Lysis Of Thrombus Research Articles

Clots, Collaterals, and the Intracranial Arterial Tree

See related article, p 2061. Acute ischemic stroke is a story of two parts; a thrombus blocks anterograde blood flow within the intracranial arterial tree while tiny vessels called collaterals sustain the brain until the thrombus is cleared. The location, size, and type of thrombus along with the degree and extent of collaterals likely determine the patient’s clinical symptoms, the likelihood of treatment success and the patient’s prognosis. A major focus of acute stroke research has been to image and measure various thrombus and collateral characteristics that help predict patient outcomes. In vitro studies show that larger clots are less likely to lyse with thrombolytic agents, whereas clots with more surface area exposed to flowing blood are more likely to lyse early.1 This information can be used to create a theoretical framework for thrombus lysis within the intracranial arterial tree.2 Thrombi in proximal arteries such as the internal carotid or the M1 segment of the middle cerebral artery are likely to have greater volume than thrombi in smaller more distal arteries. Independent of thrombus volume, longer thrombi within the cylindrical framework of the intracranial arterial tree are likely to have less relative surface area (at the proximal and distal ends) exposed to blood flow. Poor collateral status is likely to result …

A CASE OF EFFECTIVE ANTICOAGULANT THERAPY IN A PATIENT WITH CORONARY HEART DISEASE, CHRONIC HEART FAILURE, ATRIAL FIBRILLATION, AND LEFT VENTRICULAR THROMBOSIS

Objective: to describe effective treatment in a patient with stent thromboses and a left ventricular (LV) thrombus resistant to therapy with the novel anticoagulants clopidogrel and prasugrel. Materials and methods. Patient P.V., aged 53 years, was admitted to the Department of Cardiology with complaints of dyspnea, lower limb edema, general weakness, palpitation, reduced urine output, and elevated body temperature. His medical history showed myocardial infarction experienced three times, coronary stenting using 3 drug-eluting stents, and stent thromboses. Echocardiography (EchoCG) revealed a mobile thrombus with a total area of 11 cm 2 in the area of chronic LV aneurysm. Results. According to the data of EchoCG conducted over time, there was a decrease in thrombus sizes to 3.06 cm 2 during rivaroxaban therapy, their subsequent increase up to 9.25 cm 2 after anticoagulant therapy that was discontinued without permission, and final lysis of a LV thrombus following the intake of rivaroxaban 20 mg/day during one month. Conclusion. LV thrombus lysis in the rivaroxaban-treated patient with post-infarction cardiosclerosis and stent thromboses resistant to therapy with clopidogrel and prasugrel was described in this case.

Localization and identification of thrombin and plasminogen activator activities in model human thrombi by in situ zymography.

Human thrombi vary in their susceptibility to lysis and this is clinically important. Several potential contributory factors were examined in this study by using model thrombi, created under flow; these provide a robust, reproducible and easily-manipulated system. Here we identify the plasminogen activators (PA) active in model thrombi of known age and define the cellular and plasma contribution to activity in different areas. The cell-rich head of model thrombi had strong thrombin and PA activity, with coagulant activity also at the tail. Thrombin activity decreased as model thrombi were aged. PA activity in the thrombus head also decreased on ageing of thrombi but activity emerged around the thrombi, including the tail. Activity in the head of fresh model thrombi was primarily due to uPA, with some contribution from tPA. Experiments with thrombi prepared from platelet-rich plasma and added leucocytes showed that uPA activity at the head of fresh thrombi was derived from PMN. Older thrombi had tPA activity around the tail of the thrombus; this activity occurred in the absence of cells. This study highlights the importance of PMN-derived uPA activity in the lysis of fresh thrombi, with activity originating in the leucocyte-rich head. It also shows that thrombi are dynamic structures in which fibrin can be repeatedly laid down and lysed, observations that are relevant to therapeutic lysis and potential rethrombosis.

