Viral Coagulopathy in Patients With COVID-19: Treatment and Care.

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.

In vitro demonstration of focused ultrasound thrombolysis using bifrequency excitation.

Focused ultrasound involving inertial cavitation has been shown to be an efficient method to induce thrombolysis without any pharmacological agent. However, further investigation of the mechanisms involved and further optimization of the process are still required. The present work aims at studying the relevance of a bifrequency excitation compared to a classical monofrequency excitation to achieve thrombolysis without any pharmacological agent. In vitro human blood clots were placed at the focus of a piezoelectric transducer. Efficiency of the thrombolysis was assessed by weighing each clot before and after sonication. The efficiencies of mono- (550 kHz) and bifrequency (535 and 565 kHz) excitations were compared for peak power ranging from 70 W to 220 W. The thrombolysis efficiency appears to be correlated to the inertial cavitation activity quantified by passive acoustic listening. In the conditions of the experiment, the power needed to achieve 80% of thrombolysis with a monofrequency excitation is reduced by the half with a bifrequency excitation. The thermal effects of bifrequency and monofrequency excitations, studied using MR thermometry measurements in turkey muscle samples where no cavitation occurred, did not show any difference between both types of excitations when using the same power level.

High-intensity focused ultrasound (HIFU) for dissolution of clots in a rabbit model of embolic stroke.

It is estimated that only 2-6% of patients receive thrombolytic therapy for acute ischemic stroke suggesting that alternative therapies are necessary. In this study, we investigate the potential for high intensity focused ultrasound (HIFU) to initiate thrombolysis in an embolic model of stroke. Iron-loaded blood clots were injected into the middle cerebral artery (MCA) of New Zealand White rabbits, through the internal carotid artery and blockages were confirmed by angiography. MRI was used to localize the iron-loaded clot and target the HIFU beam for treatment. HIFU pulses (1.5 MHz, 1 ms bursts, 1 Hz pulse repetition frequency, 20 s duration) were applied to initiate thrombolysis. Repeat angiograms and histology were used to assess reperfusion and vessel damage. Using 275 W of acoustic power, there was no evidence of reperfusion in post-treatment angiograms of 3 rabbits tested. In a separate group of animals, 415 W of acoustic power was applied and reperfusion was observed in 2 of the 4 (50%) animals treated. In the last group of animals, acoustic power was further increased to 550 W, which led to the reperfusion in 5 of 7 (∼70%) animals tested. Histological analysis confirmed that the sonicated vessels remained intact after HIFU treatment. Hemorrhage was detected outside of the sonication site, likely due to the proximity of the target vessel with the base of the rabbit skull. These results demonstrate the feasibility of using HIFU, as a stand-alone method, to cause effective thrombolysis without immediate damage to the targeted vessels. HIFU, combined with imaging modalities used to identify and assess stroke patients, could dramatically reduce the time to achieve flow restoration in patients thereby significantly increasing the number of patients which benefit from thrombolysis treatments.

A multiparameter test of clot formation and fibrinolysis for in-vitro drug screening.

A large spectrum of methods has been used in both routine and scientific studies of the hemostatic system. The particular interest of the investigators has been focused on methods simultaneously evaluating clotting and fibrinolysis processes. The aim of the present study was to develop an optical method for overall evaluation of clot formation and lysis (CL-test) that could be used in drug screening. The CL-test was performed in citrate plasma diluted with Tris-buffered saline. Thrombin was applied for plasma clotting (0.5 IU/ml), while tissue plasminogen activator (60 ng/ml) was used for fibrinolysis activation. Clot formation and lysis were monitored in thermostatic conditions (37 degrees C) as a continuous record of transmittance change. By means of own computer program, kinetic parameters of the processes studied and plasma overall clot formation and fibrinolysis potential, expressed as the area under the clotgeneration and fibrinolysis curves, were calculated. The CL-test was developed and checked by evaluation of the effect, on clot formation and lysis, of various concentrations of acetylsalicylic acid (a drug that affects hemostasis), aprotinin (fibrinolysis activator) and venoruton (fibrinolysis inhibitor). The obtained results confirmed that the test we propose for monitoring clot formation, stabilization and lysis is sensitive and enables precise estimation of the processes studied. In our opinion, it can be a useful tool in drug screening investigations.

Local antithrombotic therapy using a novel porous balloon catheter.

The efficacy of local treatment of thrombosis with low-dose antithrombotic drugs (heparin: 30 U/kg, or argatroban: 0.02 mg/kg) was investigated using a novel porous balloon catheter. This novel balloon catheter can deliver drug into arterial walls without causing vascular trauma. Thrombus formation was significantly inhibited in balloon-injured and locally-treated iliac arteries compared with control balloon-injured arteries in 12 dogs. In the systemic high-dose delivery group (ten times as high as the low dose), thrombus formation in injured arteries was significantly less than that of controls in 7 dogs. Low-dose systemic delivery was not effective at inhibiting this thrombus formation. Thus, local treatment with an antithrombotic drug using this novel porous balloon catheter can prevent thrombosis without influencing systemic coagulability.

[Regional hyperthermic fibrinolytic perfusion as ultima ratio in critical ischemia of the lower extremities]. / Regionale hypertherme Fibrinolytika-Perfusion als ultima ratio bei kritischer Ischämie der unteren Extremitäten.

