Hereditary hemorrhagic telangiectasia (HHT), synonymous with Osler-Weber-Rendu Syndrome, is an inherited vascular disorder which affects multiple organ systems. HHT patients often have significant delays in diagnosis due to phenotypically variable and heterogeneous medical presentations.

 Hematologists and oncologists are uniquely poised to aid in the identification of these patients and assist in their care, and it is important for the practicing clinician to familiarize oneself with the symptoms of HHT to avoid overlooking the diagnosis. These patients may seek medical attention from the development of iron deficiency anemia (IDA) or may be referred to a hematologist for evaluation for a bleeding disorder due to epistaxis or gastrointestinal (GI) bleeding. Without an accurate diagnosis, patients can experience morbidity and mortality arising from untreated HHT.

Of note, the autosomal dominant inheritance pattern

 of HHT can affect multiple generations in the same family and has an estimated prevalence of 1 in 5000.

 Therefore, it stands to reason that identification of patients with HHT may also render a benefit to their affected biological relatives through detection of this inherited disorder. This underscores the importance of taking a careful family history. To best assist these patients and their families, clinicians must learn to recognize HHT.

HHT should typically be considered in adults with recurrent epistaxis, iron deficiency, telangiectasias, or arteriovenous malformations (AVMs) identified upon routine imaging or procedures, but other presentations are also possible. This multi-system disorder causes abnormal vasculature in multiple anatomic locations and can differ significantly in individual patients. Common sites for AVMs include the lungs, skin, liver, GI tract, nose, and brain with variability in the location, number, and sizes of AVMs. Patients commonly have visible telangiectasias in mucocutaneous locations such as the mouth or lips, or cutaneous locations such as the fingertips or face. Bleeding may manifest at the location of AVMs, and the bleeding phenotype ranges from mild to severe. Indeed, there may be variability in bleeding phenotypes in members of the same family.

Over 90% of HHT patients in adulthood will experience epistaxis, and most of these patients will also develop cutaneous telangiectasias, so these 2 features provide a useful clue to the diagnosis on an initial history and exam.

 Recurrent gastrointestinal (GI) bleeding can also occur in up to 30% of these patients

 related to visceral AVMs. Manifestations in the cardiopulmonary system and central nervous system (CNS) may include high output cardiac failure, pulmonary hypertension, cerebrovascular accident, headaches, seizures, or even CNS abscesses. Some patients with HHT unfortunately may have both bleeding and thrombosis as well.

An additional challenge for the hematologist could include the recognition of a small subset of HHT patients within the large number of patients with IDA non-related to HHT. With such potentially for variability, the Curacao Criteria aids clinicians as the consensus diagnostic criteria for HHT.

The criteria include recurrent epistaxis, telangiectasias in classical locations (such as lips, tongue, fingertips, ears), the presence of visceral AVMs (hepatic, pulmonary, cerebral), and a confirmed first degree relative with HHT. Scoring of the criteria range from “0” to “≥3” and rate the likelihood of HHT as “unlikely” to “definite” respectively based on the number of criteria present. Diagnosis may be established either by the Curacao Criteria or by the identification of a pathogenic mutation.

 are causative of a majority of HHT cases, however rarely 

 Multigene panel testing is available to evaluate the most common mutations.

 The identification of a familial mutation can aid other biological relatives in diagnosis through targeted testing of first-degree relatives in the setting of a known pathogenic mutation. Genetic testing may be particularly useful in younger family members with a milder bleeding phenotype, since the bleeding symptoms of HHT often develop later in life, typically beginning at a median age of 12 years with high rates of epistaxis by age 40.

Once the diagnosis of HHT has been established, additional resources become available for specialized clinical care at HHT Centers of Excellence (COE) nationally and internationally.

 Referral to COE provides access to multidisciplinary expertise in management of HHT. These centers have received certification for the knowledge and resources they provide for patients. They typically have experience in the management of HHT with multiple specialty approaches. There are 31 COE in North America currently.