Abstract TP81: Faster Start of IV tPA Does not Decrease the Need for Endovascular Thrombectomy in Acute Ischemic Stroke

Background: Recent patient series have shown IV tPA to more often lyse cerebral thrombi when started sooner after symptom onset in patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). This association has been attributed to less fibrin-cross-linking and less compaction of thrombi. We sought to determine if this phenomenon would make endovascular thrombectomy less often needed among AIS-LVO patients treated hyperacutely with IV tPA. Methods: In a prospectively maintained registry, we identified patients receiving IV tPA at 2 academic medical centers from March 2005 - May 2015. Inclusion criteria were: 1) LVO seen on CTA or MRA before (or early during) infusion of IV tPA and 2) follow-up vessel imaging within 6h of IV tPA initiation, using CT, MR or catheter angiogram. Degree of thrombus lysis with IV tPA alone was rated using the arterial occlusive lesion (AOL) Scale. Results: Among the 166 patients, average age was 72.4 (±13.4), 52.4% were female and pretreatment NIHSS was 13.9 (±8.4). Onset to needle time (OTN) was median 105 min (IQR 79-129) and door to needle time 44 min (27-65). Initial vessel imaging modality was MRA in 68.7% and CTA in 31.3%. Early post-tPA vessel imaging modality was catheter angiogram in 63.8%, MRA in 33.7% and CTA in 2.4%. Time from tPA initiation to recanalization assessment was faster when post-tPA vessel imaging was catheter angiogram vs MRA/CTA, 72 min (45.5-116.5) vs 232 min (185-283), p<0.001. In cases assessed with early post-treatment catheter angiogram, IV tPA yielded complete recanalization in 17%, partial in 6.6%, and none in 76.4%. In cases assessed with MRA/CTA, IV tPA yielded complete recanalization in 30%, partial in 35%, and none in 35%. Recanalization within the 6h window was visualized more often when imaged with later CTA/MRA than with earlier catheter angiogram (p<0.001). Among patients going directly to catheter angiography, OTN for IV tPA was not different between recanalizers and non-recanalizers, 106 vs 98 min, p = 0.53. Discussion: Among large vessel acute ischemic stroke patients, the rate of complete recanalization with IV tPA alone is only 1 in 6, and faster OTN time is not associated with increased recanalization. All AIS-LVO patients should proceed to thrombectomy as swiftly as possible.

Sol Ventrikül Apeks Trombüsünün Trombolitik Tedavi ile Başarıyla Çözülmesi

Sol ventrikül içerisinde gelişmiş olan trombüslerin tedavisinde net bir yaklaşım bulunmamaktadır. Emboli riski yüksek ve cerrahi müdahalenin mümkün olmadığı sol ventrikül trombüslerinde trombolitik tedavi uygulanabilmektedir. Sol ventrikül trombüslerinde trombolitik doz şeması ve infüzyon süresi ile ilgili net bir bilgi bulunmamaktadır. Ankilozan spondilit nedeni ile takip edilen 37 yaşındaki erkek olgu, 3 gün önce başlayan nefes darlığı şikâyeti ile başvurdu. Ekokardiyografisinde sol ventrikül sistolik fonksiyonlarında azalma ve sol ventrikül apeksinde hareketli trombüs saptandı. Olguya yüksek cerrahi risk nedeni ile 100 mg t-PA verilmesi planlandı. İnfüzyonun dördüncü saatinde yapılan ekokardiyografide trombüsün tamamen kaybolduğu görüldü. Tedavi dozu ve infüzyon süresini belirlemede erken ve sık aralıklı ekokardiyografik değerlendirme etkili bir seçenek olabilir.

Ultrasound dynamics lysis apex thrombus as an objective criterion of effectiveness of anticoagulation therapy in venous thrombosis

To assess the effectiveness of anticoagulant therapy (ACT) for the treatment of patients with deep venous thrombosis (DVT) of the lower extremities. The study considered ultrasonic characteristics of lysis of the proximal part of thrombus: localization and nature of venous thrombosis, the length and diameter of the proximal floating part of the thrombus, and duration of the venous thrombosis. Depending on the ACT options patients were divided into 3 groups: Group 1 (18 patients) received rivaroxaban, group 2 (19 patients) received enoxaparin sodium with subsequent transition to warfarin, and 3 group (19 patietns) received enoxaparin sodium, followed by administration of rivaroxaban. Treatment with rivaroxaban was preferable over standard ACT with enoxaparin/warfarin with regards to the lysis of thrombus when duration of thrombosis did not exceed 10 days. In 10.5% of patients who received warfarin flotation of thrombi remained for 14 days; the length of the floating part of the thrombi did not exceed 3 cm. Such circumstances and inability to reach a therapeutic INR value required cava filter placement. Treatment with enoxaparin sodium followed by the administration of rivaroxaban was found to be the most efficient ACT regimen as there was no negative dynamics of ultrasound characteristics of lysis of thrombi at any duration of the disease.

