Antithrombotic Therapy in Cancer Patients with Cardiovascular Diseases: Daily Practice Recommendations by the Hemostasis Working Party of the German Society of Hematology and Medical Oncology (DGHO) and the Society for Thrombosis and Hemostasis Research (GTH e.V.).

Active cancer by itself but also chemotherapy is associated with an increased risk of cardiovascular disease (CVD) and especially coronary artery disease (CAD) and atrial fibrillation (AF). The frequency of CVD, CAD, and AF varies depending on comorbidities (particularly in older patients), cancer type, and stage, as well as the anticancer therapeutic being taken. Many reports exist for anticancer drugs being associated with CVD, CAD, and AF, but robust data are often lacking. Because of this, each patient needs an individual structured approach concerning thromboembolic and bleeding risk, drug-drug interactions, as well as patient preferences to evaluate the need for anticoagulation therapy and targeting optimal symptom control. Interruption of specific cancer therapy should be avoided to reduce the potential risk of cancer progression. Nevertheless, additional factors like thrombocytopenia and anticoagulation in the elderly and frail patient with cancer cause additional challenges which need to be addressed in daily clinical management. Therefore, the aim of these recommendations is to summarize the available scientific data on antithrombotic therapy (both antiplatelet and anticoagulant therapy) in cancer patients with CVD and in cases of missing data providing guidance for optimal careful decision-making in daily routine.

Deciphering the genetic basis of immune thrombocytopenia: current evidence for genetic predisposition in adult ITP.

Immune thrombocytopenia (ITP) is the consequence of a complex, still incompletely understood immunological dysregulation. Proposed mechanisms include autoantibody-induced platelet destruction, impaired platelet production as well as abnormalities in T-cell immunity, such as T helper cells (Th1) polarization, a high proportion of Th17 cells, and a reduced number of regulatory T cells. Although the etiology of ITP is incompletely understood and considered multifactorial in most cases, genetic variants are thought to play a key role in susceptibility to ITP, especially in persistent or chronic ITP. Efforts are currently underway to uncover possible predisposing genetic factors for the development of ITP. Single-nucleotide polymorphisms and copy number variations have been identified in several immune-related genes, such as cytokine genes, Fcγ receptor genes or T-cell costimulation genes, and have been associated with patients' susceptibility to ITP. However, because of the clinical heterogeneity and low incidence of ITP it remains challenging to perform genetic analyses with sufficiently large sample size within informative patient populations, highlighting the need for collection of well-annotated biomaterials in clinical trials or registry projects. Another significant challenge is to go beyond performing association studies alone and to establish genotype-phenotype associations, thus proving causality between a genetic alteration and ITP pathogenesis. This review summarizes our current knowledge on genetic alterations identified as potential predisposing factors for the development of ITP in adults, thereby addressing signaling pathways considered critical for ITP pathogenesis.

[Use of Thrombopoetin-Receptor-Agonists (TPO-RA) in patients with liver cirrhosis before invasive procedures]. / Einsatz von Thrombopoetin-Rezeptor-Agonisten (TPO-RA) vor invasiven Eingriffen bei Patienten mit Leberzirrhose.

Advanced chronic liver disease is accompanied with relevant changes in the corpuscular and plasmatic coagulation system. Due to thrombocytopenia that is regularly observed in these patients, platelet transfusions are often performed prior invasive procedures to prevent possible bleeding complications. However, platelet transfusions are associated with clinically significant adverse events and economically relevant health care costs. Thus, avoiding unnecessary platelet transfusions remains pivotal in daily clinical practice. The first step is to carefully check if increasing platelet counts prior to a planned invasive procedure is really necessary. Nowadays, two well-tolerated thrombopoetin-receptor agonists (TPO-RAs), Avatrombopaq and Lusutrombopaq, to treat thrombocytopenia preemptively before an invasive procedure in patients with liver cirrhosis are available. This review provides a guide for clinician when to increase platelet counts prior an invasive procedure in patients with liver cirrhosis and helps to identify situations in which the use of TPO-RA may be reasonable.

Venous Thromboembolism in Women with Cancer with an Additional Focus on Breast and Gynecological Cancers.

