI, contact cedures. Patients with other disease, especially lympho- elevated aPTT pathway proteins: XII, prekallikrein, high proliferative disorders, should be screened if they have molecular weight kininogen) excess bleeding or bruising. Specific factor inhibitor (same list as above) Patients with acquired VWD have variable responses Heparin to therapy for acute bleeding.3,8,9 Desmopressin is ef- Lupus anticoagulant fective in many patients with acquired VWD type 1 and Elevated PT, Multiple coagulation factor deficiencies type 2, but the magnitude and duration of effect are elevated aPTT Liver disease often reduced.10 For bleeding patients, high doses of Disseminated intravascular the antihemophilic factor/von Willebrand factor com- coagulation plex concentrate HumateP are indicated, with careful Isolated factor X, V, or II deficiency monitoring of levels.11 For patients with very strong Specific factor inhibitor inhibitors that factor concentrates cannot overcome High hematocrit (>60%, spurious) or severe, life-threatening bleeding, administration of 12 High heparin levels recombinant factor VIIa may prove useful. Severe vitamin K deficiency ACQUIRED FACTOR VIII INHIBITORS Low fibrinogen (<50–80 mg/dL) Dysfibrinogenemia Factor VIII deficiency due to autoantibodies is Dilutional the most frequently acquired coagulation factor defi- 13,14 Dysproteinemia ciency complication in older cancer patients. Un- like patients with congenital hemophilia, patients with aPTT = activated partial thromboplastin time; PT = prothrombin time. acquired inhibitors often have ecchymoses covering large areas of their body and can have massive muscle and soft tissue bleeding. Patients will have prolonged aPTTs, a screening test for a factor inhibitor with a COAGULATION DEFECTS 50:50 mix that does correct, and a low factor VIII level. For severe or life-threatening bleeding, recombinant ACQUIRED VON WILLEBRAND DISEASE factor VIIa is the treatment of choice.15 The

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