Towards a multi-physics modelling framework for thrombolysis under the influence of blood flow.

Thrombolytic therapy is an effective means of treating thromboembolic diseases but can also give rise to life-threatening side effects. The infusion of a high drug concentration can provoke internal bleeding while an insufficient dose can lead to artery reocclusion. It is hoped that mathematical modelling of the process of clot lysis can lead to a better understanding and improvement of thrombolytic therapy. To this end, a multi-physics continuum model has been developed to simulate the dissolution of clot over time upon the addition of tissue plasminogen activator (tPA). The transport of tPA and other lytic proteins is modelled by a set of reaction–diffusion–convection equations, while blood flow is described by volume-averaged continuity and momentum equations. The clot is modelled as a fibrous porous medium with its properties being determined as a function of the fibrin fibre radius and voidage of the clot. A unique feature of the model is that it is capable of simulating the entire lytic process from the initial phase of lysis of an occlusive thrombus (diffusion-limited transport), the process of recanalization, to post-canalization thrombolysis under the influence of convective blood flow. The model has been used to examine the dissolution of a fully occluding clot in a simplified artery at different pressure drops. Our predicted lytic front velocities during the initial stage of lysis agree well with experimental and computational results reported by others. Following canalization, clot lysis patterns are strongly influenced by local flow patterns, which are symmetric at low pressure drops, but asymmetric at higher pressure drops, which give rise to larger recirculation regions and extended areas of intense drug accumulation.

Combined lysis of thrombus with ultrasound and systemic tissue plasminogen activator for emergent revascularization in acute ischemic stroke (CLOTBUST-ER): An update

Background: Continuous exposure of intracranial arterial occlusions to pulsed wave ultrasound enhances tissue plasminogen induced recanalization. Our hypothesis is that sonothrombolysis can improve functional outcomes of stroke patients receiving tPA therapy. Methods: The primary objective is to evaluate the efficacy of a novel transcranial ultrasound device and systemic tPA (Target) compared to systemic tPA alone (Controls) in subjects with acute ischemic stroke and NIHSS scores 10 or greater. This is a randomized (1:1), placebo-controlled, multi-site, phase 3 clinical trial to evaluate the efficacy and safety of a novel ultrasound device, as an adjunctive therapy to tPA treatment in subjects with acute ischemic stroke: total projected enrollment 824 patients with interim analyses at ⅓ and ⅔ of enrollment. Current Status: CLOTBUST-ER had active enrollment at approximately 70 sites in 14 countries worldwide. DSMB recommended to stop the trial after second interim analysis. Functional outcomes are still being assessed via modified Rankin Scores at 90 days and the primary endpoint will be analyzed using ordinal shift statistical analysis. Final results will be presented at ISC 2016. Conclusions: CLOTBUST-ER is the first phase three multinational randomized blinded clinical trial of sonothrombolysis for treatment of acute ischemic stroke. ClinicalTrials.gov Trial Registry ID: NCT01098981.

