Mechanical Venous Thrombectomy for Deep Venous Thrombosis in Cancer Patients: A Single-Center Retrospective Study.

PURPOSE: Venous thromboembolism (VTE) is a major contributor to the mortality of cancer patients. Mechanical thrombectomy (MT) is an endovascular technique that physically removes a thrombus without thrombolytics. The purpose of this study was to evaluate safety, efficacy, and clinical outcomes following MT for lower extremity DVT in cancer patients. METHODS: This single-center, retrospective study evaluated outcomes following MT of lower extremity DVT in cancer patients from November 2019 to May 2023. The primary outcome measure was clinical success, defined as a decrease in Villalta score by at least 2 points following the intervention. Secondary outcomes included repeat intervention-free survival and overall survival. Technical success was defined as restoring venous flow with mild (< 10%) or no residual filling defect. RESULTS: In total, 90 patients and 113 procedures were included. Technical and clinical success was achieved in 81% and 87% of procedures performed. Repeat intervention-free survival at 1 month, 3 months, and 6 months post-procedure was 92%, 82%, and 77%, respectively. The complication rate was 2.7%. Pathologic analysis of the extracted thrombus revealed tumor thrombus in 18.4% (18/98) samples. Overall survival for the study cohort was 87% at 1 month, 74% at 3 months, and 62% at 6 months. Patients who were found to have tumor thrombi were noted to have a decreased overall survival compared to patients with non-tumor thrombi (P = 0.012). CONCLUSION: MT is safe and efficacious in reducing cancer patients' VTE-related symptoms. The high rate of tumor thrombus in thrombectomy specimens suggests this phenomenon is more common than suspected.

Checkpoint inhibitors.

Immune checkpoint inhibitors are a class of antineoplastic therapies that unleash immune cells to kill malignant cells. These medications commonly cause immune-related adverse effects due to activated adaptive and innate immune cells, autoantibody production, and/or cytokine dysregulation. Hematologic toxicities are rare and of uncertain mechanism, and therefore management is often based on experiences with familiar conditions involving these perturbed immune responses. Management is challenging because one must attend to the hematologic toxicity while simultaneously attending to the malignancy, with the imperative that therapeutic effects be maintained or minimally interrupted when possible.

Measurement of adherence and health-related quality of life during anticoagulation therapy in cancer-associated venous thromboembolism (VTE): a multicenter quantitative study.

PURPOSE: Therapy for cancer-associated venous thromboembolism (VTE) includes long-term anticoagulation, which may have substantial impact on the health-related quality of life (HRQL) of patients. We assessed patient-reported outcomes to characterize the HRQL associated with VTE treatment and to begin to examine those HRQL elements impacting anticoagulation adherence (AA). METHODS: Participants were adult cancer patients with confirmed symptomatic acute lower extremity deep venous thrombosis. Patients were excluded if there was an indication for anticoagulation other than VTE, ECOG performance status >3, or life expectancy < 3 months. Participants were assessed with a self-reported adherence tool. HRQL was measured with a 6-domain questionnaire using a seven-point Likert scale. Evaluations were performed at 30 days and 3 months after enrollment. For the primary objective, an overall adherence rate was calculated at each time point of evaluation. For the HRQL domains, non-parametric testing was used to compare results between subgroups. RESULTS: Seventy-four patients were enrolled. AA and HRQL at 30 days and 3 months were assessed in 50 and 36 participants, respectively. At 30 days the AA rate was 90%, and at 3 months it was 83%. In regard to HRQL, patients suffered frequent and moderate-severe distress in the domains of emotional and physical symptoms, sleep disturbance, and limitations to physical activity. An association between emotional or physical distress and AA was observed. CONCLUSION: Patients with VTE suffer a substantial impairment of their HRQL. Increased emotional distress correlated with better long-term AA. These results can be used to inform additional research aimed at developing novel strategies to improve AA.

Safety and Effectiveness of Direct Oral Anticoagulants for the Treatment of Gastrointestinal Cancer-Associated Venous Thromboembolism.