 To learn more or to locate the nearest COE, please visit: 

https://curehht.org/understanding-hht/get-support/hht-treatment-centers/

In summary, HHT may cause significant morbidity and mortality in multiple generations within families, many of whom do not yet have an identified name for their underlying diagnosis. Hematologists and oncologists should consider this not uncommon bleeding disorder for applicable patients with the goals of alleviation of the suffering associated with untreated HHT and to assist the patient in establishing care at a COE if possible.

Jennifer R. Green, MD, is director of the Hematology/Oncology Fellowship Program at Vanderbilt University Medical Center in Nashville, Tennessee.

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HHT Mutation Database. University of Utah. Accessed March 9, 2023. https://arup.utah.edu/database/HHT/

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Hammill AM, Wusik K, Kasthuri RS. Hereditary hemorrhagic telangiectasia (HHT): a practical guide to management. 

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Articles

Hematologists and oncologists are uniquely poised to aid in the identification of patients with hereditary hemorrhagic telangiectasia and assist in their care, and it is important for the practicing clinician to familiarize oneself with the symptoms of hereditary hemorrhagic telangiectasia to avoid overlooking the diagnosis.

Spotlight on a Rare Hematologic Disorder: Hereditary Hemorrhagic Telangiectasia

Venous thromboembolism (VTE) is a common diagnosis indicating a blood clot located in a vein.

 Most hematology/oncology fellows will care for patients with this diagnosis throughout their training and long after their graduation from fellowship. Despite the prevalence of VTE, there are many nuances to its management. Here are some practical considerations when treating a patient with an acute VTE.

Step 1: Consider Characteristics of the Clot

Hematologists are often consulted to assess for underlying etiologies of VTE, for recommendations about duration of anticoagulation, or for assistance with selecting agents for therapeutic anticoagulation. Many factors contribute to this multifaceted evaluation, such as collecting a thorough medical history from the patient with consideration to pertinent, ongoing risk factors for the development of thrombosis. These basic pieces of information can help a hematologist determine whether additional laboratory testing is warranted.

One of the first steps is to evaluate the location of the thrombus, which can provide important clues about the underlying disease state. The most common VTEs are lower-extremity deep vein thrombosis (DVT) and pulmonary embolism (PE). However, uncommon thrombi such as those found in the cerebral venous, splanchnic venous, and portal vein may alert the hematologist to the possibility of an underlying cause. These thrombi warrant consideration for underlying precipitants such as myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria, catastrophic thrombin-generating states, underlying liver disease, malignancy, and other conditions.

In addition, it is important to determine whether a clot was precipitated by known risk factors for thrombosis. These were historically called “provoked” clots, though recent nomenclature trends have been moving away from this term. This information can identify transient risk factors, such as estrogen exposure from oral contraceptive use, perioperative states, and illness-related immobility. In these situations, current guidelines typically recommend definitive courses of anticoagulation after transient risk factors have been removed.

Conversely, patients may have ongoing thrombotic risk factors, such as active inflammatory bowel disease, cancer, or others. In these cases, extended-duration anticoagulation may be warranted following a more in-depth assessment of the individual risks and benefits of continuing anticoagulation.

It may be easier to characterize potential thrombotic risk factors around the time of initial VTE diagnosis. Patients and family members may be more likely to recall potential thrombosis triggers in the acute setting; thus, inpatient hematology consultation may be beneficial in identifying risk factors. However, some patients may be too ill to provide this detailed history at the time of the initial event and may benefit from outpatient follow-up intervals to clarify risk factors and discuss thrombosis history in detail.

Bleeding is the most common adverse effect of any anticoagulant medication. Assessing bleeding risk will help determine whether anticoagulation should be started, optimize choice of anticoagulant, and potentially inform the duration of anticoagulation. For most patients with an acute VTE, the benefits of initiating anticoagulation outweigh the risks of bleeding. Exceptions may include acute central nervous system bleeding events concurrent with an acute VTE, when the addition of anticoagulation may result in life-threatening expansion or hemorrhage.

