Material strengths of shear-induced platelet aggregation clots and coagulation clots.

Arterial occlusion by thrombosis is the immediate cause of some strokes, heart attacks, and peripheral artery disease. Most prior studies assume that coagulation creates the thrombus. However, a contradiction arises as whole blood (WB) clots from coagulation are too weak to stop arterial blood pressures (> 150 mmHg). We measure the material mechanical properties of elasticity and ultimate strength for Shear-Induced Platelet Aggregation (SIPA) type clots, that form under stenotic arterial hemodynamics in comparison with coagulation clots. The ultimate strength of SIPA clots averaged 4.6 ± 1.3 kPa, while WB coagulation clots had a strength of 0.63 ± 0.3 kPa (p < 0.05). The elastic modulus of SIPA clots was 3.8 ± 1.5 kPa at 1 Hz and 0.5 mm displacement, or 2.8 times higher than WB coagulation clots (1.3 ± 1.2 kPa, p < 0.0001). This study shows that the SIPA thrombi, formed quickly under high shear hemodynamics, is seven-fold stronger and three-fold stiffer compared to WB coagulation clots. A force balance calculation shows a SIPA clot has the strength to resist arterial pressure with a short length of less than 2 mm, consistent with coronary pathology.

Mechanisms of Pulmonary Vasculopathy in Acute and Long-Term COVID-19: A Review.

Despite the end of the pandemic, coronavirus disease 2019 (COVID-19) remains a major public health concern. The first waves of the virus led to a better understanding of its pathogenesis, highlighting the fact that there is a specific pulmonary vascular disorder. Indeed, COVID-19 may predispose patients to thrombotic disease in both venous and arterial circulation, and many cases of severe acute pulmonary embolism have been reported. The demonstrated presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within the endothelial cells suggests that direct viral effects, in addition to indirect effects of perivascular inflammation and coagulopathy, may contribute to pulmonary vasculopathy in COVID-19. In this review, we discuss the pathological mechanisms leading to pulmonary vascular damage during acute infection, which appear to be mainly related to thromboembolic events, an impaired coagulation cascade, micro- and macrovascular thrombosis, endotheliitis and hypoxic pulmonary vasoconstriction. As many patients develop post-COVID symptoms, including dyspnea, we also discuss the hypothesis of pulmonary vascular damage and pulmonary hypertension as a sequela of the infection, which may be involved in the pathophysiology of long COVID.

Myocardial ischemia-reperfusion injury released cellular fibronectin containing domain A (CFN-EDA): A destructive positive loop amplifying arterial thrombosis formation and exacerbating myocardial reperfusion injury.

Previous research has identified intravascular platelet thrombi in regions affected by myocardial ischemia-reperfusion (MI/R) injury and neighbouring areas. However, the occurrence of arterial thrombosis in the context of MI/R injury remains unexplored. This study utilizes intravital microscopy to investigate carotid artery thrombosis during MI/R injury in rats, establishing a connection with the presence of prothrombotic cellular fibronectin containing extra domain A (CFN-EDA) protein. Additionally, the study examines samples from patients with coronary artery disease (CAD) both before and after coronary artery bypass grafting (CABG). Levels of CFN-EDA significantly increase following MI with further elevation observed following reperfusion of the ischemic myocardium. Thrombotic events, such as thrombus formation and growth, show a significant increase, while the time to complete cessation of blood flow in the carotid artery significantly decreases following MI/R injury induced by ferric chloride. The acute infusion of purified CFN-EDA protein accelerates in-vivo thrombotic events in healthy rats and significantly enhances in-vitro adenosine diphosphate and collagen-induced platelet aggregation. Treatment with anti-CFN-EDA antibodies protected the rat against MI/R injury and significantly improved cardiac function as evidenced by increased end-systolic pressure-volume relationship slope and preload recruitable stroke work compared to control. Similarly, in a human study, plasma CFN-EDA levels were notably elevated in CAD patients undergoing CABG. Post-surgery, these levels continued to rise over time, alongside cardiac injury biomarkers such as cardiac troponin and B-type natriuretic peptide. The study highlights that increased CFN-EDA due to CAD or MI initiates a destructive positive feedback loop by amplifying arterial thrombus formation, potentially exacerbating MI/R injury.

Elevated plasma levels of factor VIII enhance arterial thrombus formation on erosive smooth muscle cell-rich neointima but not normal intima in rabbits.

