Thrombus Volume Reduction Research Articles

Combination of an Anti-Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor and Immunotherapy as a Neoadjuvant Approach in Renal Cell Carcinoma With Associated Inferior Vena Cava Tumor Thrombus: A Single-Center Experience and Review of Literature

Introduction: Renal cell carcinoma (RCC) has a predisposition to vascular invasion that manifest as an inferior vena cava tumor thrombus (IVC TT). Radical nephrectomy with an IVC thrombectomy is associated with high morbidity. We present our single-center experience on the neoadjuvant use of the combination of anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI) and immune check point inhibitor (IO) for patients with RCC with IVC TT. Patient and Methods: Five patients with RCC and associated IVC TT received a neoadjuvant combination anti-VEGF TKI and IO. The IVC TT reduction was evaluated. The extent of tumor thrombus was defined based on the Mayo Classification, and TT volume was measured by the largest anteroposterior diameter. The safety of therapy, perioperative outcome, and number of patients who were able to undergo definitive surgery are described. Results: Two (40%) had a reduction in IVC TT based on the Mayo Classification. Tumor thrombus volume reduction was seen in all patients (100%). Four of 5 patients (80%) were able to have surgery. Conclusion: The neoadjuvant combination of an anti-VEGF TKI and IO is effective in reducing the extent of IVC TT. Prospective research is needed to characterize the safety, and long-term outcomes of this approach.

Predictors of non-stenting strategy for acute coronary syndrome caused by plaque erosion: four-year outcomes of the EROSION study.

The EROSION study demonstrated that patients with an acute coronary syndrome (ACS) caused by plaque erosion could be treated with antithrombotic therapy without stenting. However, the long-term prognosis of this strategy is still unclear. The aim of this study was to test whether a non-stenting antithrombotic strategy was still effective at four-year follow-up and to explore potential predictors of long-term prognosis. This study was a long-term follow-up of the EROSION study. Follow-up was conducted by phone call or clinical visit. Patients were divided into two groups - those with target lesion revascularisation (the TLR group), and the non-TLR group. Out of 55 patients who completed one-month follow-up, 52 patients finished four-year follow-up. The median duration was 4.8 years (range, 4.2-5.8 years). The majority of patients remained free from events, and all patients were free from hard endpoints (death, myocardial infarction, stroke, bypass surgery, or heart failure). Only one patient had gastrointestinal bleeding, and 11 patients underwent TLR. Patients in the non-TLR group had more optical coherence tomography (OCT) thrombus reduction from baseline to one month; 95% of patients in the non-TLR group versus 45% in the TLR group (p=0.001) met the primary endpoint (thrombus volume reduction >50%). Angiographic results showed that the TLR group had less improvement in diameter stenosis (p=0.014) at one month compared with the non-TLR group. Four-year follow-up findings reconfirmed the safety of an antithrombotic therapy without stenting for ACS caused by erosion. Patients with better response to antithrombotic therapy in the first month were less likely to require stent implantation during the next four years.

Quantitative Volumetric Comparison of Direct Oral Anticoagulant and Vitamin K Antagonist Treatment for Pulmonary Thrombus Reduction During the Acute Phase in Symptomatic Patients

Recent clinical trials' findings have revealed the therapeutic noninferiority of direct oral anticoagulant (DOAC) to standard therapy with vitamin K antagonist (VKA) in patients with pulmonary thromboembolism (PTE). However, few studies have quantitatively analyzed thrombus reduction in the pulmonary artery. This observational study included 38 symptomatic PTE patients with stable hemodynamics. All patients received an intravenous heparin bolus followed by continual heparin injections immediately after the PTE diagnosis. The heparin was discontinued after edoxaban therapy began in the DOAC group (n=22) or after the therapeutic range for the prothrombin time-international normalized ratio was achieved in the VKA group (n=16). The thrombus volumes in the pulmonary arteries were quantitatively analyzed using contrast-enhanced computed tomography scans, and they were compared at baseline and at 2 weeks after admission. The pulmonary thrombus volumes declined in the VKA and DOAC groups from 7.9 to 4.2 cm3 (P=0.048) and from 7.1 to 3.7 cm3 (P < 0.01), respectively, and the thrombus reduction rates did not differ significantly between the groups (-34% vs. -64%, respectively; P=0.38). The fibrinogenolysis parameter changes during the14 days after admission were similar in both groups. Compared with the VKAgroup, the average hospital stay was 9days shorter in the DOAC group. There were no in-hospital deaths, and 1 case experienced major bleeding in the VKA group. In relation to pulmonary artery thrombus volume reduction, DOAC monotherapy for PTE may be comparable with standard therapy involving VKAs.