Some gastrointestinal (GI) bleeds may become life-threatening with the addition of anticoagulation. Areas of anatomic abnormality such as arterio-venous malformations, ulcers, and tumors tend to bleed more readily with the addition of anticoagulation. Definitively managing an underlying anatomic abnormality may help the patient tolerate anticoagulation and decrease the risk of bleeding. Examples may include a resection or radiation of an oozing site of malignancy or an endoscopic intervention on a GI bleed. It is important to remember that bleeding issues at the time of initial evaluation may prohibit anticoagulation for several weeks.

Frequent reassessment of tolerance for a particular anticoagulant provides an opportunity to individualize the approach for each patient. If a patient is taking an injectable anticoagulant such as enoxaparin, it may be useful to assess the patient within 2 to 4 weeks of starting injectable anticoagulants to ensure they are tolerating the injections.

Other factors that may increase bleeding risk include age 60 years or older, history of prior bleeding, active cancer, chronic hepatic or renal disease, thrombocytopenia, anemia, and other comorbidities including hypertension, poor functional capacity, and recent surgery. Use of the externally validated VTE-BLEED score may provide a frame-work for the identification of patients at risk for major bleeding during long-term anticoagulation.

Step 3: Consider Anticoagulation Options in Special Populations

There are certain patient populations or circumstances that may affect approaches to management of VTE.

Patients with acute DVT and absolute contraindications to anticoagulation caused by concurrent acute bleeding may be considered for retrievable inferior vena cava (IVC) filter placement. It is paramount to ensure prompt removal of IVC filters once anticoagulation can be restarted, as there is mounting evidence of harm from lack of retrieval.

 Of note, the 2019 American Society of Clinical Oncology Clinical Practice Update did not recommend IVC filters for patients with a chronic DVT diagnosed more than 4 weeks prior.

It is important to note that certain special populations with unique anticoagulation needs exist beyond the scope of this article, including patients who are pregnant, where low molecular weight heparins (LMWHs) or unfractionated heparins have long been the standard of care. Chronic kidney disease and hepatic disease are scenarios where the degree of organ dysfunction may dictate the choice of anticoagulation.

 Useful data for anticoagulation selection can be assessed by evaluation of the creatinine clearance, Child-Pugh score for cirrhosis, and review of the drug package insert for dosing guidance.

Direct oral anticoagulants may be relatively contraindicated in the setting of cirrhosis with a Child-Pugh score greater than B or C, depending on the agent. LMWHs are relatively contraindicated in renal insufficiency. Warfarin may be difficult to manage if the international normalized ratio is increased at baseline. Additional patient populations with specific anticoagulation considerations include patients with antiphospholipid antibody syndrome, active cancers, gastric bypass or other GI resection surgeries, and heparin-induced thrombocytopenia.

Centers for Disease Control and Prevention. What is venous thromboemolism? February 7, 2020. Accessed April 29, 2022. bit.ly3ywp9Ky

Kresoja KP, Ebner M, Rogge NIJ, et al. Prediction and prognostic importance of in-hospital major bleeding in a real-world cohoty of patients with pulmonary embolism. 

2019;1(290):144-149. doi: 10.1016/j/ijcard.2019.03.017

Klok FA, Barco S, Konstantinides SV. External validation of the VTE-BLEED score for predicting major bleeding in stable anticoagulated patients with venous thromboembolism. 

2017;117(6):1164-1170. doi:10.1160/TH16-10-0810

Choosing Wisely. IVC filters and acute VTE. October 30, 2018. https://www.choosingwisely.org/clinician-lists/american-society-hematology-inferior-vena-cava-filters-in-patients-with-acute-vte/. Accessed May 4, 2022

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Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO Clinical Practice Guideline Update. 

2020;38(5):496-520. doi:10.1200/JCO.19.01461

Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis adn pulmonary embolism. 

2020;4(19):4693-4738. doi:10.1182/bloodadvances.2020001830

Becattini C, Agnelli G. Acute treatment of venous theomboembolism. 

2020;135(5):305-316. doi:10.1182/blood.2019001881

Lyman GH, Carrier M, Ay C, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. 

