Disorders Of Primary Hemostasis Research Articles

Point-of-Care Testing in Patients with Hereditary Disorders of Primary Hemostasis: A Narrative Review.

Inherited disorders of primary hemostasis, such as von Willebrand disease and congenital platelet disorders, can cause extensive, typically mucocutaneous bleeding. Assays to diagnose and monitor these disorders, such as von Willebrand factor activity assays and light transmission aggregometry, are performed in specialized hemostasis laboratories but are commonly not available in local hospitals. Due to the complexity and relative scarcity of these conventional assays, point-of-care tests (POCT) might be an attractive alternative in patients with hereditary bleeding disorders. POCTs, such as thromboelastography, are increasingly used to assess hemostasis in patients with acquired hemostatic defects, aiding clinical decision-making in critical situations, such as during surgery or childbirth. In comparison, the use of these assays in patients with hereditary hemostasis defects remains relatively unexplored. This review aims to give an overview of point-of-care hemostasis tests in patients with hereditary disorders of primary hemostasis. A summary of the literature reporting on the performance of currently available and experimental POCTs in these disorders is given, and the potential utility of the assays in various use scenarios is discussed. Altogether, the studies included in this review reveal that several POCTs are capable of identifying and monitoring severe defects in the primary hemostasis, while a POCT that can reliably detect milder defects of primary hemostasis is currently lacking. A better understanding of the strengths and limitations of POCTs in assessing hereditary defects of primary hemostasis is needed, after which these tests may become available for clinical practice, potentially targeting a large group of patients with milder defects of primary hemostasis.

Gingival bleeding is a useful clinical feature in the diagnosis of hereditary bleeding disorders in children.

The search for hereditary bleeding disorders (HBD) prior to invasive procedures in children is primarily based on personal and family bleeding history. Although several scores are available, they have only been evaluated in specific situations or in adults. Our monocentric retrospective study aimed to analyze the association between clinical history and four scores (HEMSTOP, PBQ, ISTH-BAT, TOSETTO) and the diagnosis of MHC in children referred to the University Hospital of Montpellier for hemostasis investigations. A total of 117 children were retrospectively included in the study. Of these, 57 (49%) were diagnosed with HBD, with 30 having primary bleeding disorders and 27 having coagulation disorders. The diagnosis of HBD was significantly associated with gingival bleeding, which was present in 30% of HBD patients. In our population, only the HEMSTOP score showed an association with the diagnosis of HBD, but it was positive in only 48% of patients. By including gingival bleeding as a factor, we modified the HEMSTOP score, which increased its sensitivity from 0.45 to 0.53. When examining primary bleeding disorders, the modified HEMSTOP score, with the inclusion of gingival bleeding, enables us to diagnose 63% of patients (see Fig.1). Conclusion: Therefore, gingival bleeding should be considered a useful factor in bleeding history for HBD diagnosis. Adding this symptom to a screening score such as HEMSTOP improves its sensitivity. To confirm our findings, a prospective study is required. Trial registration: Study registration number: NCT05214300. What is Known: • Screening for hereditary bleeding disorder diseases is a necessity and a challenge in children. • Minor disorders of primary hemostasis are the most common, but often escape standard coagulation tests. What is New: • Gingival bleeding is a frequent symptom that is easy to investigate and may point to a primary hemostasis disorder. • Adding the gingival bleeding item to a routine screening score such as HEMSTOP improves sensitivity.

ТРУДНОСТИ ВЕРИФИКАЦИИ ПРИЧИН ГЕМОРРАГИЧЕСКОГО СИНДРОМА В ПРАКТИКЕ ВРАЧА-НЕОНАТОЛОГА

Problems related to the study of the coagulation status of patients during the neonatal period are well known to neonatologists. Hemorrhagic disorders in the period of the newborn can be caused by deficiency of vitamin K-dependent factors, intrauterine infection, hereditary coagulopathy, primary and secondary disorders of platelet hemostasis and a number of other reasons. Clinical manifestations of hemorrhagic syndrome in a newborn child are non-specific, allowing to suspect the type of blood flow, however, conducting selective hemostatic therapy is possible only after laboratory identification of the disease. Among congenital coagulopathies, hemophilia A is the most frequently encountered, while clinical manifestations of the disease occur during the neonatal period only in the case of the presence of a severe form of the disease. Meanwhile, in the practice of pediatricians and neonatologists, vascular tumors are encountered quite rarely, including Kazabach-Merritt syndrome – a potentially life-threatening condition in which hemangioendotheliomas grow rapidly and reach gigantic sizes, combined with severe thrombocytopenia and coagulopathy. In this article, two clinical cases of severe hemophilia A in newborn boys with basic factor VIII activity of less than 1% are presented, as well as a case of infantile hemangioendothelioma of the liver in a newborn baby. In the article, the directions of the laboratory search for disorders of primary and secondary hemostasis were analyzed, which allowed the diagnosis to be clarified and the appropriate hemostatic therapy to be selected.