Danaparoid sodium-based anticoagulation therapy for portal vein thrombosis in cirrhosis patients

BackgroundPortal vein thrombosis (PVT) is a common complication of cirrhosis. However, in patients with PVT and cirrhosis, there is no clear evidence supporting effective treatment modalities. In this study, we examined the effectiveness and safety of anticoagulation therapy using danaparoid sodium for PVT in patients with cirrhosis.MethodsThis retrospective study assessed 52 cirrhotic patients with PVT treated with danaparoid sodium for 2 weeks between November 2008 and September 2018. The primary outcome measure was the post-treatment status of PVT assessed by reduction in thrombus volume and safety of the therapeutic intervention. PVT status was evaluated with contrast-enhanced computed tomography (CECT). All patients received 1250 units of danaparoid sodium twice daily by intravenous injection for 14 days. Patients on antithrombin III (AT-III) combination therapy were additionally administered 1500 units of AT-III on days 1–5 and days 8–12. Effectiveness was evaluated by CECT from between days 13 and 18. The secondary outcome measure was the prognosis of PVT.ResultsAll patients showed reduction in PVT volume without complications. Return of plasma AT-III level to > 70% during the treatment period contributes to ≥75% reduction of PVT volume. The prognosis in PVT patients depends on hepatic reserve capacity. When limited to Child-Pugh B and C liver cirrhosis patients, a ≥ 75% reduction of PVT volume improved the prognosis.ConclusionsDanaparoid sodium-based anticoagulation therapy was effective and safe for PVT in patients with cirrhosis. Return of plasma AT-III level to the normal range during the treatment period contributes to reduction of PVT volume. A reduction of ≥75% in PVT volume may improve the prognosis of Child-Pugh B and C decompensated cirrhosis patients with PVT.

Intra-coronary thrombus evolution during acute coronary syndrome: regression assessment by serial optical coherence tomography analyses

Aims: Time-domain optical coherence tomography (TD-OCT) allows assessment of the anatomy and features of unstable coronary artery lesions, including discrimination between the thrombotic and atherosclerotic plaque components. We sought to investigate the feasibility of thrombus quantification and its monitoring in patients with high thrombotic burden acute coronary syndromes (ACS). Methods: Patients were suitable for inclusion if they presented with an ACS that was successfully revascularized by manual thrombo-aspiration with a residual large thrombus burden on coronary angiography and initial TD-OCT analysis. These patients underwent a second procedure with TD-OCT analysis after several days of optimal anti-thrombotic therapy and benefited eventually from an intra-coronary stent. Coronary lesion stenosis degree was determined by quantitative coronary angiography (QCA). TD-OCT analysis included measurement of thrombus score (as defined by ESC consensus document), thrombus volume, length and minimal luminal area (MLA), which were quantified by serial area measurement within the athero-thrombotic culprit lesion. Results: Seventeen patients fulfilled inclusion criteria. The OCT image quality was suitable for thrombus quantification in n=14 subjects (86% men/ age=57.9±4.5y/ 93% STEMI). Low molecular weight heparin anticoagulation and dual antiplatelet therapy were given to all patients between the two procedures (mean delay: 3.9.±0.3 days). No adverse events were observed during study time. The values of thrombus score and thrombus volume among individuals highly correlated together rho= 0.8, p<0.0001). We observed a progressive reduction of thrombus burden between the two analyses, as assessed by the significant reductions in thrombus score (22.1±2.6 vs. 10.4±1.4, p=0.001), thrombus volume (9.6±2.4 vs. 4.2±1.2 mm3, p=0.003), length (11.1±1.4 vs. 7.6±0.9 mm, p=0.03) and increase of MLA (2.5±0.4 mm2 vs. 1.7±0.2 mm2, p=0.01). However, the degree of stenosis analyzed by QCA didn't significantly decrease over time. The thrombus burden reduction was time dependent, as the greatest reductions of thrombus score and volume were observed for the longer optimal medical therapy times. The percentages of thrombus score and volume reduction were highly correlated with the inter-OCT analyses delay (respectively r=0.75 and r=0.87, p<0.01 for both). The observed thrombus volume reduction rate was evaluated to 12% of the initial volume per day of optimal medical therapy. Conclusion: TD-OCT assessment of thrombus volume in patients with ACS is feasible, safe and could allow in vivo clot regression monitoring.