BACKGROUND: Patients with gastrointestinal cancer (GICA) are at high risk for venous thromboembolism (VTE). Data from randomized clinical trials in cancer-associated VTE suggest that direct oral anticoagulants (DOACs) conferred similar or superior efficacy but a heterogeneous safety profile in patients with GICA. We compared the safety and effectiveness of DOACs in patients with GICA and VTE at MD Anderson Cancer Center. MATERIALS AND METHODS: This was a retrospective chart review of patients with GICA and VTE receiving treatment with DOACs for a minimum of 6 months. Primary outcomes were the proportion of patients experiencing major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and recurrent VTE. Secondary outcomes were time to bleeding and recurrent VTE. RESULTS: A cohort of 433 patients with GICA who were prescribed apixaban (n = 300), or rivaroxaban (n = 133) were included. MB occurred in 3.7% (95% confidence interval [CI] 2.1-5.9), CRNMB in 5.3% (95% CI 3.4-7.9), and recurrent VTE in 7.4% (95% CI 5.1-10.3). The cumulative incidence rates of CRNMB and recurrent VTE were not significantly different when comparing apixaban to rivaroxaban. CONCLUSION: Apixaban and rivaroxaban had a similar risk of recurrent VTE and bleeding and could be considered as anticoagulant options in selected patients with GICA and VTE.

External validation of a novel electronic risk score for cancer-associated thrombosis in a comprehensive cancer center.

Venous thromboembolism (VTE) is a significant complication for cancer patients undergoing systemic therapy. We performed an independent external validation for a recently derived and validated a novel electronic health record (EHR) VTE risk score in a comprehensive cancer center. Adult patients with incident cancer diagnoses were identified from MD Anderson Cancer Center Tumor Registry 1/2017-1/2021. Baseline covariates extracted at the time of first-line systemic therapy included demographics, cancer site/histology, stage, treatment, complete blood count, body mass index, recent prolonged hospitalization, and history of VTE or paralysis. VTE was ascertained using an institution-specific natural language processing radiology algorithm (positive predictive value of 94.8%). The median follow-up for 21 142 cancer patients was 8.1 months. There were 1067 (5.7%) VTE within 6 months after systemic therapy. The distribution of the novel score for 0-, 1, 2, 3, 4, 5+ was 5661, 3558, 3462, 3489, 2918, and 2054; while the corresponding 6-month VTE incidence was 1.3%, 3.1%, 5.4%, 7.3%, 9.3%, and 13.8%, respectively (c statistic 0.71 [95% CI 0.69-0.72] with excellent calibration). In comparison, the Khorana score had a c statistic of 0.64 [95% CI 0.62-0.65]. The two risk scores had 80% concordance; the novel score reclassified 20% of Khorana score (3530 low-to-high with 9.0% VTE; 734 high-to-low with 3.4% VTE) and led to a 25% increment in VTEs captured in the high-risk group. In conclusion, the novel score demonstrated consistent discrimination and calibration across cohorts with heterogenous demographics. It could become a new standard to select high-risk populations for clinical trials and VTE monitoring.

Hematologic complications of immune checkpoint inhibitors.

Immune checkpoint inhibitors are a class of antineoplastic therapies that unleash immune cells to kill malignant cells. There are currently 7 medications that have been approved by the US Food and Drug Administration for the treatment of 14 solid tumors and 2 hematologic malignancies. These medications commonly cause immune-related adverse effects as a result of overactive T lymphocytes, autoantibody production, and/or cytokine dysregulation. Hematologic toxicities are rare and of uncertain mechanism, and therefore management is often based on experiences with familiar conditions involving these perturbed immune responses, such as autoimmune hemolytic anemia, immune thrombocytopenia, and idiopathic aplastic anemia. Management is challenging because one must attend to the hematologic toxicity while simultaneously attending to the malignancy, with the imperative that effective cancer therapy be maintained or minimally interrupted if possible. The purpose of this review is to help clinicians by providing a clinical and pathophysiological framework in which to view these problems.

Durability of partial splenic artery embolization on platelet counts for cancer patients with hypersplenism-related thrombocytopenia.

PURPOSE: Partial splenic artery embolization (PSAE) has shown promise in increasing platelet counts in cancer patients with hypersplenism-related thrombocytopenia. The purpose of this study was to identify response predictors and to longitudinally evaluate PSAE efficacy and durability in a large cohort of cancer patients with hypersplenism-related thrombocytopenia. METHODS: A single-institution, IRB-approved, HIPAA-compliant retrospective review of all PSAEs for thrombocytopenia between 2012 and 2015 was performed. Patients were classified as complete responders (CR, no platelet value < 100 × 109/L following PSAE), partial responders (PR, initial increase in platelets but subsequent decrease in platelets < 100 × 109/L), and non-responders (NR, platelets never > 100 × 109/L following PSAE). RESULTS: Of the 98 patients included in the study, 58 had CR (59%), 28 had PR (29%), and 12 patients had NR (12%). The percent splenic tissue embolized was significantly greater in the CR group compared to the PR group (P = 0.001). The percent volume of splenic tissue embolized was linearly correlated with the magnitude of platelet increase without a minimum threshold. At least one line of chemotherapy was successfully restarted in 97% of patients, and 41% of patients did not experience recurrence of thrombocytopenia for the duration of their survival. The major complication rate was 8%, with readmission following initial hospitalization for persistent "post-embolization syndrome" symptoms the most common. CONCLUSIONS: In cancer patients with hypersplenism-related thrombocytopenia, PSAE is a safe intervention that effects a durable elevation in platelet counts across a range of malignancies and following the re-initiation of chemotherapy.