BACKGROUND: Plaque erosion, a type of coronary atherothrombosis, involves superficial injury to smooth muscle cell (SMC)-rich plaques. Elevated levels of coagulation factor VIII (FVIII) correlate with an increased ischemic heart disease risk. FVIII may contribute to thrombus formation on eroded plaques. AIMS: We aimed to elucidate the role of elevated FVIII in arterial thrombus formation within SMC-rich neointima in rabbits. METHODS AND RESULTS: We assessed the effect of recombinant human FVIII (rFVIII) on blood coagulation in vitro and platelet aggregation ex vivo. An SMC-rich neointima was induced through balloon injury to the unilateral femoral artery. Three weeks after the first balloon injury, superficial erosive injury and thrombus formation were initiated with a second balloon injury of the bilateral femoral arteries 45 min after the administration of rFVIII (100 IU/kg) or saline. The thrombus area and contents were histologically measured 15 min after the second balloon injury. rFVIII administration reduced the activated partial thromboplastin time and augmented botrocetin-induced, but not collagen- or adenosine 5'-diphosphate-induced, platelet aggregation. While rFVIII did not influence platelet-thrombus formation in normal intima, it increased thrombus formation on SMC-rich neointima post-superficial erosive injury. Enhanced immunopositivity for glycoprotein IIb/IIIa and fibrin was observed in rFVIII-administered SMC-rich neointima. Neutrophil count in the arterial thrombus on the SMC-rich neointima correlated positively with thrombus size in the control group, unlike the rFVIII group. CONCLUSIONS: Increased FVIII contributes to thrombus propagation within erosive SMC-rich neointima, highlighting FVIII's potential role in plaque erosion-related atherothrombosis.

Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl3 model.

BACKGROUND: Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, and we investigated whether CTSK is involved in chronic stress-related thrombosis, focusing on stress serum-induced endothelial apoptosis. METHODS AND RESULTS: Eight-week-old wild-type male mice (CTSK+/+) randomly divided to non-stress and 3-week restraint stress groups received a left carotid artery iron chloride3 (FeCl3)-induced thrombosis injury for biological and morphological evaluations at specific timepoints. On day 21 post-stress/injury, the stress had enhanced the arterial thrombi weights and lengths, in addition to harmful alterations of plasma ADAMTS13, von Willebrand factor, and plasminogen activation inhibitor-1, plus injured-artery endothelial loss and CTSK protein/mRNA expression. The stressed CTSK+/+ mice had increased levels of injured arterial cleaved Notch1, Hes1, cleaved caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16IN4A, p22phox, gp91phox, intracellular adhesion molecule-1, TNF-α, MCP-1, and TLR-4 proteins and/or genes. Pharmacological and genetic inhibitions of CTSK ameliorated the stress-induced thrombus formation and the observed molecular and morphological changes. In cultured HUVECs, CTSK overexpression and silencing respectively increased and mitigated stressed-serum- and H2O2-induced apoptosis associated with apoptosis-related protein changes. Recombinant human CTSK degraded γ-secretase substrate in a dose-dependent manor and activated Notch1 and Hes1 expression upregulation. CONCLUSIONS: CTSK appeared to contribute to stress-related thrombosis in mice subjected to FeCl3 stress, possibly via the modulation of vascular inflammation, oxidative production and apoptosis, suggesting that CTSK could be an effective therapeutic target for CPS-related thrombotic events in patients with CCVDs.

Multimodal detection and analysis of microplastics in human thrombi from multiple anatomically distinct sites.