Cancer-associated venous thromboembolism (VTE) is common in women with cancer. Many clinical practice guidelines provide guidance for prevention and treatment; however, there are no specific recommendations for women. This is unfortunate because the proportion of women with breast- and gynecological cancers is high among patients with cancer-associated VTE. Thromboembolism often heralds cancer progression and poor prognosis and should-besides adequate anticoagulant management-also prompt reassessment and, if necessary, changes in cancer treatment. Recently, the new class of direct-acting oral anticoagulants (DOACs) has started to replace low-molecular-weight heparin as standard thromboprophylaxis and therapy in cancer patients. They are very effective, but they also carry a relevant risk of bleeding. Therefore, despite their ease of use, not every tumor patient qualifies for a DOAC, and this is especially true for gynecological tumor patients. Each prescription must be weighed individually. This review addresses specific aspects of VTE prophylaxis and management in women with cancer. Every physician who treats breast and gynecological cancers should be familiar with prophylaxis, diagnosis, and therapy of cancer-associated VTE. At the same time, patients should be informed by their physician what symptoms to look for and whom to contact if these symptoms occur, even outside of office hours and on weekends.

Primary Thromboprophylaxis in Patients with Malignancies: Daily Practice Recommendations by the Hemostasis Working Party of the German Society of Hematology and Medical Oncology (DGHO), the Society of Thrombosis and Hemostasis Research (GTH), and the Austrian Society of Hematology and Oncology (ÖGHO).

Patients with cancer, both hematologic and solid malignancies, are at increased risk for thrombosis and thromboembolism. In addition to general risk factors such as immobility and major surgery, shared by non-cancer patients, cancer patients are exposed to specific thrombotic risk factors. These include, among other factors, cancer-induced hypercoagulation, and chemotherapy-mediated endothelial dysfunction as well as tumor-cell-derived microparticles. After an episode of thrombosis in a cancer patient, secondary thromboprophylaxis to prevent recurrent thromboembolism has long been established and is typically continued as long as the cancer is active or actively treated. On the other hand, primary prophylaxis, even though firmly established in hospitalized cancer patients, has only recently been studied in ambulatory patients. This recent change is mostly due to the emergence of direct oral anticoagulants (DOACs). DOACs have a shorter half-life than vitamin K antagonists (VKA), and they overcome the need for parenteral application, the latter of which is associated with low-molecular-weight heparins (LMWH) and can be difficult for the patient to endure in the long term. Here, first, we discuss the clinical trials of primary thromboprophylaxis in the population of cancer patients in general, including the use of VKA, LMWH, and DOACs, and the potential drug interactions with pre-existing medications that need to be taken into account. Second, we focus on special situations in cancer patients where primary prophylactic anticoagulation should be considered, including myeloma, major surgery, indwelling catheters, or immobilization, concomitant diseases such as renal insufficiency, liver disease, or thrombophilia, as well as situations with a high bleeding risk, particularly thrombocytopenia, and specific drugs that may require primary thromboprophylaxis. We provide a novel algorithm intended to aid specialists but also family practitioners and nurses who care for cancer patients in the decision process of primary thromboprophylaxis in the individual patient.

Romiplostim in adults with newly diagnosed or persistent immune thrombocytopenia.

Introduction: Three distinct phases are recognized in immune thrombocytopenia (ITP): newly diagnosed (≤3 months after diagnosis), persistent (>3-12 months after diagnosis), and chronic (>12 months). Several international guidelines/expert recommendations have been released in the past 2 years regarding the treatment of newly diagnosed/persistent ITP. Areas covered: Across the guidelines/expert recommendations, thrombopoietin receptor agonists (TPO-RAs), including romiplostim (the focus of this review), are recommended in newly diagnosed or persistent ITP for patients who fail to respond to corticosteroids or intravenous immunoglobulin (or where these are contraindicated). To identify data relating to romiplostim in adults with newly diagnosed or persistent ITP, we conducted a search of PubMed (with no time limit applied) and abstracts from 2019 EHA/ASH meetings using the term 'romiplostim.' Expert opinion: The findings from nine clinical trials, six real-world studies and ten case reports provide insight into the early use of romiplostim, which could help to reduce exposure to the adverse effects associated with prolonged corticosteroid use, as well as reduce the risk of severe bleeding. Additionally, given the durable responses observed in patients with newly diagnosed/persistent ITP, as well as the potential for treatment-free responses following discontinuation, romiplostim might help to avoid the need for subsequent treatment.

Factors Influencing the Choice between DOACs and LMWHs: A Survey of German Physicians on the Treatment of Cancer-Associated Venous Thromboembolism.

Recently direct-acting oral anticoagulants (DOACs) have become a new therapeutic option besides parenteral anticoagulants to treat cancer-associated venous thromboembolism (VTE). With this survey we wanted to identify factors influencing the choice between low-molecular-weight heparin and DOACs among physicians treating cancer patients. A questionnaire was presented at several medical educational activities on cancer care and VTE management between August 2018 and January 2019. One hundred fifteen physicians returned their surveys. The two most compelling arguments pro DOAC were when the patient had no chemotherapy and when he expressed unwillingness to apply injections. The two most important arguments against DOACs were if the patient had problems with taking oral medications or when he had a history of severe bleeding. This survey shows that future studies need to consider many more factors, particularly patient preferences and physician concerns on bleeding risk, to improve their applicability in daily practice.