A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia.

Ibrutinib is highly efficacious and used at 420 mg/d for treatment of chronic lymphocytic leukemia (CLL). We previously demonstrated a decline in Bruton's tyrosine kinase (BTK) protein levels in CLL cells after 1 cycle of ibrutinib, suggesting ibrutinib dose could be lowered after the first cycle without loss of biological effect. To test this postulate, a pilot study (NCT02801578) was designed to systematically reduce ibrutinib dosing within the same patient with CLL over the course of three 28-day cycles. After an initial cycle of 420 mg/d, the dose was reduced to 280 mg/d in cycle 2, and then to 140 mg/d in cycle 3. Eleven patients began study treatment, and 9 completed the 3 cycles. Plasma and intracellular pharmacokinetics (PK), BTK occupancy, and pharmacodynamic (PD) response at different doses of ibrutinib were compared. Plasma and intracellular levels of ibrutinib were dose-dependent, and even the lowest dose was sufficient to occupy, on average, more than 95% of BTK protein. In concert, BTK downstream signaling inhibition was maintained with 140 mg/d ibrutinib in cycle 3, and there were comparable reductions in total and phospho-BTK (Tyr223) protein levels across 3 cycles. Reductions of plasma chemokine CCL3 and CCL4 levels, considered to be biomarkers of ibrutinib response, were similar during the 3 cycles. These PK/PD data demonstrate that after 1 cycle of ibrutinib at the standard 420 mg/d dose, the dose can be reduced without losing biological activity. Clinical efficacy of lower doses needs to be systematically evaluated. Such dose reductions would lower drug cost, lessen untoward toxicity, and facilitate rationale-based combinations. This trial was registered at www.clinicaltrials.gov as #NCT02801578.

Recurrence of venous thromboembolism among adults acute leukemia patients treated at the University of Texas MD Anderson Cancer Center: Incidence and risk factors.

The purpose was to determine the incidence and risk factors for venous thromboembolism (VTE) recurrence among adult acute leukemia patients. We performed a retrospective study of adult acute leukemia patients who were treated at our institution between November 1999 and May 2005. Medical records of 139 patients with an initial VTE were reviewed and followed up to May 2010 for VTE recurrence. Of these 139 patients [86 with acute myelogenous leukemia (AML), 53 with acute lymphocytic leukemia (ALL)], 27 (19.4%, 16 AML and 11 ALL) had VTE recurrence. The overall incidence rate of VTE was 8.6 per 100 person-years (median follow-up time: 0.9years). It was 5.9 and 12.4 per 100 person-years among ALL and AML patients, respectively. The cumulative proportion of recurrent VTE was 2.16%, 10.9%, 16.6%, 25.9%, 30.6%, and 34.2% at 1month, 6months, 1year, 3years, 5years, and 7years, respectively. In a multivariate Cox hazards model, significant predictors for VTE recurrence included catheter thrombosis [adjusted hazard ratio (aHR)]:6.3, 95%CI:1.17-34.0), prior history of hematologic cancer (aHR:4.2, 95%CI:1.5-11.2), chronic lung disease (aHR: 3.4, 95%CI:0.92-12.5), psychological disorder (aHR: 4.3, 95%CI:1.5-12.2), and liver disease (aHR: 3.8, 95%CI: 1.04-14.3). VTE recurrence is common among adult acute leukemia patients and it continues up to 7years after the initial episode. Catheter thrombosis, a history of hematologic malignancy antecedent to acute leukemia, and lung, liver and psychiatric co-morbidities increase the patient risk for VTE recurrence. Further studies should be conducted to improve the prevention of VTE recurrence in leukemia patients.

Platelets are not hyperreactive in patients with ovarian cancer.

