Von Willebrand factor A1 domain affinity for GPIbα and stability are differentially regulated by its O-glycosylated N-linker and C-linker

Hemostasis in the arterial circulation is mediated by binding of the A1 domain of the ultralong protein von Willebrand factor to GPIbα on platelets to form a platelet plug. A1 is activated by tensile force on VWF concatemers imparted by hydrodynamic drag force. The A1 core is protected from force-induced unfolding by a long-range disulfide that links cysteines near its N and C-termini. The O-glycosylated linkers between A1 and its neighboring domains, which transmit tensile force to A1, are reported to regulate A1 activation for binding to GPIb, but the mechanism is controversial and incompletely defined. Here, we study how these linkers, and their polypeptide and O-glycan moieties, regulate A1 affinity by measuring affinity, kinetics, thermodynamics, hydrogen deuterium exchange (HDX), and unfolding by temperature and urea. The N-linker lowers A1 affinity 40-fold with a stronger contribution from its O-glycan than polypeptide moiety. The N-linker also decreases HDX in specific regions of A1 and increases thermal stability and the energy gap between its native state and an intermediate state, which is observed in urea-induced unfolding. The C-linker also decreases affinity of A1 for GPIbα, but in contrast to the N-linker, has no significant effect on HDX or A1 stability. Among different models for A1 activation, our data are consistent with the model that the intermediate state has high affinity for GPIbα, which is induced by tensile force physiologically and regulated allosterically by the N-linker.

Congenital isolated absence of a single cusp of pulmonary valve

A 25-year-old, previously asymptomatic female, presented to the outpatient clinic with episodic palpitations for past 6 months. She was acyanotic and showed no peripheral stigmata of infective endocarditis. Transthoracic echocardiography revealed dilated right ventricle with severe low-pressure pulmonary regurgitation. A cardiac computed tomography angiography performed for evaluation of pulmonary arterial circulation and intracardiac anatomy revealed isolated absence of posterior pulmonary cusp. The two other (right anterior and left anterior) cusps were normal and covered only part of the valve orifice, resulting in pulmonary insufficiency. The main pulmonary artery showed asymmetric dilatation. No other structural heart defects were noted.

P.205 Association Between Vein of Galen Aneurysmal Malformation and Hirayama Disease: A Clue into Pathophysiology?

Background: Hirayama Disease (HD) is a rare disorder consisting of insidious onset of unilateral weakness and atrophy of the forearm and intrinsic hand muscles. Vein of Galen aneurysmal malformations (VGAMs) are rare congenital cerebral vascular malformations, consisting of high-flow arteriovenous shunting between a persistent median prosencephalic vein and arterial feeders. Methods: 14 years old boy known for VGAM presented with left-sided HD. His cervical MRI revealed enlarged epidural with anterior, left-ward displacement of the posterior dura and spinal cord. He underwent surgical treatment by laminotomies, along with tenting of an autologous duroplasty to the overlying laminae. Results: We decided to combine epidural venous plexus coagulation with posterior duraplasty and dural fixation using tenting suture which led to a favorable clinical outcome has not been previously proposed in the literature. We hypothesize that in this context, an abnormal vasculature could also predispose to posterior epidural venous plexus engorgement, anterior dural displacement in cervical flexion, and microvascular changes in the anterior spinal arterial circulation, leading to the progressive anterior horn cell ischemia that lead to the clinical phenotype of HD. Conclusions: The association between HD and VGAM in this patient may provide clues with regard to the pathophysiology of HD.

Thrombosis in pre- and post-vaccination phase of COVID-19

Acute infections may be complicated by thrombosis occurring in the venous and arterial circulation. This may be observed in patients with community-acquired pneumonia (CAP) and also in patients with coronavirus 2019 (COVID-19), that is a pandemic characterized by severe acute respiratory syndrome (SARS-CoV-2) needing mechanical ventilation and intensive care unit treatment. However, the type and rate of thrombosis can vary according to the cause of pneumonia as is more frequently complicated by arterial thrombosis in CAP, while an equal incidence of venous and arterial thrombosis occurs in SARS-CoV-2. The mechanisms of disease are overall platelet-related in CAP while activation of both platelets and clotting system is implicated in the pathogenesis of thrombosis in SARS-CoV-2; this finding could imply a different therapeutic approach of the two settings. Thrombosis may also occur in subjects vaccinated against SARS-CoV-2 even if its incidence is not so high (1/100 000); this rare effect occurs more prevalently in young women, is independent from known risk factors of thrombosis, is caused by antibodies against platelet PF4 and is counteracted by treatment with immunoglobulin and glucocorticoids.

