Lupus Anticoagulant Antibodies Research Articles

Evaluation of the Determination of Dabigatran, Rivaroxaban, and Apixaban in Lupus Anticoagulant-Positive Patients.

Background: The effect of direct oral anticoagulants (DOAC) on laboratory tests dependent on the production of their targets, factor IIa and factor Xa, is a well-known problem and can cause both false positive and negative results. In particular, the situation in patients who develop lupus anticoagulant (LA) antibodies is highly complex. To evaluate the effectiveness of DOAC therapy in lupus-positive patients, 31 samples were enrolled in this retrospective study. All patient samples were spiked with three types of DOAC (dabigatran, DABI; rivaroxaban, RIVA; and apixaban, API) in a concentration that significantly influenced the screening test for LA and thus can mask the presence of LA. Subsequently, the DOAC was always unbound by the DOAC-Stop procedure. DOAC levels before and after binding were determined by functional assays, followed by liquid chromatography coupled with mass spectrometry (LC-MS) analysis. Methods: The determination of DOAC levels was performed by direct thrombin assay and determination of anti-Xa activity with specific calibration as functional tests for DABI and xabans (API and RIVA). To determine concentration levels of API, DABI, and RIVA, our in-house LC-MS method was used. Results: The results of LA-positive samples show significant differences between functional tests and the LC-MS method both before and after DOAC binding. Conclusions: The acute findings of the presence of LA-type antibodies fundamentally affects the determination of DOAC by functional tests, and in this case, it is necessary to use LC-MS analysis to determine the true value. If patients treated with DOAC develop LA of medium and higher titers, we do not recommend checking DOAC levels with functional tests.

Concordance and discordance among antiphospholipid syndrome screening assay

Abstract Introduction/Objective The lupus anticoagulant (LA) panel utilizing dilute Russell’s viper venom and LA-responsive APTT remains the front-line screen for detecting the presence of clinically significant antibodies in the diagnosis of antiphospholipid syndrome. Receiving anticoagulant therapy limits the utility of clotting-based methods due to increased risk of false positive results. Anti-cardiolipin (aCL) and anti-ß2-glycoprotein I (a2GßPI) antibody titers have also been employed for the detection of anti-phospholipid antibodies; however, they are not influenced by anticoagulation therapy. The International Society on Thrombosis and Haemostasis recommends that all three tests should be performed to appropriately assess the risk of lupus anticoagulant/antiphospholipid antibodies. In this study, the concordance and discordance of rates of among these three assays were examined. Methods/Case Report The electronic medical record was mined according to lab tests codes for the results of the LA panel, aCL and a2GßPI antibody titers for all patients having at least one resulted study at the University of Cincinnati Medical Center in Cincinnati, Ohio, over a one-year period (2020). Results were compared to determine rates of concordance and discordance among the assays as well as Spearman’s correlation. Non-parametric binary regression analysis was applied to explore the relationship connecting aCL and a2GßPI titers to LA panel findings. Results (if a Case Study enter NA) Strong concordance was seen between the results of LA panels and antibody titer assays. A weak but significant positive correlation was found among the three assays. A robust logarithmic relationship was developed from which the LA panel result could be predicted utilizing outcomes from aCL and a2GßPI antibody titer findings. Conclusion These data further support the reliability of aCL and a2GßPI titers in the evaluation of antiphospholipid syndrome. Furthermore, the robust relationship among these three assays suggests that antibody titers may provide a reliable diagnostic avenue for patients actively undergoing anticoagulation therapy.

Характеристика когнітивної дисфункції у хворих на системний червоний вовчак

The purpose of the study was to explore the structure of cognitive impairment in patients with systemic lupus erythematosus and to determine the factors associated with its development. Materials and methods. Advanced examination of 64 patients with systemic lupus erythematosus was carried out. Neurological disorders were diagnosed in 54 patients (84.38% of patients). These patients were included in the main study group (group 1). In 10 (15.62% of patients) patients, these manifestations were not found and they entered the control group (group 2). The object of the study was cognitive impairment in patients with systemic lupus erythematosus. To assess the cognitive status of patients, the Montreal Cognitive Assessment Scale was used, a widely used questionnaire that evaluates cognitive functions across multiple domains. The laboratory study included blood tests to identify the type and titer of antinuclear antibodies, lupus anticoagulant, and antiphospholipid antibodies, in particular, anti-cardiolipin antibodies. Results and discussion. It was found that the complaints that patients usually present to describe impaired cognitive functions (such as "memory deterioration", "memory impairment", "decreased attention", "difficulty concentrating", etc.) were among the most common in patients with systemic lupus erythematosus. Thus, complaints of memory impairments were expressed by 37 patients (57.81% CI 45.71-69.91), impaired attention and concentration – 41 patients (64.06% CI 52.31-75.82), and between these complaints a strong correlation was established (r = 0.83; p <0.001). The results of the examination of patients using the Montreal Cognitive Assessment Scale showed that the average indicator among all examined is 25.0 (22.0; 27.5) points in the main group – 24.0 (22.0; 26.0) points, which is statistically significantly less (p <0.001) compared with the control group – 28.0 (27.0; 29.0) points. It was found that among patients who scored less than 26 points on the Montreal Cognitive Assessment Scale, there was a statistically significant decrease in indicators in the domains of memory, attention, and speech (p <0.001). It was found that there is a correlation between the presence of anti-cardiolipin antibodies with CD (determined by the Montreal Cognitive Assessment Scale) (rs = -0.56; p <0.001), the same correlation was found in relation to lupus anticoagulant (rs = -0.56; p <0.001). Conclusion. Cognitive dysfunction is one of the most common neurological manifestations of systemic lupus erythematosus. Among the examined patients, decrease in indicators in the domains of memory, attention and speech is the most often observed. Cognitive dysfunction may be associated with the production of certain classes of autoantibodies: antiphospholipid antibodies (in particular, anti-cardiolipin antibodies) and lupus anticoagulant

Hypercoagulability in patients with indirect carotid cavernous fistulas.

