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.

Comparison of assays measuring extracellular vesicle tissue factor in plasma samples: communication from the ISTH SSC Subcommittee on Vascular Biology.

BACKGROUND: Scientific and clinical interest in extracellular vesicles (EVs) is growing. EVs that expose tissue factor (TF) bind factor VII/VIIa and can trigger coagulation. Highly procoagulant TF-exposing EVs are detectable in the circulation in various diseases, such as sepsis, COVID-19, or cancer. Many in-house and commercially available assays have been developed to measure EV-TF activity and antigen, but only a few studies have compared some of these assays. OBJECTIVES: The International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Subcommittee on Vascular Biology initiated a multicenter study to compare the sensitivity, specificity, and reproducibility of these assays. METHODS: Platelet-depleted plasma samples were prepared from blood of healthy donors. The plasma samples were spiked either with EVs from human milk or EVs from TF-positive and TF-negative cell lines. Plasma was also prepared from whole human blood with or without lipopolysaccharide stimulation. Twenty-one laboratories measured EV-TF activity and antigen in the prepared samples using their own assays representing 18 functional and 9 antigenic assays. RESULTS: There was a large variability in the absolute values for the different EV-TF activity and antigen assays. Activity assays had higher specificity and sensitivity compared with antigen assays. In addition, there was a large intra-assay and interassay variability. Functional assays that used a blocking anti-TF antibody or immunocapture were the most specific and sensitive. Activity assays that used immunocapture had a lower coefficient of variation compared with assays that isolated EVs by high-speed centrifugation. CONCLUSION: Based on this multicenter study, we recommend measuring EV-TF using a functional assay in the presence of an anti-TF antibody.

Anticoagulation in COVID-19 patients - An updated systematic review and meta-analysis.

BACKGROUND: Thromboembolic events are common complications of COVID-19. Clinical study results on safety and efficacy of anticoagulation in COVID-19 are controversial. MATERIAL AND METHODS: This report is the second update of our systematic review with meta-analysis on randomized controlled trials (RCTs) comparing standard thromboprophylaxis, intermediate or therapeutic dose anticoagulation or no anticoagulation in COVID-19 in- and outpatients. We searched eligible studies up to 5 October 2023. Certainty of evidence was assessed using GRADE. RESULTS: For this update we included fourteen new RCTs and a total of 27 RCTs with 16,789 patients. Certainty of evidence ranged from very low to high depending on outcome and comparison. Standard thromboprophylaxis with low dose anticoagulation may have little or no effect for COVID-19 outpatients compared to no anticoagulation. In inpatients with moderate or severe COVID-19, intermediate dose anticoagulation may decrease any thrombotic events or death, but may increase major bleeding compared to standard thromboprophylaxis. Therapeutic dose anticoagulation decreases thrombotic events or deaths in inpatients with moderate COVID-19, but probably has little or no effect in patients with severe COVID-19 compared to standard thromboprophylaxis with low or intermediate dose anticoagulation. With therapeutic dose anticoagulation, the risk of major bleeding probably increases regardless of COVID-19 severity. We are uncertain on the effect of thromboprophylaxis with low dose anticoagulation compared to no anticoagulation in the post-discharge setting. CONCLUSIONS: Hospitalized, moderately-ill COVID-19 patients may benefit from intermediate or therapeutic dose anticoagulation, while critically ill patients may not. Risk of major bleeding must be considered.

Recommendations for reporting tissue and circulating tumour (ct)DNA next-generation sequencing results in non-small cell lung cancer.

