How I treat the co-occurrence of venous and arterial thromboembolism: anticoagulation, antiplatelet therapy, or both?

ABSTRACT: Arterial and venous thromboses are classically considered distinct disease states, with arterial thrombosis mediated predominantly by platelets and therefore, treated with antiplatelet therapy, and venous thrombosis mediated by the plasmatic coagulation system and treated with anticoagulation. However, co-occurrence of arterial and venous events is common, and there is increasing evidence of shared risk factors and pathophysiologic overlap. This presents a management challenge: does the patient with venous and arterial thrombosis, require anticoagulation, antiplatelet therapy, or both? Herein, we present a structured approach to the evaluation and management of patients with venous thrombosis who are also at risk for or have a history of an arterial thromboembolic event. We emphasize the importance of defining the indications for antithrombotic therapy, as well as the evaluation of factors that influence both thrombotic and bleeding risk, including disorder-specific and patient-specific factors, as well as the inherent risk balance of antithrombotic therapy regimens. We illustrate this approach in 4 cases, discussing the unique considerations and recent updates in the management of venous thrombosis, acute noncardioembolic ischemic stroke, coronary artery disease and acute myocardial infarction, and peripheral artery disease after revascularization.

How I treat unexplained arterial thrombosis.

Most arterial thrombotic events have a clear atherosclerotic or cardioembolic etiology, but hematologists are frequently asked to assist in the diagnosis and management of a patient with a nonatherosclerotic and noncardioembolic arterial event, referred to here as an unexplained arterial thrombosis. Because there is an assorted list of factors that can precipitate an arterial event, we present a systematic diagnostic approach to ensure consideration of not only primary hypercoagulable disorders, but also pro-thrombotic medications or substances, vascular and anatomic abnormalities, and undiagnosed systemic disorders, such as malignancy and autoimmune diseases. We also review existing literature of the role of hypercoagulable disorders in arterial thrombosis and discuss our approach to thrombophilia workup in patients after an unexplained arterial event. We conclude with 3 representative cases to both illustrate the application of the outlined diagnostic schema and discuss common management considerations, specifically the selection of anticoagulation vs antiplatelet therapy for secondary prevention.

An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer.

BACKGROUND: Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. METHODS: A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded. RESULTS: Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0-2). Fifty percent of patients were Caucasian, 45% African-American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug-drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. CONCLUSIONS: Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02158507 . Registered on 12 September 2014.

Current Practice and Clinical Utility of Thrombophilia Testing in Hospitalized Patients with Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Testing for thrombophilic disorders is often performed in patients after cryptogenic ischemic stroke in an attempt to identify a hematologic explanation for the event. However, the role of commonly tested thrombophilias in ischemic stroke is poorly defined. There is limited evidence to quantify how these disorders affect ischemic stroke risk and testing practices are highly variable. METHODS: Retrospective evaluation of thrombophilia testing practices and clinical outcomes was performed in hospitalized patients with acute ischemic stroke (n = 1898) at a large academic hospital over a two-year period. Variables assessed included testing components, timing of testing, number of abnormal results, and frequency of change in clinical management prompted by abnormal results. A provider survey was also performed to assess perceptions of current testing practices and provider understanding of testing indications. RESULTS: Thrombophilia testing was performed in 190 (10%) patients admitted for acute ischemic stroke. Of those tested, 137 (72.1%) had at least one abnormal result, but this decreased to 37.4% when elevated factor VIII activity was excluded. An abnormal result prompted initiation of anticoagulation in only 4 patients (2%). The provider survey indicated that all providers (100%) were selecting thrombophilia tests using a pre-existing order set and were interested in additional education on testing indications and interpretation. Comparison to similar studies at other institutions revealed significant variation in testing practices, and a small proportion of patients in which testing prompted a change in management (1-8%). CONCLUSIONS: Thrombophilia testing is frequently obtained in hospitalized patients with acute ischemic stroke, yet testing only changed management in 2% of patients. Efforts to improve provider education and the stewardship of testing are needed to ensure appropriate evaluation and treatment of patients with acute ischemic stroke.

Quality improvement approaches to heparin-induced thrombocytopenia: a scoping review.