To assess patients with indirect carotid-cavernous fistulas (CCF) for evidence of hypercoagulable state (HS) by combination of comprehensive medical questionnaire and laboratory testing. Patients with confirmed diagnosis of CCF treated between 2003 and 2019 were included and administered a questionnaire screening for HS risk factors and undergone laboratory investigations which included complete blood count (CBC), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibody titres), Factor V Leiden, prothrombin, protein C, protein S, antithrombin III, homocysteine, prothrombin G20210, CALR and JAK2 mutation screening. Participants with abnormal laboratory testing and/or past history of ischemic stroke, atrial fibrillation, cancer or hypercoagulability-associated hereditary disorders were deemed to have HS. Twenty-two patients were enrolled. Seventeen were women and the mean age at diagnosis was 60. Fourteen (64%) had evidence of HS: six on medical history, three with laboratory evidence and five with both. Eight (36%) had current abnormal hypercoagulability markers. One had a diagnosis of Klippel-Trenaunay Syndrome, but no others had evidence of hereditary thrombophilia. Nine were on anti-coagulation initiated after diagnosis of stroke or atrial fibrillation discovered on average 5.5 years after the diagnosis of CCF. A total of 64% percent of patients with previous indirect CCF had evidence of underlying HS indicating that hypercoagulability might play a role in the pathogenesis of CCF. The results support need for comprehensive testing for underlying HS in patients with indirect CCFs to better identify, manage, and prevent further thromboembolic events.

Schizophrenia Genetics and Neuropsychiatric Features in Childhood-onset Systemic Lupus Erythematosus.

We examined the association between schizophrenia genetic susceptibility loci and neuropsychiatric systemic lupus erythematosus (NPSLE) features in childhood-onset SLE (cSLE) participants. Study participants from the Lupus Clinic at the Hospital for Sick Children, Toronto, met ≥ 4 of the American College of Rheumatology and/or SLE International Collaborating Clinics SLE classification criteria and were genotyped using the Illumina Multi-Ethnic Global Array or the Global Screening Array. Ungenotyped single-nucleotide polymorphisms (SNPs) were imputed, and ancestry was genetically inferred. We calculated 2 additive schizophrenia-weighted polygenic risk scores (PRS) using (1) genome-wide significant SNPs (P < 5 × 10-8), and (2) an expanded list of SNPs with significance at P < 0.05. We defined 2 outcomes compared to absence of NPSLE features: (1) any NPSLE feature, and (2) subtypes of NPSLE features (psychosis and nonpsychosis NPSLE). We completed logistic and multinomial regressions, first adjusted for inferred ancestry only and then added for variables significantly associated with NPSLE in our cohort (P < 0.05). We included 513 participants with cSLE. Median age at diagnosis was 13.8 years (IQR 11.2-15.6), 83% were female, and 31% were of European ancestry. An increasing schizophrenia genome-wide association PRS was not associated with NPSLE (OR 1.04, 95% CI 0.87-1.26, P = 0.62), nor with the NPSLE subtypes, psychosis (OR 0.97, 95% CI 0.73-1.29, P = 0.84) and other nonpsychosis NPSLE (OR 1.08, 95% CI 0.88-1.34, P = 0.45), in ancestry-adjusted models. Results were similar for the model including covariates (ancestry, malar rash, oral/nasal ulcers, arthritis, lymphopenia, Coombs-positive hemolytic anemia, lupus anticoagulant, and anticardiolipin antibodies) and for the expanded PRS estimates. We did not observe an association between known risk loci for schizophrenia and NPSLE in a multiethnic cSLE cohort. This work warrants further validation.

A SYSTEMATIC LITERATURE REVIEW OF BUDD-CHIARI SYNDROME IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Antiphospholipid syndrome is associated with multiple and recurrent episodes of arterial and venous thrombosis, thrombocytopenia, spontaneous fetal losses, and high levels of antiphospholipid antibodies. These antibodies can also be present in systemic lupus erythematosus (SLE), and predispose patients with Lupus to a hypercoagulable state. Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction that can lead to hepatic congestion and it is deeply associated with acquired or inherited hypercoagulable states. Therefore, the aim of this study was to conduct a systematic literature review to analyze the association between Budd-Chiari syndrome and SLE. A systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Articles were selected from PubMed/Medline, SciELO and LILACS databases in August 2021 using the search terms [Lupus] OR [SLE] AND [Budd-Chiari syndrome]. The inclusion criterion was limited to observational studies, case reports or case series that reported an association between Budd-Chiari syndrome and SLE. Language was restricted to English, Spanish or Portuguese. Among 76 articles initially identified, 31 were eligible for this review after full texts were read. The vast majority of the studies have linked the antibodies lupus anticoagulant and anticardiolipin as etiological factors of BCS in patients with lupus. One study has reported six cases in which factor V Leiden was strongly related to SLE, suggesting that this mutation should also be investigated in patients with lupus and BCS. Few studies have mentioned isolated deficiency of protein C and/or protein S as common etiologies of BCS in patients with lupus. Studies suggest that Lupus anticoagulant can be sought in patients with idiopathic hepatic venous thrombosis. Possible mechanisms by which antiphospholipid antibodies induce thrombotic events in patients with SLE have been suggested: it can bind to platelet membrane phospholipids and accentuate their adhesion and aggregation ability, it can interfere in the interactions of proteins C and S and impair the formation of the coagulation control complex (activated protein C, protein S and factor V). Budd-Chiari syndrome can be a rare complication in patients with SLE. A methodical search for hepatic vein occlusion in patients with SLE who develop unexplained hepatomegaly should be performed. In addition, screening for lupus anticoagulant and anticardiolipin antibodies should take place to reduce the percentage of apparently idiopathic BCS cases.

