Prothrombotic State Research Articles

Good metabolic control is associated with decreased circulating factor VIIa– antithrombin complexes in type 2 diabetes: a cross-sectional study

BackgroundDiabetes is associated with a prothrombotic state that contributes to cardiovascular (CV) events in type 2 diabetes (T2DM). Activated factor VII (FVIIa)– antithrombin (AT) complexes are indicative of tissue factor (TF) exposure and have been associated with thromboembolic risk in coronary artery disease. To our knowledge there have been no reports on FVIIa-AT complexes in T2DM, therefore we assessed factors that determine FVIIa-AT complexes in this disease and the impact of higher complexes on a prothrombotic state.MethodsIn 108 T2DM patients (mean age 63.8 years, 52.8% men, median HbA1c of 6.9 [interquartile range 6.1–8.2] %) and 83 age- and sex-matched non-diabetic subjects, we measured FVIIa-AT complexes. Metabolic control of T2DM involved fasting glucose, glycated hemoglobin (HbA1c), albumin/creatinine ratio (ACR), and lipid levels. To characterize a prothrombotic state, we determined thrombin generation parameters, fibrinolysis markers, and plasma fibrin clot properties.ResultsFVII-AT complexes in T2DM patients were similar to controls (73.6 [59.4–91.7] vs. 79.6 [59.2–97.1]pM, respectively, p = 0.30). The T2DM patients with FVIIa-AT in the top vs. the bottom quartile had a larger prevalence of active smoking and insulin use, along with higher fasting glucose (+ 36.4%), HbA1c (+ 27.4%), ACR (+ 72.8%), total cholesterol (+ 34.5%), and LDL-cholesterol (+ 80%). FVIIa-AT complexes showed no associations with in vitro thrombin generation potential, plasma fibrin clot properties, or fibrinolysis variables. On multivariable analysis HbA1c, ACR, and total cholesterol remained independently associated with FVIIa-AT complexes in T2DM.ConclusionsThis is the first study to show that in T2DM higher FVIIa-AT complexes are associated with markers of dyslipidemia and glycemia control, indicating that TF-induced coagulation activation could be suppressed by achieving treatment targets.Graphical abstract

Periodontal disease: A systemic condition.

For decades, periodontitis has been considered to be a local inflammatory disease of the periodontal tissues in the oral cavity. Initially, associations of periodontitis with a multitude of noncommunicable diseases were each studied separately, and relationships were shown. The associations of periodontitis with morbidities, such as cardiovascular diseases, rheumatoid arthritis, diabetes mellitus, respiratory diseases, have been demonstrated. As most such studies were cross-sectional in nature, questions about causality cannot be univocally answered. And periodontitis as an independent risk factor for one systemic disease, becomes even more difficult to assess since recently periodontitis has also been associated with multimorbidity. Periodontitis and many systemic diseases share environmental, lifestyle and genetic risk factors, and share immunopathology. Moreover, suffering from one common noncommunicable disease may increase the susceptibility for another such chronic disease; the systemic effects of one condition may be one of various risk factors for another such disease. The overarching effect of any systemic disease is it causing a pro-inflammatory state in the individual; this has also been shown for periodontitis. Moreover, in periodontitis a prothrombotic state and elevated immunological activity have been shown. As such, when we consider periodontal disease as another systemic disease, it can affect the susceptibility and progression of other systemic diseases, and importantly, vice versa. And with this, it is not surprising that periodontitis is associated with a variety of other noncommunicable diseases. The medical definition of a systemic disease includes diseases that affect different organs and systems. Thus, the aim of this opinion paper is to propose that periodontitis should be considered a systemic disease in its own right and that it affects the individual's systemic condition and wellbeing. The dental and medical profession and researchers alike, should adapt this paradigm shift, advancing periodontal disease out of its isolated anatomical location into the total of chronic noncommunicable diseases, being for some conditions a comorbid disease and, vice versa, comorbidities can affect initiation and progression of periodontal disease.

