Proton-beam Therapy for Locally Advanced Hepatocellular Carcinoma With Inferior Vena Cava Tumor Thrombus: Case Report.

BACKGROUND/AIM: We report on a case of locally advanced hepatocellular carcinoma (HCC) accompanied by an inferior vena cava tumor thrombus (IVCTT), treated successfully with proton-beam therapy (PBT). CASE REPORT: A 63-year-old male presented with a primary, single HCC with IVCTT, without metastasis to the intrahepatic region, lymph nodes, or distant organs. The clinical staging was identified as T4N0M0 Stage IIIB. The patient's liver function was classified as Child-Pugh class A (score: 6), with a modified albumin-bilirubin (mALBI) grade of 2a. The patient had liver cirrhosis due to non-alcoholic steatohepatitis. Magnetic resonance imaging revealed a nodular tumor measuring 13.2×8.9×9.8 cm across segments 1, 6, 7, and 8, along with IVCTT. The patient received PBT, with a total dose of 72.6 Gy (relative biological effectiveness) delivered in 22 fractions. Throughout the PBT treatment, the patient experienced no acute toxicities and completed the therapy as planned. Twelve months following PBT, the patient was alive without evidence of local recurrence, lymph node involvement, or distant organ metastasis. The only late toxicity observed was a mild worsening of the mALBI grade. CONCLUSION: We observed a favorable local response with manageable toxicities in a patient with locally advanced HCC and IVCTT treated with PBT. While this is a single case report, our findings suggest that PBT could be considered a viable treatment option for HCC with IVCTT.

Rodent Inferior Vena Cava Venoplasty Balloon Model.

Balloon venoplasty is a commonly used clinical technique to treat deep vein stenosis and occlusion as a consequence of trauma, congenital anatomic abnormalities, acute deep vein thrombosis (DVT), or stenting. Chronic deep venous obstruction is histopathologically characterized by thrombosis, fibrosis, or both. Currently, no direct treatment is available to target these pathological processes. Therefore, a reliable in vivo animal model to test novel interventions is necessary. The rodent survival inferior vena cava (IVC) venoplasty balloon model (VBM) allows the study of balloon venoplasty in non-thrombotic and post-thrombotic conditions across multiple time points. The local and systemic effect of coated and uncoated venoplasty balloons can be quantified via tissue, thrombus, and blood assays such as real-time polymerase chain reaction (RT-PCR), western blot, enzyme-linked immunosorbent assay (ELISA), zymography, vein wall and thrombus cellular analysis, whole blood and plasma assays, and histological analysis. The VBM is reproducible, replicates surgical human interventions, can identify local vein wall-thrombi protein changes, and allows multiple analyses from the same sample, decreasing the number of animals required per group.

Neutrophil extracellular traps formation may be involved in the association of propranolol with the development of portal vein thrombosis.

BACKGROUND & AIMS: Nonselective ß blockers (NSBBs) facilitate the development of portal vein thrombosis (PVT) in liver cirrhosis. Considering the potential effect of NSBBs on neutrophils and neutrophil extracellular traps (NETs), we speculated that NSBBs might promote the development of PVT by stimulating neutrophils to release NETs. MATERIALS AND METHODS: Serum NETs biomarkers were measured, use of NSBBs was recorded, and PVT was evaluated in cirrhotic patients. Carbon tetrachloride and ferric chloride (FeCl3) were used to induce liver fibrosis and PVT in mice, respectively. After treatment with propranolol and DNase I, neutrophils in peripheral blood, colocalization and expression of NETs in PVT specimens, and NETs biomarkers in serum were measured. Ex vivo clots lysis analysis was performed and portal vein velocity and coagulation parameters were tested. RESULTS: Serum MPO-DNA level was significantly higher in cirrhotic patients treated with NSBBs, and serum H3Cit and MPO-DNA levels were significantly higher in those with PVT. In fibrotic mice, following treatment with propranolol, DNase I significantly shortened the time of FeCl3-induced PVT formation, lowered the peripheral blood neutrophils labelled by CD11b/Ly6G, inhibited the positive staining of H3Cit and the expression of H3Cit and MPO proteins in PVT tissues, and reduced serum nucleosome level. Furthermore, the addition of DNase I to tissue plasminogen activator (tPA) significantly accelerated clots lysis as compared with tPA alone. Propranolol reduced portal vein velocity in fibrotic mice, but did not influence coagulation parameters. CONCLUSION: Our study provides a clue to the potential impact of NETs formation on the association of NSBBs with the development of PVT.