ACTIVATION OF PROTEIN C IN THE IN VITRO THROMBOLYSIS

Physiological conditions of formation and subsequent lysis of thrombus were reconstituted in vitro in our research. Thrombus formation was initiated either by addition of exogenous thrombin or by contact of blood with anionic surface, which stimulates spontaneous coagulation of blood. Tissue plasminogen activator and/or protein C were previously added in the blood sample. The time of the beginning and total degradation of formed thrombi as well as the level of PC in lysates was controlled then. Only an addition of protein C alone or in combination with tissue plasminogen activator led to the most effective lysis of thrombi: their residual weight was 18% and 5% comparing to control. Addition of exogenous tissue plasminogen activator alone or in combination with protein C caused a 83% and 74% decrease of PC level in lysates of spontaneously formed thrombi, and 72% and 56% decrease for thrombi formed by thrombin, respectively. Without an addition of tissue plasminogen activator protein C level in lysates of thrombi formed by thrombin was 54% down on spontaneously formed thrombi. Thus, changes of PC concentration in isolated volume of clot seem to be controlled by thrombin at the stage of thrombus formation and by fibrinolytic system at the stage of fibrinolysis. Concentration of PC in lysates from clots formed by exogenous thrombin was decreasing over the next 10 hours of thrombolysis, which can also be the evidence of the interaction between the fibrinolytic and PC activation systems. A hypothesis is. formulated about an existence of endothelium-independent mechanism of PC activation in blood plasma with blood cells participation, which effectiveness increases in the process of thrombolysis.

Quantification of Fibrinolysis Using Velocity Curves Measured with Thromboelastometry in Children with Congenital Heart Disease.

In this pilot study, we hypothesized that velocity parameters obtained from changes in clot amplitude (A) and clot elasticity (E) measured with thromboelastometry (ROTEM, Tem International GmbH, Munich, Germany) could improve detection of fibrinolysis in whole blood obtained from children undergoing surgery for congenital heart disease. Whole blood samples were obtained after induction of general anesthesia. Seven conditions were studied: native whole blood (baseline) and samples with progressive tissue-type plasminogen activator (t-PA) concentrations (102, 255, 512, 1024, 1535, and 2539 units/mL). We calculated velocity curves based on changes in clot amplitude and elasticity between different time points using ROTEM data. The analysis allowed for the determination of the following parameters: the maximum rate of thrombus formation based on amplitude or elasticity and the maximum rate of thrombus lysis measured based on amplitude (MTL) or maximum rate of thrombus lysis measured based on elasticity (MTLe). We compared these parameters with the lysis in relation to maximal clotting firmness and measured 30 minutes after the clotting time (LI30, in percent). Concentrations of t-PA ≥ 255 units/mL resulted in a decrease in LI30 (mean difference, 255 units/mL versus baseline, -31.05%, P < 0.0001) and the maximum rate of thrombus formation based on amplitude (mean difference, 255 units/mL versus baseline, -7.5, P = 0.005). Concentrations of t-PA ≥ 512 units/mL resulted in changes in maximum rate of thrombus formation based on elasticity (mean difference, 512 units/mL versus baseline, -10.9, P = 0.010), MTL (mean difference, 255 units/mL versus baseline, -3.2, P = 0.016), and MTLe (mean difference, 255 units/mL versus baseline, -7.8, P = 0.004). For t-PA concentrations ≥ 512 units/mL, clot formation was abolished. The area under the receiver operating characteristics curves did not differ between LI30, MTL, and MTLe for the detection of minimal fibrinolytic activation (102 units/mL; 0.74, 0.75, and 0.72, respectively, P = 0.708), whereas sensitivity and specificity of the cutoff values 97% for LI30, -0.3 for MTL, and -0.5 for MTLe were 52% and 85%, 83% and 45%, and 83% and 45%, respectively. Velocity curves based on the amplitudes or clot elasticity could provide objective measurement of clot growth and clot lysis kinetics, allowing detection of even minor fibrinolysis. Further studies are needed to assess the clinical relevance of these parameters.

Plasminogen associates with phosphatidylserine-exposing platelets and contributes to thrombus lysis under flow

AbstractThe interaction of plasminogen with platelets and their localization during thrombus formation and fibrinolysis under flow are not defined. Using a novel model of whole blood thrombi, formed under flow, we examine dose-dependent fibrinolysis using fluorescence microscopy. Fibrinolysis was dependent upon flow and the balance between fibrin formation and plasminogen activation, with tissue plasminogen activator-mediated lysis being more efficient than urokinase plasminogen activator-mediated lysis. Fluorescently labeled plasminogen radiates from platelet aggregates at the base of thrombi, primarily in association with fibrin. Hirudin attenuates, but does not abolish plasminogen binding, denoting the importance of fibrin. Flow cytometry revealed that stimulation of platelets with thrombin/convulxin significantly increased the plasminogen signal associated with phosphatidylserine (PS)-exposing platelets. Binding was attenuated by tirofiban and Gly-Pro-Arg-Pro amide, confirming a role for fibrin in amplifying plasminogen binding to PS-exposing platelets. Confocal microscopy revealed direct binding of plasminogen and fibrinogen to different platelet subpopulations. Binding of plasminogen and fibrinogen co-localized with PAC-1 in the center of spread platelets. In contrast, PS-exposing platelets were PAC-1 negative, and bound plasminogen and fibrinogen in a protruding “cap.” These data show that different subpopulations of platelets harbor plasminogen by diverse mechanisms and provide an essential scaffold for the accumulation of fibrinolytic proteins that mediate fibrinolysis under flow.