Non-small cell lung cancer is a heterogeneous disease and molecular characterisation plays an important role in its clinical management. Next-generation sequencing-based panel testing enables many molecular alterations to be interrogated simultaneously, allowing for comprehensive identification of actionable oncogenic drivers (and co-mutations) and appropriate matching of patients with targeted therapies. Despite consensus in international guidelines on the importance of broad molecular profiling, adoption of next-generation sequencing varies globally. One of the barriers to its successful implementation is a lack of accepted standards and guidelines specifically for the reporting and clinical annotation of next-generation sequencing results. Based on roundtable discussions between pathologists and oncologists, we provide best practice recommendations for the reporting of next-generation sequencing results in non-small cell lung cancer to facilitate its use and enable easy interpretation for physicians. These are intended to complement existing guidelines related to the use of next-generation sequencing (solid and liquid). Here, we discuss next-generation sequencing workflows, the structure of next-generation sequencing reports, and our recommendations for best practice thereof. The aim of these recommendations and considerations is ultimately to ensure that reports are fully interpretable, and that the most appropriate treatment options are selected based on robust molecular profiles in well-defined reports.

Varicose vein surgery after acute isolated superficial vein thrombosis in daily practice: INSIGHTS-SVT study.

OBJECTIVE: The aim of this study was to assess the utilization of surgical interventions in patients diagnosed with superficial vein thrombosis (SVT) and its potential association with the occurrence of venous thromboembolism (VTE) and bleeding events. METHODS: INSIGHTS-SVT, a prospective, non-interventional, multicenter study in Germany, investigated the management and outcomes of patients with acute SVT who received conservative and/or invasive treatments at the discretion of the treating physician. RESULTS: Among the 872 patients with 12-month data, 657 had medical therapy only, and 215 patients underwent vascular surgery (70 within 3 months of SVT diagnosis, 136 between months 4 and 12, and nine had an intervention in both periods). The most commonly performed procedures included endovenous thermal ablation, ligation of the saphenofemoral or saphenopopliteal junction, and vein stripping. The primary outcome of symptomatic VTE was observed in 5.8% of conservatively treated patients and 6.3% of those who underwent surgical intervention. Additionally, the secondary outcome of recurrent or extended SVT was documented in 4.7% of conservatively treated patients and 5.3% of invasively treated patients. Bleeding events occurred in 1.4% of conservatively treated patients and 2.1% of surgically treated patients. These differences were statistically not significant. Furthermore, our analysis indicated a potential protective effect associated with surgical treatments, such as ligation of the saphenofemoral or saphenopopliteal junction, stripping and endovenous thermal ablation, concerning the endpoint of VTE for patients when applied after 3 months from the index SVT event. CONCLUSIONS: In line with previous research, our study suggests that surgical interventions are not frequently employed in the management of SVT, although they may be warranted in select cases. Nevertheless, additional research is essential to gain a deeper understanding of the indications, criteria, and benefit of surgical interventions in the treatment of SVT.

The role of vasculature and angiogenesis in respiratory diseases.

In European countries, nearly 10% of all hospital admissions are related to respiratory diseases, mainly chronic life-threatening diseases such as COPD, pulmonary hypertension, IPF or lung cancer. The contribution of blood vessels and angiogenesis to lung regeneration, remodeling and disease progression has been increasingly appreciated. The vascular supply of the lung shows the peculiarity of dual perfusion of the pulmonary circulation (vasa publica), which maintains a functional blood-gas barrier, and the bronchial circulation (vasa privata), which reveals a profiled capacity for angiogenesis (namely intussusceptive and sprouting angiogenesis) and alveolar-vascular remodeling by the recruitment of endothelial precursor cells. The aim of this review is to outline the importance of vascular remodeling and angiogenesis in a variety of non-neoplastic and neoplastic acute and chronic respiratory diseases such as lung infection, COPD, lung fibrosis, pulmonary hypertension and lung cancer.

Circulating Tumor Cells and Thromboembolic Events in Patients with Glioblastoma.