Endothelial PTP1B Deletion Promotes VWF Exocytosis and Venous Thromboinflammation.

BACKGROUND: Endothelial activation promotes the release of procoagulant extracellular vesicles and inflammatory mediators from specialized storage granules. Endothelial membrane exocytosis is controlled by phosphorylation. We hypothesized that the absence of PTP1B (protein tyrosine phosphatase 1B) in endothelial cells promotes venous thromboinflammation by triggering endothelial membrane fusion and exocytosis. METHODS: Mice with inducible endothelial deletion of PTP1B (End.PTP1B-KO) underwent inferior vena cava ligation to induce stenosis and venous thrombosis. Primary endothelial cells from transgenic mice and human umbilical vein endothelial cells were used for mechanistic studies. RESULTS: Vascular ultrasound and histology showed significantly larger venous thrombi containing higher numbers of Ly6G (lymphocyte antigen 6 family member G)-positive neutrophils in mice with endothelial PTP1B deletion, and intravital microscopy confirmed the more pronounced neutrophil recruitment following inferior vena cava ligation. RT2 PCR profiler array and immunocytochemistry analysis revealed increased endothelial activation and adhesion molecule expression in primary End.PTP1B-KO endothelial cells, including CD62P (P-selectin) and VWF (von Willebrand factor). Pretreatment with the NF-κB (nuclear factor kappa B) kinase inhibitor BAY11-7082, antibodies neutralizing CD162 (P-selectin glycoprotein ligand-1) or VWF, or arginylglycylaspartic acid integrin-blocking peptides abolished the neutrophil adhesion to End.PTP1B-KO endothelial cells in vitro. Circulating levels of annexin V+ procoagulant endothelial CD62E+ (E-selectin) and neutrophil (Ly6G+) extracellular vesicles were also elevated in End.PTP1B-KO mice after inferior vena cava ligation. Higher plasma MPO (myeloperoxidase) and Cit-H3 (citrullinated histone-3) levels and neutrophil elastase activity indicated neutrophil activation and extracellular trap formation. Infusion of End.PTP1B-KO extracellular vesicles into C57BL/6J wild-type mice most prominently enhanced the recruitment of endogenous neutrophils, and this response was blunted in VWF-deficient mice or by VWF-blocking antibodies. Reduced PTP1B binding and tyrosine dephosphorylation of SNAP23 (synaptosome-associated protein 23) resulting in increased VWF exocytosis and neutrophil adhesion were identified as mechanisms, all of which could be restored by NF-κB kinase inhibition using BAY11-7082. CONCLUSIONS: Our findings show that endothelial PTP1B deletion promotes venous thromboinflammation by enhancing SNAP23 phosphorylation, endothelial VWF exocytosis, and neutrophil recruitment.

PDIA2 has a dual function in promoting androgen deprivation therapy induced venous thrombosis events and castrate resistant prostate cancer progression.

Androgen deprivation therapy (ADT) is the first line of treatment for metastatic prostate cancer (PCa) that effectively delays the tumor progression. However, it also increases the risk of venous thrombosis event (VTE) in patients, a leading cause of mortality. How a pro-thrombotic cascade is induced by ADT remains poorly understood. Here, we report that protein disulfide isomerase A2 (PDIA2) is upregulated in PCa cells to promote VTE formation and enhance PCa cells resistant to ADT. Using various in vitro and in vivo models, we demonstrated a dual function of PDIA2 that enhances tumor-mediated pro-coagulation activity via tumor-derived extracellular vehicles (EVs). It also stimulates PCa cell proliferation, colony formation, and xenograft growth androgen-independently. Mechanistically, PDIA2 activates the tissue factor (TF) on EVs through its isomerase activity, which subsequently triggers a pro-thrombotic cascade in the blood. Additionally, TF-containing EVs can activate the Src kinase inside PCa cells to enhance the AR signaling ligand independently. Androgen deprivation does not alter PDIA2 expression in PCa cells but enhances PDIA2 translocation to the cell membrane and EVs via suppressing the clathrin-dependent endocytic process. Co-recruitment of AR and FOXA1 to the PDIA2 promoter is required for PDIA2 transcription under androgen-deprived conditions. Importantly, blocking PDIA2 isomerase activity suppresses the pro-coagulation activity of patient plasma, PCa cell, and xenograft samples as well as castrate-resistant PCa xenograft growth. These results demonstrate that PDIA2 promotes VTE and tumor progression via activating TF from tumor-derived EVs. They rationalize pharmacological inhibition of PDIA2 to suppress ADT-induced VTE and castrate-resistant tumor progression.