036: In vivo monitoring of intra-coronary thrombus regression by serial optical coherence tomography analysis: feasibility and first-in-man results

Time-domain optical coherence tomography (TD-OCT) allows assessment of the anatomy and features of unstable coronary artery lesions, including discrimination between the thrombotic and atherosclerotic plaque components. We sought to investigate the feasibility of thrombus quantification and its monitoring in patients with high thrombotic burden acute coronary syndromes. Patients with successfully revascularized acute coronary syndromes and a large thrombus burden on initial coronary angiography who beneficiated from repeated TD-OCT examinations in our institution were suitable for inclusion. Coronary lesion stenosis degree was determined by quantitative coronary angiography (QCA) methods. Thrombus volume, maximal surface and minimal luminal area (MLA) were quantified by serial area measurement within the athero-thrombotic culprit lesion in 1 mm intervals before any stenting. Eleven patients underwent 2 consecutive TD-OCT examinations. The OCT image quality was suitable for thrombus quantification in n=9 subjects (89% men/ age=62.4±5.7y/ 89% STEMI). All patients were under anticoagulant and dual antiplatelet therapy between the two procedures (mean delay: 4.1±0.4 days). No adverse events were observed following OCT analysis. We measured a progressive reduction of thrombus burden between the two analysis, as assessed by the decrease of thrombus volume (5.3±1.7 vs.11.0±3.4 mm3, p=0.004), length (7.4±1.0 vs. 10.9±1.8 mm, p=0.02) and increase of MLA (2.5±0.6 mm2 vs. 1.8±0.3 mm2, p=0.02). However, the degree of stenosis analyzed by QCA didn’t significantly decrease over time (49.7±4.6% vs. 55.7±6.6%, p= 0.15). The thrombus volume reduction was time dependent, as witnessed by the high correlation between the percentage of thrombus volume decrease and the delay between analysis (R=0.87, p=0.002). The observed thrombus volume reduction rate was evaluated to 12% of the initial volume per day under medical therapy. TD-OCT assessment of thrombus volume in patients with ACS is feasible, safe and could allow in vivo clot regression monitoring.

Identification of a fibrin-independent platelet contractile mechanism regulating primary hemostasis and thrombus growth

AbstractA fundamental property of platelets is their ability to transmit cytoskeletal contractile forces to extracellular matrices. While the importance of the platelet contractile mechanism in regulating fibrin clot retraction is well established, its role in regulating the primary hemostatic response, independent of blood coagulation, remains ill defined. Real-time analysis of platelet adhesion and aggregation on a collagen substrate revealed a prominent contractile phase during thrombus development, associated with a 30% to 40% reduction in thrombus volume. Thrombus contraction developed independent of thrombin and fibrin and resulted in the tight packing of aggregated platelets. Inhibition of the platelet contractile mechanism, with the myosin IIA inhibitor blebbistatin or through Rho kinase antagonism, markedly inhibited thrombus contraction, preventing the tight packing of aggregated platelets and undermining thrombus stability in vitro. Using a new intravital hemostatic model, we demonstrate that the platelet contractile mechanism is critical for maintaining the integrity of the primary hemostatic plug, independent of thrombin and fibrin generation. These studies demonstrate an important role for the platelet contractile mechanism in regulating primary hemostasis and thrombus growth. Furthermore, they provide new insight into the underlying bleeding diathesis associated with platelet contractility defects.