Primary Hemostasis Disorders as a Cause of Heavy Menstrual Bleeding in Women of Reproductive Age.

Heavy menstrual bleeding (HMB) is a common clinical condition affecting adolescent and adult women and compromising their quality of life. Primary hemostasis disorders, affecting platelet plug formation, can be the underlying cause of HMB. They comprise a heterogeneous group of diseases with Von Willebrand disease (VWD) being the most commonly diagnosed; other disorders in this group that have been linked to HMB include (a) Glanzmann thrombasthenia, (b) Bernard-Soulier syndrome, (c) Hermansky-Pudlak syndrome, (d) immune thrombocytopenia (ITP), and (e) Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD). Diagnosing these diseases can be challenging, as the basic laboratory investigations can be within the normal range. Thus, identification of specific clinical features and a thorough hematologic workup can be very important, providing the correct diagnosis. Proper diagnosis of the underlying disorder is important, as management may vary accordingly. Although disease-specific management guidelines exist for some of these disorders such as VWD and ITP, due to the rarity of most primary hemostasis disorders, the best approach for the management of HMB in these women remains elusive. The goal of this study was to create an informative, comprehensive review of the primary hemostasis disorders that have been linked to HMB. This study provides a summary of the basic published information regarding epidemiology, pathophysiology, clinical phenotype, diagnosis, and treatment of HMB in those diseases and serves as a reference guide for further reading.

The disorders of blood oxygen transport function, hemostasis indicators and endothelium functional state in patients with ruptured arterial aneurysms and the development of delayed cerebral ischemia

Introduction. Rupture of cerebral aneurysms (CA) with the development of intracranial hemorrhage (ICH), complicated in some cases by vascular spasm and delayed cerebral ischemia (DCI), is due to the complex multifactorial genesis of the disease, including changes in the blood oxygen transport function (BOTF), activation of endothelial cells with a release of vasoregulators, reactive oxygen species, inflammatory proteins, as well as disturbances in the hemostasis system.Purpose – to study the indicators of BOTF, primary and secondary hemostasis and the content of some vasoregulatory metabolites in the pre- and postoperative periods in patients with ruptured CA with the development of DCI and without DCI.Materials and methods. The group with DCI included 45 patients; in the group without DCI were 14 people. Clinical-neurological and neuroimaging examinations were carried out, and parameters of BOTF, primary and secondary hemostasis, nitrate/nitrite, angiotensin-converting enzyme (ACE), and PAI-1 concentrations in venous blood were studied before and on days 10–12 after microsurgical clipping of the CA.Results. We diagnosed mild neurological disorders according to the NIHSS scale, confirmed by neuroimaging studies of the brain in the group of DCI patients. It was shown an increase in thrombin-dependent platelet aggregation velocity to 30.6 (24.3; 32.4) AU/min at norm 21.8 (20.3; 24.9) (U, p=0.009) before surgery; and after surgery it was up to 37.4 (30; 44.7) relative to the norm (U, p=0.001). Before surgery, the following was observed: PT shortening to 11.6±0.7 sec at norm 13.2±1.1 (t, p˂0.001), fibrinogen concentration increasing to 4.35 (3.8; 4.8) g/L at norm 3.9 (3.6; 4.1) g/L (U, p = 0.01) and PAI-1 up to 3.9 (2.6; 4.8) ng / mL at norm 2 .7 (2.2; 4.1). After surgery, PT was 11.9±1.1 (t, p˂0.001); fibrinogen - 4.4 (3.9; 4.8) (U, p=0.024), PAI-1 - 4.6 (4.1; 6.7) (U, p=0.0004) respectively. Before surgery, p50 was increased to 28.1 (26.2; 31.6) mm Hg at norm 25.2 (24.3; 26.8) (U, p=0.025); after surgery, it was up to 28.5 (26.8; 30.7) (U, p=0.03) and the ratio of nitrates/nitrites to ACE was reduced to 0.12 (0.08; 0.15) at norm 0.22 (0.15; 0.32) (U, p˂0.001); after - up to 0.11 (0.08; 0.19) (U, p˂0.001) respectively.Conclusion. There has been revealed significant disorders of primary and secondary hemostasis with fibrinolysis inhibition, a decrease in the affinity of hemoglobin to oxygen at the p50 rate and an imbalance of the content of vasoregulatory metabolites in patients with DCI before and after aneurysm clipping, which can be considered as significant factors in the development of DCI after aneurysmal ICH.