Experimental multiparametric magnetic resonance imaging characterization of iliocaval venous thrombosis pathological changes.

OBJECTIVE: Iliocaval thrombotic obstruction is a challenging condition, especially because thrombus age and corresponding pathological remodeling at presentation are unknown, which directly impacts management. Our aim was to assess the ability of magnetic resonance imaging (MRI) in determining age thresholds of experimentally created inferior vena cava (IVC) thrombosis in pigs. METHODS: We used a previously described swine model of IVC thrombosis. The animals underwent MRI at baseline, immediately after thrombosis creation, and after a follow-up period extending from 2 to 28 days. Thirteen pigs were divided into three groups according to disease chronicity: acute group (AG; n = 5), subacute group (SAG; n = 4), and chronic group (CG; n = 4), with a mean thrombosis age of 6.4 ± 2.5 days, 15.7 ± 2.8 days, and 28 ± 5.7 days, respectively. A T1-weighted volumetric interpolated breath-hold examination sequence was used to anatomically delineate IVC thrombus as a region of interest. Three other MRI sequences were used to assess the thrombus signal. RESULTS: The Kruskal-Wallis test showed a statistically significant difference in T1 relaxation times after contrast injection (P = .026) between the three groups of chronicity. The AG (360.2 ± 102.5 ms) was significantly different from the CG (336.7 ± 55.2 ms; P = .003), and the SAG (354.1 ± 89.7 ms) was significantly different from the AG (P = .027). There was a statistically significant difference in native T2 relaxation times (P = .038) between the three groups. The AG (160 ± 86.7 ms) was significantly different from the SAG (142.3 ± 55.4 ms; P = .027), and the SAG was significantly different from the CG (178.4 ± 11.7 ms; P = .004). CONCLUSIONS: This study highlighted MRI characteristics in a swine model that might have the potential to significantly differentiate subacute and chronic stages from an acute stage of deep vein thrombosis in humans. Further clinical studies in humans are warranted. CLINICAL RELEVANCE: In addition to providing a better understanding of venous thrombosis remodeling over time, magnetic resonance imaging has the potential to be a tool that could allow us to characterize the composition of venous thrombus over an interval, allowing for a refined analysis of the local evolution of venous thrombosis. We propose a noninvasive and innovative method to characterize different thresholds of chronicity with magnetic resonance imaging features of central deep vein thrombosis of the inferior vena cava experimentally obtained using a totally endovascular in vivo swine model, mimicking human pathophysiology. Being able to determine these features noninvasively is critical for vascular specialists when it comes to choosing between fibrinolytic therapy, percutaneous thrombectomy, or surgical management.

Time-dependent ultrastructural changes during venous thrombogenesis and thrombus resolution.

BACKGROUND: Deep vein thrombosis is a common vascular event that can result in debilitating morbidity and even death due to pulmonary embolism. Clinically, patients with faster resolution of a venous thrombus have improved prognosis, but the detailed structural information regarding changes that occur in a resolving thrombus over time is lacking. OBJECTIVES: To define the spatial-morphologic characteristics of venous thrombus formation, propagation, and resolution at the submicron level over time. METHODS: Using a murine model of stasis-induced deep vein thrombosis along with scanning electron microscopy and immunohistology, we determine the specific structural, compositional, and morphologic characteristics of venous thrombi formed after 4 days and identify the changes that take place during resolution by day 7. Comparison is made with the structure and composition of venous thrombi formed in mice genetically deficient in plasminogen activator inhibitor type 1. RESULTS: As venous thrombus resolution progresses, fibrin exists in different structural forms, and there are dynamic cellular changes in the compositions of leukocytes, platelet aggregates, and red blood cells. Intrathrombus microvesicles are present that are not evident by histology, and red blood cells in the form of polyhedrocytes are an indicator of clot contraction. Structural evidence of fibrinolysis is observed early during thrombogenesis and is accelerated by plasminogen activator inhibitor type 1 deficiency. CONCLUSION: The results reveal unique, detailed ultrastructural and compositional insights along with documentation of the dynamic changes that occur during accelerated resolution that are not evident by standard pathologic procedures and can be applied to inform diagnosis and effectiveness of thrombolytic treatments to improve patient outcomes.