OA27 A Thrombus Tale

Abstract Introduction Non catheter related arterial thrombosis is very rare in children. Our patient had a peripheral arterial thrombus with no risk factors apart from a background of recurrent Henoch-Schönlein Purpura (HSP). He had no history of trauma. Thrombosis as a complication of HSP is extremely rare with onlyeight case reports so far in children and among those eight, there is only one resembling our case with an arterial thrombus. We considered other causes of thrombosis and screened our patient for thrombophilia, infection and malignancy. Case description Our patient, a 12-year-old boy with a background of recurrent HSP for the last two years, presented with a rash on the left 2nd toe followed by blackish discolouration of the distal part of the same toe, a few days later. His initial presentation with purpuric rash, arthralgia, and abdominal pain was diagnosed as HSP and he required no intervention required for this. He continued to have regular flares of his HSP every six weeks, and these were self-limiting. His last flare was in February 2024. In April 2024, his feet appeared dusky and mottled. He presented to his local hospital with a rash on the tip of his left 2nd toe which turned gangrenous. He was otherwise systemically well. He was initially treated with antibiotics and acyclovir as a swab from the lesions grew staphylococcus aureus and the rash was bullous initially. He was referred to our tertiary rheumatology and haematology teams at Nottingham due to worsening ischemia and an absent left dorsalis pedis pulse. His examination revealed normal blood pressure, mottled, dusky lower legs, warm left foot with a faint petechial rash near left malleolus, absent left Dorsalis pedis pulse and an ischemic tip of left 2nd toe. Bilateral femoral and upper limb pulses were well felt. His respiratory, cardiovascular, abdomen & musculoskeletal examination were normal apart from an antalgic gait. His clotting and thrombophilia screen including antiphospholipid screen was normal. His D dimer was raised at 1894ug/l. A duplex scan of his left leg showed occlusions in the distal anterior and posterior tibial artery as well as in the dorsalis pedis artery with no emboli. His inflammatory markers and autoantibodies were normal. Infection screen including mycoplasma, CMV, EBV and ASOT titres were all negative. Echo was normal. A skin biopsy from the toe revealed IgA vasculitis. Discussion We had a multidisciplinary team (MDT) discussion with haematology, vascular surgery and dermatology. As per the MDT discussion, he was given a pulse of intravenous methylprednisolone after careful consideration weighing the risk versus benefit of steroids adding to the pro thrombotic state versus active vasculitis causing narrowing of the arteries. He was also commenced on Aspirin at 1 mg/kg/day. There was marked improvement in his symptoms with improvement in the discolouration and pain, his d-dimer reduced, and he was able to mobilise comfortably. We felt that active vasculitis could be causing the vascular event. As immunology screen was negative and the skin biopsy was confirmatory of HSP. There was no thrombus specifically mentioned in the duplex but with D-dimer being raised it was a reasonable assumption was that there was a thrombus occluding the peripheral arteries. As his HSP was recurring quite frequently and was bothersome, as well as the thought that the recurrences might contribute to further vascular events and complications, we started our patient on Azathioprine. We have also sent genetic tests and awaiting a catheter angiogram to complete the investigation process. Key learning points • Consider vasculitis as one of the differentials in a child with unexplained venous or arterial thrombosis. • In a child with recurrent HSP, keep an open mind for rare complications that may occur. • Recurrent HSP in an older child may need immunosuppression. • Treatment considerations in a case with vasculitis with a thrombus has to be in close connection with haematology to decide on anticoagulation and its implications on the young person and their lifestyle. • Should there be any other investigations done or alternative diagnosis though of at this point?

Refining the Prothrombotic State in Atrial Fibrillation with Left Atrial Appendage 3D Echocardiography

Refining the Prothrombotic State in Atrial Fibrillation with Left Atrial Appendage 3D Echocardiography

High-dose atorvastatin and rosuvastatin reduce the levels of neutrophil extracellular trap-related proteins in coronary artery disease: association with prothrombotic state.

Neutrophil extracellular trap (NET) formation is involved in atherothrombosis. We sought to investigate whether statins affect neutrophil extracellular traps activation and release (NETosis) in coronary artery disease (CAD), and whether such changes show associations with statin‑induced additional effects. We studied 130 patients with advanced CAD before and at least 6 months after initiation of high‑dose statin therapy with rosuvastatin 40 mg/d or atorvastatin 80 mg/d. The levels of circulating citrullinated histone H3 (H3cit), myeloperoxidase (MPO), and neutrophil elastase (NE) were assessed as proteins associated with NETosis along with thrombin generation, plasma clot permeability (Ks), clot lysis time (CLT), and fibrinolysis inhibitors. Following statin therapy intensification, we observed reduced accumulation of H3cit (-30.4%), MPO (-28.1%), and NE (-25.5%; all P <0.001), all not associated with low‑density lipoprotein cholesterol (LDL‑C) lowering (-25%). However, H3cit level was lower in 50 patients (38.5%) who achieved the target LDL‑C below 1.8 mmol/l (-16.5%; P = 0.004), and in 19 patients (14.6%) with LDL‑C below 1.4 mmol/l (-25.5%; P = 0.001), as compared with the remaining individuals. The reductions in H3cit and MPO levels were associated with a 42.9% decrease in C‑reactive protein (CRP) level on high‑dose statins (R = 0.855; P <0.001 and R = 0.25; P = 0.004, respectively), along with increases in Ks and reduction in thrombin activatable fibrinolysis inhibitor (TAFI) activity, but not with CLT or thrombin generation (all |R|, 0.24-0.4; P <0.01). In multivariable analysis, changes in CRP (β = 0.771; P <0.001), TAFI activity (β = 0.125; P = 0.013), and fibrinogen level (β = 0.106; P = 0.034) were independently associated with a decrease in H3cit concentration. We showed for the first time that high‑dose statins can reduce the level of NET‑related proteins in association with anti‑inflammatory and antithrombotic actions in CAD patients.