BACKGROUND: Microplastic (MP) pollution has emerged as a significant environmental concern worldwide. While extensive research has focused on their presence in marine organisms and ecosystems, their potential impact on human health, particularly on the circulatory system, remains understudied. This project aimed to identify and quantify the mass concentrations, polymer types, and physical properties of MPs in human thrombi surgically retrieved from both arterial and venous systems at three anatomically distinct sites, namely, cerebral arteries in the brain, coronary arteries in the heart, and deep veins in the lower extremities. Furthermore, this study aimed to investigate the potential association between the levels of MPs and disease severity. METHODS: Thrombus samples were collected from 30 patients who underwent thrombectomy procedures due to ischaemic stroke (IS), myocardial infarction (MI), or deep vein thrombosis (DVT). Pyrolysis-gas chromatography mass spectrometry (Py-GC/MS) was employed to identify and quantify the mass concentrations of the MPs. Laser direct infrared (LDIR) spectroscopy and scanning electron microscopy (SEM) were used to analyse the physical properties of the MPs. Demographic and clinical information were also examined. A rigorous quality control system was used to eliminate potential environmental contamination. FINDINGS: MPs were detected by Py-GC/MS in 80% (24/30) of the thrombi obtained from patients with IS, MI, or DVT, with median concentrations of 61.75 µg/g, 141.80 µg/g, and 69.62 µg/g, respectively. Among the 10 target types of MP polymers, polyamide 66 (PA66), polyvinyl chloride (PVC), and polyethylene (PE) were identified. Further analyses suggested that higher concentrations of MPs may be associated with greater disease severity (adjusted ß = 7.72, 95% CI: 2.01-13.43, p < 0.05). The level of D-dimer in the MP-detected group was significantly higher than that in the MP-undetected group (8.3 ± 1.5 µg/L vs 6.6 ± 0.5 µg/L, p < 0.001). Additionally, LDIR analysis showed that PE was dominant among the 15 types of identified MPs, accounting for 53.6% of all MPs, with a mean diameter of 35.6 µm. The shapes of the polymers detected using LDIR and SEM were found to be heterogeneous. INTERPRETATION: This study presents both qualitative and quantitative evidence of the presence of MPs, and their mass concentrations, polymer types, and physical properties in thrombotic diseases through the use of multimodal detection methods. Higher concentrations of MPs may be associated with increased disease severity. Future research with a larger sample size is urgently needed to identify the sources of exposure and validate the observed trends in the study. FUNDING: This study was funded by the SUMC Scientific Research Initiation Grant (SRIG, No. 009-510858038), Postdoctoral Research Initiation Grant (No. 202205230031-3), and the 2020 Li Ka Shing Foundation Cross-Disciplinary Research Grant (No. 2020LKSFG02C).

In vivo assessment of dual-function submicron textured nitric oxide releasing catheters in a 7-day rabbit model.

Catheter-induced thrombosis is a major contributor to infectious and mechanical complications of biomaterials that lead to device failure. Herein, a dualfunction submicron textured nitric oxide (NO)-releasing catheter was developed. The hemocompatibility and antithrombotic activity of vascular catheters were evaluated in both 20 h in vitro blood loop and 7 d in vivo rabbit model. Surface characterization assessments via atomic force microscopy show the durability of the submicron pattern after incorporation of NO donor S-nitroso-N-acetylpenicillamine (SNAP). The SNAP-doped catheters exhibited prolonged and controlled NO release mimicking the levels released by endothelium. Fabricated catheters showed cytocompatibility when evaluated against BJ human fibroblast cell lines. After 20h in vitro evaluation of catheters in a blood loop, textured-NO catheters exhibited a 13-times reduction in surface thrombus formation compared to the control catheters, which had 83% of the total area covered by clots. After the 7 d in vivo rabbit model, analysis on the catheter surface was examined via scanning electron microscopy, where significant reduction of platelet adhesion, fibrin mesh, and thrombi can be observed on the NO-releasing textured surfaces. Moreover, compared to relative controls, a 63% reduction in the degree of thrombus formation within the jugular vein was observed. Decreased levels of fibrotic tissue decomposition on the jugular vein and reduced platelet adhesion and thrombus formation on the texture of the NO-releasing catheter surface are indications of mitigated foreign body response. This study demonstrated a biocompatible and robust dual-functioning textured NO PU catheter in limiting fouling-induced complications for longer-term blood-contacting device applications. STATEMENT OF SIGNIFICANCE: Catheter-induced thrombosis is a major contributor to infectious and mechanical complications of biomaterials that lead to device failure. This study demonstrated a robust, biocompatible, dual-functioning textured nitric oxide (NO) polyurethane catheter in limiting fouling-induced complications for longer-term blood-contacting device applications. The fabricated catheters exhibited prolonged and controlled NO release that mimics endothelium levels. After the 7 d in vivo model, a significant reduction in platelet adhesion, fibrin mesh, and thrombi was observed on the NO-releasing textured catheters, along with decreased levels of fibrotic tissue decomposition on the jugular vein. Results illustrate that NO-textured catheter surface mitigates foreign body response.

Thrombus histology does not predict stroke etiological subtype but influences recanalization.