2021;5(4):927-974. doi:10.1182/bloodadvances.2020003442

Most hematology/oncology fellows will care for patients with venous thromboembolism throughout their training and long after their graduation from fellowship. Here are some practical considerations when treating a patient with an acute VTE.

Practical Considerations for Fellows Treating VTE

One challenging hematologic scenario dreaded by both fellows and faculty involves a rapidly bleeding patient in danger of exsanguination. Conversely, the ability to successfully intervene can be quite rewarding and save lives. What follows are practical points for trainees to approach the initial evaluation for a bleeding-disorder patient.

History is vital to inform differential diagnosis and target lab evaluation. Important aspects include timing and details surrounding the bleeding events, reviewing medications/substance use, and family history.1 Important considerations include:

 Clinically relevant hemorrhage in infancy or childhood is suggestive of an inherited/ congenital bleeding disorder. Hemorrhage in adulthood should prompt an evaluation for an acquired coagulation disorder, a delayed manifestation of a mild congenital bleeding disorder, or a medication effect.

 Is the bleeding spontaneous or only with trauma or invasive procedures? This may indicate severity and provide clues to an underlying diagnosis.

 Primary involvement of mucosal surfaces, epistaxis, gingival bleeding, or spontaneous bruising may indicate a platelet disorder. Hemarthroses, muscle bleeds, or soft tissue hemorrhages suggest a coagulationfactor disorder.

 What procedures were performed and was hemostasis achieved? Was factor prophylaxis used? Be sure to ask about dental work, major surgeries, and the timing of hemorrhage. Noting a need for interventions or blood transfusions also helps gauge severity of bleeding disorders.

 It can be difficult to objectively characterize menstrual cycle severity given its inherently subjective nature and the variable methods of quantifying blood loss. However, menstrual bleeding that interferes with daily activities, cycles lasting longer than 7 days, or the presence of clots larger than 1 cm can be considered clinically significant bleeding. These symptoms could be suggestive of von Willebrand disease (VWD) or another congenital bleeding disorder.

 The bleeding assessment tool, or BAT, helps with consistent reporting of the presence of bleeding and severity. It assists with evaluation for inherited bleeding disorders.

 Severe hemophilia A or B typically has bleeding in infancy, spontaneous hemarthroses, or muscle bleeds. VWD includes mucocutaneous bleeding, heavy menses, or perioperative bleeding. Uremia or liver disease may manifest with ecchymoses, purpura, epistaxis, or bleeding at sites of intravenous access.

 Other relatives with a similar bleeding history, even if there is no formal diagnosis, may suggest inherited bleeding disorder and inheritance patterns.

 Care should be taken to review any over-the-counter medications: Nonsteroidal antiinflammatory medications, turmeric, St. John’s wort, and garlic can worsen bleeding.

 Excessive alcohol use may point to liver disease as a bleeding contributor. Illicit substance use may suggest a need for evaluation for contamination with brodifacoum, a longacting vitamin K antagonist.

assessment of the joints for stigmata of prior or current hemarthroses;

evaluation for bruising or petechiae, as this may be suggestive of thrombocytopenia, a platelet disorder, or VWD;

assessment for telangiectasias, particularly on skin, oral mucosa, or fingertips. This may be suggestive of hereditary hemorrhagic telangiectasia; and

evaluation for hypermobile joints suggestive of Ehlers-Danlos syndrome or a collagen vascular disorder.

Labs are often needed to formalize a diagnosis. Although steps 1 and 2 will inform which tests are needed, the results may confirm the clinician’s opinion.

 Initial labs include a complete blood count, prothrombin time (PT) evaluating the extrinsic coagulation pathway, and an activated partial thromboplastin time (aPTT) evaluating the intrinsic pathway. A platelet function analyzer (PFA-100) may be helpful in screening for platelet dysfunction or VWD. Additionally, fibrinogen should be drawn to evaluate for disseminated intravascular coagulation or dysfibrinogenemia.