Mucin 1 and venous thrombosis in tumor-bearing mice and patients with cancer.

INTRODUCTION: Mucins released from epithelial tumors have been proposed to play a role in cancer-associated thrombosis. Mucin1 (MUC1) is a transmembrane mucin that is overexpressed in a variety of human malignancies, including breast and pancreatic cancer. We analyzed the association of MUC1 and venous thrombosis in a mouse tumor model and in patients with cancer. MATERIALS AND METHODS: We used a human pancreatic cancer cell line HPAF-II that expresses a high level of MUC1. We grew HPAF-II tumors in the pancreas of Crl:NU-Foxn1nu male mice. MUC1 in plasma and extracellular vesicles (EVs) isolated from plasma was measured using an enzyme-linked immunosorbent assay. MUC1 in EVs and venous thrombi from tumor-bearing mice was assessed by western blotting. We measured MUC1 in plasma from healthy controls and patients with stomach, colorectal or pancreatic cancer with or without venous thromboembolism. RESULTS AND DISCUSSION: MUC1 was detected in the plasma of mice bearing HPAF-II tumors and was associated with EVs. MUC1 was present in venous thrombi from mice bearing HFAP-II tumors. Recombinant MUC1 did not induce platelet aggregation. Levels of MUC1 were higher in patients with pancreatic cancer compared with healthy controls. In contrast to the mouse model, MUC1 was present in EV-free plasma in samples from healthy controls and patients with cancer. There was no significant difference in the levels of MUC1 in cancer patients with or without VTE. Our data did not find any evidence that MUC1 contributed to VTE in patients with cancer.

Platelet factor 4 promotes deep venous thrombosis by regulating the formation of neutrophil extracellular traps.

The presence of neutrophil extracellular traps (NETs) in thrombotic diseases has been extensively studied. The exact mechanism of NET formation in deep venous thrombosis (DVT) has not been largely studied. This study is aimed to explore the role of NETs and their interaction with platelet factor 4 (PF4) in DVT. In plasma samples from 51 healthy volunteers and 52 DVT patients, NET markers and PF4 were measured using enzyme-linked immunosorbent assays (ELISA). NET generation in blood samples from healthy subjects and DVT patients was analyzed by confocal microscopy and flow cytometry. The plasma levels of NETs were significantly elevated in DVT patients, and neutrophils from patients showed a stronger ability to generate NETs after treatment. PF4 was upregulated in plasma samples from DVT patients and mediated NET formation. NETs enhanced procoagulant (PCA) via tissue factor and activating platelets to induce procoagulant activity. In addition, we established an inferior vena cava ligation (IVC) model to examine the role of NETs in thrombogenicity in DVT. In conclusion, NET formation was mediated by PF4 and enhance the procoagulant activity in DVT.

Renal cell carcinoma and venous tumor thrombus: predicting sarcomatoid dedifferentiation through preoperative IVIM-based MR imaging.

PURPOSE: To evaluate the value of preoperative intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and conventional MRI indicators in identifying sarcomatoid dedifferentiation in renal cell carcinoma (RCC) and tumor thrombus. METHODS: From September 2016 to April 2023, consecutive patients with RCC and tumor thrombus who received routine MRI examination and IVIM-DWI before radical resection were enrolled prospectively. Kaplan-Meier method with log-rank test was used to calculate and compare the survival probability. The preoperative imaging features were analyzed. Univariate and multivariable logistic regression analyses were employed to identify independent predictors of sarcomatoid dedifferentiation. The predictive ability was evaluated by receiver operating characteristic (ROC) curves. RESULTS: Twenty-two patients (15.3%) of the 144 patients in the training set (median age, 58.0 years [IQR, 52.0-65.0 years]; 108 men) and 11 patients (22.4%) of the 49 patients in the test set (median age, 58.0 years [IQR, 53.0-63.0 years]; 38 men) had sarcomatoid dedifferentiated tumors. Patients with sarcomatoid-differentiated tumors had poor progress-free survival in the training set and test set (P < 0.001 and P = 0.007). f value (P = 0.011), mN stage (P = 0.007), and necrosis (P = 0.041) were independent predictors for predicting sarcomatoid dedifferentiation in the training set. The model combining conventional MRI features and f value had AUCs of 0.832 (95% CI 0.755-0.909) and 0.825 (95% CI 0.702-0.948) in predicting sarcomatoid dedifferentiation in the training set and test set. CONCLUSION: It is feasible to preoperatively identify sarcomatoid dedifferentiation based on IVIM-DWI and conventional MR imaging indicators.