Patients with glioblastoma (GBM) are at increased risk for arterial and venous thromboembolism (TE). Risk factors include surgery, the use of corticosteroids, radiation, and chemotherapy, but also prothrombotic characteristics of the tumor itself such as expression of tissue factor, vascular endothelial growth factor, or podoplanin. Although distant metastases are extremely rare in this tumor entity, circulating tumor cells (CTCs) have been detected in a significant proportion of GBM patients, potentially linking local tumor growth characteristics to systemic hypercoagulability. We performed post hoc analysis of a study, in which GBM patients had been investigated for CTCs. Information on TE was retrieved from electronic patient charts. In total, 133 patients (median age, 63 years; interquartile range, 53-70 years) were analyzed. During follow-up, TE was documented in 14 patients (11%), including 8 venous and 6 arterial events. CTCs were detected in 26 patients (20%). Four (15%) patients with CTCs had a TE compared with 10 (9%) patients without CTCs. There was no difference in the frequency of TE events between patients with and those without detectable CTCs (p = 0.58). In summary, although our study confirms a high risk of TE in GBM patients, it does not point to an obvious association between CTCs and vascular thrombosis.

Prevention of thromboembolic events after radical prostatectomy in patients with hereditary thrombophilia due to a factor V Leiden mutation by multidisciplinary coagulation management.

Objective: To examine the perioperative impact of factor V Leiden mutation on thromboembolic events' risk in radical prostatectomy (RP) patients. With an incidence of about 5%, factor V Leiden mutation is the most common hereditary hypercoagulability among Caucasians and rarer in Asia. The increased risk of thromboembolic events is three- to seven-fold in heterozygous and to 80-fold in homozygous patients. Methods: Within our prospectively collected database, we analysed 33 006 prostate cancer patients treated with RP between December 2001 and December 2020. Of those, patients with factor V Leiden mutation were identified. All patients received individualised recommendation of haemostaseologists for perioperative anticoagulation. Thromboembolic complications (deep vein thrombosis and pulmonary embolism) were assessed during hospital stay, as well as according to patient reported outcomes within the first 3 months after RP. Results: Overall, 85 (0.3%) patients with known factor V Leiden mutation were identified. Median age was 65 (interquartile range: 61-68) years. There was at least one thrombosis in 53 (62.4%) patients and 31 (36.5%) patients had at least one embolic event in their medical history before RP. Within all 85 patients with factor V Leiden mutation, we experienced no thromboembolic complications within the first 3 months after surgery. Conclusion: In our cohort of patients with factor V Leiden mutation, no thromboembolic events were observed after RP with an individualised perioperative coagulation management concept. This may reassure patients with this hereditary condition who are counselled for RP.

Multisite Thrombosis in a Patient with Paroxysmal Nocturnal Hemoglobinuria.

CASE: Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare bone marrow disorder caused by acquired mutations in the phosphatidylinositol glycan class A gene, which lead to a partial or total loss of the cellular complement regulators CD55 and CD59.1 In addition to complement-mediated hemolysis and cytopenia, venous and arterial thromboses at multiple and/or unusual sites are a common complication and occur in up to 44% of patients in historic PNH cohorts.1 2.

Relapsing Polychondritis with Tracheobronchial Involvement: A Detailed Description of Two Pediatric Cases and Review of the Literature.

Relapsing polychondritis (RP) is a rare immune-mediated disease that primarily affects the cartilaginous structures of the ears, nose and airways. The clinical spectrum ranges from mild to severe disease characterized by progressive destruction of cartilage in the tracheobronchial tree leading to airway obstruction and acute respiratory failure. Early diagnosis is crucial to prevent irreversible airway damage and life-threatening complications. Due to its rarity and variability of symptoms, the diagnosis of RP is often delayed particularly in childhood. To address this and increase awareness of this rare disease, we present a detailed case report of two adolescent females affected by RP. We aim to describe the clinical findings, consequences of a delayed diagnosis and provide a review of the current literature.

Effect of factor XI inhibition on tumor cell-induced coagulation activation.