Spirulan from blue-green algae inhibits fibrin and blood clots: its potent antithrombotic effects.

We investigated in vitro and in vivo fibrinolytic and antithrombotic activity of spirulan and analyzed its partial biochemical properties. Spirulan, a sulfated polysaccharide from the blue-green alga Arthrospira platensis, exhibits antithrombotic potency. Spirulan showed a strong fibrin zymogram lysis band corresponding to its molecular mass. It specifically cleaved Aα and Bβ, the major chains of fibrinogen. Spirulan directly decreased the activity of thrombin and factor X activated (FXa), procoagulant proteins. In vitro assays using human fibrin and mouse blood clots showed fibrinolytic and hemolytic activities of spirulan. Spirulan (2 mg/kg) showed antithrombotic effects in the ferric chloride (FeCl3 )-induced carotid arterial thrombus model and collagen and epinephrine-induced pulmonary thromboembolism mouse model. These results may be attributable to the prevention of thrombus formation and partial lysis of thrombus. Therefore, we suggest that spirulan may be a potential antithrombotic agent for thrombosis-related diseases.

Dutch Randomized Trial Comparing Standard Catheter-Directed Thrombolysis and Ultrasound-Accelerated Thrombolysis for Arterial Thromboembolic Infrainguinal Disease (DUET)

Purpose: To report the results of the Dutch randomized trial comparing standard catheter-directed and ultrasound-accelerated thrombolysis (UST) for the treatment of arterial thromboembolic occlusions. Methods: The DUET study ( controlled-trials.com ; identifier ISRCTN72676102) was designed to assess whether UST can reduce therapy time significantly compared with standard thrombolysis (ST). Sixty patients (44 men; mean age 64 years) with recently (7–49 days) thrombosed infrainguinal native arteries or bypass grafts causing acute limb ischemia (Rutherford category I or IIa) were randomized to ST (n=32) or UST (n=28). The primary outcome was the duration of thrombolysis needed for uninterrupted flow (>95% thrombus lysis), with outflow through at least 1 below-the-knee artery. Continuous data are presented as means ± standard deviations. Results: Thrombolysis was significantly faster in the UST group (17.7±2.0 hours) than in the ST group (29.5±3.2 hours, p=0.009) and required significantly fewer units of urokinase (2.8±1.6×106 IU in the ST group vs. 1.8±1.0×106 IU in the UST group, p=0.01) for uninterrupted flow. Technical success was achieved in 27 (84%) patients in the ST group vs. 21 (75%) patients in the UST group (p=0.52). The combined 30-day death and severe adverse event rate was 19% in the ST group and 29% in the UST group (p=0.54). The 30-day patency rate was 82% in the ST group as compared with 71% in the UST group (p=0.35). Conclusion: Thrombolysis time was significantly reduced by UST as compared with ST in patients with recently thrombosed infrainguinal native arteries or bypass grafts.

Abstract W P27: Quantitative Measurement Of Blood Flow Around Intravascular Thrombus Using CT Perfusion T0 Maps