Hemostatic disorders associated with extracorporeal membrane oxygenation.

Hemostatic disorders are common during extracorporeal membrane oxygenation (ECMO)-therapy. This includes both bleeding and thrombotic complications. Particularly bleeding is often associated with fatal outcome. The early identification of hemorrhagic diathesis and the diagnosis of the underlying pathology are essential. A distinction into device-, disease-, and drug-related disorders appears reasonable. However, both correct diagnosis and therapy can be challenging and sometimes counterintuitive. Since bleeding seems to be more frequent and dangerous compared to thrombosis, the understanding of coagulation disorders and minimizing anticoagulation has been focused in recent years. Due to progress in membrane coating and configuration of modern ECMO circuits it is even possible to perform ECMO without any anticoagulation in well selected cases. It became apparent that routine laboratory tests are likely to miss severe coagulation disorders during ECMO-therapy. Better understanding can also help to individualize anticoagulation in patients and hence preventing complications. Acquired von Willebrand syndrome, platelet dysfunction, waste coagulopathy as well as silent hemolysis should be taken into account when bleeding or thromboembolic complications appear. Recognizing impaired intrinsic fibrinolysis may favour intensified anticoagulation even in patients exhibiting signs of bleeding. Drug monitoring with standard coagulation tests, viscoelastic tests and anti-Xa-levels as wells as screening for disorders of primary hemostasis should be implemented in clinical routine to guide physicians through complex anticoagulative therapy. The patient's coagulative status should be interpreted taking the underlying disease and current therapy into account in order to enable a personalized approach to hemostasis in patients treated with ECMO.

A rare combination of immune thrombocytopenia and disaggregation thrombocytopathy: course and termination of pregnancy complicated by COVID-19 (Clinical case)

Immune thrombocytopenia (ITP) is an autoimmune disease which is characterized by antibody-mediated destruction of platelets by the reticuloendothelial system. The rate of ITP is 3.3 per 100,000 adults per year with a prevalence of 9.5 per 100,000 adults. Pregnancy does not increase the frequency or severity of ITP, but ITP can significantly affect pregnancy and cause bleeding in women.Pregnancy requires regular control of the number of platelets: monthly in the I and II trimesters, every 2 weeks – in the III trimester, and weekly control near the delivery date. Indications for treatment are determined by the pregnant woman condition, not the fetus, since it has not been proven that the treatment reduces the risks of thrombocytopenia in newborns with the development of cerebral hemorrhage.The drug of the first line of treatment of such pathology is prednisolone at a dose of 1 mg/kg orally once a day. An increase in the number of platelets is usually observed within 3-7 days, the maximum response is determined after 2-3 weeks. If necessary, the dose can be increased. When the required level of platelets is reached, the dose can be gradually reduced by 10-20 % to the minimum dose necessary to maintain the number of platelets at an acceptable level.Thrombocytopathy can be the cause of primary hemostasis disorders, even if the number of platelets in the blood is normal. For diagnosis, tests are carried out to detect the aggregation ability of platelets. In addition, flow cytometry can be used, which makes it possible to detect the defects of surface membrane receptors, as well as defects of the end point of secretion.ITP is a common cause of thrombocytopenia after viral infections. The onset of this pathology is more often detected in the second and third weeks after the onset of COVID-19. The treatment aim is to prevent the significant bleeding in patients with COVID-19.The article presents a clinical case of a pregnant woman with ITP and thrombocytopathy, whose pregnancy was complicated by COVID-19. The patient complained on bleeding gums, the appearance of hematomas on the skin. Medical treatment of the main disease included prednisolone, eltrombopag, intravenous human immunoglobulin, transfusion of platelet concentrate. At 34–35 weeks of pregnancy alive boy was born with a body weight of 2800 g, length of 49 cm, 7–8 points on the Apgar scale.

Diagnosing Czech Patients with Inherited Platelet Disorders.