The prothrombotic state in patients with type 2 diabetes mellitus and ischemic heart failure: an association with endothelial dysfunction

Abstract Background Heart failure (HF) is associated with a substantial prothrombotic state and an increased risk of thromboembolism, regardless of the presence of atrial fibrillation (AF). Although oral anticoagulation in HF with known AF is recommended, there is no conclusive evidence supporting clinical benefits of chronic anticoagulation in HF subjects without AF. Other factors enhancing prothrombotic state, often concomitant with HF, are type 2 diabetes mellitus (T2D) and coronary artery disease (CAD). T2D as well as CAD are independently associated with a hypercoaguability due to multiple mechanisms including endothelial dysfunction and oxidative stress. Dysfunction of endothelium was observed in patients with HF, however a little is known about its influence on prothrombotic state in a very high risk HF population. Purpose This study aimed to investigate whether the prothrombotic state in patients with T2D, CAD, and HF, depends on the left ventricular ejection fraction (LVEF) or endothelial function. Methods We assessed 54 patients with stable chronic HF, CAD, and T2D. Based on the echocardiography examination 28 of them were those with HF with reduced ejection fraction (HFrEF) and 26 of them were classified as HF with preserved ejection fraction (HFpEF) according to current guidelines. Fibrin clot density reflected by clot permeability (Ks) and thrombin generation were evaluated. Endothelial function was determined in flow-mediated (FMD) and nitroglycerin-mediated dilatation (NMD) tests of the brachial artery. Results Subjects in both groups were comparable in terms of cardiovascular risk factors except for lower glomerular filtration rate (GFR) by 18.1%. HFrEF patients had lower Ks by 20.3%, along with higher endogenous thrombin potential (ETP) by 18.9% and maximum thrombin level (Peak) by 24.1% as compared with HFpEF. While there were no differences in FMD and NMD between subjects, we found negative correlations of NMD with ETP and Peak (r=-0.448, P=0.001; r=-0.304, P=0.034, respectively). Moreover, the proportion of NMD and FMD along with GFR and LVEF were also significantly associated with both thrombogram parameters (&amp;lt;0.01 for all). By the multivariate analysis of the whole population, NMD, LVEF, low-density lipoprotein and GFR were independent predictors of ETP (R2=0.530, P&amp;lt;0.001) while NMD, LVEF, and GFR predicted Peak levels (R2=0.327, P=0.002). Conclusion We showed for the first time that patients with ischemic etiology of HFrEF and T2D presented altered fibrin clot properties and enhanced thrombin generation compared to HFpEF subjects. It might be hypothesized that endothelial dysfunction induced by T2D could intensify hypercoagulability in patients with HF.Figurę 1

Utilization of endovascular thrombectomy in patients with antiphospholipid syndrome and acute ischemic stroke

Abstract Background Antiphospholipid syndrome (APS) is a prothrombotic state and can cause acute ischemic stroke (AIS) particularly in younger individuals. Purpose Given the recent widespread adoption of endovascular thrombectomy (EVT) in patients with AIS, we aimed to evaluate the current trends and utilization of this technique in patients with APS. Methods We used National Readmission Database (NRD) to identify patients admitted between 2016 and 2020 with a primary diagnosis of AIS and a concurrent diagnosis of APS using relevant ICD-10 CM codes. Results Our analysis identified a total of 2,535,777 patients admitted for AIS, of which 7209 had a concomitant diagnosis of APS. The median age in patients with APS was 55 compared to 71 in non-APS patients (p &amp;lt; 0.001). APS patients also exhibited a lower prevalence of comorbidities such as coronary artery disease (4% vs. 28%; p &amp;lt; 0.001), congestive heart failure (CHF) (15% vs. 19%; p &amp;lt; 0.001), atrial fibrillation (14% vs. 26%), and diabetes (12% vs. 18%; p &amp;lt; 0.001). Systemic lupus erythematosus (SLE) was the most prevalent concurrent autoimmune disease in the APS cohort (19%). Patients with APS were significantly more likely to undergo EVT compared to their non-APS counterparts (5.2% vs. 3.5%; p &amp;lt; 0.001). Mortality was higher in non-APS likely due to older age compared to non-APS but didn’t reach statistical significance (4.4% vs 3.7%, p=0.070). Notably, the length of hospital stay was significantly higher for patients with APS (median: 6 days) compared to the non-APS group (median: 3 days; p &amp;lt; 0.001). Furthermore, we observed a steady increase in the utilization of EVT in patients with APS and AIS from 2016 (3.7%) to 2020 (6.8%; p = 0.02). Conclusion Our findings demonstrate that patients with AIS and concurrent APS are more likely to undergo endovascular thrombectomy, potentially due to a higher stroke burden. Additionally, the study revealed a progressive increase in the use of EVT for this specific patient population.

