September 2017 Case Cedars-Sinai Skip to content Close Select your preferred language English عربى 简体中文 繁體中文 فارسي עִברִית 日本語 한국어 Русский Español Tagalog English English عربى 简体中文 繁體中文 فارسي עִברִית 日本語 한국어 Русский Español Tagalog Translation is unavailable for Internet Explorer Cedars-Sinai Home 1-800-CEDARS-1 1-800-CEDARS-1 Close Find a Doctor Locations Programs & Services Health Library Patient & Visitors Community My CS-Link Education clear Go Close Academics Academics Faculty Development Community Engagement Calendar Research Research Areas Research Labs Departments & Institutes Find Clinical Trials Research Cores Research Administration Basic Science Research Clinical & Translational Research Center (CTRC) Technology & Innovations News & Breakthroughs Education Graduate Medical Education Continuing Medical Education Graduate School of Biomedical Sciences Professional Training Programs Medical Students Campus Life Office of the Dean Simulation Center Medical Library Program in the History of Medicine About Us All Education Programs Departments & Institutes Faculty Directory Anatomic and Clinical Pathology Residency Back to Anatomic and Clinical Pathology Residency Application Information Explore the Residency Training Curriculum Autopsy Pathology Rotation Bone and Soft Tissue Head and Neck Pathology Rotation Breast Pathology Rotation Cardiovascular Pathology Rotation Clinical Chemistry Rotation Coagulation Rotation Cytopathology Rotation Dermatopathology Rotation Forensic Pathology Rotation Frozen Section Rotation Gastrointestinal and Liver Pathology Genitourinary Pathology Rotation Genomic Pathology Rotation Gynecologic Pathology Rotation Hematopathology Rotation Laboratory Management Rotation Microbiology Rotation Neuropathology Rotation Pulmonary and Mediastinal Pathology Rotation Renal Pathology Rotation Transfusion Medicine Rotation Surgical Pathology Pathology Physician Scientist Training Program Residents Graduates Case of the Month Archive Publications Leadership Frequently Asked Questions September 2017 Case Authors Kimberly Lally (Resident), Alice Runge (CLS), Oksana Volod (Faculty) Subject Coagulation Clinical History 37-year-old male with history of ischemic cardiomyopathy presents with decompensated heart failure and undergoes total artificial heart (TAH) implantation. On post-op day 8, he develops multiple acute cerebral vascular accidents despite anticoagulation with heparin infusion. The patient has no significant family history and physical exam. Differential Diagnosis As there was no observed increase in PTT and no apparent difference in R values using TEG despite heparin administration, these findings are suggestive of heparin resistance (HR). While HR may be attributed to several causes, the most common is antithrombin III deficiency, which may be congenital or acquired. Other causes of HR include increased thrombin, increased heparin clearance, increased heparin-binding protein levels (i.e. acute phase reactants), and increased factor VIII levels. Additional Work-Up Hemoglobin 7.1 g/dL (normal 13 – 17 g/dL) PT 17.3 sec (normal 11.9 – 14.4 seconds) PTT 31 sec (normal 22 – 37 seconds) -- on heparin therapy Platelet count 413 x 103/μL (normal 150 – 450 x 103/μL) Heparin level 0.12 IU/mL Antithrombin III activity 58% (normal 80 – 120%) Final Diagnosis Heparin resistance due to antithrombin III deficiency Discussion Heparin resistance (HR) is defined as the inability to reach therapeutic anticoagulation as evidenced by a lack of response in activated partial thromboplastin time (aPTT) despite high doses (>35,000 IU/d) of heparin administration, as well as by adverse clinical outcomes. Antithrombin III (AT) deficiency is the most common cause of HR and acquired deficiency of AT has been reported to occur at an incidence of approximately 20% in patients on mechanical circulatory support devices (MCSD). While antithrombin is a naturally-occurring inhibitor of thrombin (factor IIa) and factor Xa, unfractionated heparin further potentiates AT activity by increasing its anticoagulant effects by up to 1000-fold. Heparin binds to AT causing a conformational change, which drastically increases its rate of inactivation of thrombin (Figure 2). Because heparin directly requires the presence of AT in order to exert its anticoagulatory effect, AT deficiency will result in HR. Some heparin assays incorporate AT as part of the assay. If these assays are used, the heparin level will appear to be adequate (i.e. the patient properly anticoagulated), when in reality, they are not. These assays will mask an AT deficiency, whereas heparin assays that use the patient’s AT reflect the actual anticoagulation status. Similarly, thromboelastography (TEG) will show no difference in the reaction time (R value) between CK (citrated kaolin sample) and CKH (CK sample with heparinase). The R value represents the time in minutes until initial fibrin formation and is a direct function of coagulation factor activity. If heparin effect is present, the R value of the heparinized sample (CKH) would be shortened. However, since there was no significant difference between R values [R(CK) – R(CKH)] in this patient, it is evident there was no heparin effect despite the patient having been on continuous heparin infusion, thus indicating HR. The low AT activity (58%) suggests the HR is likely due to acquired AT deficiency in this critically ill patient. It is recommended that this subset of patients on MCSD receive short and long term anticoagulation, however due to their tendency to develop acquired AT deficiency, it may be necessary to prevent HR by administrating exogenous AT. If HR is suspected and AT activity is less than 60%, heparin should first be reduced to 500 IU/h in order to prevent bleeding complications, and then AT may be administered with a goal AT activity of greater than 80%. Heparin dosage may subsequently be adjusted. If overlap with Coumadin is required for long-term anticoagulation, a direct thrombin inhibitor (DTI) such as argatroban may also be considered as an option. It is important to always be aware of the possibility of HR and manage the patient appropriately in order to prevent adverse clinical outcomes. References Bharadwai J, Jayaraman C, Shrivastava R. Heparin resistance. Lab Hematol. 2003;9(3):125-31. Maurin N. Heparin resistance and antithrombin deficiency. Med Klin (Munich). 2009 Jun 15;104(6):441-9. Doi: 10.1007/s00063-009-1093-8. Epub 2009 Jun 16. Beresford, C.H. Antithrombin III deficiency. Blood reviews 2.4(1998);239-250. Young E, et. al. Heparin binding to plasma proteins, an important mechanism for heparin resistane. Thrombosis and haemostasis 67.6 (1992);639-643. Koster, Andreas, et al. Management of heparin resistance during cardiopulmonary bypass: the effect of five different anticoagulation strategies on hemostatic activation. Journal of cardiothoracic and vascular anesthesia 17.2 (2003): 171-175. Hirsh, J., et al. Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation 53.4 (1976): 691-695. Anderson, J. A. M., and E. L. Saenko. Editorial I Heparin resistance. British journal of anaesthesia 88.4 (2002): 467-469. Have Questions or Need Help If you have questions or would like to learn more about the Anatomic and Clinical Pathology Residency Program at Cedars-Sinai, please call or send a message to Academic Program Coordinator, LeeTanya Marion-Murray. Department of Pathology and Laboratory Medicine 8700 Beverly Blvd., Room 8709 Los Angeles, CA 90048-1804 310-423-6941 send a message Please ensure Javascript is enabled for purposes of website accessibility