Electroencephalographic Findings in a Cohort of Egyptian Systemic Lupus Erythematosus Patients with Neuropsychiatric Manifestations

Abstract Background and Objective Neuropsychiatric manifestations are frequently reported in 75% of Systemic Lupus Erythematosus (SLE) patients and that varied from mild subtle signs: headache or mood disturbance to life threatening conditions: acute confusional state, major fits, stroke or transverse myelitis. Electroencephalography (EEG) was used to determine whether there is a lateralized pattern of electrophysiologic dysfunction in SLE patients or not. So, this study was done to describe EEG findings in a cohort of Egyptian SLE patients with Neuropsychiatric SLE (NPSLE), its possible correlation with any of the disease activity parameters and comparing them to patients with Non-NPSLE. Patients and Methods This case-control study was conducted on 60 SLE patients who fulfilled the 2015 ACR/SLICC Classification Criteria for SLE. They were classified into 2 groups: 30 patients with NPSLE as cases and 30 patients without NPSLE (Non-NPSLE) as controls. All patients were subjected to detailed medical history taking together with full clinical examination and calculations of SLE disease activity using the SLE disease activity index (SLEDAI) score. Laboratory investigations including CBC, ESR, CRP, BUN, creatinine, urine analysis, P/C ratio, C3, C4, Lupus Anticoagulant (LAC) and Anticardiolipin (ACL) antibodies and EEG were done for all patients. MRI brain was done for patients with NPSLE. Results There were 6 neuropsychiatric manifestations in the NPSLE group; the commonest was seizure disorders (43.3%), followed by psychosis (20.0%), cerebrovascular disease (16.7%), acute confusional state (13.3%), headache (10.0%) and lastly demyelinating syndrome (6.7%). SLEDAI score was higher in NPSLE group (Median=16) than nonNPSLE group (Median=4) (P &amp;lt; 0.01). ACL IgM positivity was higher in NPSLE group (P &amp;lt; 0.05). 53.3% of NPSLE group had abnormal MRI brain findings, the most common finding was periventricular white matter lesion (23.3%), followed by infarction (13.3%), subcortical white matter lesion and demyelinating lesion (6.7%). Lastly was sinus thrombosis, cerebral edema and encephalomalacia (3.3% each). 12 patients out of 30 (40.0%) with NPSLE had EEG abnormalities, while all 30 patients with non-NPSLE had no EEG abnormalities. The most common EEG abnormalities in NPSLE group were diffuse slowing (20.0%), followed by generalized epileptiform activity (13.3%), and lastly temporal epileptiform activity (6.7% each). 50% of patients with abnormal EEG had normal MRI. 13 patients out of 30 with NPSLE had seizure disorders (43.3%), 8 of them had abnormal EEG (61.5%). Conclusion Not all patients with NPSLE must have abnormal brain MRI or EEG. EEG is a useful assistant tool in diagnosing and studying the different manifestations of NPSLE especially seizure disorder and acute confusional state, but it cannot be used as a screening test alone for detecting NPSLE and must be supplemented by neuroimaging studies.

A CASE REPORT ON EXTENSIVE ARTERIAL THROMBOSIS AS A COMPLICATION OF COVID-19 INFECTION

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Coronavirus disease (COVID-19) is a global health crisis. It is associated with increased activation of the clotting system leading to thrombotic complications in 5 to 23% of cases[1]. It is known to cause significant venous thromboembolism and few cases with arterial thrombosis with increased risk of life-threatening complications like myocardial infarction, ischemic stroke, splenic infarct, and left ventricular clot have been reported[2]. CASE PRESENTATION: A 70-year-old female with a past medical history of coronary artery disease, Hypertension, COPD, recent COVID-19 (3 weeks ago) not requiring admission to hospital presented to the hospital with bilateral leg and forearm pain. Leg pain was worse with activity. She had feeble peripheral pulses on palpation.She underwent Computed Tomography angiography which showed extensive arterial thrombosis involving the distal abdominal aorta, left common iliac artery, superior mesenteric artery, and also showed an area of wedge-shaped infarction in the spleen. She had a thrombus at the apex of the left ventricle, with incidental 1.3 cm spiculated mass in the left lung. There was no evidence of venous thromboembolism in imaging.She was started on therapeutic anticoagulation with heparin. After multidisciplinary discussion with Hematology, Vascular surgery, and Cardiology, her anticoagulation was changed to Enoxaparin. She was managed medically. Workup including JAK2, beta-2 glycoprotein antibodies, lupus anticoagulant, and anticardiolipin antibodies was negative. DISCUSSION: The exact mechanisms that activate coagulation cascade in SARS-CoV-2 infection are still unknown, but they are found to be associated with increased thrombogenesis. SARS-CoV-2 viral infection can activate the plasmatic clotting system by activating multiple procoagulant pathways. Angiotensin-converting enzymes 2 are normally found on various cells such as lymphocytes, alveolar cells, monocytes/macrophages, and platelets. In SARS-CoV-2 infection, Surface S protein of SARS-CoV-2 binds to its target transmembrane receptor( ACE2 protein) and down-regulates the expression of ACE2 protein. It leads to the accumulation of angiotensin II in the body which interacts with platelets and endothelial cells leading to further promotion of clot formation[3]. This was the likely cause of hypercoagulable state in our patient leading to thrombosis. CONCLUSIONS: An extensive arterial clot can be the initial presentation in COVID-19 patients and can be treated promptly with anticoagulation. Early introduction of prophylactic anticoagulation is necessary to prevent clot formation. REFERENCE #1:.Thromboinflammation and the hypercoagulability of COVID-19. Connors JM, Levy JH J Thromb Haemost.2020 Jul;18(7):1559-1561. REFERENCE #2: Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV, and lessonsfrom the past.Giannis D, Ziogas IA, Gianni P J Clin Virol. 2020 Jun;127():104362. REFERENCE #3: Smith S A, Mutch N J, Baskar D, Rohloff P, Docampo R, Morrissey J H. Polyphosphate modulates bloodcoagulation and fibrinolysis. Proc Natl Acad Sci U S A. 2006;103(04):903–908. DISCLOSURES: No relevant relationships by Sumit Gami, source=Web Response No relevant relationships by Subash Ghimire, source=Web Response No relevant relationships by Sushmita Khadka, source=Web Response No relevant relationships by Shobha Mandal, source=Web Response