Introduction: Anterograde blood flow around thrombus and extent of retrograde collateral filling can affect thrombus lysis with IV tPA. Current assessment of blood flow around thrombus is however very subjective. The aim of the present study is to validate a newly devised method to quantify blood flow around thrombus using CT perfusion (CTP) T0 maps. Methods: From the Prove-IT stroke-imaging database, perfusion CT and DSA images of stroke patients treated with IV tPA and/or IA thrombolysis were analyzed. We generated maps that measure delay in arrival time of contrast within the intracranial arterial tree (T0 maps) from that of the chosen arterial input function. A “positive sloped” regression line of T0 values from distal clot interface to at least 14 pixels (median 68 pixels) along the artery profile indicated presence of occult anterograde flow. Anterograde flow thus measured using the T0 maps was compared with anterograde flow assessed on first angiography of subsequent IA procedure. Results: Of 37 patients (mean age 66 ± 13.5 years, 20 female), 35 (94.6%) were treated with IV tPA before DSA. Median time from CTP to first run angiography was 83 mins (IQR 53-100 mins). Positive slope were noted in 10 patients. Patients who had anterograde flow on first angiography were 10. Compared with anterograde flow on first run angio, positive slope on T0 map had a sensitivity of 80%, specificity of 92.6% and a positive predictive value of 80% and negative predictive value of 92.6%. In patients with anterograde flow on first angiography, median T0 time at proximal clot interface was 0.1 seconds (IQR 0-0.1) and at distal clot interface was 0.7 seconds (IQR 0.5-3.1). In patients without any anterograde flow on first angio, median T0 time at proximal clot interface was 0.1 seconds (IQR 0-0.3) while that at distal clot interface was 3.7 seconds (IQR 2.1-5.6). Conclusions: The slope method on CTP T0 maps and measurement of T0 values around clot reliably measure presence of anterograde blood flow through thrombus.

(Tissue PET) Vascular metabolic imaging and peripheral plasma biomarkers in the evolution of chronic aortic dissections.

Despite adequate medical management, dissection of the descending aorta (type B) may develop complications, including aneurysmal progression and eventually rupture. Partial false lumen thrombosis has been identified as a marker of adverse evolution in chronic dissection. The aim of this study was to test the ability of complementary information, provided by (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) and peripheral biomarkers, to add pathophysiological significance and a prognostic value to morphological data. We explored serial aortic (18)F-FDG uptake by PET/CT imaging and plasma biomarkers in a series of 23 patients with type B dissection to predict complications from initial data and to investigate potential associations with aneurysmal expansion during follow-up. Complications occurred in 17 patients. Acute initial characteristics associated with complications were male gender (P = 0.021), arterial hypertension (P = 0.040), aortic dissection diameter (P = 0.0086), partial thrombosis of the false channel (P = 0.0046), and enhanced focal (18)F-FDG uptake (P = 0.045). During follow-up (mean 16.7 ± 8.0 months), aneurysmal expansion was associated with false lumen morphology (P< 0.0001), quantitative (18)F-FDG uptake, (P = 0.0029), elevated plasma concentrations of biomarkers of platelets (P-selectin, P = 0.0009) and thrombin activation (TAT complexes, P = 0.0075), and fibrinolysis (PAP complexes, P < 0.0001; D-dimers, P = 0.0006). Plasma markers of coagulation and fibrinolysis were related to false channel morphology, suggesting that thrombus biological dynamics may drive progressive expansion of type B dissections. Enhanced FDG uptake may be considered as a complementary imaging marker associated with secondary complications in type B dissections. During follow-up, aneurysmal progression is related to PET/CT and biomarkers of thrombus renewal and lysis.

Abdominal aortic aneurysms revisited: MDCT with multiplanar reconstructions for identifying indicators of instability in the pre- and postoperative patient.

Rupture of an abdominal aortic aneurysm is commonly a fatal event. Multidetector computed tomographic (CT) signs of frank aortic rupture are usually readily apparent and widely understood. However, diagnosing an impending aortic rupture on the basis of imaging findings can prove more difficult. CT is the primary modality used for serial imaging in patients with aortic aneurysm and may show findings indicative of aortic instability. Therefore, it is critical that radiologists be familiar with the CT findings of aortic instability to avert the potential complications of hemorrhage, end organ or limb ischemia, and death. Various preoperative CT indicators have been previously described in both research investigations and review articles. A large baseline aneurysm size and a rapid increase in size over time are associated with a higher risk for rupture. The importance of obtaining accurate measurements with multiplanar reconstructions and the role of new semiautomated tools for obtaining accurate, reproducible measurements are discussed. Additional CT findings that reflect aortic aneurysm instability include luminal expansion with lysis of thrombus, intramural hemorrhage (ie, the crescent sign), periaortic hemorrhage, a penetrating atherosclerotic ulcer, and contained rupture (ie, the draped aorta sign). After open or endovascular aneurysm repair, CT is routinely used to monitor for graft complications. In this setting, radiologists should understand that the presence of an endoluminal stent or surgical graft does not preclude aortic rupture. Online supplemental material is available for this article.

