Priapism, hemoglobin desaturation, and red blood cell adhesion in men with sickle cell anemia.

Priapism is a serious, but episodic, complication of sickle cell disease (SCD). We had previously reported that subjects with SCD had variable red blood cell (RBC) adhesion to the immobilized sub-endothelial protein laminin (LN). We examined adhesion to LN in a microfluidic device, of RBCs from men with homozygous sickle cell anemia. Adhesion under hypoxic, but not ambient, conditions was greater in men with a history of priapism, with median adhesion of 529 RBCs per 32 mm2/unit area (range 5-5248) rising to 3268 RBCs per 32 mm2/unit area (range 49-18,368, P = 0.004), under ambient and hypoxic conditions, respectively (n = 14). This was not seen in RBCs from men without a history of priapism (median 402 (range 14-785) and 122 (range 31-4112) RBCs per 32 mm2/unit area, ambient and hypoxic conditions, respectively (P = N.S., N = 12)). We also observed an association between hypoxia-enhanced RBC adhesion in vitro and a history of hemoglobin desaturation in vivo independent of priapism. Prolonged Hb desaturation may increase sickle polymer formation and RBC damage, resulting in enhanced RBC adhesion, hemolysis, and endothelial dysfunction. The identification of distinct RBC phenotypes could prompt clinical evaluation for suitability for novel or under-used therapies, like oxygen.

An epidemiologic study comparing cancer- and noncancer-associated venous thromboembolism in a racially diverse Southeastern United States county.

Background: Cancer-associated venous thromboembolism (CA-VTE) represents a major cause of morbidity and mortality in patients with cancer. Despite poor outcomes, there is an ongoing knowledge gap in epidemiologic data related to this association. Objectives: To compare venous thromboembolism (VTE) characteristics, risk factors, and outcomes between patients with and without active cancer in a racially diverse population. Methods: Our surveillance project occurred at the 3 hospitals in Durham County, North Carolina, from April 2012 through March 2014. Electronic and manual methods were used to identify unique Durham County residents with VTE. Results: We identified 987 patients with VTE during the surveillance period. Of these, 189 patients had active cancer at the time of their VTE event. Patients with CA-VTE were older (median age: 69 years vs 60 years, P < .0001) and had a lower body mass index (median body mass index: 26.0 kg/m2 vs 28.4 kg/m2, P = .0001) than noncancer patients. The most common cancers in our cohort were gastrointestinal, breast, genitourinary, and lung. The proportion of VTE cases with pulmonary embolism (PE) was greater in the cancer cohort compared with that in the noncancer cohort (58.2% vs 44.0%, P = .0004). Overall survival was lower in the CA-VTE group than in patients without cancer (P < .0001). Black patients with CA-VTE had lower proportion of PE (52.3% vs 67.1%, P = .05) but had decreased survival (P < .0003) in comparison with White patients. Conclusion: Future studies may be needed to continue to evaluate local and national VTE data to improve VTE prevention strategies and CA-VTE outcomes.

Surprise diagnosis of acquired von Willebrand syndrome in a patient previously thought to have type III von Willebrand disease: evaluation and periprocedural management.

Acquired von Willebrand syndrome (AVWS) is a rare disorder that is characterised by an acquired deficiency of von Willebrand factor. AVWS was suspected in a patient with type III von Willebrand disease (VWD) who did not respond to factor replacement therapy. Given the crucial implications for management, we describe this patient's clinical presentation, diagnosis and periprocedural management. To facilitate pericardiocentesis, periprocedural management included steroids, intravenous immunoglobulin and factor replacement therapy. In other patients with suspected immune-mediated AVWS, a similar approach may be effective. This case also highlights the importance of distinguishing AVWS from inherited VWD.

Thrombotic microangiopathies: An illustrated review.