THE CLOT THICKENS: DOES THE JOHNSON & JOHNSON COVID-19 VACCINE INCREASE THE RISK OF THROMBUS IN A HYPERCOAGULABLE STATE?

TOPIC: Pulmonary Vascular Disease TYPE: Fellow Case Reports INTRODUCTION: The 2019 coronavirus disease (COVID-19) has hematologic manifestations in addition to respiratory. COVID-19 is associated with a state of hypercoagulability. Evidence shows correlation with degree of hypercoagulability and severity of disease. Patients with severe COVID-19 were reported to have venous and arterial thrombi causing organ dysfunction and death. There was an urgent need for vaccination against SARS-CoV-2. Companies, including Johnson & Johnson (J&J), have released their vaccine. Recently, the Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) reported six cases of cerebral venous sinus thrombosis, which led to a pause in J&J vaccine administration. We present a case of a woman with antiphospholipid syndrome (APS) who developed acute deep venous thrombosis (DVT) after receiving the J&J vaccine while therapeutic with warfarin. CASE PRESENTATION: Ms G is a 54-year-old black woman with history of APS and severe COVID-19 infection. Prior APS panel for lupus anticoagulant antibody (Ab) on initial and repeat testing was positive. Anticardiolipin and beta-2 glycoprotein Ab were negative. Her complication from APS included chronic left lower extremity DVT since 2018. She was compliant with warfarin. She received the J&J vaccine twenty days prior to the present visit. Fifteen days after receiving the vaccine, she developed bilateral lower extremity swelling and calf pain, left worse than right. On exam, vital signs were within normal limits. She had 1+ non-pitting edema and tenderness in her left calf, worse compared to the right. Complete blood count showed platelets 172x10^9/L (ref range: 167-378x10^9/L). INR 3.03, prothrombin time 33 seconds (ref range: 9.8-12.9). COVID-19 IgG titer 8.08 index (S/C) (ref range: 0-1.39). Heparin-induced thrombocytopenia (HIT) screen was negative. Venous doppler ultrasound showed an acute femoral-to-peroneal DVT in the right leg and a chronic femoral DVT in the left leg. Due to recent joint statement by the CDC and FDA advising against heparin in patients with new thrombi after receiving the J&J vaccine due to HIT-like behavior of these thrombi, the patient was treated with rivaroxaban and is currently doing well. DISCUSSION: APS is an autoimmune disease that causes a chronic hypercoagulable state from antiphospholipid antibodies, which make patients prone to develop thrombi. Correlation has been shown between severity of COVID-19 and degree of inflammation. Severe illness leads to generation of excessive inflammatory cytokines and chemokines, endothelial dysfunction, and a host of other pathways to increase risk of thrombosis. CONCLUSIONS: With the recent discovery of the J&J vaccine potentially creating a HIT-like state, the risk of developing DVT in a patient with known hypercoagulable state (such as APS and severe COVID-19) appears elevated. Due to this finding, we recommend caution in giving the J&J vaccine. REFERENCE #1: Abou-Ismail, Mouhamed Yazan et al. "The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management.” Thrombosis research vol. 194 (2020): 101-115. doi:10.1016/j.thromres.2020.06.029 DISCLOSURES: No relevant relationships by David Rutenberg, source=Web Response No relevant relationships by Yumeng Zhang, source=Web Response

Adrenal Insufficiency Revealing a Bilateral Adrenal Hemorrhage-Adrenal Infarction Related to Antiphospholipid Syndrome

In June 2020, a 54-year-old female presented with severe fatigue that had been worsening over the past few weeks. She had a history of primary triple positive (lupus anticoagulant, anticardiolipin and anti-β2GP1 antibodies) antiphospholipid syndrome (APS) revealed 19 years ago by a venous thromboembolism, and had been long-term treated with warfarin.

Indication and outcome of lupus anticoagulant and antiphospholipid antibodies testing in routine clinical practice.

ObjectivesLupus anticoagulans (LACs) and aPLs, both further summarized as aPL, are frequently assessed in routine daily clinical practice in diagnostic workups for suspected autoimmune diseases or to test for underlying risk factors in patients with thrombosis or obstetric complications. The aim of this study was to determine the prevalence of aPL positivity in patients with an indication for aPL testing in routine clinical practice.MethodsIn this retrospective single-centre study, indication for aPL testing, aPL test results and clinical data were collected for patients tested between June 2015 and April 2018.ResultsDuring the study period, 16 847 single aPL tests were performed in 2139 patients. In 212 patients one or more positive aPL test was found, confirmed in 43.9% with a second positive test. Indications for aPL testing were diagnostic workup/follow-up of autoimmune diseases (33.6%), thrombosis (21.4%) and obstetric complications (28%). Seventy-four patients (3.5% of all patients) fulfilled the criteria of APS, of whom 51% were newly diagnosed. Second positive aPL titres and titres of APS patients were significantly higher compared with positive aPL titres at the first measurement (P < 0.05). Patients with indications of arterial thrombosis and diagnostic workup/follow-up of autoimmune diseases had significantly higher levels of aCL IgG and anti-β2 glycoprotein I (β2GPI) IgG compared with patients with other indications.ConclusionThe prevalence of one or more positive aPL test was 9.9% and APS was diagnosed in 3.5% of the patients. Patients with arterial thrombosis had significantly higher anti-β2GPI IgG and aCL IgG, which should be confirmed in future studies.