Elastic Behavior and Platelet Retraction in Low- and High-Density Fibrin Gels

Fibrin is a biopolymer that gives thrombi the mechanical strength to withstand the forces imparted on them by blood flow. Importantly, fibrin is highly extensible, but strain hardens at low deformation rates. The density of fibrin in clots, especially arterial clots, is higher than that in gels made at plasma concentrations of fibrinogen (3–10 mg/mL), where most rheology studies have been conducted. Our objective in this study was to measure and characterize the elastic regimes of low (3–10 mg/mL) and high (30–100 mg/mL) density fibrin gels using shear and extensional rheology. Confocal microscopy of the gels shows that fiber density increases with fibrinogen concentration. At low strains, fibrin gels act as thermal networks independent of fibrinogen concentration. Within the low-strain regime, one can predict the mesh size of fibrin gels by the elastic modulus using semiflexible polymer theory. Significantly, this provides a link between gel mechanics and interstitial fluid flow. At moderate strains, we find that low-density fibrin gels act as nonaffine mechanical networks and transition to affine mechanical networks with increasing strains within the moderate regime, whereas high-density fibrin gels only act as affine mechanical networks. At high strains, the backbone of individual fibrin fibers stretches for all fibrin gels. Platelets can retract low-density gels by >80% of their initial volumes, but retraction is attenuated in high-density fibrin gels and with decreasing platelet density. Taken together, these results show that the nature of fibrin deformation is a strong function of fibrin fiber density, which has ramifications for the growth, embolization, and lysis of thrombi.

Outcomes in children with deep vein thrombosis managed with percutaneous endovascular thrombolysis.

Our center has developed a multidisciplinary approach to percutaneous endovascular thrombolysis with the goal of improving outcomes in children with thrombosis. There is little data describing the safety and efficacy of endovascular thrombolysis and the frequency of post-thrombotic syndrome after thrombolysis in children. Retrospective analysis of children undergoing percutaneous endovascular thrombolysis to determine (1) the safety and efficacy of this procedure and (2) the frequency of the diagnosis of post-thrombotic syndrome after thrombolysis. We reviewed the medical and imaging databases for children who underwent percutaneous endovascular thrombolysis for deep venous thrombosis (DVT) between November 2008 and June 2013 at our institution. Demographic data were reviewed for the technical success and complications of thrombolysis and the last assigned post-thrombotic syndrome score using standardized scoring tools. Forty-one children ages 3 months to 21 years (median age: 15 years; 44% male) underwent percutaneous endovascular thrombolysis between November 2008 and June 2013. Upper extremity DVT occurred in 13 patients (32%); lower extremity DVT occurred in 28 patients (68%). All 41 patients received thrombolysis grading; 90% of those patients achieved greater than 50% thrombus lysis. Twenty-eight patients received formal post-thrombotic syndrome scoring and 4 (14%) met diagnostic criteria for post-thrombotic syndrome. One major bleeding episode and one pulmonary embolism occurred with no long-term sequelae. Endovascular thrombolysis for DVT in children is safe, effective at thrombus removal and may reduce the incidence of post-thrombotic syndrome. Randomized or larger clinical trials would be needed to determine the long-term benefits of endovascular thrombolysis.

Assessment of early thromboelastometric variables from extrinsically activated assays with and without aprotinin for rapid detection of fibrinolysis.