In 19 patients (male-female: ratio 10:9; median age 67.1 (42-90) years) with a critical ischaemia of the lower extremities either after failed attempt of revascularization (n = 4) or because of lacking possibility for vessel reconstruction measures (n = 16) a regional extremity perfusion with a fibrinolytic agent has been performed using a heart lung machine. In one patient both lower extremities were treated. In the first 30 minutes of the total 60 minutes perfusion time on average 31 mg (20-50 mg) of recombinant tissue-plasminogen activator (Actilyse) have been added to the perfusion solution. In order to enhance the fibrinolysis-activity the perfusion solution was warmed up to 40 degrees C. Systemic side effects have not been observed. Two patients died postoperatively because of their underlying diseases (mesenteric artery embolism, myocardial infarction), two patients experienced postoperative haemorrhage and one patient had a wound infection. In 11 cases (55%) an opening of the stem-arteries has been reached. Seven of these were successfully revascularized with a femoro-crural bypass in a following operation. Nine extremities (45%) remained without opening of the stem-arteries, however, in four cases (20%) an improved radiographic contrast of the collaterals has been reached. 11 (61%) of the followed-up extremities were successfully revascularized. Amputation has been performed in seven cases (39%). The regional hyperthermic perfusion with fibrinolytic drugs enables a reopening of the stem-arteries and the creation of accepting vessels for vascular procedures in primarily inoperable arterial occlusions.

Induction of thrombolysis and prevention of thrombus formation by local drug delivery with a double-occlusion balloon catheter.

The efficacy of the local delivery of an antithrombotic drug in preventing thrombosis and enabling thrombolysis was investigated in 29 dogs. An antithrombotic drug (heparin, 25 U/kg), or an antithrombin (argatroban, 0.05 mg/kg) was infused into injured canine iliac arteries, using a double-occlusion balloon catheter, and the preventive effect of the drug was evaluated. Local delivery of low-dose tissue-type plasminogen activator (t-PA; Tisokinase, 50,000 U; Kowa, Nagoya and Asahi Chemical Industries, Fuji, Japan) into thrombosed canine iliac arteries, using the same catheter, or intravenous infusion of low-dose or high-dose t-PA (30,000 U/kg) was also performed. Angiographically, stenotic thrombosis was 2% by local delivery of argatroban and 7% by local delivery of heparin (P < 0.01 vs each control; 47% and 51% respectively). Thrombotic stenosis, as observed by angiography, decreased from 91% to 9% after local delivery of t-PA, and from 94% to 52% in controls. Local delivery of t-PA effectively reduced the thrombus size (P < 0.01 vs control). After systemic intravenous delivery of low-dose t-PA, no reduction of residual thrombotic stenosis, was observed. Reduction of residual thrombotic stenosis after intravenous delivery of high-dose t-PA, was similar to that achieved by local delivery of the drug. Angioscopy demonstrated a similar trend. High-dose drug delivery reduced systemic coagulability. Local delivery of an antithrombotic drug, using a double-occlusion balloon catheter, effectively prevented thrombus formation, and local delivery of t-PA induced thrombolysis without exerting a significant influence on coagulability.

Pharmacomechanical thrombolysis of experimental pulmonary emboli. Rapid low-dose intraembolic therapy.

We utilized low-dose intraembolic urokinase (UK) infusions in a canine model of experimental pulmonary embolism (PE) and compared the arteriographic extent of thrombolysis with three other treatment regimens. Group 1 animals (n = 16) received the intraembolic UK infused directly into the PE offering the mechanical effect of the infusion combined with pharmacologic thrombolysis. In the group 2 animals (n = 5), UK was delivered via a guide catheter placed proximal to the clot. Group 3 animals (n = 6) were treated with a direct intraembolic saline solution infusion. Group 4 (n = 7) received only intravenous heparin. The arteriographic extent of thrombolysis was graded 1+ to 3+. The extent of thrombolysis was 2.88+ in the group 1 animals and was significantly greater than in groups 2, 3, or 4 (p = 0.003, 0.0005, and 0.0001, respectively). Fibrinogen levels did not significantly decrease with intraembolic treatment (p = 0.07). Delivery of UK directly into emboli in an experimental canine PE model appears to elicit a combined mechanical and pharmacologic effect resulting in extensive thrombolysis.

Thrombolytic therapy in peripheral arterial occlusive disease: mechanisms of action and drugs available.

Catheter-directed thrombolytic therapy has become an important part of the treatment of patients with acute arterial and graft occlusion. The underlying pharmacologic principle is the activation of plasminogen, bound to fibrin within the thrombus. Guide-wire passage reliably predicts success of catheter-directed thrombolysis. The underlying disease process leading to thrombosis should be accurately identified and promptly corrected to reduce the probability of recurrent occlusion. Streptokinase (SK), urokinase (UK) and recombinant tissue plasminogen activator (rt-PA) are the three agents used to treat peripheral arterial occlusive disease. The evolution from SK to UK and rt-PA and improvements in techniques and delivery systems have led to improved success rates and lower complication rates. Patient selection, basic technical considerations and overall results are discussed here. The currently available thrombolytic agents, as well as those being developed, are reviewed to provide background information for current and future applications.