A single-center study was conducted on 120 patients with inherited disorders of primary hemostasis followed at our hematological center. These patients presented a variety of bleeding symptoms; however, they had no definitive diagnosis. Establishing a diagnosis has consequences for the investigation of probands in families and for treatment management; therefore, we aimed to improve the diagnosis rate in these patients by implementing advanced diagnostic methods. According to the accepted international guidelines at the time of study, we investigated platelet morphology, platelet function assay, light-transmission aggregometry, and flow cytometry. Using only these methods, we were unable to make a definitive diagnosis for most of our patients. However, next-generation sequencing (NGS), which was applied in 31 patients, allowed us to establish definitive diagnoses in six cases (variants in ANKRD26, ITGA2B, and F8) and helped us to identify suspected variants (NBEAL2, F2, BLOC1S6, AP3D1, GP1BB, ANO6, CD36, and ITGB3) and new suspected variants (GFI1B, FGA, GP1BA, and ITGA2B) in 11 patients. The role of NGS in patients with suspicious bleeding symptoms is growing and it changes the diagnostic algorithm. The greatest disadvantage of NGS, aside from the cost, is the occurrence of gene variants of uncertain significance.

Pathophysiology of Blood Vein Thrombotitis Hemostasis Disorders

Annotation: Primary or vascular platelet hemostasis disorders include thrombocytopenia, thrombocytopathy, and vasopathy. Hemorrhages are characteristic of the clinic of these diseases, with the appearance of hemorrhagic rashes on the skin as a result of increased permeability of the capillary wall, bleeding from the nose, metro and menorrhagia, resulting in the development of severe posthemorrhagic anemia. Hemorrhagic diathesis in this group and includes many nosologies acquired over a lifetime. Almost all disorders lead to life-threatening hemorrhages

Gerinnungsdiagnostik im klinischen Alltag – Teil 1

This article on coagulation diagnostics is published in two parts covering five common clinical scenarios for coagulation diagnostics. Part1 deals with the diagnostics prior to invasive interventions and coagulation diagnostics to clarify atendency to bleeding. The global parameters Quick and activated partial thromboplastin time are established for monitoring certain anticoagulants; however, they are not predictive with respect to the risk of bleeding prior to elective invasive interventions. In this context, disorders of primary hemostasis are frequent, which are insufficiently detected by the global parameters. Most clinical bleeding tendencies are due to acquired causes. These include anticoagulants and diseases which can be accompanied by tendency to bleeding. For coagulation tests preanalytical issues are essential in order to avoid false results. The interpretation should always be made in the context of the current physiological state.

Congenital and acquired disorders of primary hemostasis

Congenital and acquired disorders of primary hemostasis

Baseline mean platelet volume is a strong predictor of major and life-threatening bleedings after transcatheter aortic valve replacement

Bleeding following transcatheter aortic valve replacement (TAVR) has important prognostic implications. This study sought to evaluate the impact of baseline mean platelet volume (MPV), a routinely used marker of platelet reactivity, on bleeding events in a contemporary real-world TAVR cohort. Patients undergoing TAVR between February 2010 and May 2019 with available preprocedural MPV were included. Low MPV (L-MPV) was defined as MPV ≤ 10 fL and high MPV (H-MPV) as MPV > 10 fL. The primary endpoint was the occurrence of major/life-threatening bleeding complications (MLBCs) at one year follow-up. Among 1,111 patients, 398 (35.8%) had L-MPV and 713 (64.2%) had H-MPV. The rate of MLBCs at 1 year was higher in L-MPV patients compared with H-MPV patients (22.9% vs. 17.7% respectively, P = 0.034). L-MPV was associated with vascular access-site complications (36.2% vs. 28.9%, P = 0.012), early (< 30 days) major bleeding (15.6% vs. 9.4%, P < 0.01) and red blood cell transfusion > 2 units (23.9% vs. 17.5%, P = 0.01). No impact of baseline MPV on overall death, cardiovascular death and ischemic events (myocardial infarction and stroke) was evidenced. Multivariate analysis using Fine and Gray model identified preprocedural hemoglobin (sHR 0.84, CI95% [0.75–0.93], P = 0.001), preprocedural L-MPV (sHR 1.64, CI95% [1.16–2.32], P = 0.005) and CT-ADP post-TAVR (sHR 2.71, CI95% [1.87–3.94], P < 0.001) as predictors of MLBCs (Fig. 1, Table 1). Preprocedural MPV was identified as an independent predictor of MLBCs one year after TAVR, regardless of the extent of platelet inhibition and primary hemostasis disorders. MPV should be regarded as a simple, common and valuable biomarker of bleeding prediction after TAVR.