Altered fibrin clot properties and elevated von Willebrand Factors level are associated with progression to permanent atrial fibrillation during follow-up: a cohort study

Abstract Introduction Little is known about association of prothrombotic markers and atrial fibrillation (AF) progression to permanent arrythmia (PerAF). Formation of denser and poorly lysable fibrin clots have been observed in AF including patients with sinus rhythm in association with stroke and bleeding risk. We investigated whether altered fibrin clot properties and other prothrombotic state markers may contribute to AF transition to PerAF. Methods In the cohort study, in 226 anticoagulated AF patients (median age 69 years, median CHA2DS2-VASc of 3)with paroxysmal (n=83, 36.7%) or persistent (n=143, 63.3%) arrythmia we assessed at baseline plasma clot permeability (Ks), lysis time (CLT), and fibrinolysis involved proteins, including plasminogen activator inhibitor type 1 (PAI-1) along with von Willebrand factor (vWF) antigen. We recorded patients with PerAF during a median follow-up of 58 months. Results PerAF was documented in 62 (27.4%, 5.7%/year) subjects. These patients were older, with larger prevalence of heart failure (HF), higher body mass index by 9.6%, more often presented persistent AF and had longer history of arrythmia by 60%. We observed by 25.7% longer CLT and similar Ks, compared with the remainders, along with higher levels of vWF by 29% and PAI-1 by 21.3%. By multivariable analysis CLT, vWF and HF were independently associated with PerAF (R2=0.697, P&amp;lt;0.001). A cut-off CLT value of ≥105 min had a sensitivity of 88.7% and specificity of 78.7% in prediction of PerAF (area under curve 0.892, 95% confidence interval 0.848-0.935, P&amp;lt;0.001). Conclusion Impaired global fibrinolysis and elevated vWF levels are independently associated with faster progression to PerAF despite anticoagulation.Figure1

Predictors of 1-year follow-up period MACE in patients with NSTEMI

Abstract Background Identifying viable predictors of MACE in NSTEMI continues to pose a challenge in the field of cardiology. Unraveling these factors will elucidate crucial mechanisms underlying adverse post-infarction outcomes and identify key strategies for optimizing treatment. Aim Evaluation by using the multi-marker panel the biomarkers having a high predictive value regarding the risk of MACE developing in patients with NSTEMI. Methods The study embraced 550 patients with NSTEMI treated by angioplasty. A panel of 67 biomarkers was quantitatively determined by ELISA, immune assay and flow cytometry on admission in the blood linked to the most important mechanisms conceptually involved in post-infarction evolution (inflammation, endothelial dysfunction, hemostasis disorders, oxidative stress, NETosis, Ang 1-7/Ang II axis etc.) The rate of MACE (cardiac death, stroke, myocardial reinfarction) was estimated in a follow-up period of 18 months. In order to underline the overt predictors, the hazard ratio CI (95%) was assayed. 60 healthy persona formed control series. Results Upon admission, the circulating levels of 62 out of 67 biomarkers in patients with NSTEMI significantly deviated from control values. The MACE rate during 1-st year after revascularization was 28% (154 pts). According to hazard ratio (HR) the maximal predictive power regarding MACE risk of 1-year follow-up period was unraveled for 3 markers: endothelial microparticles (EMs), platelet-derived microvesicles (PMVs) and von Willebrand/ADAMTS13 ratio. For EMs – HR 2.21 CI (1.19-3.84; p&amp;lt;0.01); for PMVs - HR 2.56 CI (1.43-3.96; p&amp;lt;0.01); for von Willebrand/ADAMTS13 ratio - HR 2.94 CI (1.77-4.73; p&amp;lt;0.01). EMs-CD62E exceeded control level by 77,6% (325.6±101.5 vs 183.2±67.7 Ms/µL); PMVs-CD62P by 129% (378.6±87.4 vs 165.5±59.6 MVs/µL) and von Willebrand/ADAMTS13 ratio by 88% (2.52±1.88 vs 1.34±1.11). These predictors have not been adjusted to age, gender and cardiovascular risk factors. Conclusion Considering the pathophysiological significance of the highlighted predictors of MACE (EMs, PMPs and the von Willebrand/ADAMTS13 ratio) endothelial dysfunction and an activated prothrombotic state emerge as pivotal mechanism in the adverse progression of NSTEMI. THUS, these predictors should indicate a focus on corrective therspy targets.

Unraveling the thrombin–Alzheimer’s connection: Oral anticoagulants as potential neuroprotective therapeutics