BACKGROUND: Cancer-associated thrombosis is a frequent complication in patients with malignancies. While factor XI (FXI)/FXIa inhibition is efficacious in preventing postoperative venous thromboembolism, its role in tumor cell-induced coagulation is less defined. OBJECTIVES: We thus aimed to provide mechanistic insights into FXI/FXIa inhibition in tumor cell-induced coagulation activation. METHODS: Procoagulant activity (PCA) of 4 different tissue factor (TF) expressing tumor cell lines was analyzed by single-stage clotting and thrombin generation assay in the presence of a FXIa inhibitor, BMS-262084 (BMS), an inhibitory FXI antibody (anti-FXI), or peak and trough concentrations of rivaroxaban or tinzaparin. Further, tumor cell-induced platelet aggregation was recorded. Recombinant human TF served as positive control. RESULTS: Although BMS and anti-FXI potently inhibited FXIa amidolytic activity, both inhibitors efficiently mitigated recombinant human TF- and tumor cell-induced fibrin clot formation and platelet aggregation only in the presence of low TF PCA. The anticoagulant effects showed an inverse correlation with the magnitude of cellular TF PCA expression. Similarly, BMS markedly interfered with tumor cell-induced thrombin generation, with the most prominent effects on peak and total thrombin. In addition, anticoagulant effects of FXIa inhibition by 10 µM BMS were in a similar range to those obtained by 600 nM rivaroxaban and 1.6 µM tinzaparin at low TF PCA levels. However, rivaroxaban and tinzaparin also exerted marked anticoagulant activity at high TF PCA levels. CONCLUSION: Our findings indicate that FXI/FXIa inhibition interferes with tumor cell-induced coagulation activation only at low TF PCA expression levels, a finding with potential implications for future in vivo studies.

Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure.

ABSTRACT: Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained before 2020 (n = 188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n = 3; cerebral venous sinus thrombosis, n = 4), thrombocytopenia (median platelet count nadir, 49 × 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10 minutes in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis, and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines.

Determinants of Late Venous Thromboembolic Events After Acute Isolated Superficial Vein Thrombosis in Daily Practice: 12 Month Results of the INSIGHTS-SVT Study.

OBJECTIVE: Long term incidence of symptomatic venous thromboembolism (VTE) and bleeding events in patients with superficial vein thrombosis (SVT) was investigated. METHODS: In this prospective, observational study, patients with acute SVT were treated at the discretion of the responsible physician. The primary efficacy outcome was symptomatic VTE including deep vein thrombosis (DVT), pulmonary embolism (PE), and recurrent or extending SVT. The primary safety outcome was clinically relevant bleeding, recorded at periodic clinic visits over a 12 month period. RESULTS: The mean age of 872 patients with 12 month follow up was 60.6 ± 14.5 years, 64.5% were female, 80.1% had chronic venous disease (defined as chronic venous insufficiency and or varicose veins), and 41.9% had a history of VTE. They were receiving fondaparinux in 62.1% (mean duration 34.9 ± 15.7 days), low molecular weight heparin (LMWH) in 25.0% (mean duration 26.2 ± 23.2 days), any other anticoagulants in 6.2%, and no anticoagulant in 6.7%. At 12 months, 108 patients (14.3%) achieved the primary efficacy outcome. The most common VTE event was recurrent or extending SVT in 11.0%, followed by symptomatic DVT in 2.7%, symptomatic PE in 2.4%, hospitalisation due to VTE in 1.8%, and death in 1.1%. Clinically relevant bleeding events occurred in 2.1% of patients, and major bleedings in 0.3%. By drug, the rate of the primary efficacy outcome was highest in the LMWH group (22.4%) and lowest in the fondaparinux group (10.4%). In a multivariable model, patients with events between three months and 12 months were significantly more likely to have higher BMI (hazard ratio [HR] 1.06; p = .002), history of VTE (HR 2.89; p = .002), and severe systemic infections (HR 7.59; p = .006). CONCLUSION: The risk of symptomatic VTE remained elevated over 12 months of follow up. Therefore, anticoagulation beyond 45 days may be considered in patients with risk factors. [ClinicalTrials.gov identifier: NCT02699151.].

Regulation of coagulation activation in newly diagnosed AML by the heme enzyme myeloperoxidase.