Device for modeling of intra-arterial circulation: application in experimental cardiology

Purpose of study Using an original device for modeling of intra-arterial blood circulation, to study the features of intravascular hemodynamics with a regular heart rhythm and with various rhythm disturbances. Material and methods We used an original device developed by us to simulate intra-arterial circulation (Document of invention No. RU 202780 U1). The main part of the device is a glass tube of a rotameter with a length of 365 mm, an inlet end with a diameter of 20 mm, an outlet end of 16.5 mm, which is a model of an arterial vessel. Flexible silicone tubes are attached to the rotameter on both sides, with free ends connected to an electric pump, with various modes of operation (imitation of pulse waves with regular rhythm, premature ventricular contractions (PVCs), atrial fibrillation (AF). An aqueous solution of glycerin was introduced into a closed system diluted with water corresponding to the viscosity of the blood. A 5 mm long silk thread was alternately installed inside the tube, an intravascular piezoelectric crystal pressure probe connected to an oscilloscope. Also it was injected inside the tube a dye - clerical ink. Results With electric pump, we simulated the spreading of the pulse wave in regular heart rate, PVCs and AF. We observed the effect of a pressure wave (deflection of a silk thread, the appearance of a turbulent flow when using a dye) on the walls of the rotameter, with the formation of standing, reflected waves during the PVCs and AF. The pressure probe registered an increase in pressure inside the tube during the spread of the 1st post-extrasystolic contraction wave up to 58%, the wave after a long pause of more than 2 seconds with AF by 44% compared to the regular rhythm. Conclusion A device for modeling of intra-arterial circulation allows a wide range of experimental work in cardiology, normal and pathological physiology, and biophysics. FUNDunding Acknowledgement Type of funding sources: None.

Ep.We.1001Name That Tune - Acccuracy of Interpreting Hand-Held Doppler Audio Signals in the Assessment of Peripheral Arterial Circulation

Aims Interpretation of Doppler audio signals among non-podiatrist has not been thoroughly investigated. This study analyses the accuracy of interpretation of Doppler audio signals among clinicians. Methods A single-centre prospective single blind study was used. Clinicians in the vascular department and with prior vascular experience in a district general hospital participated in interpreting 15 12-second Doppler audio signals (5 monophasic, 5 biphasic and 5 triphasic) into either ‘monophasic’, ‘biphasic’ and ‘triphasic’ using a Huntleigh’s Dopplex DMXTM digital hand-held Doppler ultrasound with visual waveform display covered. After all the audio signals were graded, the waveforms of each doppler signals are shown on the hand-held doppler display to reveal the correct responds. Results 8 clinicians were involved; 5 had less than 6 months of vascular experience. Out of 15 audio signals, the mean number correct grading of signals was 10.1. There is no difference in number of correct grading of the 3 waveforms (monophasic 3.5 out of 5, biphasic 3.25 out of 5, triphasic 3.5 out of 5). There is also no difference in responses between clinicians with less than 6 months and more than 6 months of vascular experience (p = 0.82). Conclusions There is a need for further ongoing education among clinicians in the use of hand held Doppler and interpretation of its audio signals. Reliability of Doppler examination in vascular assessment is also in contention, and further studies are required. The use of digital hand-held Doppler with visual wave form display will significantly improve accuracy of interpretation

Patent Foramen Ovale and Cryptogenic Stroke: Challenges in Diagnosis and Management

A patent foramen ovale (PFO) is a common disorder that affects between 20-34% of the adult population. This condition is a benign finding for most people. However, In some the PFO can open widely and enabling paradoxical embolism to transit from venous to arterial circulation, which is associated with stroke and systemic embolization. There are still unclear to date regarding the effectiveness of pharmacological anticoagulant therapy, defined as antithrombin or antiplatelet therapy, which has proven to be more beneficial for patients with PFO and cryptogenic stroke. In addition, surgical and transcutaneous PFO closure has been proposed for secondary prevention of stroke in patients with cryptogenic stroke with PFO. Both catheter-based and surgical modes of closure have been shown to reduce the incidence of subsequent embolism substantially. This review will discuss the evidence regarding the relationship between PFO and cryptogenic stroke and decision making for management strategies.