Reduced Thrombus Formation in Native Blood of Homozygous Factor VII-Deficient Patients at High Arterial Wall Shear Rate

Inhibition of thrombin formation in flowing native blood reduces thrombus formation on subendothelium, dacron, or collagen fibrils at arterial wall shear rates of 450 to 650 s-1. In the present study, we have investigated the role of low levels of factor VII (FVII) in thrombus formation on collagen fibrils at arterial wall shear rates of 650 s-1 (coronary arteries), 2,600 s-1 (mildly stenosed arteries), and 10,510 s-1 (severely stenosed arteries) in parallel-plate perfusion chambers. In the perfusion chamber with the highest wall shear rate, thrombus formation took place at the apex of an eccentric stenosis, which reduced the cross-sectional area of the blood flow channel by 80%, thus simulating thrombus formation at an atherosclerotic plaque rupture. Native blood from 21 healthy volunteers and 12 homozygous FVII-deficient patients was drawn by a pump directly from an antecubital vein over a surface of fibrillar collagen positioned in the respective perfusion chambers. The patients had FVII coagulant activities ranging from 1.3% to 4.5% and FVII antigen levels of 16% to 23% of normal. Immunoaffinity purification of the patients' FVII followed by electrophoresis (sodium dodecyl sulfate-polyacrylamide gel electrophoresis [SDS-PAGE]) and immunoblotting showed a protein with similar molecular mass as normal FVII. In the perfusion studies, a reduction in thrombus volume of 54% of normal (P < .007) at 10,510 s-1 was observed. The deposition of fibrin on the thrombogenic surface and the plasma level of fibrinopeptide A (FPA) in blood samples collected distal to the perfusion chamber were concomitantly reduced (P < .002 and P < .04, respectively). The plasma FPA level was also reduced at 2,600 s-1 (P < .04), but not at 650 s-1. However, at the lower shear conditions, the thrombus volume and the fibrin deposition were within the ranges observed in normal blood. The platelet-collagen adhesion was not affected at any of the three shear conditions. Thus, low plasma levels of FVII result in significantly less formation of thrombin and fibrin in and around growing platelet masses at high shear condition. This may weaken the thrombus stability and reduce platelet recruitment, thereby lowering thrombus volume. In support of this theory, one patient with afibrinogenemia had an 83% reduction in thrombus volume at this high shear condition.

Reduced thrombus formation in native blood of homozygous factor VII- deficient patients at high arterial wall shear rate

Inhibition of thrombin formation in flowing native blood reduces thrombus formation on subendothelium, dacron, or collagen fibrils at arterial wall shear rates of 450 to 650 s-1. In the present study, we have investigated the role of low levels of factor VII (FVII) in thrombus formation on collagen fibrils at arterial wall shear rates of 650 s-1 (coronary arteries), 2,600 s-1 (mildly stenosed arteries), and 10,510 s-1 (severely stenosed arteries) in parallel-plate perfusion chambers. In the perfusion chamber with the highest wall shear rate, thrombus formation took place at the apex of an eccentric stenosis, which reduced the cross-sectional area of the blood flow channel by 80%, thus simulating thrombus formation at an atherosclerotic plaque rupture. Native blood from 21 healthy volunteers and 12 homozygous FVII- deficient patients was drawn by a pump directly from an antecubital vein over a surface of fibrillar collagen positioned in the respective perfusion chambers. The patients had FVII coagulant activities ranging from 1.3% to 4.5% and FVII antigen levels of 16% to 23% of normal. Immunoaffinity purification of the patients' FVII followed by electrophoresis (sodium dodecyl sulfate-polyacrylamide gel electrophoresis [SDS-PAGE]) and immunoblotting showed a protein with similar molecular mass as normal FVII. In the perfusion studies, a reduction in thrombus volume of 54% of normal (P &lt; .007) at 10,510 s-1 was observed. The deposition of fibrin on the thrombogenic surface and the plasma level of fibrinopeptide A (FPA) in blood samples collected distal to the perfusion chamber were concomitantly reduced (P &lt; .002 and P &lt; .04, respectively). The plasma FPA level was also reduced at 2,600 s-1 (P &lt; .04), but not at 650 s-1. However, at the lower shear conditions, the thrombus volume and the fibrin deposition were within the ranges observed in normal blood. The platelet-collagen adhesion was not affected at any of the three shear conditions. Thus, low plasma levels of FVII result in significantly less formation of thrombin and fibrin in and around growing platelet masses at high shear condition. This may weaken the thrombus stability and reduce platelet recruitment, thereby lowering thrombus volume. In support of this theory, one patient with afibrinogenemia had an 83% reduction in thrombus volume at this high shear condition.