Portal Vein Thrombosis in Adult Omani Patients-a Retrospective Study

Objective:To study the occurrence of portal vein thrombosis (PVT) in Omani patients.Methods:This is a Retrospective analysis performed on patients diagnosed with PVT which was confirmed by radiological imaging from two tertiary hospitals over a 10 year period.Results:A total of 39 PVT patients were enrolled in this study, with 15(38.5%) showing cirrhosis of liver whereas, 24(61.5%) were classified as non-cirrhotic. Non cirrhotic PVT patients were further subdivided as acute or chronic; 15 (62.5%) had an acute non-cirrhotic PVT whereas the remaining 9 (37.5%) had chronic PVT. PVT were more common in males i.e. 25(64.1%) in contrast to 14(35.9%) females (p=0.02, Chi Square test). Abdominal pain in 64%, nausea in 31.1%, and fever in 20%, gastrointestinal bleeding (hematemesis or melena) 14%, and weight loss in 10%. Demonstrable ascites and splenomegaly were seen in 28% and 38% respectively. Amongst the 18 patients who were tested (majority of non-cirrhotic PVT patients) for an underlying thrombophilia, 4/10(40%) had protein C deficiency, 5/10(50%) had protein S deficiency, and 2/6(33.3%) had antithrombin deficiency. Antiphopholipid antibodies (anti-cardiolipin, lupus anticoagulant and anti-beta2 glycoprotein antibodies) were found in 4/16 (25%) patients, V617F JAK mutation was positive in 3/15 (20%) of patients. Factor V Leiden mutation, prothrombin G20210A mutation, hyperhomocystinemia, and paroxysmal nocturnal hemoglobinuria PNH (tested 7, 4, 2 and 1 patients, respectively) were all negative. Local factors were seen 8 (20.5%) patients of PVT; six had cholangitis and one patient had cholecystitis with and liver abscess. Cirrhosis of liver was the only risk factor in 15(38.5%) patients. However, 8 (53%) cirrhosis patients had hepatocellular carcinoma which is considered as risk for PVT. 13 (33.3%) patients in this study had an underlying malignancy. 8 cases were HCC all noted in cirrhosis patients. Three patients had Cholangiocarcinoma, and one patient had recto-sigmoid carcinoma, and one patient had carcinoma of head pancreas. 18(46.2%) PVT patients received immediate anticoagulation with heparin followed by warfarin, 16 patients (66.7%) were non-cirrhotic PVT. Thrombectomy was done for one patient. 7 (17.9%) patients with acute non-cirrhotic PVT had full recovery and 6(15.4%) of total PVT patients died. 26 (66.7%) patients had no detail follow up as they were lost or their care had been transferred to local hospital but we concluded their condition was stableConclusions:This is the first study reflects the real life practice of portal vein thrombosis which occur due to inherited and acquired prothrombotic conditions and happen as a complications of local and malignant causes. We have studied the prevalence, clinical presentation, treatment given and outcomes. Causative factors were found in 36 patients (92.3%) of the present cohort, etiological screening seems worthwhile in every case with PVT. Significant number of PVT found to have underlying malignancies. Thrombophilia screening may not be cost-effective. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Thrombotic Microangiopathy Associated with Pregnancy: Various Outcomes in Different Disorders

Thrombotic microangiopathy (TMA) associated with pregnancy can be fulminant and fatal disorder. Pregnancy outcomes and survival of patients depend on the precise diagnose and appropriate treatment approaches. When a pregnant or postpartum woman presents with sudden and severe microangiopathic hemolytic anemia and thrombocytopenia, conditions that require urgent care must be considered: preeclampsia with severe features (PE/HELLP syndrome), thrombotic thrombocytopenic purpura (TTP), catastrophic antiphospholipid syndrome (CAPS), complement-mediated thrombotic microangiopathy (atypical hemolytic-uremic syndrome, aHUS). The distinction among these syndromes is often unclear because they share multiple clinical features. Overlap between PE/HELLP and TTP, CAPS and aHUS is also apparent from the fact that pregnancy can be a trigger for TMA before and after delivery. These disorders, especially PE imitators, are very important as the causes of maternal and fetal death.Since 2010 we observed 104 patients with pregnancy-associated TMA. Women's age at the time of pregnancy was 32,04±0,83 years old, delivery performed at 34,89±0,74 gestation weeks. The reasons of TMA defined as PE/HELLP in 71 (68,3%) women (main signs: blood pressure more than 160 mm systolic or 110 mm diastolic, platelet count <100 x 10⁹/l and/or abnormal liver function, renal insufficiency, pulmonary edema, cerebral symptoms, eclampsia - generalized seizures, peripartum cardiomyopathy), aHUS- 32 (30,8%), TTP-1 (0,9%) (ADAMTS13 level less than 10%). All of them required preterm operative delivery. Therapeutic plasma exchange (1-9 procedures) performed in 88 (84,6%). ADAMTS13 level assessed before plasma therapy (45-84%, excluding the TTP case), as well as lupus anticoagulant (LA) and antiphospholipid antibodies (APLA) (negative in all patients). In cases of aHUS we use eculizumab in 14/32 (43,75%), but a full course with subsequent successful discontinuation of the drug was received only by one patient. 13/14 patients received 1 to 6 injections of eculizumab.Overall mortality rate was 10 (9,6%), It is noteworthy that only patients with aHUS died- 10/32 (31,25%). Antenatal fetal death occured in 16 (15,4%), among them 12/32 (37,5%) were diagnosed with aHUS. The condition of patients with PE/HELLP improved on 1-3 days after delivery in all cases. In aHUS patients, life-threatening complications persisted and even progressed after delivery: massive uterine bleeding required hysterectomy occurred in 23,2%, acute kidney injury registered in 100% patients, neurological symptoms had 61%, respiratory distress syndrome- 55%, dilated cardiomyopathy- 16,7%. 61,3% required hemodialysis, 51,8%- respiratory care. All of patients who died had 2 “waves” of TMA: first wave has damaged 2-5 organs without any proved infections, but treated with antibacterial combination. Second TMA wave was fatal due to superimposed septic disorders, resistant to antibiotic therapy. Patients on eculizumab treatment had more severe disease at debut with shorter history of aHUS and responded well to eculizumab. Survival of aHUS patients on eculizumab treatment was 71,4%, without it - 64,7%.Therapeutic approaches in TMA associated with pregnancy are different and survival of patients depends on a timely diagnosis. Clinical vigilance requires for early detection of TMA. After that is necessary as soon as possible investigate the ADAMTS13 level to avoid TTP, and LA and APLA to avoid CAPS. Plasma exchange may be first urgent step of treatment in all cases of TMA, but after clarifying the diagnosis therapy should be adjusted. Timely diagnosis and effective approaches including early prescribed targeted therapy in aHUS patients can improve the survival rate and pregnancy outcomes. DisclosuresNo relevant conflicts of interest to declare.