In Alzheimer&amp;rsquo;s disease (AD), toxic amyloids formed by amyloid-&amp;beta; (A&amp;beta;) proteins and tau are implicated in the development of inflammatory, vascular, and neurodegenerative brain disorders. Thrombin has also been recognized as a proteopathic factor involved in A&amp;beta;-induced neurovascular dysfunction. Vascular A&amp;beta; activates the contact system in the blood, stimulating the production of inflammatory bradykinin and procoagulant thrombin. Thrombin, in turn, triggers inflammation, platelet activation, and the formation of fibrinolysis-resistant, A&amp;beta;-containing fibrin clots, leading to A&amp;szlig;-type cerebral amyloid angiopathy and associated neuropathology. Targeting thrombin with oral anticoagulants can normalize proinflammatory and prothrombotic states, counteracting the neurovascular consequences of AD. Pre-clinical studies have shown that such interventions preserve vascular and blood&amp;ndash;brain barrier integrity, improve cerebral blood flow and brain perfusion, and reduce parenchymal accumulations of toxic A&amp;beta;, tau, fibrin(ogen), and thrombin. These effects mitigate neuroinflammatory and neurodegenerative processes, ultimately preserving cognitive functions for a longer period. Recent observational clinical studies in patients with atrial fibrillation (AF) demonstrated that treatment with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) reduced the risk of dementia by up to 48% compared to non-users. The anti-dementia effects were most prominent in elderly patients but were also observed in individuals with low AF risk or newly diagnosed AF. In addition, DOACs reduced the risk of intracranial hemorrhage by approximately 50% compared to VKAs. The current review highlights the potential neuroprotective role of DOACs in AD. By preventing excessive thrombin generation caused by A&amp;beta; pathology, DOACs could protect vascular and neuronal functions, thereby slowing cognitive decline. DOACs, such as dabigatran, apixaban, and rivaroxaban, warrant further clinical investigation for their potential repurposing as disease-modifying therapeutics in AD.

Heparin-Induced Thrombocytopenia (HIT) in Postoperative Cardiac Surgery: Case Report

Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening complication of heparin exposure. Unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) are drugs that are widely used in patients undergoing cardiac surgery and that have made it possible to avoid and treat countless venous and arterial thrombotic problems. However, its use is also associated with a paradoxical reaction that leads to a potentially very serious prothrombotic state, which annually causes numerous amputations or fatal outcomes. Although the number of amputations per HIT is not known, recent studies describe an incidence of approximately 3-4%. Therefore, below, we present a woman undergoing cardiac surgery that begins in the post-surgical period with thrombocytopenia associated with arterial thrombosis, complicated by limb amputation due to HIT.

Impact of Duration of Parkinsonism and Antiparkinsonian Drugs on Coagulation Parameters in Patients with Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder involving depletion of dopaminergic neurons. Pathogenetic mechanisms leading to striatonigral degeneration are debatable. Chronic inflammation is proposed as one of the mechanisms. In any disease with underlying inflammation, immune system mediators called cytokines are released, leading to a procoagulant state. Our aim was to study the coagulation parameters in patients with PD and find their correlation with disease duration and antiparkinsonian drugs. This cross-sectional study was conducted between January 2021 and December 2021 in a tertiary care center. Sixty-eight patients with PD were subcategorized based on disease duration (<5 and ≥5 years), number of antiparkinsonian drugs (one drug and ≥2 drugs), and levodopa equivalent daily dose (LEDD; <350 and ≥350 mg). Hemoglobin (Hb), prothrombin time (PT), fibrinogen, bleeding time, and platelet aggregation study with adenosine diphosphate and collagen were assessed. In our cohort of 68 patients, 53 were men and 15 were women. Mean disease duration was 5.97 ± 4.37 years. Hb was negatively associated with LEDD (P = 0.012) and duration of the disease (P = 0.02). Similarly, PT was negatively associated with disease duration (P = 0.041) and number of antiparkinsonian drugs (P = 0.03). LEDD showed a positive association with collagen-induced platelet aggregation (P = 0.03). In our study, patients using multiple antiparkinsonian drugs and higher LEDD were observed to have a prothrombotic state. Further studies are needed to confirm these findings.

Rivaroxaban, in combination with low-dose aspirin, is associated with a reduction in proinflammatory and prothrombotic circulating vesicle signatures in patients with cardiovascular disease

BackgroundDespite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD. ObjectivesWe hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime. MethodsA cohort of stable CVD patients (N = 40) who participated in the COMPASS trial and were previously randomized to receive aspirin were prospectively recruited and assigned a revised regimen of open-label aspirin plus rivaroxaban. Blood samples were obtained at baseline (aspirin only) and 6-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis. ResultsThe COMPASS regime fundamentally altered small (<200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up. ConclusionThe observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.

Cerebral venous sinus thrombosis - Current updates in the Asian context.

Background Cerebral venous sinus thrombosis (CVT) is a life-threatening cause of stroke in Asian countries. South Asia, comprising of India, Pakistan and Bangladesh and contributed to 40% of strokes in women. Major CVT registries are from the western nations, which differs from the Asian countries with respect to epidemiology, gender biases and risk factors. This review focusses on the various aspects of relevance in evaluation and management of patients with CVT in the Asian context. Summary The incidence of CVT is higher in Asia than in Western nations. Young age, female gender, especially in pregnancy and puerperal period, and dehydration appear to be the critical risk factors. Tropical infections like malaria, scrub typhus, and flaviviral encephalitis predispose to CVT. There is a higher prevalence of inherited thrombophilia in the Asian cohorts, contributing to prothrombotic states. Anticoagulation and supportive management offer excellent outcomes. Newer anticoagulants are safe and efficacious. In medically refractory cases, endovascular treatment offers modest benefits. Decompressive hemicraniectomy, when done early, offers mortality benefits in patients with large hemorrhagic venous infarctions. Key messages CVT is an important cause of stroke with high-burden in South Asian countries. Establishment of robust registries is the need of the hour; to study the natural history, course and outcomes and to develop management algorithms tailored to the available resources.

