Catastrophic antiphospholipid syndrome: challenging case and importance of multidisciplinary evaluation and management.

Our case depicts a challenging diagnosis of catastrophic antiphospholipid syndrome in a young patient with a heterogenous presentation with extensive clinical course, a wide range of investigations, including multimodality imaging, and multidisciplinary expertise, to initiate prompt treatment addressing multiorgan thrombotic injury.

Complement Biosensors Identify a Classical Pathway Stimulus in Complement-Mediated Hemolytic Uremic Syndrome.

Unlabelled: Complement-mediated hemolytic uremic syndrome (CM-HUS) is a thrombotic microangiopathy characterized by germline variants or acquired antibodies to complement proteins and regulators. Building upon our prior experience with the modified Ham (mHam) assay for ex vivo diagnosis of complementopathies, we have developed an array of cell-based complement "biosensors'' by selective removal of complement regulatory proteins (CD55 and CD59, CD46, or a combination thereof) in an autonomously bioluminescent HEK293 cell line. These biosensors can be used as a sensitive method for diagnosing CM-HUS and monitoring therapeutic complement blockade.

A machine learning approach to predict mortality due to immune-mediated thrombotic thrombocytopenic purpura.

Background: Mortality due to immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains significant. Predicting mortality risk may potentially help individualize treatment. The French Thrombotic Microangiopathy (TMA) Reference Score has not been externally validated in the United States.

The 2022 review of the 2019 American Society of Hematology guidelines on immune thrombocytopenia.

The 2019 American Society of Hematology (ASH) guidelines for immune thrombocytopenia (ITP) included recommendations on the management of adults (recommendations 1-9) and children (recommendations 10-21) with primary ITP . We describe here the results of a review of the 2019 guidelines by a working group of experts requested by ASH to inform decision-making about the need for and timing of a guideline revision. An updated Medline and Embase search applied the same search terms as in the 2019 ASH guidelines, limited to systematic reviews and clinical trials, from May 2017 to July 2022.

How to diagnose and manage antiphospholipid syndrome.

Antiphospholipid antibodies (aPL) are autoimmune antibodies directed toward phospholipids or phospholipid-protein complexes, particularly those containing β2-glycoprotein I (β2GPI). Persistently positive aPL accompanied by arterial or venous thrombosis, or recurrent pregnancy loss, constitutes the antiphospholipid syndrome (APS). Several types of aPL with different specificities have been defined and may be detected in the clinical lab, including lupus anticoagulants (detected using clotting assays) and anticardiolipin, anti-β2GPI and anti-prothrombin/phosphatidylserine antibodies (detected by ELISA); each of the last 3 aPL may be either IgG, IgM, or IgA, though IgA antibodies are not included in criteria for APS.

Factor XII promotes the thromboinflammatory response in a rat model of venoarterial extracorporeal membrane oxygenation.

Background: Factor XII (FXII) is a multifunctional protease capable of activating thrombotic and inflammatory pathways. FXII has been linked to thrombosis in extracorporeal membrane oxygenation (ECMO), but the role of FXII in ECMO-induced inflammatory complications has not been studied. We used novel gene-targeted FXII- deficient rats to evaluate the role of FXII in ECMO-induced thromboinflammation.

Protection of β2GPI Deficient Mice from Thrombosis Reflects a Defect in PAR3-facilitated Platelet Activation.

Background: Antibodies to β2-glycoprotein I (β2GPI) cause thrombosis in antiphospholipid syndrome, however the role of β2GPI itself in regulation of coagulation pathways is not well understood.

Methods: We developed β2GPI-deficient mice by deleting exon 2 and 3 of using CRISPR/Cas9 and compared the propensity of wild-type (WT) and mice to develop thrombosis using rose bengal and FeCl -induced carotid thrombosis, laser-induced cremaster arteriolar injury, and inferior vena cava (IVC) stasis models. We also compared tail bleeding times and assessed platelet activation in WT and mice in the absence and presence of exogenous β2GPI.

LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer.

Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success of this therapy in the treatment of HR repair deficient cancers has not translated to HR-proficient cancers. Our studies identify the novel role of non-receptor lymphocyte-specific protein tyrosine kinase (LCK) in the regulation of HR repair in endometrioid epithelial ovarian cancer (eEOC) model.

A Post-Pandemic Enigma: The Cardiovascular Impact of Post-Acute Sequelae of SARS-CoV-2.

COVID-19 has become the first modern-day pandemic of historic proportion, affecting >600 million individuals worldwide and causing >6.5 million deaths. While acute infection has had devastating consequences, postacute sequelae of SARS-CoV-2 infection appears to be a pandemic of its own, impacting up to one-third of survivors and often causing symptoms suggestive of cardiovascular phenomena.

C1 inhibitor deficiency enhances contact pathway-mediated activation of coagulation and venous thrombosis.

C1 inhibitor (C1INH) is a multifunctional serine protease inhibitor that functions as a major negative regulator of several biological pathways, including the contact pathway of blood coagulation. In humans, congenital C1INH deficiency results in a rare episodic bradykinin-mediated swelling disorder called hereditary angioedema (HAE). Patients with C1INH deficiency-associated HAE (C1INH-HAE) have increased circulating markers of activation of coagulation.

Anti-HK antibody inhibits the plasma contact system by blocking prekallikrein and factor XI activation in vivo.

A dysregulated plasma contact system is involved in various pathological conditions, such as hereditary angioedema, Alzheimer disease, and sepsis. We previously showed that the 3E8 anti-high molecular weight kininogen (anti-HK) antibody blocks HK cleavage and bradykinin generation in human plasma ex vivo. Here, we show that 3E8 prevented not only HK cleavage but also factor XI (FXI) and prekallikrein (PK) activation by blocking their binding to HK in mouse plasma in vivo.

Emerging Therapies in Antiphospholipid Syndrome.

The antiphospholipid syndrome (APS) is the most common cause of acquired immune-mediated thrombophilia. This syndrome is broadly defined by the presence of arterial or venous thrombosis, or pregnancy morbidity, in the presence of high levels of antiphospholipid antibodies. Despite recognition of this disorder more than 50 years ago, a fundamental unifying pathogenesis has not been determined.

Old is new again: emergence of thromboembolic complications in cancer patients on immunotherapy.

Cancer immunotherapy has emerged as one of the most important new treatments for cancer in many years, moving rapidly to front-line therapy for several cancers. Cancer immunotherapy is based on treatment with immune checkpoint inhibitors (ICI), which are monoclonal antibodies directed toward immunoregulatory proteins including PD-1, PD-L1 and CTLA-4. ICI inhibit interactions between these proteins and their ligands, disabling physiologic immune regulatory networks and enhancing anti-tumor immunity.

Thromboembolism in Patients with Metastatic Urothelial Cancer Treated with Immune Checkpoint Inhibitors.

Background: Immunotherapy has become one of the mainstays for metastatic urothelial carcinoma treatment. Whether immune checkpoint inhibitor therapy increases thromboembolism (TE) risk is unknown.

Objective: We investigated the incidence of arterial thromboembolism (ATE) and venous thromboembolism (VTE) events and its associated outcomes in patients with metastatic urothelial cancer treated with immune checkpoint inhibitors.

Development and performance of a hereditary hemorrhagic telangiectasia-specific quality-of-life instrument.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by arteriovenous malformations and telangiectasia, with primary clinical manifestations of epistaxis and gastrointestinal bleeding and resultant anemia. HHT negatively affects health-related quality of life (HR-QoL); however, existing tools to measure HR-QoL are not HHT specific. Our objective was to develop an HHT-specific HR-QoL (HHT-QoL) instrument and evaluate its performance in a cross-sectional survey of individuals with HHT.