Anti-phospholipid antibodies in women presenting with preterm delivery because of preeclampsia or placental insufficiency

Objective:To assess the proportion of women presenting with preterm delivery because of preeclampsia or placental insufficiency (PREPI) with anti-phospholipid antibodies (APLA).Material and Methods:This was a prospective cohort study conducted at an obstetrics and gynecology department. Women, aged 20-40 years, with preeclampsia who delivered before 34 weeks were cases while those who delivered before 34 weeks but did not have preeclampsia acted as controls. Both groups had APLA measured at diagnosis and 12-weeks postnatally. Anti-phospholipid antibody syndrome (APS) was diagnosed according to Sapporo’s criteria.Results:The study included 98 cases and 106 controls. Both cases and controls were similar in terms of age, gestational age and parity. The frequency of APS positivity was 17.3% in cases but only 3.8% in controls (p=0.001). Cases were more likely to be of Baloch ethnicity (34.7% vs. 11.3%, p=0.001), have a history of miscarriage (25.5% vs. 13.2%, p=0.026), use aspirin (p<0.001) or low molecular weight heparin (p<0.001), and be obese (p<0.001) than controls. Cases were more likely to have lupus anticoagulant antibodies (82.4% vs. 75%).Conclusion:Our study confirms a high prevalence of APLA in women who have preterm delivery due to PREPI. An opportunity to screen these women should be made, so that proper counselling can be given and future pregnancies can be managed in an appropriate and timely manner.

Associations with thrombosis are stronger for antiphosphatidylserine/prothrombin antibodies than for the Sydney criteria antiphospholipid antibody tests in SLE.

ObjectivesAntiphosphatidylserine/prothrombin complex antibodies (aPS/PT) are risk factors for thrombosis, yet further validation of their clinical relevance in different ethnic groups is required. We investigated the performance of aPS/PT of IgA/G/M isotypes among Sudanese and Swedish systemic lupus erythematosus (SLE) patients.MethodsConsecutive SLE patients/matched controls from Sudan (n = 91/102) and Sweden (n = 332/163) were included. All patients fulfilled the 1982 ACR SLE classification criteria. IgA/G/M of aPS/PT, anti-cardiolipin and anti-β2glycoprotein I (anti-β2GPI) were tested in both cohorts, and lupus anticoagulant (LA) also in the Swedish cohort. Clinical antiphospholipid syndrome-related events and atherosclerosis, measured as carotid plaques were assessed for associations. Univariate and multivariate analyses adjusting for cardiovascular risk factors were performed.ResultsSudanese SLE patients had higher levels of IgM aPS/PT, but using national cut-offs, the frequency of positivity was similar to Swedish patients for all isotypes. Among Swedish patients, all isotypes of aPS/PT associated with venous thromboembolism (VTE), while only IgA aPS/PT associated with arterial thrombosis (AT). aPS/PT antibodies associated strongly with LA and they were, independently, the best predictor for VTE. Double positivity for aPS/PT and anti-β2GPI associated with higher VTE risk than the conventional triple positivity. Carotid plaques did not associate with any antiphospholipid antibody.ConclusionsIgA aPS/PT associated with AT, and the association of IgG/M aPS/PT with VTE outperforms LA and criteria antiphospholipid antibodies in Swedish SLE patients. Furthermore, double positivity for aPS/PT and anti-β2GPI performed better than conventional triple positivity. Future studies need to address if aPS/PT can replace LA, as this would simplify clinical procedures.

Double positivity of anti-β2-glycoprotein I domain I and anti-phosphatidylserine/prothrombin antibodies enhances both thrombosis and positivity of anti-ADAMTS13 antibody.