BACKGROUND: There is conflicting data on whether clot retrieved from mechanical thrombectomy can predict stroke etiology or the success of recanalization. We aimed to analyse the relation between thrombus histology and stroke aetiology as well as recanalization. METHODOLOGY: Histopathological analysis of clots retrieved from patients with acute ischemic stroke and large vessel occlusion was done. Quantification of the amount of fibrin, red blood cells(RBC), platelets and white blood cells (WBC) in the clots were done. The clinical, imaging data and recanalization parameters were collected. The correlation between clot composition and stroke etiology as well as recanalization were analysed. RESULTS: Of the 77 patients, the mean age was 58. 67 ± 12.96 years. The stroke etiology were cardioembolism 44(57.1 %), large artery atherosclerosis 13(16.8 %), other determined aetiology 4(5.1 %) and undetermined in 16(20.7 %) patients. There was no significant correlation between the proportions of RBC-rich, platelet-rich and fibrin-rich thrombi and the stroke etiology. The susceptibility vessel sign was associated with RBC-rich clot(92.3 % vs 7.7 %, p = .03). All RBC-rich clots(100 %) had good recanalization(p = .05). Platelet-rich clots needed less number of passes(64.7 % vs 35.3 %, p = .006) and reduced groin puncture to recanalization time(87.9 % vs 12.1 %, p = .033). WBC-rich clots required lesser number of passes(57.5 % vs 42.5 %, P = .044). In multivariate analysis, WBC-rich clots (OR 0.230, CI 0.07-0.78, p = .018) showed an independent association with reduced recanalization attempts, while platelet-rich clots showed reduced recanalization time(OR 0.09, CI 0.01-0.63, p = .016). CONCLUSION: There was no correlation between thrombus histology and the etiological stroke subtype. However, clot composition predicted the degree of recanalization and number of passes.

A tempo-spatial controllable microfluidic shear-stress generator for in-vitro mimicking of the thrombus.

Pathological conditions linked to shear stress have been identified in hematological diseases, cardiovascular diseases, and cancer. These conditions often exhibit significantly elevated shear stress levels, surpassing 1000 dyn/cm2 in severely stenotic arteries. Heightened shear stress can induce mechanical harm to endothelial cells, potentially leading to bleeding and fatal consequences. However, current technology still grapples with limitations, including inadequate flexibility in simulating bodily shear stress environments, limited range of shear stress generation, and spatial and temporal adaptability. Consequently, a comprehensive understanding of the mechanisms underlying the impact of shear stress on physiological and pathological conditions, like thrombosis, remains inadequate. To address these limitations, this study presents a microfluidic-based shear stress generation chip as a proposed solution. The chip achieves a substantial 929-fold variation in shear stress solely by adjusting the degree of constriction in branch channels after PDMS fabrication. Experiments demonstrated that a rapid increase in shear stress up to 1000 dyn/cm2 significantly detached 88.2% cells from the substrate. Long-term exposure (24 h) to shear stress levels below 8.3 dyn/cm2 did not significantly impact cell growth. Furthermore, cells exposed to shear stress levels equal to or greater than 8.3 dyn/cm2 exhibited significant alterations in aspect ratio and orientation, following a normal distribution. This microfluidic chip provides a reliable tool for investigating cellular responses to the wide-ranging shear stress existing in both physiological and pathological flow conditions.

The interaction of platelet-related factors with tumor cells promotes tumor metastasis.

Platelets not only participate in thrombosis and hemostasis but also interact with tumor cells and protect them from mechanical damage caused by hemodynamic shear stress and natural killer cell lysis, thereby promoting their colonization and metastasis to distant organs. Platelets can affect the tumor microenvironment via interactions between platelet-related factors and tumor cells. Metastasis is a key event in cancer-related death and is associated with platelet-related factors in lung, breast, and colorectal cancers. Although the factors that promote platelet expression vary slightly in terms of their type and mode of action, they all contribute to the overall process. Recognizing the correlation and mechanisms between these factors is crucial for studying the colonization of distant target organs and developing targeted therapies for these three types of tumors. This paper reviews studies on major platelet-related factors closely associated with metastasis in lung, breast, and colorectal cancers.

Multimaterial decomposition in dual-energy CT for characterization of clots from acute ischemic stroke patients.