Background: Heparin-induced thrombocytopenia (HIT) is a relatively uncommon condition characterized by 2 exceedingly common phenomena in hospitalized patients: thrombocytopenia and heparin exposure. Consequently, HIT is frequently overdiagnosed and inappropriately treated. These issues are the focus of many quality improvement (QI) initiatives. Objectives: In this scoping review, we identified and characterized all published QI studies on improving the diagnosis and management of HIT. Methods: We conducted a systematic literature search through April 2022 for studies reporting on QI interventions regarding the diagnosis, treatment, and/or prevention of HIT. Results: Thirty studies were included in the final review. Studies were separated into 5 groups based on the focus of the interventions: increasing HIT recognition, reducing HIT incidence, reducing HIT overdiagnosis, promoting safer HIT management, and creating HIT task forces. Nine studies focused on the implementation of 4Ts score calculator into electronic medical record orders for HIT testing, while only 1 evaluated the impact of reducing unfractionated heparin use in favor of low-molecular-weight heparin. Six studies focused on the implementation of direct thrombin inhibitor management protocols, while none evaluated the use of alternative anticoagulants in HIT management. Conclusion: The bulk of published HIT QI research focused on reducing overdiagnosis and promoting safer direct thrombin inhibitor therapy, while minimal attention has been devoted to HIT prevention and the use of evidence-based alternative HIT therapies.

Challenges in the diagnosis of thrombotic thrombocytopenic purpura.

INTRODUCTION: Immune-mediated TTP (iTTP) is a rare condition without pathognomonic signs and symptoms. For this reason, the diagnosis of iTTP may be delayed or even missed, with potentially catastrophic consequences. AREAS COVERED: The authors performed an extensive literature review on the diagnosis of iTTP and its challenges combined with their own experience in a referral center for patients with iTTP. EXPERT OPINION: Although a definitive diagnosis of iTTP depends on the ADAMTS13 activity result, timely testing is rarely available at many centers to which patients present. If less complex tests were to become available, they would decrease the chances of late and/or missed diagnoses of iTTP throughout the world. While clinical scores to estimate the likelihood of iTTP exist, they are not well known, and can be misleading if used in the wrong context. Furthermore, the three scoring systems (PLASMIC, Bentley, and French) only moderately correlate with each other, which further complicates the landscape. The existence of these scores and how they should be used in practice is but one opportunity that can be seized through more robust programs to educate nonspecialist clinicians on how to recognize and treat patients with iTTP.

From Activated Partial Thromboplastin Time to Antifactor Xa and Back Again.

OBJECTIVES: Monitoring is essential to safe anticoagulation prescribing and requires close collaboration among pathologists, clinicians, and pharmacists. METHODS: We describe our experience in the evolving strategy for laboratory testing of unfractionated heparin (UFH). RESULTS: An intrainstitutional investigation revealed significant discordance between activated partial thromboplastin time (aPTT) and antifactor Xa (anti-Xa) assays, prompting a transition from the former to the latter in 2013. With the increasing use of oral factor Xa inhibitors (eg, apixaban, rivaroxaban, edoxaban, betrixaban), which interfere with the anti-Xa assay, we adapted our protocol again to incorporate aPTT in patients admitted on oral Xa inhibitors who require transition to UFH. CONCLUSIONS: Our experience demonstrates key challenges in anticoagulation and highlights the importance of clinical pathologists in helping health systems adapt to the changing anticoagulation landscape.

Pitfalls in Diagnosing Thrombotic Thrombocytopenic Purpura in Sickle Cell Disease.

Thrombotic thrombocytopenia purpura is characterised by microangiopathic haemolytic anaemia and red cell fragmentation on the peripheral smear, neurological involvement and thrombocytopenia. Diagnosis in the context of sickle cell disease can be challenging due to the inherent haemolytic state and the multitude of other associated complications of the latter. Specifically, fat embolism syndrome characterised by respiratory failure, neurological impairment and thrombocytopenia can be misdiagnosed this way. Confirmation of a diagnosis of thrombotic thrombocytopenic purpura requires demonstration of very low levels (<10%) of the metalloproteinase ADAMTS13 which in fat embolism syndrome is normal. Existing scoring systems used to estimate the pre-test probability for thrombotic thrombocytopenic purpura cannot be applied in patients with sickle cell disease due to the chronic underlying haemolysis. Here, we analyse the diagnostic approach in published cases of thrombotic thrombocytopenic purpura affecting patients with sickle-cell disease. The vast majority of cases were characterised by severe respiratory failure before any other manifestation, a feature of fat embolism syndrome but not of thrombotic thrombocytopenic purpura, and all received red cell transfusion prior to receiving therapeutic plasma exchange. Despite the potential overestimation of the pre-test probability using the existing scoring systems, a large number of cases still scored low. There were no cases with documented low ADAMTS13. In the majority this was not tested, while in the 3 cases that ADAMTS13 was tested, levels were normal. Our review suggests that due to many overlapping clinical and laboratory features thrombotic thrombocytopenic purpura may be erroneously diagnosed in sickle cell disease instead of other complications such as fat embolism syndrome and confirmation with ADAMTS13 testing is essential.

Unexplained arterial thrombosis: approach to diagnosis and treatment.