Shear rate-dependent impairment of thrombus growth on collagen in nonanticoagulated blood from patients with von Willebrand disease and hemophilia A

Thrombus formation on collagen fibrils was quantified at venous (100/s) and arterial (650/s and 2,600/s) wall shear rates in blood from patients with various subtypes of von Willebrand disease (vWD) and with hemophilia A (HA). Nonanticoagulated blood was drawn directly from an antecubital vein over purified type III collagen fibrils exposed in parallel-plate perfusion chambers. Blood-collagen interactions were differentiated and quantified by morphometry as platelet adhesion, thrombus height, thrombus volume, and deposition of fibrin strands. Sixteen patients with vWD, including four type III, six type I, four type IIA, and two type IIB, were compared with 26 normal subjects and nine patients with HA, including six severe HA and three mild HA. Platelet adhesion and thrombus formation at 2,600/s were significantly decreased in blood from patients with vWD type III, IIA, and IIB, but not in blood from patients with type I and in HA. The abnormal thrombus formation was apparently not related to the decreased levels of factor VIII (F.VIII), because thrombus height and volume were normal in severe and mild HA. Thrombus formation at 650/s was also significantly decreased in patients with vWD type III, IIA, and IIB and slightly reduced in type I. Significant reduction in thrombus volume and height was also observed in blood from patients with severe HA, but not in mild HA. Thrombus dimensions were not affected at 100/s in the vWD subtypes. However, significantly decreased thrombus height and virtually absent fibrin deposition were observed in blood from patients with severe HA. Apparently, F.VIII supports thrombus formation at low and intermediate shear conditions, presumably through the generation of thrombin. In contrast, von Willebrand factor (vWF) mediates not only platelet adhesion, but also thrombus formation at intermediate and high shear rates. Thus, the relative contribution of coagulation (F.VIII) and platelet function (vWF) in thrombus formation appears to be shear rate dependent, but having optimal effects at different shear conditions.

Shear Rate-Dependent Impairment of Thrombus Growth on Collagen in Nonanticoagulated Blood From Patients With von Willebrand Disease and Hemophilia A

AbstractThrombus formation on collagen fibrils was quantified at venous (100/s) and arterial (650/s and 2,600/s) wall shear rates in blood from patients with various subtypes of von Willebrand disease (vWD) and with hemophilia A (HA). Nonanticoagulated blood was drawn directly from an antecubital vein over purified type III collagen fibrils exposed in parallel-plate perfusion chambers. Blood-collagen interactions were differentiated and quantified by morphometry as platelet adhesion, thrombus height, thrombus volume, and deposition of fibrin strands. Sixteen patients with vWD, including four type III, six type I, four type IIA, and two type IIB, were compared with 26 normal subjects and nine patients with HA, including six severe HA and three mild HA. Platelet adhesion and thrombus formation at 2,600/s were significantly decreased in blood from patients with vWD type III, IIA, and IIB, but not in blood from patients with type I and in HA. The abnormal thrombus formation was apparently not related to the decreased levels of factor VIII (F.VIII), because thrombus height and volume were normal in severe and mild HA. Thrombus formation at 650/s was also significantly decreased in patients with vWD type III, IIA, and IIB and slightly reduced in type I. Significant reduction in thrombus volume and height was also observed in blood from patients with severe HA, but not in mild HA. Thrombus dimensions were not affected at 100/s in the vWD subtypes. However, significantly decreased thrombus height and virtually absent fibrin deposition were observed in blood from patients with severe HA. Apparently, F.VIII supports thrombus formation at low and intermediate shear conditions, presumably through the generation of thrombin. In contrast, von Willebrand factor (vWF) mediates not only platelet adhesion, but also thrombus formation at intermediate and high shear rates. Thus, the relative contribution of coagulation (F.VIII) and platelet function (vWF) in thrombus formation appears to be shear rate dependent, but having optimal effects at different shear conditions.