VOLUME 49ㆍNUMBER 2 REVIEW BLOOD RESEARCH June 2014 ARTICLE Hypercoagulable states: an algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulants Megan O. Nakashima, Heesun J. Rogers Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, United States p-ISSN 2287-979X / e-ISSN 2288-0011 Abstract http://dx.doi.org/10.5045/br.2014.49.2.85 Hypercoagulability can result from a variety of inherited and, more commonly, acquired Blood Res 2014;49:85-94. conditions. Testing for the underlying cause of thrombosis in a patient is complicated both by the number and variety of clinical conditions that can cause hypercoagulability as well Received on May 31, 2014 as the many potential assay interferences. Using an algorithmic approach to hyper- Revised on June 17, 2014 coagulability testing provides the ability to tailor assay selection to the clinical scenario. Accepted on June 19, 2014 It also reduces the number of unnecessary tests performed, saving cost and time, and preventing potential false results. New oral anticoagulants are powerful tools for manag- Correspondence to ing hypercoagulable patients; however, their use introduces new challenges in terms of Heesun J. Rogers, M.D., Ph.D. test interpretation and therapeutic monitoring. The coagulation laboratory plays an essen- Department of Laboratory Medicine, Cleveland Clinic, 9500 Euclid Avenue tial role in testing for and treating hypercoagulable states. The input of laboratory pro- (L-11), Cleveland, OH 44195, United States fessionals is necessary to guide appropriate testing and synthesize interpretation of Tel: ＋216-445-2719 results. Fax: ＋216-444-4414 E-mail: [email protected] Key Words Hypercoagulability, Algorithmic approach, Antiphospholipid syndrome, Ⓒ 2014 Korean Society of Hematology Direct oral anticoagulant, Venous thromboembolism setting of a strong family history, VTE in an unusual vascular INTRODUCTION site (cerebral, hepatic, mesenteric, or renal veins), neonatal purpura fulminans, warfarin-induced skin necrosis, and re- Hypercoagulability, also known as thrombophilia, de- current pregnancy loss [5, 6]. scribes a group of hereditary and acquired conditions which confer a propensity to develop thrombi in the veins, arteries, 1. Clinical history and sources of interference or both. Based on current knowledge, antiphospholipid syn- Many assays used in the laboratory evaluation of hyper- drome is the most prevalent hypercoagulable state, followed coagulability are affected by concurrent clinical conditions by factor V Leiden (FVL) mutation, prothrombin gene and medications. Whenever possible, a thorough clinical G20210A mutations, elevated factor VIII, and hyperhomocy- history including site of thrombosis, previous bleeding or steinemia. Less common disorders include deficiencies in thrombotic events, other medical disorders (i.e., liver, auto- antithrombin, protein C, or protein S. immune, or cardiovascular disease), pregnancy, medications The prevalence of thrombosis is higher in individuals with (including but not limited to anticoagulants), and family a personal and/or family history of thrombosis than in the history should be elicited. These are essential for appropriate general population. Acquired and hereditary risk factors for test selection and interpretation of results; sources of interfer- thrombophilia are summarized in Table 1 [1, 2]. Although ence for specific assays are described in the following patients with hypercoagulable risk factors are at a great risk sections. Tests should be performed at least 4–6 weeks after for developing a thrombotic event, not all patients with an acute thrombotic event or discontinuation of anti- hypercoagulable risk factors will develop clinically relevant coagulant/thrombolytic therapies including warfarin, hep- thrombosis; conversely, not all patients with thrombosis will arin, direct thrombin inhibitors (DTIs), direct factor Xa in- have an identifiable hypercoagulable state [2-4]. hibitors, and fibrinolytic agents [1, 4, 5]. If abnormal results Diagnostic thrombophilia testing is indicated in patients are found during acute illness or anticoagulant therapy, test- with idiopathic or recurrent venous thromboembolism ing should be repeated in a new specimen when the patient (VTE), first VTE at a young age (＜40 years), VTE in the is stable and after anticoagulant therapy is discontinued. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 86 Megan O. Nakashima and Heesun J. Rogers Table 1. Acquired and hereditary risk factors for thrombophilia. Acquired factors Hereditary factors Major surgery/trauma Activated protein C resistance/factor V Leiden Immobilization (e.g., hip/knee replacement, prolonged cast, Prothrombin gene G20210A mutation stroke, bedridden because of illness) Protein C deficiencya) Solid or hematologic malignancies Protein S deficiencya) Pregnancy Antithrombin deficiencya) Oral contraceptives Hyperhomocysteinemiaa) Estrogen replacement therapy Elevated factor VIII activitya) Antiphospholipid antibody syndrome Dysfibrinogenemiaa) Heparin-induced thrombocytopenia Paroxysmal nocturnal hemoglobinuria Obesity Nephrotic syndrome Smoking a)Can be hereditary or acquired. Fig. 1. Comprehensive hypercoa- gulability testing panel using a diagnostic algorithm. Abbreviat- ions: aPTT, activated partial throm- boplastin time; B2GP1, beta2 glycoprotein 1; CRP, C-reactive protein; DRVVT, dilute Russell’s Viper Venom test; MTHFR, me- thylenetetrahydrofolate reductase; PL, phospholipid; PNP, platelet neutralization procedure; PT, pro- thrombin time; SNP, single nu- cleotide polymorphism. Alternatively, thrombophilia testing may be delayed until all hypercoagulable defects. Selection of the most informative acute clinical conditions have subsided. The exception is tests may differ depending on location and type (venous DNA analysis for genetic mutations, which is not generally or arterial) of thrombosis. Fig. 1 outlines a testing algorithm affected by other medical issues or anticoagulant therapy. to maximize diagnostic potential in patients with thrombo- philia while avoiding unnecessary and potentially expensive 2. Algorithmic approach to laboratory testing tests. Testing should be performed in a step-wise manner No single laboratory test is yet available that can identify beginning with high-yield screening tests followed by appro- Blood Res 2014;49:85-94. bloodresearch.or.kr Hypercoagulability: algorithmic approach 87 priate specific confirmatory tests. These comprehensive pan- phospholipid (e.g., DRVVT confirmatory ratio, hexagonal els generate multiple test results that can each be affected phospholipid neutralization ratio, platelet neutralization). (4) by a variety of clinical conditions and drugs. Comprehensive Presence of specific factor inhibitors (especially factor VIII narrative interpretation by coagulation specialists is neces- inhibitors) and anticoagulant drugs (heparin or DTI) should sary to synthesize test results, correctly interpret them ac- be excluded [10, 11, 13-15]. In addition to the ISTH guideline cording to the patient’s clinical condition, and provide appro- (2009) and updated British Committee for Standards in priate guidance to clinicians [2, 7]. In some patients with Haematology (2012) guidelines, the Clinical and Laboratory thrombophilia, it may be best to test for all recognized heredi- Standards Institute recently published the first LA guideline tary risk factors, both common and uncommon [5, 7, 8]. [11, 16, 17]. Although all guidelines aim to standardize and harmonize methodologies and improve the quality of LA testing, identifying LA remains a diagnostic challenge. SPECIFIC HYPERCOAGULABLE Paradoxically, LAs prolong clot-based assays in vitro while DISORDERS AND LABORATORY STUDIES predisposing to thrombosis in vivo. In fact, approximately 30% of LA patients will experience thrombosis. In approx- 1. Antiphospholipid syndrome imately 15% of patients with deep vein thrombosis (DVT), Antiphospholipid syndrome (APS) is the most common clotting is attributable to LA [2, 18]. Because no single test cause of acquired thrombophilia. Antiphospholipid anti- is available to detect LA, laboratory testing for LA consists bodies (APAs) are acquired autoantibodies directed against of a panel of assays following a diagnostic algorithm (Fig. phospholipid-protein complexes and are present in 3–5% 1). To maximize diagnostic potential, at least 2 assays based of the general population. APAs are associated with increased on different principles should be performed to evaluate for risk of both arterial and venous thrombosis and recurrent each of the 4 ISTH criteria. If fewer than 4 diagnostic criteria pregnancy loss [9, 10]. APAs can arise spontaneously (pri- are met but clinical suspicion for LA exists, the panel is mary) or in association with another condition (secondary). interpreted as indeterminate and should be repeated at a Also known as lupus anticoagulants (LA) because of their later date [9-11, 19]. prevalence in patients with systemic lupus erythematosus Acute thrombotic events or acute phase responses with (SLE), APAs are extremely heterogeneous and can be directed elevated factor VIII can cause false-negative results. Throm- against a wide variety of anionic phospholipids, including bin time