 Based on the initial screening lab test results, further targeted testing may be performed. Prolongation of the PT and/or the aPTT suggests a clotting factor deficiency or the presence of an inhibitor. A solely prolonged PT indicates an extrinsic coagulation pathway abnormality, and a prolonged aPTT alone suggests an intrinsic coagulation pathway defect. Dual prolonged PT and aPTT lab tests suggest a common pathway malfunction (Table 1).

 Remember to repeat a prolonged aPTT from a peripheral lab draw prior to doing additional testing, as it is common for catheterassociated heparin contamination to cause an isolated prolonged aPTT. If it persists, perform a “mixing study” next. An equal amount of patient plasma and normal pooled plasma are mixed at a ratio of 1:1. The test “corrects” when the PT or aPTT normalizes and thus suggests a factor deficiency that improved with the addition of normal plasma. If the patient’s PT or aPTT remains prolonged and does not correct, this indicates the presence of a factor inhibitor. This information can be combined with the prior results to aid in selection of factor activities to measure as clinically directed.

 Thrombin time measures the conversion of fibrinogen to fibrin. This lab may be helpful if there is a suspicion of anticoagulant use (direct thrombin inhibitor) or a fibrinogen disorder (Table 2).

The assessment and evaluation of the history, physical exam, and laboratory testing in a patient with a bleeding disorder are complex and multifaceted. The hematologist plays an essential role in the collection and review of these data. Management of individual conditions is outside the scope of this article; however, once a diagnosis is confirmed, management is much simplified.

Recall that if one does not at least consider the diagnosis, one will certainly fail to recognize it. The correct diagnosis is the foundation on which all management of bleeding disorders hinges. Without this cornerstone, one cannot hope to proceed to effective hemostatic control.

Hunt BJ. Bleeding and coagulopathies in critical care. 

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Rodeghiero F, Tosetto A, Abshire T, et al; ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. 

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Michelle Chi, MD and Jennifer R. Green, MD, share practical points for trainees to approach the initial evaluation for a bleeding-disorder patient.

Assessing Bleeding Disorders: Keys for Hem/Onc Fellows

 to reference the same entity: the study and management of nonmalignant disorders of the blood. It is a discipline unto itself, distinct from its sister field, malignant hematology. The scope of practice can be broad and includes thrombotic and hemorrhagic disorders, transfusion medicine, hemoglobin disorders including sickle cell disease and thalassemia, anemia, thrombocytopenia, leukocytosis, leukopenia, and disorders of iron metabolism.

In many health care systems, classical hematologists function as stewards of cost-intensive, specialty-related medications that are often complex and require content knowledge, experience, and clinical expertise for appropriate management.

 Others find roles as systems-based hematologists, defined as a specialty-trained physician, employed by a hospital medical center or a health system, who optimizes individual patient care as well as the overall system of health care delivery for patients with blood disorders.

 Duties of these professionals can include implementing health care initiatives for the management of thrombosis or bleeding, working in conjunction with anticoagulation oversight clinics, and standardizing management of therapeutic phlebotomy.

To characterize the future of the workforce for this diverse field, results of an American Society of Hematology (ASH) survey of practicing hematologists projected that nearly 25% of hematologists specializing in nonmalignant disorders would reach retirement age by 2018.

 This was expected to have a profound impact on creating a workplace shortage.

 The study results cited several influences, including the age of the workforce

 and decreasing rates of graduate selection of nonmalignant hematology as a primary area of focus.

 Other influences included salary discrepancies between nonmalignant hematology and malignant hematology/oncology, lack of mentorship, and uncertainty regarding nonmalignant hematology job opportunities in nonacademic settings.

 Physicians practicing in adult nonmalignant hematology disorders are now seeing the results of this decreasing specialist collective in clinical care and research.

Educational programs have historically been tasked with attempts to address the shrinking pool of classical hematologists. Prior research showed that only 20% of hematology/oncology fellowship graduates pursued an academic career with a clinical research focus, and only 8% pursued an academic career as a clinicianeducator.

 Of the 20%, less than 6% selected careers in nonmalignant hematology.

 A great demand exists for well-trained physicians.