Primary hemostatic disorders drive early and late major bleedings of patients with atrial fibrillation after transcatheter aortic valve replacement

Patients with atrial fibrillation (AF) are likely to have multiple co-morbidities which lead to a poor prognosis including bleeding events. Closure time adenosine diphosphate (CT-ADP) is a primary hemostasis point-of-care test used as a surrogate marker of high molecular weight multimers defect of Von Willebrand factor. Our prior studies suggest that prolongation of CT-ADP (> 180 sec) after TAVR is a determinant of major/life-threatening bleeding complications (MLBCs). To evaluate the impact of post-procedural CT-ADP > 180 sec on bleeding events in TAVR patients with AF. We included 878 patients from our prospective TAVR registry. Bleeding complications were assessed according to the VARC-2 criteria. Major adverse cardiac and cerebrovascular events (MACCE) was defined as a composite of all-cause death, myocardial infarction, stroke, and heart failure hospitalization after TAVR. Primary endpoint was 1-year MLBCs and the second endpoint was 1-year MACCE. Patients with AF had a higher incidence of all-cause mortality (15% vs. 8%, P = 0.002), MACCE (29% vs. 20%, P = 0.002), and MLBCs (20% vs. 12%, P = 0.001) within 1-year compared to non-AF patients. When the cohort was split into 4 subgroups according to AF and CT-ADP > 180 sec, patients with AF and CT-ADP > 180 sec had the highest risk of MLBCs (log-rank test; P < 0.001) ( Fig. 1 ). Multivariate Cox regression analysis confirmed that the patients with AF and CT-ADP > 180 sec had 4.6-fold higher risk of MLBCs within 1 year compared to non-AF patients with CT-ADP ≤ 180 sec (hazard ratio: 4.60; 95% confidence interval: 2.18-9.68; P < 0.001) ( Fig. 1 ). Among TAVR patients, AF with post-procedural CT-ADP > 180 sec was identified as a strong predictor of MLBCs at 1-year follow-up. Our study suggest that persistent primary haemostasis disorders contribute to a higher risk of bleeding events particularly in AF patients and may be considered for a tailored and risk-adjusted antithrombotic therapy after TAVR.

Impact of Primary Hemostasis Disorders on Late Major Bleeding Events among Anticoagulated Atrial Fibrillation Patients Treated by TAVR.

Background: Bleeding events are among the striking complications following transcatheter aortic valve replacement (TAVR), and bleeding prediction models are crucially warranted. Several studies have highlighted that primary hemostasis disorders secondary to persistent loss of high-molecular-weight (HMW) multimers of the von Willebrand factor (vWF) and assessed by adenosine diphosphate closure time (CT-ADP) may be a strong predictor of late major/life-threatening bleeding complications (MLBCs). Pre-existing atrial fibrillation (AF) is a frequent comorbidity in TAVR patients and potentially associated with increased bleeding events after the procedure. Objectives: This study evaluated the impact of ongoing primary hemostasis disorders, as assessed by post-procedural CT-ADP > 180 s, on clinical events after TAVR among anticoagulated AF patients. Methods: An ongoing primary hemostasis disorder was defined by post-procedure CT-ADP > 180 s. Bleeding complications were assessed according to the Valve Academic Research Consortium-2 (VARC-2) criteria. The primary endpoint was the occurrence of late MLBCs at one-year follow-up. The secondary endpoint was a composite of mortality, stroke, myocardial infarction, and rehospitalization for heart failure. Results: In total, 384 TAVR patients were included in the analysis. Of these patients, 57 patients (14.8%) had a prolongated CT-ADP > 180 s. Increased MLBCs were observed in patients with CT-ADP > 180 s (35.1% versus 1.2%; p < 0.0001). Conversely, the occurrence of the composite endpoint did not differ between the groups. Multivariate analysis identified CT-ADP > 180 s (HR 28.93; 95% CI 9.74–85.95; p < 0.0001), bleeding history, paradoxical aortic stenosis (AS), and major vascular complications following TAVR as independent predictors of late MLBCs. Conclusion: Among patients with anticoagulated AF, a post-procedural CT-ADP > 180 s was identified as a strong independent predictor of late MLBCs. These findings suggest that persistent primary hemostasis disorders contribute to a higher risk of late bleeding events and should be considered for a tailored, risk-adjusted antithrombotic therapy after TAVR.

Acute spinal cord compression due to spinal subdural hematoma after spinal anaesthesia in-patient under anticoagulant drug