Rituximab induced cerebral venous sinus thrombosis in a patient with anti-N-methyl-d-aspartate receptor-antibody encephalitis: a case report and review of literature

BackgroundCerebral venous sinus thrombosis has not been reported in anti-N-methyl-d-aspartate receptor-antibody encephalitis in the absence of an underlying thrombotic state while rituximab induced cerebral venous sinus thrombosis is rarely reported. We report a patient with anti-N-methyl-d-aspartate receptor-antibody encephalitis without a prothrombotic state who developed cerebral venous sinus thrombosis following rituximab treatment.Case presentationA 15-year-old Sri Lankan girl who had been in remission following an episode of anti-N-methyl-d-aspartate receptor-antibody encephalitis 2 years ago, presented with a relapse of anti-N-methyl-d-aspartate receptor-antibody encephalitis characterized by recurrent seizures, mutism, and cognitive abnormalities. Since response was inadequate to first-line immunotherapy, she was administered four doses of rituximab at weekly intervals. Two days after the fourth dose, she developed increasing headaches, and her cranial magnetic resonance venogram confirmed the development of cerebral venous sinus thrombosis. Screening for prothrombotic states were negative. She made an unremarkable recovery following anticoagulation.ConclusionThis case highlights the occurrence of the rare but serious complication of cerebral venous sinus thrombosis following rituximab in the context of anti-N-methyl-d-aspartate receptor-antibody encephalitis and informs the clinician to be wary of new onset headache in patients with anti-N-methyl-d-aspartate receptor-antibody encephalitis treated with immunotherapy.

Thrombotic complications in pregnancy: a case-based review of the evidence

Pregnancy is a prothrombotic state due to an estrogen-driven shift in the coagulation system, increased venous stasis, and external restriction of blood flow caused by the gravid uterus. Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in pregnancy. Preventing, recognizing, and treating thrombosis in pregnancy, as well as the postpartum period, often challenges decision making in the clinical setting. In early pregnancy, guidance with respects to thrombophilia testing and anticoagulation in increasing the likelihood of live birth among patients with recurrent miscarriages is evolving. This review explores emerging data that support clinical decision making in thrombosis care in women with common thrombotic complications in pregnancy. The first case outlines VTE diagnosis in pregnancy, initial anticoagulation management, management around delivery and postpartum, and subsequent long-term anticoagulation treatment. The second case examines testing for inherited and acquired thrombophilia in the setting of recurrent miscarriage and the management of obstetric antiphospholipid syndrome. Lastly, the third case reviews VTE risk assessment and prevention in pregnancy and the postpartum period, as well as duration and dose of postpartum thromboprophylaxis. Review of these common clinical scenarios surrounding thrombotic complications in pregnancy demonstrates recent advances in high-quality data, current gaps in knowledge, and variation in expert opinion. Ultimately, multidisciplinary discussion and teamwork remain key to optimal, safe care. Clinicians must prioritize collaborative, high-quality trials and prospective clinical management studies to better understand and define best practice in this population.

8614 Low Dose Sublingual Estradiol Decreases Protein S, Generating a Potentially Pro-thrombotic Profile: Interim Results of a Controlled Prospective Pilot Study of Treatment-Naïve Trans Women

Abstract Disclosure: S. Bar On: None. I. Yaish: None. M. Barzilai: None. Y. Greenman: None. G. Gindis: None. Y. Moshe: None. K.M. Tordjman: None. Background: Sublingual estradiol (SLE) for gender-affirming hormone therapy (GAHT) of transgender women (TW) might obviate the need for an anti-androgen, and mitigate pro-coagulant changes. We recently showed that 2 mg E, divided into 4 daily sublingual doses, offers no clinical advantage over the same dose given orally in combination with cyproterone acetate (CPA)1. Furthermore, we showed that after each sublingual administration, serum estradiol (sE2) peaked to levels, the likes of which are achieved only during induction of ovulation with gonadotrophins. Hypothesis and Aim: Given the exceedingly high peak sE2 measured under SLE-GAHT, we hypothesized it could lead to partial acquired Protein S deficiency, a recognized pro-thrombotic state and risk factor for venous thromboembolic events (VTE). Our aim was to assess the hemostatic system under SLE in comparison with the standard combined oral (CO) approach. Design and Methods: In this ongoing open label study, treatment-naïve TW are assigned in a 1:1 ratio (15 in each arm) to either standard CO (2 mg E2 with 10 mg CPA once daily), or to SLE with 2 mg sublingual estradiol divided into 4 daily dose for 6 months (6M). An extensive battery of hemostatic biomarkers, including free Protein S antigen (fPS), are assessed at baseline (BL) and at 6M. Results: We herein report on 27 subjects (15 CO/12 SLE) who initiated treatment, 17 of whom have already completed it. The median age of the cohort is 20 y (IQR 19-27; range 18-42]. There were no BL differences between the groups. At 6M, none of the hemostatic markers differed between the groups except for fPS, which was significantly lower in the SLE group 79.7%±11.6% vs. 104.6%±5.6%, P=0.039. By paired comparisons for the entire group, fPS decreased from 104%.2±5.2% at BL to 95.8%±5.9% at 6M, P=0.003. This was entirely accounted for by the change in the SLE group, in which fPS went down from 95.7%±10.3% to 79.7%±11.6%, P&amp;lt;0.001; with some values reaching the fPS deficiency range. In contrast, fPS, remained unchanged under CO 108.9%±5.7% and 104.5%±5.2%, at BL and 6M respectively, P=0.153. Conclusions: The most notable interim finding was a clinically significant decrease in fPS under low dose SLE. Given the extreme peaks of sE2 we previously reported with this protocol, an acquired deficiency of this natural anti-coagulant was expected. These preliminary findings support our hypothesis, and raise the concern that GAHT of TW with chronic SLE might carry an increased long-term risk for VTE. 1 Yaish I, Gindis G, Greenman Y, et al. Sublingual Estradiol Offers no Apparent Advantage Over Combined Oral Estradiol and Cyproterone Acetate for Gender-Affirming Hormone Therapy of Treatment-Naive Trans Women: Results of a Prospective Pilot Study. Transgend Health. 2023;8(6):485-493. Published 2023 Dec 13. doi:10.1089/trgh.2023.0022 Presentation: 6/2/2024