Advanced Renal Cell Carcinoma With Inferior Vena Cava Thrombus Treated With a Combination of Preoperative Lenvatinib and Pembrolizumab.

BACKGROUND/AIM: Lenvatinib plus pembrolizumab combination therapy is a safe and effective treatment for patients with advanced renal cell carcinoma (RCC). However, there are no reports of the use of lenvatinib and pembrolizumab combination therapy for RCC with an inferior vena cava (IVC) tumor thrombus. Herein, we describe a case in which pembrolizumab and lenvatinib combination therapy was effectively used to treat RCC with the IVC tumor thrombus extending to the right atrium. CASE REPORT: A 73-year-old man was diagnosed with a right renal tumor with the IVC tumor thrombus extending to the right atrium and multiple pulmonary metastases (cT3cN0M1). Using a computed tomography-guided renal tumor biopsy, the tumor was diagnosed as clear cell RCC. The International Metastatic RCC Database Consortium risk classification was poor according to three risk factors, and lenvatinib and pembrolizumab combination therapy was initiated. The primary renal tumor shrunk, the IVC tumor thrombus that reached the right atrium was reduced from level 4 to level 2, and the lung metastases disappeared 4 months after treatment initiation. Thereafter, a robot-assisted deferred cytoreductive nephrectomy was successfully performed. Pathologically, owing to the preoperative combination therapy, most of the tumor tissue was necrotic; however, some viable cells were present in the primary tumor and IVC tumor thrombus. Eight months following the operation, the patient remains recurrence-free. CONCLUSION: Treatment with lenvatinib and pembrolizumab combination therapy led to tumor shrinkage and allowed robot-assisted nephrectomy in a patient with advanced RCC with the IVC tumor thrombus extending to the right atrium, corroborating the efficacy of the treatment.

Notoginsenoside Fc alleviates oxidized low-density lipoprotein-induced endothelial cell dysfunction and upregulates PPAR-γ in vitro.

BACKGROUND: Deep venous thrombosis (DVT) is a prevalent vascular disease and a major cause of morbidity and mortality worldwide. Notoginsenoside Fc (NFc) is a protopanaxadiol-type saponin that has been shown to have beneficial effects on several disorders. However, its function in DVT is unclear. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low-density lipoprotein (ox-LDL) to mimic DVT in vitro and treated with NFc to investigate its functions. CCK-8 assay was utilized for measuring cell viability. Western blotting was used for detecting protein levels of proinflammatory cytokines, apoptosis-related markers, and peroxisome proliferator-activated receptor-γ (PPAR-γ). Flow cytometry was performed for cell apoptosis detection. Levels of oxidative stress-related markers were examined by the DCFH-DA method and ELISA. RT-qPCR was utilized for the measurement of PPAR-γ mRNA level. RESULTS: NFc increased the viability and suppressed inflammation, apoptosis, and oxidative stress in ox-LDL-treated HUVECs. NFc treatment induced upregulation of PPAR-γ in HUVECs. CONCLUSION: NFc mitigates ox-LDL-induced dysfunction of HUVECs.

Management and Outcomes of Wilms Tumor With Suprarenal Intravascular Extension: A Pediatric Surgical Oncology Research Collaborative Study.

OBJECTIVE: The purpose of this study was to describe management and outcomes from a contemporary cohort of children with Wilms tumor complicated by inferior vena caval thrombus. BACKGROUND: The largest series of these patients was published almost 2 decades ago. Since then, neoadjuvant chemotherapy has been commonly used to manage these patients, and outcomes have not been reported. METHODS: Retrospective review of 19 North American centers between 2009 and 2019. Patient and disease characteristics, management, and outcomes were investigated and analyzed. RESULTS: Of 124 patients, 81% had favorable histology (FH), and 52% were stage IV. IVC thrombus level was infrahepatic in 53 (43%), intrahepatic in 32 (26%), suprahepatic in 14 (11%), and cardiac in 24 (19%). Neoadjuvant chemotherapy using a 3-drug regimen was administered in 82% and postresection radiation in 90%. Thrombus level regression was 45% overall, with suprahepatic level showing the best response (62%). Cardiopulmonary bypass (CPB) was potentially avoided in 67%. The perioperative complication rate was significantly lower after neoadjuvant chemotherapy [(25%) vs upfront surgery (55%); P =0.005]. CPB was not associated with higher complications [CPB (50%) vs no CPB (27%); P =0.08]. Two-year event-free survival was 93% and overall survival was 96%, higher in FH cases (FH 98% vs unfavorable histology/anaplastic 82%; P =0.73). Neither incomplete resection nor viable thrombus cells affected event-free survival or overall survival. CONCLUSIONS: Multimodal therapy resulted in excellent outcomes, even with advanced-stage disease and cardiac extension. Neoadjuvant chemotherapy decreased the need for CPB to facilitate resection. Complete thrombectomy may not always be necessary.