Although a few antiphospholipid syndrome (APS) occurs with acquired thrombotic thrombocytopenic purpura (TTP), the relationship between antiphospholipid antibodies (aPL) and anti-ADAMTS13 (anti-a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) antibody remains uncertain. We investigated the relationship between high-risk thrombotic aPL and anti-ADAMTS13 antibody. Two hundred and thirty-seven patients with positive lupus anticoagulant and/or anticardiolipin antibody were included. Anti-β2GPI (anti-β2-glycoprotein I), anti-β2GPIdI (anti-β2-glycoprotein I domain I), anti-PS/PT (anti-phosphatidylserine and prothrombin), ADAMTS13 activity, and anti-ADAMTS13 antibody were measured. Double positivity of anti-β2GPI and anti-PS/PT increased thrombotic risk more than three-fold and showed increased positivity of anti-ADAMTS13 antibody in comparison with the double negative group. Double positivity of anti-β2GPIdI and anti-PS/PT presented both effects even more. In the linear regression analysis, double positivity of anti-β2GPI and anti-PS/PT independently affected the anti-ADAMTS13 antibody level (β = 1.982, P = 0.042). Our results revealed that double positivity of anti-β2GPI or anti-β2GPIdI and anti-PS/PT increased not only thrombotic risk but also the positivity of anti-ADAMTS13 antibody, especially indicating anti-β2GPIdI showed a higher synergistic effect with anti-PS/PT. We suggest a possible association of anti-ADAMTS13 antibody with a high thrombotic risk of APS. Double positivity of anti-β2GPI (anti-β2-glycoprotein I) and anti-PS/PT (anti-phosphatidylserine and prothrombin) antibodies enhanced not only thrombotic risk but also positivity of anti-ADAMTS13 (anti-a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) antibody. Furthermore, double positivity of anti-β2GPIdI (anti-β2-glycoprotein I domain I) combined with anti-PS/PT even more elevated both thrombosis and positivity of anti-ADAMTS13 antibody. Double positivity of β2GPI and anti-PS/PT was found as an independently significant contributing factor to anti-ADAMTS13 antibody level. We suggest the association between anti-ADAMTS13 antibody and the pathophysiology of antiphospholipid syndrome, which should be further evaluated.

Comparative analysis of prothrombotic activity in patients with myocardial infarction with and without obstructive coronary artery disease

Aim.To compare parameters of prothrombotic activity in patients with myocardial infarction (MI) with obstructive (MICAD) and non-obstructive coronary artery disease (MINOCA).Material and methods.The study included 40 patients with MI, which were divided into experimental (n=19) and control group (n=21). Three patients (15,7%) with acute myocarditis were excluded from the analysis. Hemostasiological and hematological blood tests were studied upon admission, on the 2nd, 4th, 7th days from hospitalization. Blood samples for protein C, antithrombin, von Willebrand factor (VWF), plasminogen, homocysteine were performed on 4th±1 day from hospitalization. To determine the IgG/IgM anticardiolipin (aCL) and anti-beta 2 glycoprotein I (β2-GPI) antibodies in order to diagnose antiphospholipid syndrome (APS), the ORGENTEC Anti- β2-Glycoprotein I IgG/IgM ELISA enzyme immunoassay was used. Blood tests for lupus anticoagulant were performed using an ACL-Top 700 analyzer (Werfen) with HemosIL SynthASil dRVVT screen/dRVVT confirm and with a SCT screen/SCT confirm quartz activator.Results.According to the data obtained, it was found that patients with MINOCA had a significantly lower level of plasminogen (p=0,007), as well as a higher level of homocysteine (p=0,03). For such indicators as protein C, antithrombin, ejection fraction, differences between the groups were not revealed (p&lt;0,05). At the same time, protein C deficiency was detected in 2 (12,5%) patients with MINOCA and in 1 (5,3%) patient in the control group. Antithrombin deficiency was detected in 2 (12,5%) patients with MINOCA and in 2 (9,5%) patients with MICAD. An increase in the level of ejection fraction was found in 6 (37,5%) patients in the study group and in 7 (33,3%) patients in the control group. There were no differences in levels of lupus anticoagulant, aCL and β2-GPI antibodies (p&gt;0,05). There was a higher platelet count in patients with MINOCA on the 2ndand 4thdays of acute MI (p=0,46 and p=0,01, respectively). However, the hemoglobin level in patients with MINOCA was significantly lower on admission, 4thand 7thday of MI (p=0,02, p=0,03 and p=0,04, respectively).Conclusion.According to the study results, in patients with MINOCA and MICAD, differences in blood thrombotic activity were revealed. A higher level of homocysteine and a lower level of plasminogen were determined in patients with MINOCA. For such parameters as protein C, antithrombin, VWF, aCL and β2-GPI antibodies, differences between the groups were not determined. According to laboratory data, patients with MINOCA showed higher platelet count, but lower levels of hemoglobin and hematocrit in the early postinfarction period.

Catastrophic antiphospholipid syndrome presented as ruptured papillary muscle during puerperium in a patient with systemic lupus erythematosus

Catastrophic antiphospholipid syndrome (CAPS) is a rare and serious phenomenon that requires prompt recognition and treatment. The authors present the case of a puerperal woman with systemic lupus erythematosus (SLE) admitted to the emergency room with headache, blurred vision, thoracic pain, and purpuric lesions on both ears. Echocardiogram revealed global decrease in left ventricular function while cardiac and inflammatory markers were elevated. Three days after admission she developed cardiogenic shock due to rupture of mitral papillary muscle which required emergent cardiac surgery, with replacement of the mitral valve; treatment with anticoagulation, high-dose glucocorticoids, and intravenous immunoglobulins were initiated. Cardiac and brain MRI revealed signs of ischemic lesions in both organs. Histopathology analysis of the placenta and papillary muscle showed signs of ischemia secondary to microvascular thrombosis. Based on the clinical demonstration of thrombosis in three organs, and the presence of lupus anticoagulant antibodies, a diagnosis of probable CAPS was established. This case highlights the importance of a high level of suspicion of CAPS, particularly in patients with risk factors, and the value of immediate adequate treatment. Moreover, the rupture of a papillary muscle with histologically consistent signs of antiphospholipid syndrome expands the spectrum of involvement of this disease and should be considered as a rare but life-threatening possibility in patients with myocardial injury.