Although thromboelastometry (ROTEM®) and thrombelastography can be used for bedside diagnosis of fibrinolysis, the time needed for detection is often prolonged. Since untreated fibrinolysis can result in consumption of coagulation factors and bleeding, early diagnosis and decision making are desirable. Accordingly, we assessed ROTEM variables from extrinsically activated assays with (APTEM) and without (EXTEM) addition of aprotinin for their ability to rapidly identify fibrinolysis. Specifically, we tested the hypotheses that prolonged clotting time, clot formation time, low clot firmness (at 5, 10, 15, and 20 minutes, designated A5, A10, A15, and A20, respectively), low maximum clot firmness (MCF) in EXTEM assays, and differences in these variables from parallel APTEM and EXTEM assays (designated as Δvariables) predict fibrinolysis. Data from 411 thromboelastometric measurements (obtained from 352 patients) with fibrinolysis and from 2537 measurements without fibrinolysis (obtained from 1605 patients) were assessed and analyzed using receiver operating characteristics. Data were analyzed as a pooled fibrinolysis cohort, and subanalyses were performed from sets assigned to categories of fibrinolysis related to the timing of thrombus lysis (i.e., a decrease of clot firmness to <15% of MCF within 30, 45, and 60 minutes, respectively). A lower 95% confidence limit of the area under the receiver operating characteristic curve (AUC [SE] <0.6) was considered a failure to substantially improve detection of increased fibrinolysis. AUCs were compared to identify the variable providing the best predictive association with fibrinolysis. As a secondary end point, optimum cutoff values at the point estimate corresponding to the greatest Youden index were calculated along with the respective sensitivities and specificities. In the pooled cohort, clot formation time (AUC: 0.652 [0.016]), α-angle (AUC: 0.675 [0.015]), A5 (AUC: 0.718 [0.013]), A10 (AUC: 0.734 [0.0.13]), A15 (AUC: 0.752 [0.013]), A20 (AUC: 0.771 [0.013]), and MCF (AUC: 0.799 [0.012]) predicted fibrinolysis. Fibrinolysis was also predicted by ΔA15 (AUC: 0.675 [0.016]), ΔA20 (AUC: 0.719 [0.015]), and ΔMCF (AUC: 0.812 [0.013]). AUCs increased in a time-related fashion. The ability to predict subsequent fibrinolysis based on thromboelastometry was higher when it occurred early rather than later during testing. However, for prediction of late fibrinolysis, only MCF (AUC: 0.655 [0.025]) appears to be potentially clinically useful. Low early values of clot firmness in extrinsically activated thromboelastometric assays are associated with fibrinolysis and improve its early detection. Additional assays with aprotinin fail to improve the early diagnosis of fibrinolysis compared with assays without aprotinin.

Acute superior mesenteric venous thrombosis: transcatheter thrombolysis and aspiration thrombectomy therapy by combined route of superior mesenteric vein and artery in eight patients.

To assess the feasibility, effectiveness, and safety of catheter-directed thrombolysis and aspiration thrombectomy therapy by combined route of superior mesenteric vein and artery (SMV+SMA) for acute superior mesenteric venous thrombosis (ASMVT). This retrospective study reviewed eight ASMVT patients with transcatheter direct thrombolysis and aspiration thrombectomy therapy via SMV and indirect thrombolysis via SMA during a period of 14 months. The demographics, etiology, risk factors, therapeutic effect, complications, mortality, and follow-up of the study population were assessed. Anatomic and imaging classification of location and extent of thrombus at diagnosis and degree of thrombus lysis were described. Technical success was achieved with substantial improvement in symptoms and thrombus resolution after thrombolytic therapy in all patients. The local urokinase infusion by SMA and SMV was performed for 5-7 (6.13 ± 0.83) and 7-15 (12 ± 2.51) days. Anticoagulation was performed catheter-directed and then orally throughout hospitalization and after discharge. Four patients required delayed localized bowel resection after thrombolytic therapy with no death. Thrombolytic therapy was not interrupted despite minor bleeding at the puncture site in two patients and sepsis in another two postoperatively. Nearly complete removal of thrombus was demonstrated by contrast-enhanced CT scan and portography before discharge. Patients were discharged in 10-27 (19.25 ± 4.89) days after admission. No recurrence developed during the follow-up of 10-13 (12.13 ± 0.99) months. Catheter-directed thrombolytic and aspiration therapy via SMV+SMA is beneficial for ASMVT in avoiding patient death, efficient resolving thrombus, rapid improving symptoms, reversing extensive intestinal ischemia, averting bowel resection, or localizing infarcted bowel segment and preventing short bowel syndrome.