Refining MRI-based criteria for portal vein invasion in hepatocellular carcinoma: improving sensitivity beyond portal vein tumor thrombosis.

PURPOSE: To investigate the imaging features indicating portal vein invasion (PVI) of hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced MRI and to create more accurate diagnostic criteria than the presence of portal vein tumor thrombosis (PVTT) on MRI. METHODS: This retrospective study included patients with surgically resected HCC larger than 5 cm, and the presence of PVI was investigated. On MRI, we evaluated the image findings of portal vein occlusion, the parenchymal signal change caused by hemodynamic alterations of the portal vein, and their combination showing the highest odds ratio (OR) to define the diagnostic criteria for radiological PVI detection (rPVI criteria). The diagnostic performance and recurrence-free survival were compared between the rPVI criteria and the presence of PVTT using McNemar's test and Kaplan-Meier method, respectively. Interobserver agreement was evaluated using Cohen's weighted ĸ statistics. RESULTS: Of 189 enrolled patients, 25 (13.2%) had PVI on histology. To diagnose PVI on MRI, either peripheral wedge-shaped arterial peritumoral hyperemia with an abrupt cut-off of a portal vein or the presence of PVTT had the highest OR (41.67, p < 0.001). The sensitivity of PVI was significantly increased under this diagnostic criterion (64.0% to 88.0%; p = 0.031) with comparable accuracy (95.2% vs. 94.7%; p > 0.999). In terms of recurrence-free survival, the patient group with rPVI was significantly worse (p = 0.017) compared with the patients without rPVI. Interobserver agreement of radiologic findings was substantial (ĸ = 0.64). CONCLUSION: Diagnostic criteria for radiologically PVI detection increase the sensitivity more than the only presence of PVTT.

Role of platelet count in a murine stasis model of deep vein thrombosis.

Platelets are core components of thrombi but their effect on thrombus burden during deep vein thrombosis (DVT) has not been fully characterized. We examined the role of thrombopoietin-altered platelet count on thrombus burden in a murine stasis model of DVT. To modulate platelet count compared to baseline, CD1 mice were pretreated with thrombopoietin antisense oligonucleotide (THPO-ASO, 56% decrease), thrombopoietin mimetic (TPO-mimetic, 36% increase), or saline (within 1%). Thrombi and vein walls were examined on postoperative days (POD) 3 and 7. Thrombus weights on POD 3 were not different between treatment groups (p = .84). The mean thrombus weights on POD 7 were significantly increased in the TPO-mimetic cohort compared to the THPO-ASO (p = .005) and the saline (p = .012) cohorts. Histological grading at POD 3 revealed a significantly increased smooth muscle cell presence in the thrombi and CD31 positive channeling in the vein wall of the TPO-mimetic cohort compared to the saline and THPO-ASO cohorts (p < .05). No differences were observed in histology on POD 7. Thrombopoietin-induced increased platelet count increased thrombus weight on POD 7 indicating platelet count may regulate thrombus burden during early resolution of venous thrombi in this murine stasis model of DVT.

Deep vein thrombosis (DVT) is a pathology in which blood clots form in the deep veins of our body. Usually occurring in the legs, these clots can be dangerous if they dislodge and travel to the heart and are pumped into the lungs. Often these clots do not travel and heal where they formed. However, as the body heals the clot it may also cause damage to the vein wall and predispose the patient to future clots, i.e., the biggest risk factor for a second clot is the first clot. DVT can also cause symptoms of pain, swelling, and redness in the long-term, leading to post-thrombotic syndrome where the initial symptoms of the clot persist for a long time. All blood clots have common components of red blood cells, white blood cells, platelets, and fibrin in varying concentrations. Humans maintain a platelet count between 150 and 400 thousand platelets per microliter of our blood. However, diseases like cancer or medications like chemotherapy can cause a change in our body's platelet count. The effect of a changing platelet count on the size (clot burden) of DVT clot and how platelet count could affect DVT as the clot heals is not fully understood. Studying this might help us develop better targets and treat patients with a wide range of platelet counts who experience DVT. In this study, we intentionally decreased, left unchanged, and increased platelet counts in mice and then created a DVT to study what the effect of low, normal, and high platelet counts, respectively, would be on the clot burden. We observed that mice with higher platelet counts had a higher clot burden during the early part of the healing process of the clot. Within this study, we can conclude that higher platelet counts may lead to higher clot burden in DVT which furthers our understanding of how platelet count affects clot burden during DVT.