BACKGROUND: Nowadays, there is no method to quantitatively characterize the material composition of acute ischemic stroke thrombi prior to intervention, but dual-energy CT (DE-CT) offers imaging-based multimaterial decomposition. We retrospectively investigated the material composition of thrombi ex vivo using DE-CT with histological analysis as a reference. METHODS: Clots of 70 patients with acute ischemic stroke were extracted by mechanical thrombectomy and scanned ex vivo in formalin-filled tubes with DE-CT. Multimaterial decomposition in the three components, i.e., red blood cells (RBC), white blood cells (WBC), and fibrin/platelets (F/P), was performed and compared to histology (hematoxylin/eosin staining) as reference. Attenuation and effective Z values were assessed, and histological composition was compared to stroke etiology according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. RESULTS: Histological and imaging analysis showed the following correlation coefficients for RBC (r = 0.527, p < 0.001), WBC (r = 0.305, p = 0.020), and F/P (r = 0.525, p < 0.001). RBC-rich thrombi presented higher clot attenuation in Hounsfield units than F/P-rich thrombi (51 HU versus 42 HU, p < 0.01). In histological analysis, cardioembolic clots showed less RBC (40% versus 56%, p = 0.053) and more F/P (53% versus 36%, p = 0.024), similar to cryptogenic clots containing less RBC (34% versus 56%, p = 0.006) and more F/P (58% versus 36%, p = 0.003) than non-cardioembolic strokes. No difference was assessed for the mean WBC portions in all TOAST groups. CONCLUSIONS: DE-CT has the potential to quantitatively characterize the material composition of ischemic stroke thrombi. RELEVANCE STATEMENT: Using DE-CT, the composition of ischemic stroke thrombi can be determined. Knowledge of histological composition prior to intervention offers the opportunity to define personalized treatment strategies for each patient to accomplish faster recanalization and better clinical outcomes. KEY POINTS: • Acute ischemic stroke clots present different recanalization success according to histological composition. • Currently, no method can determine clot composition prior to intervention. • DE-CT allows quantitative material decomposition of thrombi ex vivo in red blood cells, white blood cells, and fibrin/platelets. • Histological clot composition differs between stroke etiology. • Insights into the histological composition in situ offer personalized treatment strategies.

A 42-year-old patient with renal cell carcinoma presenting as low back pain: A case report.

RATIONALE: Renal cell carcinoma (RCC) is the most common renal neoplasm, accounting for 2.4% of all cancers in Korea. Although the usual clinical manifestations of RCC include flank pain, hematuria, and palpable mass, RCC is generally characterized by a lack of early warning signs and is mostly discovered incidentally in advanced stage. This case report describes a 42-year-old Korean man diagnosed with giant RCC who presented with simple back pain. PATIENT CONCERNS: The clinical manifestation of a 42-year-old Korean man was chronic back pain. DIAGNOSES: Contrast-enhanced computed tomography showed a 19.1-cm sized heterogeneous enhancing mass on the right kidney and tumor thrombosis extending into inferior vena cava. INTERVENTION: Due to the large size of the tumor and extensive tumor thrombosis, the multidisciplinary team decided to administer neoadjuvant chemotherapy and an anticoagulant. Following 12 cycles of treatment with nivolumab and cabozantinib, he underwent a right radical nephrectomy with an adrenalectomy and tumor thrombectomy. OUTCOMES: Treatment was successful and posttreatment he started a cancer rehabilitation program. He was followed-up as an outpatient and no longer complains of back pain. LESSONS: RCC can manifest clinically as back pain, with diagnosis being difficult without appropriate imaging modalities. RCC should be included in the differential diagnosis of patients with low back pain, even at a young age.

Modulations of Homeostatic ACE2, CD147, GRP78 Pathways Correlate with Vascular and Endothelial Performance Markers during Pulmonary SARS-CoV-2 Infection.

The pathologic consequences of Coronavirus Disease-2019 (COVID-19) include elevated inflammation and dysregulated vascular functions associated with thrombosis. In general, disruption of vascular homeostasis and ensuing prothrombotic events are driven by activated platelets, monocytes, and macrophages, which form aggregates (thrombi) attached to the endothelium lining of vessel walls. However, molecular pathways underpinning the pathological interactions between myeloid cells and endothelium during COVID-19 remain undefined. Here, we tested the hypothesis that modulations in the expression of cellular receptors angiotensin-converting enzyme 2 (ACE2), CD147, and glucose-regulated protein 78 (GRP78), which are involved in homeostasis and endothelial performance, are the hallmark responses induced by SARS-CoV-2 infection. Cultured macrophages and lungs of hamster model systems were used to test this hypothesis. The results indicate that while macrophages and endothelial cells are less likely to support SARS-CoV-2 proliferation, these cells may readily respond to inflammatory stimuli generated by the infected lung epithelium. SARS-CoV-2 induced modulations of tested cellular receptors correlated with corresponding changes in the mRNA expression of coagulation cascade regulators and endothelial integrity components in infected hamster lungs. Among these markers, tissue factor (TF) had the best correlation for prothrombotic events during SARS-CoV-2 infection. Furthermore, the single-molecule fluorescence in situ hybridization (smFISH) method alone was sufficient to determine the peak and resolution phases of SARS-CoV-2 infection and enabled screening for cellular markers co-expressed with the virus. These findings suggest possible molecular pathways for exploration of novel drugs capable of blocking the prothrombotic shift events that exacerbate COVID-19 pathophysiology and control the disease.