INTRODUCTION: Patients with acute myeloid leukemia (AML) are at increased risk of thrombohemorrhagic complications. Overexpressed tissue factor (TF) on AML blasts contributes to systemic coagulation activation. We have recently shown that the heme enzyme myeloperoxidase (MPO) negatively regulates TF procoagulant activity (PCA) on myelomonocytic cells in vitro. We now aimed to further characterize the functional interaction of MPO and TF in AML in vivo. METHODS: We prospectively recruited 66 patients with newly diagnosed AML. TF PCA of isolated peripheral blood mononuclear cells (PBMC) was assessed by single-stage clotting assay in the presence or absence of inhibitors against MPO catalytic activity (ABAH) or against MPO-binding integrins (anti-CD18). MPO in plasma and in AML blasts was measured by ELISA, and plasma D-dimers and prothrombin fragment F1+2 were quantified by automated immunoturbidimetric and chemiluminescence assays, respectively. RESULTS: Patients with AML had significantly higher MPO plasma levels compared to healthy controls and exhibited increased levels of D-dimers and F1+2. In vivo thrombin generation was mediated by TF PCA on circulating PBMC. Ex vivo incubation of isolated PBMC with ABAH or anti-CD18 antibody resulted in either increased or decreased TF PCA. The strong and robust correlation of F1+2 with TF PCA of circulating PBMC was abrogated at MPO plasma levels higher than 150 ng/mL, indicating a modulatory role for MPO on TF-mediated in vivo thrombin generation above this threshold. CONCLUSION: Our study indicates that catalytically active MPO released by circulating myeloblasts regulates TF-dependent coagulation in patients with newly diagnosed AML in a CD18-dependent manner.

Absence of Malaria-Associated Coagulopathy in Asymptomatic Plasmodium falciparum Infection: Results From a Cross-sectional Study in the Ashanti Region, Ghana.

Background: Coagulopathy is common in acute symptomatic Plasmodium falciparum malaria, and the degree of coagulation abnormality correlates with parasitemia and disease severity. Chronic asymptomatic malaria has been associated with increased morbidity. However, the role of coagulation activation in asymptomatic, semi-immune individuals remains unclear. This study investigates the potential effect of asymptomatic P falciparum infection on coagulation activation in semi-immune Ghanaian adults. Methods: Blood from asymptomatic Ghanaian adults with P falciparum blood stage infection detectable by polymerase chain reaction (PCR) or by both PCR and rapid diagnostic test and from noninfected individuals, was investigated. Markers of coagulation activation including global coagulation tests, D-dimer, antithrombin III, fibrinogen, and von Willebrand factor antigen were tested. Furthermore, blood count, inflammation markers, and liver and kidney function tests were assessed. Results: Acquired coagulopathy was not found in asymptomatic P falciparum infection. Asymptomatic malaria was associated with significantly lower platelet counts. Systemic inflammation markers and liver and kidney function tests were not altered compared to noninfected controls. Conclusions: There is no laboratory evidence for acquired coagulopathy in adults with asymptomatic P falciparum malaria in highly endemic regions. Lack of laboratory evidence for systemic inflammation and liver and kidney dysfunction indicates that asymptomatic malaria may not be associated with significant morbidity.

Expression and Release of Tumor Cell Tissue Factor Triggers Recurrent Thromboembolism in a Patient with Endometrial Cancer.

Although cancer-associated thrombosis (CAT) is a frequent complication in patients with malignancies, its treatment remains a challenge in daily practice. Here, we report the clinical course of a 51-year-old woman presenting with a highly thrombogenic paraneoplastic coagulopathy. Despite therapeutic anticoagulation with various agents, including rivaroxaban, fondaparinux, and low-molecular-weight heparin, the patient suffered from recurrent venous and arterial thromboembolism. Locally advanced endometrial cancer was identified. Tumor cells showed strong expression of tissue factor (TF), and significant concentrations of TF-bearing microvesicles were detected in patient plasma. Coagulopathy was controlled only by continuous intravenous anticoagulation with the direct thrombin inhibitor, argatroban. Multimodal antineoplastic treatment, including neoadjuvant chemotherapy followed by surgery and postoperative radiotherapy, resulted in clinical cancer remission, which was paralleled by normalization of tumor markers, CA125 and CA19-9, D-dimer levels, and TF-bearing microvesicles. In summary, continuous anticoagulation with argatroban and multimodal anticancer treatment may be necessary to control TF-driven coagulation activation with recurrent CAT in endometrial cancer.