8614 Low Dose Sublingual Estradiol Decreases Protein S, Generating a Potentially Pro-thrombotic Profile: Interim Results of a Controlled Prospective Pilot Study of Treatment-Naïve Trans Women

Abstract Disclosure: S. Bar On: None. I. Yaish: None. M. Barzilai: None. Y. Greenman: None. G. Gindis: None. Y. Moshe: None. K.M. Tordjman: None. Background: Sublingual estradiol (SLE) for gender-affirming hormone therapy (GAHT) of transgender women (TW) might obviate the need for an anti-androgen, and mitigate pro-coagulant changes. We recently showed that 2 mg E, divided into 4 daily sublingual doses, offers no clinical advantage over the same dose given orally in combination with cyproterone acetate (CPA)[1]. Furthermore, we showed that after each sublingual administration, serum estradiol (sE2) peaked to levels, the likes of which are achieved only during induction of ovulation with gonadotrophins. Hypothesis and Aim: Given the exceedingly high peak sE2 measured under SLE-GAHT, we hypothesized it could lead to partial acquired Protein S deficiency, a recognized pro-thrombotic state and risk factor for venous thromboembolic events (VTE). Our aim was to assess the hemostatic system under SLE in comparison with the standard combined oral (CO) approach. Design and Methods: In this ongoing open label study, treatment-naïve TW are assigned in a 1:1 ratio (15 in each arm) to either standard CO (2 mg E2 with 10 mg CPA once daily), or to SLE with 2 mg sublingual estradiol divided into 4 daily dose for 6 months (6M). An extensive battery of hemostatic biomarkers, including free Protein S antigen (fPS), are assessed at baseline (BL) and at 6M. Results: We herein report on 27 subjects (15 CO/12 SLE) who initiated treatment, 17 of whom have already completed it. The median age of the cohort is 20 y (IQR 19-27; range 18-42]. There were no BL differences between the groups. At 6M, none of the hemostatic markers differed between the groups except for fPS, which was significantly lower in the SLE group 79.7%±11.6% vs. 104.6%±5.6%, P=0.039. By paired comparisons for the entire group, fPS decreased from 104%.2±5.2% at BL to 95.8%±5.9% at 6M, P=0.003. This was entirely accounted for by the change in the SLE group, in which fPS went down from 95.7%±10.3% to 79.7%±11.6%, P&amp;lt;0.001; with some values reaching the fPS deficiency range. In contrast, fPS, remained unchanged under CO 108.9%±5.7% and 104.5%±5.2%, at BL and 6M respectively, P=0.153. Conclusions: The most notable interim finding was a clinically significant decrease in fPS under low dose SLE. Given the extreme peaks of sE2 we previously reported with this protocol, an acquired deficiency of this natural anti-coagulant was expected. These preliminary findings support our hypothesis, and raise the concern that GAHT of TW with chronic SLE might carry an increased long-term risk for VTE. [1] Yaish I, Gindis G, Greenman Y, et al. Sublingual Estradiol Offers no Apparent Advantage Over Combined Oral Estradiol and Cyproterone Acetate for Gender-Affirming Hormone Therapy of Treatment-Naive Trans Women: Results of a Prospective Pilot Study. Transgend Health. 2023;8(6): 485-493. Published 2023 Dec 13. doi:10.1089/trgh.2023.0022 Presentation: 6/2/2024

D-dimer as a Predictor of ICU Admission and Mortality in COVID-19 Patients: Insights From a Two-Year Retrospective Study From a Tertiary Care Center in South India.

Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced pneumonitis results in a prothrombotic and hypercoagulable state. Prognostic indicators are crucial for identifying patients at risk of complications. D-dimer, a degradation product of cross-linked fibrin, is a specific marker for thrombosis. Elevated D-dimer levels have been strongly correlated with poor prognosis and increased severity of illness in COVID-19 patients. Given D-dimer's eight-hour half-life, periodic measurement is necessary to track disease progression. This study aimed to analyze and derive threshold and peak D-dimer values to predict outcomes in COVID-19 patients, comparing those treated in isolation wards to those requiring intensive care. Methods This two-year retrospective observational study included patients above 18 years with confirmed COVID-19. Patients were categorized into those treated in isolation wards and those admitted to the intensive care unit (ICU). Based on the outcome, they were further divided into survivors and non-survivors. Demographic and outcome-related data were collected from the hospital's laboratory information system. Serial D-dimer measurements were taken at eight time points. Statistical analysis was performed using the Mann-Whitney test for laboratory values and the chi-square test for demographic data. Receiver operating characteristic (ROC) curve analysis was utilized to derive critical D-dimer values. The area under the curve (AUC) was calculated for initial and peak D-dimer values. Results Of 2.149 patients with confirmed COVID-19, 811 (38%) presented with elevated D-dimer levels. ICU admission was required for 239 patients, either due to direct admission or worsening conditions. An initial D-dimer value of ≥0.93 mg/L FEU indicated the need for ICU admission, while a peak D-dimer value of 5.65 mg/L FEU predicted mortality. The AUC for the initial D-dimer was 0.60 (95% CI: 0.55-0.64), indicating moderate discriminatory power. The AUC for the peak D-dimer was 0.58 (95% CI: 0.54-0.62), suggesting lower predictive accuracy for peak values. Sensitivity was high for both initial (0.925) and peak (0.960) D-dimer values, although specificity was lower, especially for the peak D-dimer (0.486), resulting in a higher rate of false positives. Among the ICU patients, the age range was 27-97 years, with a mean of 53.5 years. Males were more affected than females (71% vs. 29%), with a male-to-female ratio of 1.4:1. Of the ICU patients, 64.8% recovered, while 35.2% succumbed to the disease. Younger patients (mean age: 50.5 ± 12 years) recovered faster than older patients (mean age: 64 ± 16 years), with a significant difference in recovery time (p < 0.001). Gender did not significantly impact outcomes (p = 0.743). Survivors spent less time in the ICU (3-7 days) compared to non-survivors (4-14 days) (p = 0.041). Conclusion Serial D-dimer monitoring is essential for predicting outcomes and guiding treatment in COVID-19 patients. Initial and peak D-dimer values can help identify patients requiring intensive care and those at risk of mortality, allowing for timely interventions. D-dimer levels should be integrated into routine clinical assessments for managing COVID-19 patients.

Metabolic consequences on platelet parameters: Mean platelet volume and platelet distribution width in type 2 diabetes mellitus

Background: Diabetes mellitus encompasses metabolic disorders marked by chronic hyperglycemia, leading to various complications. It is considered a prothrombotic state associated with increased platelet reactivity. Parameters such as mean platelet volume (MPV) and platelet distribution width (PDW), which are indicative of platelet size, enzymatic activity, and prothrombotic risk, can be readily assessed during routine hematological analysis, facilitating early detection of this prothrombotic state. Aims and Objectives: The study aimed to investigate the varied alterations in platelet parameters in type 2 diabetes mellitus (T2DM) patients and tried to elucidate these parameters’ predictive role in diabetes complications. Materials and Methods: This prospective cross-sectional study was conducted between February 2022 and February 2024, involving 100 patients with T2DM and 100 healthy non-diabetic individuals. MPV, PDW, fasting blood glucose (FBS), and glycated hemoglobin (HbA1c) levels were measured and analyzed. Statistical analysis was carried out using the Student’s t-test, Mann–Whitney U-test, Chi-square test, and Spearman’s correlation tests in the Statistical Package for the Social Sciences software (version 21.0). Results: Most of the patients were in the age group of 40–70 years with male predominance. In comparing the 100 diabetics and 100 non-diabetics groups, MPV and PDW levels were notably higher in diabetics (11.46±1.75 vs. 9.40±1.02 fl, 21±2.57 vs. 16.72±1.48%) with statistical significance (P&lt;0.01). Similarly, FBS and HbA1C levels were elevated among diabetics (179.38±70.25 vs. 90.64±5.93, 7.83±2.24 vs. 5.02±0.64) along with a positive correlation between platelet indices (MPV and PDW) and FBS, HbA1c levels in patients with T2DM. In addition, diabetic patients with complications exhibit significantly higher MPV, PDW, FBS, and HbA1c levels compared to those without complications. Conclusion: MPV and PDW levels show significant alterations in T2DM patients, with consistently elevated values, especially in those with complications. This underscores their potential importance as key indicators alongside glycemic indices such as FBS and HbA1c, in monitoring diabetes progression and anticipating associated complications.