Pathophysiology, diagnosis and management of cerebral venous thrombosis: A comprehensive review.

Cerebral venous thrombosis is a rare cause of stroke in young mostly female adults which is frequently overlooked due to its variable clinical and radiological presentation. This review summarizes current knowledge on it risk factors, management and outcome in adults and highlights areas for future research. Females are 3 times more commonly affected and are significantly younger than males. The presenting symptoms can range from headache to loss of consciousness. However, the often-nebulous nature of symptoms can make the diagnosis challenging. Magnetic resonance imaging with venography is often the diagnostic imaging of choice. While unfractionated or low molecular-weight heparin is the mainstay of treatment, endovascular intervention with thrombolysis or thrombectomy and decompressive craniectomy may be required depending on clinical status. Nevertheless, approximately 80% of patients have a good recovery but mortality rates of -5% to 10% are not uncommon. Diagnosing cerebral venous thrombosis can be challenging but with vigilance and expert care patients have the best chance of a good clinical outcome.

Relationship between intrathrombotic appearance of HSP27 and HSP70 and thrombus ages in a murine model of deep vein thrombosis.

Heat shock proteins (HSPs) are molecular chaperones whose primary function is cytoprotection, supporting cell survival under (sub) lethal conditions. They have been implicated in various diseases such as inflammatory diseases and cancer due to their cytoprotective and immunomodulatory effects, and their biological mechanisms have been studied. Central family members include, HSP27, which is induced by various stimuli such as heat shock, hypoxia, hyperoxia, ultraviolet exposure, and nutritional deficiency, and HSP70, which is homeostatically expressed in many organs such as the gastrointestinal tract and has anti-cell death and anti-inflammatory effects. In this study, HSP27 and HSP70 were investigated during thrombus formation and dissolution in a deep vein thrombosis model by immunohistochemistry to determine their involvement in this process and whether their expression could be used as a forensic marker. In the process of thrombus formation and lysis, HSP27 and HSP70 were found to be expressed by immunohistochemical analysis. The role of inhibitors of HSP27 and HSP70 in the pathogenesis of thrombosis in mice was also investigated. When HSP27 or HSP70 inhibitors were administered, thrombi were significantly smaller than in the control group on day 5 after inferior vena cava ligation, indicating pro-thrombotic effects HSP27 and HSP70. If HSP27- or HSP70-positive cells were clearly visible and easily identifiable in the thrombus sections, the thrombus was presumed to be more than 10 days old. Thus, the detection of intrathrombotic HSP27 and HSP70 could forensically provide useful information for the estimation of thrombus ages. Collectively, our study implied that both HSP27 and HSP70 might be molecular targets for thrombus therapy and that the detection of HSP-related molecules such as HSP27 and HSP70 could be useful for the determination of thrombus ages.

The Role of Contrast-Enhanced Ultrasound (CEUS) in the Detection of Neoplastic Portal Vein Thrombosis in Patients with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the principal primary liver cancer and one of the most frequent malignant tumors worldwide in patients with chronic liver disease. When diagnosed at an advanced stage, it is often associated with portal vein tumor thrombosis (PVTT), which heavily affects patients' prognosis. Imaging evaluation is crucial in PVTT detection and staging; computed tomography and magnetic resonance are the principal diagnostic tools. Contrast-enhanced ultrasound (CEUS) is a non-invasive and easily repeatable method that can also be used in patients with impaired renal function. It represents an important means for the identification of PVTT, particularly differentiating neoplastic and non-neoplastic thrombosis through the analysis of ultrasound enhancement characteristics of the thrombosis (arterial hyperenhancement and portal washout), thus allowing more refined disease staging, appropriate treatment planning, and response evaluation, along with prognosis assessment.