The thrombotic microangiopathies (TMAs) are a heterogenous group of disorders with distinct pathophysiologies that cause occlusive microvascular or macrovascular thrombosis, and are characterized by microangiopathic hemolytic anemia, thrombocytopenia, and/or end-organ ischemia. TMAs are associated with significant morbidity and mortality, and data on the management of certain TMAs are often lacking. The nomenclature, classification, and management of various TMAs is constantly evolving as we learn more about these rare syndromes. Thorough clinical and laboratory evaluation is essential to distinguish various TMAs and arrive at an accurate diagnosis, which is key for appropriate management. In this illustrated review, we focus on thrombotic thrombocytopenic purpura (TTP), Shiga toxin-associated hemolytic uremic syndrome, complement-mediated hemolytic uremic syndrome, hematopoietic cell transplant-associated TMA, and drug-induced TMA, and describe their incidence, pathophysiology, diagnosis, and management. We also highlight emerging complement-directed therapies under investigation for the management of complement-mediated TMAs.

Thrombopoietin receptor agonists for marrow failure: A concise clinical review.

Bone marrow failure is characterized by a disruption of hematopoietic stem cell (HSC) homeostasis and function, which causes decreased blood counts. Germline and somatic mutations within HSCs and immune dysregulation contribute to the pathogenesis of marrow failure. Allogeneic HSC transplant is a potentially curative therapy for marrow failure, although not all patients are candidates for this procedure. Immune suppressive therapy (IST) is an effective treatment for patients with aplastic anemia (AA) and select patients with myelodysplastic syndromes, but some patients fail to respond or relapse after IST. Over the past decade, the oral thrombopoietin receptor agonist eltrombopag has become a therapeutic option for AA in combination with frontline IST, and as a single agent for relapsed and refractory patients after IST. In this review, we highlight current knowledge of thrombopoietin receptor agonist mechanisms of action, and clinical indications and toxicities in patients with marrow failure, including the risk of clonal evolution.

Immune Therapies for Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized that there is an immune component to the pathogenesis of MDS and AML, but until recently, immune therapies have played a limited role in treating these diseases. Immune suppressive therapy exhibits durable clinical responses in selected patients with MDS, but the question of which patients are most suitable for this treatment remains unclear. Over the past decade, there has been remarkable progress in identifying genomic features of MDS and AML, which has led to an improved discernment of the molecular pathogenesis of these diseases. An improved understanding of immune and inflammatory molecular mechanisms of MDS and AML have also recently revealed novel therapeutic targets. Emerging treatments for MDS and AML include monoclonal antibodies such as immune checkpoint inhibitors, bispecific T-cell-engaging antibodies, antibody drug conjugates, vaccine therapies, and cellular therapeutics including chimeric antigen receptor T-cells and NK cells. In this review, we provide an overview of the current understanding of immune dysregulation in MDS and AML and an update on novel immune therapies for these bone marrow malignancies.

The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management.

The 2019 coronavirus disease (COVID-19) presents with a large variety of clinical manifestations ranging from asymptomatic carrier state to severe respiratory distress, multiple organ dysfunction and death. While it was initially considered primarily a respiratory illness, rapidly accumulating data suggests that COVID-19 results in a unique, profoundly prothrombotic milieu leading to both arterial and venous thrombosis. Consistently, elevated D-dimer level has emerged as an independent risk factor for poor outcomes, including death. Several other laboratory markers and blood counts have also been associated with poor prognosis, possibly due to their connection to thrombosis. At present, the pathophysiology underlying the hypercoagulable state is poorly understood. However, a growing body of data suggests that the initial events occur in the lung. A severe inflammatory response, originating in the alveoli, triggers a dysfunctional cascade of inflammatory thrombosis in the pulmonary vasculature, leading to a state of local coagulopathy. This is followed, in patients with more severe disease, by a generalized hypercoagulable state that results in macro- and microvascular thrombosis. Of concern, is the observation that anticoagulation may be inadequate in many circumstances, highlighting the need for alternative or additional therapies. Numerous ongoing studies investigating the pathophysiology of the COVID-19 associated coagulopathy may provide mechanistic insights that can direct appropriate interventional strategies.

Contribution of platelets, the coagulation and fibrinolytic systems to cutaneous wound healing.

Wound healing is a complex process that consists of multiple phases, each of which are indispensable for adequate repair. Timely initiation and resolution of each of these phases namely, hemostasis, inflammation, proliferation and tissue remodeling, is critical for promoting healing and avoiding excess scar formation. While platelets have long been known to influence the healing process, other components of blood particularly coagulation factors and the fibrinolytic system also contribute to efficient wound repair. This review aims to summarize our current understanding of the role of platelets, the coagulation and fibrinolytic systems in cutaneous wound healing, with a focus on how these components communicate with immune and non-immune cells in the wound microenvironment. We also outline current and potential therapeutic strategies to improve the management of chronic, non-healing wounds.