Retroperitoneal Hematoma after Bone Marrow Biopsy: The First Cut Should Not Be the Deepest.

Bone marrow biopsies are standard hematology procedures. We report the case of a patient with acute myeloid leukemia who developed retroperitoneal hematoma after the procedure. The bleeding was stopped with endovascular embolization and coiling. This case raises several issues about the standards for bone marrow biopsies and discusses the approach to patients with bleeding risk factors. We also provide a literature review.

Non-vitamin K Antagonist Oral Anticoagulants (NOAC) as an Alternative Treatment Option in Tumor-Related Venous Thromboembolism.

BACKGROUND: The risk of venous thromboembolism (VTE) is 4 to 7 times higher in cancer patients than in the normal population. Moreover, cancer patients who take anticoagulants suffer more frequently from hemorrhagic complications and VTE recurrences. Patients often find low-molecular-weight heparin (LMWH) treatment unpleasant; approximately 20% stop taking LMWH during the first six months of treatment. METHODS: Based on a non-systematic literature search, an interdisciplinary group of specialists (hematology, oncology, hemostaseology, and angiology) developed a set of recommendations concerning the treatment of tumor-related thrombosis with non-vitamin K antagonist oral anticoagulants (NOAC). RESULTS: Patient-, tumor-, and tumor-treatment-related factors and clinical situations were identified that should be considered in therapeutic decision-making in the indi- vidual case. NOAC may be an alternative that lessens the rate of VTE recurrence (though at the cost of more hemorrhagic complications), without lessening mortality. Moreover, many factors need to be considered that can limit the utility of NOAC treatment or even make it impossible. CONCLUSION: It seems likely that, in future, the treatment of tumor-related VTE will often not involve a single decision to use either NOAC or LWMH, but rather a switching of treatment in either of two directions: from LWMH to NOAC in stable phases of the underlying malignant disease, conferring better quality of life to suitable patients; or from NOAC to LWMH, e.g., in patients suffering from emesis or thrombocytopenia, to whom the greater clinical experience with LWMH, parenteral application, or stepwise dose titration can confer benefits.

[Diagnosis and Therapy of Immune thrombocytopenia]. / Diagnostik und Therapie der Immunthrombozytopenie.

Immune thrombocytopenia (ITP) is a heterogeneous disease. Diagnosis of primary ITP continues to be based on the exclusion of all known causes for secondary ITP. The new ITP classification distinguishes three categories. First line treatment consists of either dexamethasone or prednisone. The most effective options in second line treatment are splenectomy or thrombopoietin receptor agonists. The medical societies for hematology and oncology of the German-speaking countries have recently updated their guidelines on ITP.

Practice Patterns for Prophylaxis and Treatment of Venous Thromboembolism in German Cancer Patients.

BACKGROUND: Venous thromboembolism (VTE) is a serious threat for cancer patients. Guidelines recommend low-molecular-weight heparin (LMWH) for prophylaxis and treatment, but it is unknown to what extent specialists adhere to these recommendations. This survey assesses the current approach to patients with cancer-associated VTE in Germany. MATERIALS AND METHODS: A questionnaire was sent out to members of the DGHO (Deutsche Gesellschaft für Hämatologie und Onkologie), the BNHO (Berufsverband Niedergelassener Hämatologen und Onkologen) and the DGP (Deutsche Gesellschaft für Phlebologie). For most questions, more than 1 answer was possible; therefore, the total sum of percentages may exceed 100%. RESULTS: 275 specialists responded. 76% of them treat acute VTE with LMWH while 22% switch to oral treatments (vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs)) during the acute phase. For the next 3-6 months, 55% of the specialists continue LMWH, while 31% switch to VKAs and 33% to NOACs. Among those who continue LMWH for 3-6 months, 37% continue at the full dose, 26% reduce to 75% of the initial dose, and 40% even to 50%. Important factors guiding treatment decisions were the need for injections and the availability of a partner/spouse (LMWH), the need for laboratory controls (VKAs), and the number of other oral medications (NOACs). CONCLUSION: This survey reveals that practice patterns often do not follow the guideline recommendations with respect to the use of LMWH for long-term treatment of VTE in cancer patients.

Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy.

Outcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m(2) intravenously on day 1), all-trans retinoic acid (45 mg/m(2) orally on days 4-6 and 15 mg/m(2) orally on days 7-28), high-dose cytarabine (3 g/m(2)/12 h intravenously on days 1-3) and mitoxantrone (12 mg/m(2) intravenously on days 2-3) in 93 patients aged 18-60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975).