BackgroundSubdural spinal cord hematomas are very rare condition. They most often occur in patients with primary or secondary blood haemostasis disorders and following lumbar punctures. Early diagnosis and management preserve functional prognosis.Case descriptionWe report the case of a female 69-year-old patient on oral anticoagulant, Acenocoumarol 4 mg (SINTROM) for previous aortic prosthesis. The patient had undergone surgery for appendicitis under spinal anaesthesia 2 days before her admission in neurosurgery department. She was admitted in emergency for 1/5 central flaccid paraplegia with sensitive umbilical level. A spinal MRI performed showed a collection intradural in intermediate signal in T1 and hyposignal in T2 with echo gradient of 8 mm thickness extended from D8 to L2 compressing the marrow with anomalies of intramedullary signal extended from D8 to the conus medullaris. We retained indication to operate the patient early in emergency because of acute spinal cord compression. We performed T12-L2 laminectomy, durotomy and evacuated hematoma. Postoperative marked by an immediate recovery of sensitivity and an onset of motor recovery from 1/5 to 2/5 and 4/5 follow up at on year with physiotherapy.ConclusionSpinal cord compression due to subdural spinal hematomas not often described especially in patients with haemostasis blood disorders due to anticoagulants drugs. In addition, we should pay attention with lumbar puncture in these patients. Emergency surgery allows a good prognosis about recovery of neurological disorders.

Percutaneous left atrial appendage closure in patients with primary hemostasis disorders and atrial fibrillation.

We report our single-center experience with percutaneous left atrial appendage closure (LAAC) in patients with non-valvular atrial fibrillation (NVAF) and primary hemostasis disorders (HD). Consecutive patients with primary HD who underwent a percutaneous LAAC were included. Baseline characteristics, procedural data, and clinical outcomes were prospectively collected and compared with the overall LAAC cohort without HD. Since 2013, among 229 LAAC, 17 patients (7%) had a primary HD: thrombocytopenia (n = 5), myelodysplastic syndrome (n = 6), von Willebrand syndrome (n = 4), type A hemophilia (n = 1), and dysfibrinogenemia (n = 1). The HD population's age ranged from 61 to 87years, and the median CHA2DS2VASc was 5. Periprocedural plasmatic management was required in 47% of patients. The immediate LAAC implantation success rate was 100%. Patients received a direct oral anticoagulant (DOA) (n = 9), dual antiplatelet (n = 6), aspirin (n = 1), or no therapy (n = 1) during the first six postoperative weeks, followed with single antiplatelet (n = 16) or no therapy (n = 1) during lifelong. After 20months, the technical success rate and procedural success rate were 100% and 94%. Zero device-/procedure-related complication and only one life-threatening bleeding occurred. Compared to patients without HD (n = 212), a baseline history of bleeding was less frequent (53% vs 91%, p < 0.001), and more patients received a perioperative blood transfusion (47% vs 4%, p < 0.001) in the HD group. The efficacy and safety outcomes did not differ between HD and non-HD cohorts. Percutaneous LAAC in primary HD carriers appeared as safe and as effective as in overall LAAC population for stroke and bleeding prevention at midterm follow-up. Percutaneous left atrial appendage closure in patients with atrial fibrillation and primary hemostasis disorders. The percutaneous LAAC in primary hemostasis disorders and AF carriers requires a multidisciplinary approach. Cardiologist, anesthesiologist, and hematologist discussion is a cornerstone to assess anticoagulant contraindication, LAAC feasibility, periprocedural management, and follow-up (high). This multidisciplinary care is illustrated by the case of a 61-year-old male with hemophilia type A and recurrent hemarthrosis. Pre-LAAC assessment confirmed procedural indication and cactus LAA anatomy (left). After plasmatic management with factor VIII infusion, a WATCHMAN™ no. 21 was successfully implanted (middle). During follow-up, without antithrombotic regime, no ischemic or hemorrhagic complication occurred (right). LAA, left atrial appendage; LAAC, left atrial appendage closure; TEE, transesophageal echocardiography.Percutaneous LAAC in primary HD carriers appeared as safe and as effective as in overall LAAC population for stroke and bleeding prevention at midterm follow-up.

Introducing a Novel Biophysical Platelet Function Panel to Investigate Disorders of Primary Hemostasis and Bleeding of Unknown Cause