Noninferiority of Artificial Intelligence-Assisted Analysis of Ki-67 and Estrogen/Progesterone Receptor in Breast Cancer Routine Diagnostics.

Image analysis assistance with artificial intelligence (AI) has become one of the great promises over recent years in pathology, with many scientific studies being published each year. Nonetheless, and perhaps surprisingly, only few image AI systems are already in routine clinical use. A major reason for this is the missing validation of the robustness of many AI systems: beyond a narrow context, the large variability in digital images due to differences in preanalytical laboratory procedures, staining procedures, and scanners can be challenging for the subsequent image analysis. Resulting faulty AI analysis may bias the pathologist and contribute to incorrect diagnoses and, therefore, may lead to inappropriate therapy or prognosis. In this study, a pretrained AI assistance tool for the quantification of Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in breast cancer was evaluated within a realistic study set representative of clinical routine on a total of 204 slides (72 Ki-67, 66 ER, and 66 PR slides). This represents the cohort with the largest image variance for AI tool evaluation to date, including 3 staining systems, 5 whole-slide scanners, and 1 microscope camera. These routine cases were collected without manual preselection and analyzed by 10 participant pathologists from 8 sites. Agreement rates for individual pathologists were found to be 87.6% for Ki-67 and 89.4% for ER/PR, respectively, between scoring with and without the assistance of the AI tool regarding clinical categories. Individual AI analysis results were confirmed by the majority of pathologists in 95.8% of Ki-67 cases and 93.2% of ER/PR cases. The statistical analysis provides evidence for high interobserver variance between pathologists (Krippendorff's α, 0.69) in conventional immunohistochemical quantification. Pathologist agreement increased slightly when using AI support (Krippendorff α, 0.72). Agreement rates of pathologist scores with and without AI assistance provide evidence for the reliability of immunohistochemical scoring with the support of the investigated AI tool under a large number of environmental variables that influence the quality of the diagnosed tissue images.

Prevalence of perioperative asymptomatic venous thromboses of the lower extremity in 30 consecutive patients undergoing transsphenoidal surgery for Cushing's disease.

Cushing´s disease is a rare endocrinological disorder which is caused by an adrenocorticotropic hormone secreting pituitary adenoma. The condition is associated with an increased risk for venous thromboembolism. While there exist reports on symptomatic venous thromboses complicating Cushing's disease, the prevalence of incidental leg vein thromboses accompanying pituitary surgery for Cushing's disease is yet unknown. 30 consecutive patients (9 male; age 25-77 years) with histologically confirmed Cushing's disease underwent transsphenoidal adenomectomy between October 2018 and September 2019. All patients received perioperative pharmacological thromboprophylaxis. Whole leg compression ultrasound was performed within one week after surgery (median 2 days) to exclude leg vein thromboses (primary endpoint). Preoperative laboratory values including plasma cortisol and various coagulation parameters were evaluated as secondary outcome measures. A comparison was made between patients with and without thrombotic events (p value ≤ 0.05). A total of 2 out of 30 patients (6.7%; CI 0.8-24.1%) presented with asymptomatic perioperative deep vein thromboses of the lower legs. Thrombosis patients differed not significantly from their counterparts with respect to age, sex, and comorbidities, but preoperative morning plasma cortisol was significantly higher in patients with venous thromboses (421.0 ± 49.5 µg/l vs. 188.1 ± 78.2 µg/l; p = 0.01). Moreover, von Willebrand factor activity was markedly increased in one case (409.0%) compared to the mean value obtained from 28 patients without phlebothromboses (146.9 ± 60.7%; p < 0.01). Perioperative asymptomatic leg vein thrombosis can be found with the aid of compression ultrasound in a considerable proportion of patients undergoing transsphenoidal adenomectomy for Cushing's disease despite the administration of pharmacological thromboprophylaxis.