Paraneoplastic thrombocytosis has been reported in different types of solid tumors, including ovarian epithelial cancer, and found to be associated with a worse outcome. Although the effect of cancer on increasing platelet counts is well documented, the effect of cancer on platelet functions is not well known. We compared in vitro aggregation response of platelets isolated from 34 patients with ovarian cancer to those of platelets from 19 patients with benign ovarian tumors. Aggregation studies were conducted in a light transmission aggregometer, using both a high and a low dose of ADP and collagen. We evaluated platelet preactivation by measuring the plasma concentration of ß-thromboglobulin (ß-TG) and platelet factor-4 (PF-4) as markers of platelet α granule secretion, using ELISA. We found that ovarian cancer is not associated with an enhanced aggregation response of platelets to ADP or collagen, and plasma concentration of ß-TG and PF-4 is not higher in patients with ovarian cancer compared to those in patients with benign ovarian tumors.

Prognostic value of pretherapy platelet elevation in oropharyngeal cancer patients treated with chemoradiation.

The purpose of this study is to evaluate potential associations between increased platelets and oncologic outcomes in oropharyngeal cancer patients receiving concurrent chemoradiation. A total of 433 oropharyngeal cancer patients (OPC) treated with intensity-modulated radiation therapy (IMRT) with concurrent chemotherapy between 2002 and 2012 were included under an approved IRB protocol. Complete blood count (CBC) data were extracted. Platelet and hemoglobin from the last phlebotomy (PLTpre-chemoRT, Hgbpre-chemoRT ) before start of treatment were identified. Patients were risk-stratified using Dahlstrom-Sturgis criteria and were tested for association with survival and disease-control outcomes. Locoregional control (LRC), freedom from distant metastasis (FDM) and overall survival (OS) were decreased (p < 0.03, p < 0.04 and p < 0.0001, respectively) for patients with PLTpre-chemoRT value of ≥350 × 10(9) /L. Actuarial 5-year locoregional control (LRC) and FDM were 83 and 85% for non-thrombocythemic patients while patient with high platelets had 5-year LRC and FDM of 73 and 74%, respectively. Likewise, 5-year OS was better for patients with normal platelet counts by comparison (76 vs. 57%; p < 0.0001). Comparison of univariate parametric models demonstrated that PLTpre-chemoRT was better among tested models. Multivariate assessment demonstrated improved performance of models which included pretherapy platelet indices. On Bayesian information criteria analysis, the optimal prognostic model was then used to develop nomograms predicting 3-, 5- and 10-year OS. In conclusion, pretreatment platelet elevation is a promising predictor of prognosis, and further work should be done to elucidate the utility of antiplatelets in modifying risk in OPC patients.

Mechanisms of thrombogenesis in polycythemia vera.

Thrombotic and cardiovascular events are among the leading causes of death for patients with polycythemia vera (PV), and thrombosis history is a key criterion for patient risk stratification and treatment strategy. Little is known, however, about mechanisms of thrombogenesis in patients with PV. This report provides an overview of thrombogenesis pathophysiology in patients with PV and elucidates the roles of conventional and nonconventional thrombotic risk factors. In addition to several conventional risk factors for thrombosis, clinical data have implicated increased hematocrit and red blood cell adhesiveness, activated platelets, leukocytosis, and elevated JAK2(V617F) allele burden in patients with PV. Furthermore, PV-related inflammation may exacerbate thrombogenesis through varied mechanisms, including endothelial damage, inhibition of natural anticoagulant pathways, and secretion of procoagulant factors. These findings suggest a direct link between myeloproliferation and thrombogenesis in PV, which is likely to provide new opportunities for targeted antithrombotic interventions aimed at decreasing PV-related morbidity and mortality.

von Willebrand factor is a cofactor in complement regulation.

Several complement proteins interact with hemostatic factors. We discovered that von Willebrand factor (VWF) acts as a cofactor for factor I-mediated cleavage of complement C3b, thereby shutting down complement activation. The complement regulatory function of VWF multimers depends on their size. Smaller VWF multimers enhance cleavage of C3b but large and ultra-large VWF (ULVWF) multimers have no effect on C3b cleavage and permit default complement activation. We conclude that normal plasma VWF multimers prevent complement activation and steer the complement pathway toward generation of inactivated C3b (iC3b). ULVWF multimers, as are present in patients with thrombotic microangiopathy, lack an inhibitory effect on complement and permit complement activation.

Improved compliance with venous thromboembolism pharmacologic prophylaxis for patients with gynecologic malignancies hospitalized for nonsurgical indications did not reduce venous thromboembolism incidence.