 Furthermore, literature suggests that soon a large patient volume with hematologic care needs will be without a sufficient number of specialists.

These challenges may require complex solutions (

). One initiative is an expansion of easily accessible nonmalignant hematology training and educational resources for both trainees and practicing hematologists/oncologists. Many colleagues have not experienced the opportunity to train with a dedicated mentor in this specialty, as fellowship programs can vary significantly in their faculty experience with nonmalignant hematology. In fact, many programs have few available dedicated hematologists on staff for teaching and clinical care.

 Guidance and widely disseminated education can enhance practitioner comfort in the management of hematologic conditions when programs do not have an available content area expert.

Figure. Areas of Opportunity to Expand Training in Nonmalignant Hematology Disorders

Additional focus should be given to the enlistment and training from colleagues to surmount this disparity. Offering training sessions or workshops in the management of high-yield, common topics led by experienced hematology teachers for their colleagues in internal medicine, family practice, and primary care could provide a foundation for initial management of hematologic issues, improved comfort with the subject matter, and an enhanced understanding of the indications for specialist referral. Topics of interest include management of iron-deficiency anemia, simple and complex thromboses, anticoagulation oversight, bleeding evaluations, thrombotic microangiopathy presentation and identification, and the initial evaluation of cytopenias. These examples represent common scenarios with significant intersection with classical hematology.

Residency training programs may also find the opportunity to incorporate nonmalignant hematology focus into their curricula. Not only would this serve to improve proficiency and prepare trainees for the reality of their practice, but it would also be a step toward eliminating the gap in care that will be left by a workplace shortage.

A clear and prominent need also exists to train more classical hematologists to increase consultant availability across subspecialties. ASH has undertaken this issue in prior years through the creation of its Recruitment and Retention Working Group, a study collaborative with The George Washington University Fitzhugh Mullan Institute for Health Workforce Equity, and it has raised awareness through publication and educational initiatives.

 In October 2020, ASH announced that it will provide “institutional funding to develop 10 new innovative hematology-focused fellowship tracks within existing adult hematologyoncology training programs.”

 The training provided in the educational platform must lead to eligibility for American Board of Internal Medicine hematology certification. The goal of the program is to generate enough recruitment and training to add at least 50 academic hematologists in the coming years, with a focus on training hematologists in nonmalignant disorders.

 More information will follow when the request for proposals becomes available on February 15, 2021. Additional information is available at https://bit.ly/37Gmyic.

Well-informed hematologists/oncologists can also play a critical role in reshaping the trajectory of these gaps through raising awareness, participating in professional societies and continuing medical education, teaching students and trainees, and recruiting colleagues to extend these efforts. The nurture and retention of nonmalignant hematology content expertise is a critical aspect of health care that merits protection. 

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The scope of adult nonmalignant hematology can be broad and includes thrombotic and hemorrhagic disorders, transfusion medicine, hemoglobin disorders including sickle cell disease and thalassemia, anemia, thrombocytopenia, leukocytosis, leukopenia, and disorders of iron metabolism. 

Adult Nonmalignant Hematology Is an Endangered Field That Merits Protection

Director of the Vanderbilt Hemophilia/ Hemostasis Treatment Clinic,

Vanderbilt University Medical Center, Nashville, Tennessee

In the treatment of acute venous thromboembolism (VTE) associated with an underlying malignancy, direct oral anticoagulants (DOACs) are now considered acceptable for some patient populations. National Comprehensive Cancer Network Guidelines indicate that low molecular weight heparin (LMWH) is an appropriate anticoagulant for the first 6 months in patients with proximal deep vein thrombosis or pulmonary embolism.

1 LMWH is also recommended for the prevention of recurrent VTE in patients with advanced metastatic cancer.

 However, the guidelines also stipulate that for patients who prefer to avoid injections or have other limitations in the use of LMWH, apixaban (Eliquis), a DOAC, is an acceptable alternative. That means clinicians must distinguish which patients might be appropriate candidates for DOACs instead of continued use of LMWH. This is particularly challenging in the setting of an active gastrointestinal (GI) malignancy, where DOACs have shown higher rates of GI bleeding.