A subset of patients with chronic bleeding remain undiagnosed even after extensive diagnostic evaluation are labeled as “bleeding of unknown cause” (BUC). The key barrier to treating these patients is that they have a clinical bleeding tendency in the presence of normal diagnostic tests, and optimal methods for monitoring and treating patients with BUC remain unknown. While patients with BUC have symptoms of a primary hemostatic disorder, there is no diagnostic test or biomarker that can accurately identify which patients are at risk for bleeding such as those with mild Von Willebrand Disease (VWD) which comprise a broad spectrum of patients with varying degrees of bleeding. In order to fill this diagnostic gap in disorders of primary hemostasis, there is a clinical need for more assays of platelet function.To that end, we have engineered multiple new biophysical assays to assess disorders of primary hemostasis and apply this panel of platelet function testing to potentially define new bleeding disorders, characterize platelet phenotypes in patients with BUC, and refine the definition of mild VWD. Our panel of platelet function tests (Fig 1) collectively enables us to simultaneously assess different facets of primary hemostasis from the microscopic level of single-platelet physiology to hemostatic plug formation, thereby capturing various aspects of platelet function with a single blood sample. Our platelet function panel ranges from platelet adhesion and bulk clot contraction assays to spatially-regulated platelet granule secretion assay, single-platelet contraction cytometry, microfluidics, and a microengineered vascularized bleeding model. As such, we are leveraging these biophysical assays to correlate platelet function with bleeding phenotype severity and establish the dynamic range of this diagnostic panel. We have now established that our assays can be utilized to study blood samples from patients with disorders including hemophilia A, Hermansky-Pudlak Syndrome, FLI-1 mutation, and sickle cell disease among others (Fig 2), demonstrating the clinical utility of our platelet function panel.Our panel can also be used to assess the effects of novel therapeutics on different aspects of platelet function simultaneously. To investigate how crizanlizumab (p-selectin inhibitor) affects hemostatic plug formation, healthy human blood was treated with crizanlizumab. Platelet α-granule secretion enables exposure of P-selectin, and with crizanlizumab we observed restricted platelet filopodial extension and diminished α-granule exocytosis, and an overall decrease in adhered platelets to the fibrinogen micropattern (Fig 3A). The adhesion assay demonstrated a decrease in spreading and adhesion of platelets to collagen and fibrinogen with treatment (Fig 3B). Using the bleeding model, hemostasis was achieved within the normal established range and platelets contracted normally. This suggests that p-selectin has a limited role in the setting of minor injury. Utilizing the bulk contraction assay, we exhibited increased contraction early in clot formation, however over time the treated platelets contracted similarly to the control (Fig 3C). Interestingly, the effect of crizanlizumab-induced restriction of filopodial extension did not correlate with impaired bulk clot contraction or time to form hemostatic plug. Our work suggests crizanlizumab affects platelet spreading at the single-cell level but does not impair platelet function in achieving primary hemostasis at the whole blood level.Here we demonstrate the translational utility of our platelet function panel in providing a deeper understanding of platelet biophysics as it relates to hematologic conditions, with implications for investigation to include pharmaceutical applications. The versatility of this novel panel in capturing platelet function from single-platelet contraction to providing in vitro models with the bleeding device provides multiple dimensions to platelet investigation for primary hemostatic disorders and BUC that have not yet been elucidated. Ongoing research is being conducted using our comprehensive platelet function panel to investigate platelet properties in BUC and mild VWD and correlate these biophysics with bleeding phenotypes. Using this approach we aim to provide novel diagnostic testing with clinical relevance for disorders that have been incompletely characterized until now. [Display omitted] DisclosuresMeeks: National Institutes of Health: Research Funding; Hemophilia of Georgia: Research Funding; National Hemophilia Foundation: Research Funding; Spark Therapeutics: Consultancy; Sangamo Therapeutics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Takeda: Consultancy. Lam: Sanguina, Inc.: Current holder of individual stocks in a privately-held company.

Primary hemostatic disorders drive early and late major bleedings of patients with atrial fibrillation after transcatheter aortic valve replacement

Abstract Introduction Patients with atrial fibrillation (AF) are likely to have multiple co-morbidities and receive anticoagulants after TAVR, which lead to a poor prognosis including bleeding events. Closure time adenosine diphosphate (CT-ADP) is a primary hemostasis point-of-care test used as a surrogate marker of high molecular weight (HMW) multimers defect of Von Willebrand factor (VWF). Our prior studies suggest that prolongation of CT-ADP (&amp;gt;180 seconds) after TAVR is a major determinant of early and late major/life-threatening bleeding complications (MLBCs). Purpose To evaluate the impact of post-procedural CT-ADP &amp;gt;180sec on bleeding events in AF patients. Methods We included 878 patients from our prospective TAVR registry between 2010 and 2019. Bleeding complications were assessed according to the VARC-2 (Valve Academic Research Consortium-2) criteria. Major adverse cardiac and cerebrovascular events (MACCE) was defined as a composite of all-cause death, myocardial infarction, stroke, and heart failure hospitalization within 1-year after TAVR. Ongoing primary haemostasis disorder was defined by post-procedure CT-ADP &amp;gt;180sec. Primary endpoint was the occurrence of MLBCs during the first year and the second endpoint was 1-year MACCE. Results Patients with AF had a higher incidence of all-cause mortality (15% vs. 8%, p=0.002), MACCE (29% vs. 20%, p=0.002), and MLBCs (20% vs. 12%, p=0.001) within 1-year compared to non-AF patients. When the cohort was split into 4 subgroups according to AF and CT-ADP &amp;gt;180sec, patients with AF and CT-ADP &amp;gt;180sec had the highest risk of MLBCs (log-rank test; p&amp;lt;0.001) (Figure). Multivariate Cox regression analysis confirmed that the patients with AF and CT-ADP &amp;gt;180sec had 4.6-fold higher risk of MLBCs within 1 year compared to non-AF patients with CT-ADP ≤180sec (hazard ratio: 4.60; 95% confidence interval: 2.18 - 9.68; p&amp;lt;0.001). Conclusion Among TAVR patients, AF with post-procedural CT-ADP &amp;gt;180 sec was identified as a strong independent predictor of MLBCs at 1-year follow-up. Our study suggest that persistent primary haemostasis disorders contribute to a higher risk of bleeding events particularly in AF patients and may be considered for a tailored and risk-adjusted antithrombotic therapy after TAVR. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Dr Matsushita received a grant from Edwards Lifesciences.