The role of neutrophils in thrombosis.

Despite significant evidence implicating an important role for neutrophils in thrombosis, their impact on the thrombotic process has remained a matter of controversy. Until 2010, platelets, coagulation factors, fibrinogen and monocytes were implicated in the thrombotic process. Several studies conducted over the last decade now support the growing notion that neutrophils indeed do contribute significantly to this process. Neutrophils can contribute to pathologic venous and arterial thrombosis or 'immunothrombosis' by the release of neutrophil extracellular traps (NETs) and NET release is emerging as a major contributor to thrombogenesis in pathologic situations such as sepsis and malignancy. Further, blood-cell derived microparticles, including those from neutrophils, have been implicated in thrombus formation. Finally, inflammasome activation in the neutrophil identifies another important mechanism that may be operative in neutrophil-driven risk for thrombosis. The knowledge of these roles of neutrophils in thrombosis may pave the road for novel anti-thrombotic agents in the future that do not affect hemostasis.

Advances in the Treatment of Sickle Cell Disease.

Sickle cell disease (SCD) is a monogenic disorder that afflicts approximately 100,000 Americans and millions of people worldwide. It is characterized by hemolytic anemia, vaso-occlusive crises, relentless end-organ injury, and premature death. Currently, red blood cell transfusion and hydroxyurea are the major disease-modifying therapies available for SCD. Hematopoetic stem cell transplant is curative, but barriers to treatment are substantial and include a lack of suitable donors, immunologic transplant rejection, long-term adverse effects, prognostic uncertainty, and poor end-organ function, which is especially problematic for older patients. Gene therapy to correct the ßs point mutation is under investigation as another curative modality. Deeper insights into the pathophysiology of SCD have led to the development of novel agents that target cellular adhesion, inflammation, oxidant injury, platelets and/or coagulation, vascular tone, and hemoglobin polymerization. These agents are in preclinical and clinical trials. One such agent, L-glutamine, decreases red blood cell oxidant injury and is recently US Food and Drug Administration approved to prevent acute pain episodes of SCD in patients 5 years of age or older. The purpose of this review is to describe the currently established therapies, barriers to curative therapies, and novel therapeutic agents that can target sickle cell hemoglobin polymerization and/or its downstream sequelae. A PubMed search was conducted for articles published up to May 15, 2018, using the search terms sickle cell disease, novel treatments, hematopoietic stem cell transplantation, and gene therapy. Studies cited include case series, retrospective studies, prospective clinical trials, meta-analyses, online abstracts, and original reviews.

Unusual Paraneoplastic Presentation of Cholangiocarcinoma.

Introduction. Cutaneous paraneoplastic syndromes are a heterogeneous group of skin manifestations that occur in relation to many known malignancies. Paraneoplastic occurrence of SCLE has been noted but is not commonly reported. SCLE association with cholangiocarcinoma is rare. Case Presentation. A 72-year-old man with a history of extrahepatic stage IV cholangiocarcinoma presented with a pruritic rash. Cholangiocarcinoma had been diagnosed three years earlier and was treated. Five months after interruption of his chemotherapy due to a semiurgent surgery, he presented with explosive onset of a new pruritic rash, arthralgias, and lower extremity edema. Physical exam revealed a scaly erythematous rash on his arms, hands, face, neck, legs, and trunk. It was thick and scaly on sun exposed areas. Skin biopsy revealed vacuolar interface dermatitis. Immunofluorescence revealed IgM positive cytoid bodies scattered along the epidermal basement membrane zone. PET-CT scanning revealed metabolically active recurrent disease in peripancreatic and periportal region with hypermetabolic lymph nodes. Oral steroids and new regimen of chemotherapy were started. Rash improved and steroids were tapered off. Discussion. Paraneoplastic syndromes demonstrate the complex interaction between the immune system and cancer. Treatment resistant SCLE should raise a suspicion for paraneoplastic etiology.