DOAC‐Stop in lupus anticoagulant testing: Direct oral anticoagulant interference removed in most samples

BackgroundThe use of direct oral anticoagulants (DOACs) is a convenient therapeutic option for patients at risk of thrombosis. DOACs interfere with clot‐based testing for the identification of lupus anticoagulant antibodies (LACs) in patients with antiphospholipid syndrome (APS), a common cause of acquired thrombotic disease. ObjectivesTo evaluate a commercially available reagent DOAC‐Stop for the removal of DOAC interference encountered in LAC testing. Patients/MethodsWe collected a cohort of 73 test samples from patients on DOAC therapy identified at a large institutional coagulation laboratory from March to December 2019, along with samples from 40 LAC positive and negative control patients not on therapy. Samples were treated with DOAC‐Stop and tested for anti‐Xa activity and thrombin time for the removal of apixaban, rivaroxaban, argatroban, and dabigatran activity from patient samples. Treated and untreated samples were tested using the activated partial thromboplastin time, silica clotting time, and dilute Russell’s viper venom time to evaluate the reliability and utility of DOAC‐Stop. ResultsDOAC‐Stop markedly reduced DOAC interference from test samples (P < .05). DOAC‐Stop had no effect on LAC testing in the absence of DOAC therapy, permitting the identification of all LAC positive and negative controls. DOAC‐Stop removed false positives and false negatives resulting from DOAC interference and allows the identification of patients meeting criteria for the diagnosis of APS by LAC testing, as well as the detection of patients on rivaroxaban who are triple positive for APS. ConclusionsDOAC‐Stop is an effective adjunct for the clinical laboratory faced with DOAC interference in LAC testing.

Cutaneous ulcer resembling pyoderma gangrenosum in a patient with antiphospholipid syndrome

The present case presented with abrupt appearance of rapidly enlarging ulcerations over his legs that resembled PG with no atypical histopathological findings such as dermal infiltrate showing numerous neutrophils. The pathogenesis of PG-like cutaneous ulcer in the present case could be related to some abnormalities in the coagulation/fibrinolysis pathways and an abnormal immune condition that involves antiphospholipid antibodies. Cutaneous manifestations of antiphospholipid syndrome (APS) vary from livedo reticularis to cutaneous necrosis, with the appearance of associate cutaneous ulcers with sharp margins, typically over the legs.1 Classic pyoderma gangrenosum (PG), also known as ulcerative type, is characterized by rapidly progressive ulcers with violaceous indurated borders. The diagnosis remains challenging due to the lack of a gold standard diagnostic test.2 A 39-year-old man presented with a reddish necrotic and erosive lesion and cutaneous ulcers all over his legs that had appeared one month earlier. Physical examination revealed various sized necrotic ulcers include papules, vesicles, and pustules over both his legs, along with dense brown pigmentation (Figure 1A). Microscopic findings showed dermal fibrosis, intravascular hyalinized material of fibrin-containing thrombi with cell inflammation and capillary dilatation in the upper to middle dermis (Figure 1B). Antibiotic treatment alone was insufficient, and the lesion continued to gradually increase in size. He had abrupt appearance of rapidly enlarging and hemorrhagic ulcerations on his right leg. Cutaneous ulcers in the lateral femoral region of the right leg were found with undermined, overhanging, dusky purple edges, and surrounding induration and erythema (Figure 1C). Histopathological examination revealed a severe dermal infiltrate comprised of neutrophils and lymphocytic cells and capillary dilatation and thrombi in the dermis to subcutaneous fat tissue (Figure 1D). The clinical features of the cutaneous ulcer suggested a diagnosis of PG. In contrast, histopathological findings showed thrombi and vascular damage in the dermal capillary vessels with neutrophilic infiltrate. Laboratory examinations showed increased anti-cardiolipin antibodies (112 U/mL; normal range, <9 U/mL) and anti-β2 glycoprotein I antibodies (>125 U/mL; normal range 0-3.4 U/mL), and the lupus anticoagulant was detected. Abdominal contrast-enhanced computed tomography revealed thrombi, contraction, and occlusion of the abdominal aorta and iliac arteries (Figure 1E). Ultrasonography of his veins showed thrombi in the femoral veins, popliteal veins, and flounder veins. Based on these findings, he was diagnosed with APS. He responded to anticoagulation treatment with warfarin alone and his cutaneous ulcer that had initially been diagnosed as PG improved. Classic ulcerative PG is characterized by a peripheral erythematous inflammatory halo and the edges are erythematous, raised, and sometimes necrotic, with an undermining border, the size of which determines how rapidly the ulcer edge will evolve.2, 3 The present case presented with abrupt appearance of rapidly enlarging ulcerations over his legs that resembled PG with no atypical histopathological findings such as dermal infiltrate showing numerous neutrophils. There have been other reports of PG-like ulcers in patients with APS.3, 4 Recent studies have also suggested that lupus anticoagulant and anti-cardiolipin antibodies could be an important risk factor for venous ulcers of the leg.5 These antiphospholipid antibodies potentially cause repeated thrombi which lead to chronic damage of the skin and eventually to poorly healing venous ulcers over the long term. We propose that the pathogenesis of PG-like cutaneous ulcer in the present case could be related to some abnormalities in the coagulation/fibrinolysis pathways and an abnormal immune condition that involves antiphospholipid antibodies. The authors declares no conflict of interest. Approval of the research protocol and Informed Consent were performed by Tohoku Medical and Pharmaceutical University, Sendai, Japan. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A