Efficacy of radiotherapy in combined treatment of hepatocellular carcinoma patients with portal vein tumor thrombus: a real-world study.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) has an extremely poor prognosis. A previous study proved that low-dose radiotherapy (RT) could prolong the prognosis of HCC patients with PVTT. This study aims to explore the sensitivity of PVTT to RT treatment. METHODS: Patients were selected based on imaging diagnosis of HCC accompanied by PVTT and received combined treatment of radiotherapy, antiangiogenic drugs and immune checkpoint inhibitors, followed by hepatectomy or liver transplantation from January 2019 to August 2022. The efficacy was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines and pathological assessment. The sensitivity of tumor cells to the treatment was compared between the primary tumor (PT)and PVTT by analyzing their residual tumor and pathologic complete remission (PCR) incidence. RESULTS: Data from 14 patients were collected in the study. After combined treatment, the size of PVTT decreased more significantly than that of the primary tumor in the imaging study (p < 0.05). The residual cancer was significantly more restrictive than that of primary tumor in paired patients based on pathological measurement (p = 0.008). The PCR incidence of the primary tumor (21.42%) was significantly lower (p = 0.008) than that of PVTT in the pathologic study (78.57%). CONCLUSION: PVTT is more sensitive to radiotherapy treatment than the primary tumor in patients with HCC. This combination therapy might be an effective option as a downstaging therapy for patients with HCC with PVTT.

Dysfunctioning mechanical mitral valve prosthesis: When thrombus over pannus makes hinders diagnosis.

Prosthetic valve obstruction is a rare but potentially lethal complication. The most frequent causes are thrombus and pannus formation, in the absence of infectious data. Diagnosis is not always easy using cardiac CT scanning and in 46%-85% of cases thrombus and pannus coexist, complicating the diagnosis. A rapid diagnosis is essential to avoid a fatal outcome of this pathology whose mortality, despite correct treatment, is high.

Exploring the Molecular Aspects of Myeloproliferative Neoplasms Associated with Unusual Site Vein Thrombosis: Review of the Literature and Latest Insights.

Myeloproliferative neoplasms (MPNs) are the leading causes of unusual site thrombosis, affecting nearly 40% of individuals with conditions like Budd-Chiari syndrome or portal vein thrombosis. Diagnosing MPNs in these cases is challenging because common indicators, such as spleen enlargement and elevated blood cell counts, can be obscured by portal hypertension or bleeding issues. Recent advancements in diagnostic tools have enhanced the accuracy of MPN diagnosis and classification. While bone marrow biopsies remain significant diagnostic criteria, molecular markers now play a pivotal role in both diagnosis and prognosis assessment. Hence, it is essential to initiate the diagnostic process for splanchnic vein thrombosis with a JAK2 V617F mutation screening, but a comprehensive approach is necessary. A multidisciplinary strategy is vital to accurately determine the specific subtype of MPNs, recommend additional tests, and propose the most effective treatment plan. Establishing specialized care pathways for patients with splanchnic vein thrombosis and underlying MPNs is crucial to tailor management approaches that reduce the risk of hematological outcomes and hepatic complications.

Recent advances in microfluidic technology of arterial thrombosis investigations.