In recent years, several randomized controlled trials compared factor Xa inhibitor DOACs with the LMWH dalteparin (Fragmin) for preventing recurrent VTE in patients with cancer.

 In 2 of these studies, investigators concluded that rivaroxaban (Xarelto) and edoxaban (Savaysa) slightly lowered rates of recurrent VTE compared with LMWH but at the expense of higher rates of clinically relevant nonmajor bleeding, particularly GI bleeding.

The Hokusai VTE Cancer study randomized 1050 patients to LMWH followed by oral edoxaban versus subcutaneous dalteparin. This trial proved noninferiority of oral edoxaban to dalteparin with respect to the composite outcome of recurrent VTE or major bleeding at 12 months post randomization, with a 7.9% VTE recurrence rate in the edoxaban group compared with 11.3% in the dalteparin group. However, there was a significant increase in major bleeding with edoxaban (6.9%) compared with dalteparin (4%).

Analysis of the tumor types included hepatocellular, hepatobiliary, cholangiocarcinoma, and biliary cancers, all of which were associated with bleeding. This is important because the GI bleeding was not limited to patients with gastric or colorectal malignancies.

 Because the bleeding occurred in a diverse group of GI tumors, this relevant subset information should be considered when making clinical decisions for this patient population. Analysis of the Hokusai patients with VTE indicated that there were no fatal bleeding events with the use of edoxaban; however, 2 fatal bleeding events occurred among patients treated with dalteparin.

The SELECT-D study of 406 patients showed lower rates of recurrent VTE with rivaroxaban (4%) compared with dalteparin (11%) but higher rates of major bleeding (6% vs 4%, respectively) at 6 months.

 Although the rate of major bleeding was relatively low for both trial arms, there was a 3-fold increase in clinically relevant nonmajor bleeding with rivaroxaban (13%) compared with dalteparin (4%).4 Bleeding events in the Hokusai VTE Cancer study and SELECT-D trial primarily occurred in the GI tract and were higher in patients with GI cancers. In addition, the risk of bleeding is amplified in patients with preexisting GI lesions, including cancer, ulcers, and diverticulitis.

Data from the ADAM VTE trial, presented at the American Society of Hematology Annual Meeting in December 2018, also reinforced the use of apixaban in VTE associated with an underlying malignancy. The investigators concluded that a comparable number of patients in the apixaban and dalteparin arms had major bleeding as the primary endpoint (0% vs 2.1%; 

 The findings also showed improved rates of recurrent VTE with the use of apixaban compared with dalteparin (3.4% vs 14.1%, respectively; 

 Further analysis of the subset of patients with GI malignancies who were included in this trial could yield additional relevant information.

Despite the increased GI bleeding with the use of factor Xa inhibitors in patients with GI cancers, the use of DOACs is not excluded in this population. An individualized patient approach in the evaluation of hemorrhagic risk factors is recommended in these complex decisions. Medication counseling, education, and informed consent are paramount.

Consideration of relevant factors includes evaluation for concomitant use of ulcerogenic medications, impaired renal or hepatic function, and prior history of GI bleeding. This information may inform clinical decisions regarding the initiation of DOAC in patients with GI malignancies. In addition, coadministration of a proton pump inhibitor or histamine H2 receptor antagonist can significantly reduce the risk of upper GI bleeding.

More studies are needed to define how best to stratify the risks of hemorrhage among the diverse patients living with GI malignancies. Consideration of factors such as initial tumor burden, prior surgery, and the effects of systemic therapy on bleeding rates will be of interest for future study. In the absence of further data, the optimal anticoagulant takes into consideration a variety of components, including patient preference, the indication for anticoagulation, comorbidities, reversibility, and other factors relevant to the clinical scenario.

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The optimal anticoagulant takes into consideration a variety of components, including patient preference, the indication for anticoagulation, comorbidities, reversibility, and other factors relevant to the clinical scenario.

Jennifer R. Green, MD

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