Arterial thrombotic events in younger patients without a readily apparent etiology present significant diagnostic and management challenges. We present a structured approach to diagnosis with consideration of common causes, including atherosclerosis and embolism, as well as uncommon causes, including medications and substances, vascular and anatomic abnormalities, systemic disorders, and thrombophilias. We highlight areas of management that have evolved within the past 5 years, including the use of dual-pathway inhibition in atherosclerotic disease, antithrombotic therapy selection in embolic stroke of undetermined source and left ventricular thrombus, the role of closure of patent foramen ovale for secondary stroke prevention, and the thrombotic potential of coronavirus disease 2019 infection and vaccination. We conclude with a representative case to illustrate the application of the diagnostic framework and discuss the importance of consideration of bleeding risk and patient preference in determining the appropriate management plan.

Disorders of Fibrinogen and Fibrinolysis.

Fibrinogen plays a fundamental role in coagulation through its support for platelet aggregation and its conversion to fibrin. Fibrin stabilizes clots and serves as a scaffold and immune effector before being broken down by the fibrinolytic system. Given its importance, abnormalities in fibrin(ogen) and fibrinolysis result in a variety of disorders with hemorrhagic and thrombotic manifestations. This review summarizes (i) the basic elements of fibrin(ogen) and its role in coagulation and the fibrinolytic system; (ii) the laboratory evaluation for fibrin(ogen) disorders, including the use of global fibrinolysis assays; and (iii) the management of congenital and acquired disorders of fibrinogen and fibrinolysis.

Systems-based hematology: highlighting successes and next steps.

Systems-based hematology is dedicated to improving care delivery for patients with blood disorders. First defined by the American Society of Hematology in 2015, the idea of a systems-based hematologist arose from evolving pressures in the health care system and increasing recognition of opportunities to optimize the quality and cost effectiveness of hematologic care. In this review, we begin with a proposed framework to formalize the discussion of the range of initiatives within systems-based hematology. Classification by 2 criteria, project scope and method of intervention, facilitates comparison between initiatives and supports dialogue for future efforts. Next, we present published examples of successful systems-based initiatives in the field of hematology, including efforts to improve stewardship in the diagnosis and management of complex hematologic disorders (eg, heparin-induced thrombocytopenia and thrombophilias), the development of programs to promote appropriate use of hematologic therapies (eg, blood products, inferior vena cava filters, and anticoagulation), changes in care delivery infrastructure to improve access to hematologic expertise (eg, electronic consultation and disorder-specific care pathways), and others. The range of projects illustrates the broad potential for interventions and highlights different metrics used to quantify improvements in care delivery. We conclude with a discussion about future directions for the field of systems-based hematology, including extension to malignant disorders and the need to define, expand, and support career pathways.

Three neglected numbers in the CBC: The RDW, MPV, and NRBC count.

The complete blood cell count (CBC) is one of the most frequently ordered laboratory tests, but some values included in the test may be overlooked. This brief review discusses 3 potentially underutilized components of the CBC: the red blood cell distribution width (RDW), the mean platelet volume (MPV), and the nucleated red blood cell (NRBC) count. These results have unique diagnostic applications and prognostic implications that can be incorporated into clinical practice. By understanding all components of the CBC, providers can learn more about the patient's condition.

Prevalence of Measurable Disease in Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: Because of the low historical prevalence of measurable disease in metastatic castration-resistant prostate cancer (mCRPC), phase II trials have used prostate-specific antigen (PSA) and bone scan changes as primary end points. Frequent whole-body imaging and improved computed tomography technology currently identify measurable disease more frequently, warranting consideration of objective response as a major end point. PATIENTS AND METHODS: Data from reported phase III trials of mCRPC were analyzed. The proportion of patients with measurable disease, setting (pre-docetaxel [D], D-based, post-D), year of starting accrual, PSA, and the requirement for symptoms were collected. The χ2 test was used to evaluate the association of variables with measurable disease rate. RESULTS: Twenty phase III trials totaling 19,276 men with mCRPC were evaluable. Three trials (n = 1289) started accruing before 2000 and 17 trials (n = 17,987) accrued after 2000. The proportion of measurable disease rate for all trials was 47.5%. The measurable disease rate was significantly higher (P < .001) in trials that accrued after 2000 versus before 2000 (48.7% vs. 31.1%; P < .001), D-based (51.8%) or post-D patients (48.9%) compared with pre-D patients (38.6%) and in trials allowing symptomatic versus asymptomatic/minimally symptomatic patients (50.1% vs. 40.0%). CONCLUSION: The proportion of men with measurable disease was significantly higher in phase III trials of mCRPC that accrued after 2000, in D-based or post-D patients and in trials that allowed symptomatic patients. Because of the association of objective measurable changes with survival, Response Evaluation Criteria in Solid Tumors changes might warrant consideration as a major end point in phase II trials to obtain a firm signal of efficacy before launching phase III trials.