Microfluidic technology has emerged as a powerful tool in studying arterial thrombosis, allowing researchers to construct artificial blood vessels and replicate the hemodynamics of blood flow. This technology has led to significant advancements in understanding thrombosis and platelet adhesion and aggregation. Microfluidic models have various types and functions, and by studying the fabrication methods and working principles of microfluidic chips, applicable methods can be selected according to specific needs. The rapid development of microfluidic integrated system and modular microfluidic system makes arterial thrombosis research more diversified and automated, but its standardization still needs to be solved urgently. One key advantage of microfluidic technology is the ability to precisely control fluid flow in microchannels and to analyze platelet behavior under different shear forces and flow rates. This allows researchers to study the physiological and pathological processes of blood flow, shedding light on the underlying mechanisms of arterial thrombosis. In conclusion, microfluidic technology has revolutionized the study of arterial thrombosis by enabling the construction of artificial blood vessels and accurately reproducing hemodynamics. In the future, microfluidics will place greater emphasis on versatility and automation, holding great promise for advancing antithrombotic therapeutic and prophylactic measures.

What is the context? To study the mechanism of arterial thrombosis, including the platelet adhesion and aggregation behavior and the coagulation process.Microfluidic technology is commonly used to study thrombosis. Microfluidic technology can simulate the real physiological environment on the microscopic scale in vitro, with high throughput, low cost, and fast speed.As an innovative experimental platform, microfluidic technology has made remarkable progress and has found applications in the fields of biology and medicine.What is new? This review summarizes the different fabrication methods of microfluidics and compares the advantages and disadvantages of these methods. Recent developments in microfluidic integrated systems and modular microfluidic systems have led to more diversified and automated microfluidic chips in the future.The different types and functions of microfluidic models are summarized. Platelet adhesion aggregation and coagulation processes, as well as arterial thrombus-related shear force changes and mechanical behaviors, were investigated by constructing artificial blood vessels and reproducing hemodynamics.Microfluidics can provide a basis for the development of personalized thrombosis treatment strategies. By analyzing the mechanism of action of existing drugs, using microfluidic technology for high-throughput screening of drugs and evaluating drug efficacy, more drug therapy possibilities can be developed.What is the impact?This review utilizes microfluidics to further advance the study of arterial thrombosis, and microfluidics is also expected to play a greater role in the biomedical field in the future.

Shear Histories Alter Local Shear Effects on Thrombus Nucleation and Growth.

Our goal was to determine the impact of physiological and pathological shear histories on platelet nucleation and thrombus growth at various local shear rates. We designed and characterized a microfluidic device capable of subjecting platelets to shear histories reaching as high as 6700 s - 1 in a single passage. Time-lapse videos of platelets and thrombi are captured using fluorescence microscopy. Thrombi are tracked, and the degree of thrombosis is evaluated through surface coverage, platelet nucleation maps, and ensemble-averaged aggregate areas and intensities. Surface coverage rates were the lowest when platelets deposited at high shear rates following a pathological shear history and were highest at low shear rates following a pathological shear history. Early aggregate area growth rates were significantly larger for thrombi developing at high shear following physiological shear history than at high shear following a pathological shear history. Aggregate vertical growth was restricted when depositing at low shear following a pathological shear history. In contrast, thrombi grew faster vertically following physiological shear histories. These results show that physiological shear histories pose thrombotic risks via volumetric growth, and pathological shear histories drastically promote nucleation. These findings may inform region-based geometries for biomedical devices and refine thrombosis simulations.

Angiogenesis in Chronic Thromboembolic Pulmonary Hypertension: A Janus-Faced Player?

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare form of pulmonary hypertension characterized by the presence of organized thrombi that obstruct pulmonary arteries, ultimately leading to right heart failure and death. Among others, impaired angiogenesis and inflammatory thrombosis have been shown to contribute to the progression of CTEPH. In this review, we summarize the 2-faced nature of angiogenesis in both thrombus formation and resolution in the context of CTEPH and highlight the dual role of angiogenesis and neovascularization in resolving venous thrombi. Furthermore, we discuss relevant in vitro and in vivo models that support the benefits or drawbacks of angiogenesis in CTEPH progression. We discuss the key pathways involved in modulating angiogenesis, particularly the underexplored role of TGFß (transforming growth factor-beta) signaling in driving fibrosis as an integral element of CTEPH pathogenesis. We finally explore innovative treatment strategies that target angiogenic pathways. These strategies have the potential to pioneer preventive, inventive, or alternative therapeutic options for patients with CTEPH who may not qualify for surgical interventions. Moreover, they could be used synergistically with established treatments such as pulmonary endarterectomy or balloon pulmonary angioplasty. In summary, this review emphasizes the crucial role of angiogenesis in the development of in fibrothrombotic tissue, a major pathological characteristic of CTEPH.