A rare case of COVID-19 vaccine-induced thrombotic thrombocytopaenia (VITT) involving the veno-splanchnic and pulmonary arterial circulation, from a UK district general hospital

A 47-year-old woman presented with a headache to the acute medical unit, 10 days after receiving AstraZeneca vaccination for COVID-19. Brain imaging was normal, but her blood tests showed a remarkably low platelet count, mildly deranged liver function tests and a high D-dimer. Further within her hospital admission, she developed right-sided abdominal pain and chest pain, and subsequent cross-sectional imaging confirmed a small segmental pulmonary embolism, and an acute portal vein thrombosis extending to the splenic and superior mesenteric veins. On the basis of her investigations, she was diagnosed as a case of vaccine-induced thrombotic thrombocytopenia and was treated with intravenous immunoglobulins. In a time where there is a strategic goal to vaccinate the global population from COVID-19 to inhibit the spread of infection and reduce hospitalisation, this particular clinical scenario emphasises the need of all clinicians to remain vigilant for rare complications of the COVID-19 vaccination.

Analysis of flow resistance in the pulmonary arterial circulation: Implications for hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) plays an essential role in distributing blood in the lung to enhance ventilation-perfusion matching and blood oxygenation. In this study, a theoretical model of the pulmonary vasculature is used to predict the effects of vasoconstriction over specified ranges of vessel diameters on pulmonary vascular resistance (PVR). The model is used to evaluate the ability of hypothesized mechanisms of HPV to account for observed levels of PVR elevation during hypoxia. The vascular structure from pulmonary arteries to capillaries is represented using scaling laws. Vessel segments are modeled as resistive elements and blood flow rates are computed from physical principles. Direct vascular responses to intravascular oxygen levels have been proposed as a mechanism of HPV. In the lung, significant changes in oxygen level occur only in vessels less than 60 μm in diameter. The model shows that observed levels of hypoxic vasoconstriction in these vessels alone cannot account for the elevation of PVR associated with HPV. However, the elevation in PVR associated with HPV can be accounted for if larger upstream vessels also constrict. These results imply that upstream signaling by conducted responses to engage constriction of arterioles plays an essential role in the elevation of PVR during HPV.

The pivotal role of PFO in paradoxical embolism following venous sclerotherapy: a unique case report with pathological correlations

Background Vein sclerosing therapy for varicose veins remains an extremely popular procedure. Cerebrovascular accidents can be a serious complication. A patent foramen ovale (PFO) can act as a conduit to the arterial circulation, which could explain the adverse neurologic consequence of this procedure. This case provides pathologic evidence of this concept. Case summary A 66-year-old female presented with syncope after undergoing varicose vein sclerotherapy. A computed tomography angiography of the head and neck in the emergency room revealed an occluded right distal M1 middle cerebral artery. Clot retrieval was performed with final pathology revealing amorphous material consistent with an exogenous agent, polidocanol foam, which was used for the patient’s vein sclerotherapy. A transthoracic echocardiogram and transoesophageal echocardiogram showed a PFO, which was ultimately closed percutaneously. Discussion In a quarter of the population, lack of closure of the intrauterine interatrial shunt leads to the existence of a PFO. This direct communication between the atria provides an anatomical conduit for paradoxical emboli and eventually infarction of affected tissues. While a paradoxical embolism is an uncommon cause of acute arterial occlusion, it can have catastrophic sequelae. Historically, the presence of an arterial thrombus from the venous circulation has been difficult to establish unless the thrombus is visualized in transit through a PFO. Complications from vein sclerotherapy have been reported in the literature and include transient ischaemic attacks and strokes, however, this is the first case to provide pathological proof of a paradoxical embolism, which ultimately resulted in percutaneous closure of the PFO.