OBJECTIVE: National guidelines recommend prophylactic anticoagulation for all hospitalized patients with cancer to prevent hospital-acquired venous thromboembolism (VTE). However, adherence to these evidence-based recommended practice patterns remains low. We performed a quality improvement (QI) project to increase VTE pharmacologic prophylaxis rates among patients with gynecologic malignancies hospitalized for nonsurgical indications and evaluated the resulting effect on rates of development of VTE. MATERIALS AND METHODS: In June 2011, departmental VTE practice guidelines were implemented for patients with gynecologic malignancies who were hospitalized for nonsurgical indications. A standardized VTE prophylaxis module was added to the admission electronic order sets. Outcome measures included number of admissions receiving VTE pharmacologic prophylaxis within 24 hours of admission; and number of potentially preventable hospital-acquired VTEs diagnosed within 30 and 90 days of discharge. Outcomes were compared between a preguideline implementation cohort (n = 99), a postguideline implementation cohort (n = 127), and a sustainability cohort assessed 2 years after implementation (n = 109). Patients were excluded if upon admission they had a VTE, were considered low risk for VTE, or had a documented contraindication to pharmacologic prophylaxis. RESULTS: Administration of pharmacologic prophylaxis within 24 hours of admission increased from 20.8% to 88.2% immediately following the implementation of guidelines, but declined to 71.8% in our sustainability cohort (P < 0.001). There was no difference in VTE incidence among the 3 cohorts [n = 2 (4.2%) vs n = 3 (3.9%) vs n = 3 (4.2%), respectively; P = 1.00]. CONCLUSIONS: Our QI project improved pharmacologic VTE prophylaxis rates. A small decrease in prophylaxis during the subsequent 2 years suggests a need for continued surveillance to optimize QI initiatives. Despite increased adherence to guidelines, VTE rates did not decline in this high-risk population.

A retrospective study of venous thromboembolism in acute leukemia patients treated at the University of Texas MD Anderson Cancer Center.

The purpose was to determine the incidence and prevalence of venous thromboembolism (VTE) in acute leukemia patients from our institution. We conducted a retrospective study on newly diagnosed acute leukemia patients who presented at our institution from November 1999 to May 2005. Descriptive statistics and cross-tabulation were used to describe patient characteristics. Measures of morbidity were used to address VTE risk. Chi-square testing, Fisher's exact testing, Mann-Whitney analyses, or median testing were used to determine between-group differences. Data analyses were conducted using Stata version 11 (Stata Corp., College Station, TX). Two hundred and ninety-nine patients with acute lymphoblastic leukemia (ALL) and 996 patients with acute myeloid leukemia (AML) were included. After excluding patients diagnosed with VTE prior to or at the time of leukemia diagnosis, during the mean time follow-up period of 2.5 years (range: 0.0025-10.3 years), the overall incidence rate of VTE was 3.7 per 100 person-years: 4.2 per 100 person-years for ALL and 3.4 per 100 person-years for AML. Among all patients, the majority (80.6%) developed VTE within 12 months after diagnosis and during thrombocytopenia. The most common VTE was central venous catheter (CVC)-associated upper-extremity deep venous thrombosis. Pulmonary embolism occurred in 15% of ALL patients and 8% of AML patients. VTE recurred in 20.7% of ALL patients and 18.6% of AML patients. VTE occurs frequently in patients with acute leukemia. Studies are needed to identify risk factors for the development and recurrence of VTE among patients with acute leukemia and to establish more effective methods for preventing and treating VTEs in leukemia patients who have thrombocytopenia and/or CVC.

The interaction between factor H and Von Willebrand factor.

Complement factor H (fH) is a plasma protein that regulates activation of the alternative pathway, and mutations in fH are associated with a rare form of thrombotic microangiopathy (TMA), known as atypical hemolytic uremic syndrome (aHUS). A more common TMA is thrombotic thrombocytopenic purpura, which is caused by the lack of normal ADAMTS-13-mediated cleavage of von Willebrand factor (VWF). We investigated whether fH interacts with VWF and affects cleavage of VWF. We found that factor H binds to VWF in plasma, to plasma-purified VWF, and to recombinant A1 and A2 domains of VWF as detected by co-immunoprecipitation (co-IP) and surface plasmon resonance assays. Factor H enhanced ADAMTS-13-mediated cleavage of recombinant VWF-A2 as determined by quantifying the cleavage products using Western-blotting, enhanced cleavage of a commercially available fragment of VWF-A2 (FRETS-VWF73) as determined by fluorometric assay, and enhanced cleavage of ultralarge (UL) VWF under flow conditions as determined by cleavage of VWF-platelet strings attached to histamine stimulated endothelial cells. Using recombinant full-length and truncated fH molecules, we found that the presence of the C-terminal half of fH molecule is important for binding to VWF-A2 and for enhancing cleavage of the A2 domain by ADAMTS-13. We conclude that factor H binds to VWF and may modulate cleavage of VWF by ADAMTS-13.