PERCUTANEOUS LEFT ATRIAL APPENDAGE CLOSURE IN PATIENTS WITH HEMOSTASIS DISORDERS AND ANTICOAGULANT CONTRAINDICATION

<h3>BACKGROUND</h3> We report our single center experience with percutaneous left atrial appendage closure (LAAC) in patients with non-valvular atrial fibrillation (NVAF) and primary hemostasis disorders (HD). In randomized percutaneous LAAC trials, this HD population is under-represented. <h3>METHODS AND RESULTS</h3> Consecutive patients with primary HD who underwent LAAC were included. Baseline procedural characteristics and clinical events during follow-up were prospectively collected. From 2013 to 2021, 205 patients underwent percutaneous LAAC and 17 (8.2%) had proven HD: thrombocytopenia (n=5), myelodysplastic syndrome (n=6), Von Willebrand syndrome (n=4), type A hemophilia (n=1) and dysfibrinogenemia (n=1). Median age was 78 YO, CHA2DS2VASc and HAS-BLED scores were 5 and 3, respectively. Periprocedural plasmatic management was required in 47% of patients. The LAAC device implantation was successful in all cases. Post-procedural antithrombotic regimen for the first six weeks consisted of reduced direct oral anticoagulant (DOA) in 8 patients, full dose DOA in 1, dual-antiplatelet in 6, aspirin in 1 and no therapy in 1. The transesophageal echocardiography, 45 days post-procedure, showed optimal device position, adequate sealing in all patients and no clots. After this initial period post-LAAC the long-term antithrombotic regimen was single-antiplatelet in 16 patients and no therapy in 1 patient. After a median follow-up of 1.0 year (25-75 IQR: 0.4-2.2), no thrombo-embolic or bleeding events occurred. <h3>CONCLUSION</h3> The percutaneous LAAC in patients with atrial fibrillation and primary hemostasis disorders appeared to be a safe and effective alternative for stroke and bleeding prevention at mid-term follow-up. These promising results warrant larger studies to confirm our experience.

A microchip flow-chamber assay screens congenital primary hemostasis disorders.

Von Willebrand disease (VWD) and platelet function disorders (PFDs) are congenital bleeding disorders caused by primary hemostasis defects. Platelet function tests are time-consuming and require considerable amounts of blood sample, and there have been no easy-to-use assays for assessing platelet function quickly and sensitively. We report the usefulness of a microchip flow-chamber system (T-TAS® ) for detecting and/or predicting clinical severity in patients with VWD type 1 and type 2N and platelet storage pool disease. Here, we developed an application of a screening assay for primary hemostasis disorders. Microchips coated with collagen (PL-chip) and collagen/thromboplastin (AR-chip) were utilized to evaluate platelet thrombus formation (PTF) at high shear and fibrin-rich PTF at low shear, respectively, in whole blood samples from 22 patients with VWD (16 type 2A, four type 2B, two type 3) and four patients with PFDs (two BSS, two Glanzmann thrombasthenia). The time-to-increase by 10kPa (T10 ) was calculated from flow pressure curves. Also, whole blood-induced platelet aggregation was assessed using Multiplate® analysis. PL-chip T10 values ≥10min successfully distinguished patients with all types of VWD and PFDs from healthy controls, irrespective of age, bleeding scores, and von Willebrand factor levels. However, AR-chip assay incompletely distinguished between type 2A patients and healthy ones. Multiplate analysis permitted screening of PFDs and type 3 VWD, but values in type 2A partially overlapped with those in controls. PL-chip assay did not reflect the clinical severity in these patients. T-TAS with PL-chip could be a quick screening tool for congenital primary hemostasis disorder, VWD, and PFDs.