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Crosstalk of Inflammation and Coagulation in Infectious Disease and Their Roles in Disseminated Intravascular Coagulation

Introduction Viral, bacterial, fungal, and parasitic infections may all cause disturbances in hemostasis, which can eventually lead to thrombohemorrhagic complications such as disseminated intravascular coagulation (DIC), hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), or even vasculitis. Symptoms and signs may be absent in cases of subclinical activation of the coagulation cascade, or they may be overt in cases of bleeding, thrombosis, or both. None of…

Disseminated Intravascular Coagulation

An enormous amount has been written about disseminated intravascular coagulation (DIC). During the 1970s and 1980s, it was rather fashionable to report yet another new and unique “cause” of DIC. However, over the past few decades, it has become increasingly clear that DIC, rather than being a specific disease resulting from any one of innumerable causes, really represents the pathophysiologic final common pathway of the coagulation…

Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) also known as Osler-Weber-Rendu (OWR) disease is an inherited disorder that leads to the development of mucocutaneous telangiectasia and visceral organ arteriovenous malformations (AVMs). HHT is the result of mutations in key regulators of angiogenesis, which lead to disorganized development of the vascular bed. Clinically, mucocutaneous telangiectasias and recurrent epistaxis are the hallmark of this disorder, with the vast majority of affected…

Purpura and Other Hematovascular Disorders

Confined to the vascular system, blood comes into contact only with endothelial cells, which line all macrovascular, microvascular, and sinusoidal systems. Disruption of this closed system leads to bleeding—either gross bleeding (characteristic of macrovascular hemorrhage) or extravasation into tissue or potential spaces (more typical of microvascular leakage). Table 10.1 depicts the nature, causes, consequences, and therapeutic approaches to bleeding and even the types of physicians who…

Congenital and Acquired Disorders of Platelet Function and Number

Introduction Platelet dysfunction and thrombocytopenia result from a variety of inherited and acquired disorders. When a patient with mucocutaneous bleeding is first evaluated, the list of differential diagnoses is usually extensive. Elements of the medical history, the physical examination, and the laboratory workup will be critically helpful in determining whether the bleeding is due to a platelet disorder. The intent of this chapter is to provide…

Immune Thrombocytopenia

Immune thrombocytopenia (ITP), formerly called idiopathic thrombocytopenic purpura, is a common acquired bleeding disordered characterized by isolated thrombocytopenia in the absence of a clinically apparent cause. Currently there is no diagnostic test for ITP; thus establishing the diagnosis can be difficult and requires a thorough search for underlying conditions. Primary ITP (which is often simply designated “ITP”) is clinically indistinguishable from secondary ITP that occurs in…

General Aspects of Thrombocytopenia, Platelet Transfusions, and Thrombopoietic Growth Factors

Introduction Of the circulating blood cells, the platelet was the last to be fully described and its attributes determined. Although early studies by Osler, Hayam, and Bizzozero had identified small particles in the blood, these were thought to be bacteria, fragments of red blood cells (RBCs), or other hematopoietic elements. It was not until the development of a novel blood staining method by James Homer Wright…

von Willebrand Disease

von Willebrand disease (VWD), transmitted in an autosomal fashion, is the most common of the inherited bleeding disorders. It is caused by a decrease in the quantity of von Willebrand factor (VWF) or a qualitatively abnormal VWF in the circulation or both. Less commonly, VWD may present as an acquired disorder. Patients often come to medical attention for skin and mucosal bleeding symptoms such as epistaxis,…

Acquired Coagulation Disorders Caused by Inhibitors

Introduction and Overview In 1941 Lawrence and Johnson described a “circulating anticoagulant” in a patient with hemophilia who became refractory to blood transfusions for the treatment of bleeding. Over the next several years, they and others determined that this substance was an antibody contained within the γ-globulin fraction of blood and directed against antihemophilic factor, a precursor term used to describe the deficient clotting factor in…

Less Common Congenital Disorders of Hemostasis

In this chapter the less common congenital disorders of hemostasis are discussed. These include disorders of fibrinogen, prothrombin, and factors V, VII, X, and XI. (Disorders of factors VIII and IX are discussed in Chapter 3 .) In addition, the nonbleeding disorders associated with deficiencies of factor XII (Hageman factor), prekallikrein (PK), and high-molecular-weight kininogen are discussed because these disorders are characterized by prolonged partial thromboplastin…

Hemophilia A and Hemophilia B

Epidemiology and Genetics The hemophilias are the best known of the hereditary bleeding disorders. Hemophilia A or B arises as the result of a congenital deficiency of coagulation factor protein VIII or IX, respectively. Both are X-linked recessive disorders, almost exclusively affecting males, whereas daughters and mothers are carriers of the gene defect. The incidence of hemophilia A and B is equal across all ethnic and…

A Systematic Approach to the Bleeding Patient: Correlation of Clinical Symptoms and Signs With Laboratory Testing

Introduction In the current medical climate of laboratory expertise and automation, an expanded menu of increasingly sophisticated testing can provide immediately meaningful diagnostic, therapeutic, and prognostic indicators. On the other hand, economic justification and insurance “gatekeeping” often constrain the physician's ability to obtain these data. The clinical hematologist/hemostaseologist is particularly affected due to the number of esoteric laboratory assays required to provide state-of-the-art and cost-effective patient…

The Consultative Process

Life is short, and the art long, the occasion fleeting, experience fallacious, and judgment difficult. a Hippocrates (460–370 bc ) is considered to be the founder of European medicine. He lived in Greece during the Classic Period and was a contemporary of Socrates, Plato, Herodotus, and others. He is credited with three innovations in medicine: the separation of medicine as an art and science from magic,…

Regulatory Issues in Gene-Modified Immune Effector Cell Therapy

Acknowledgments Dr. Cornetta's effort was supported, in part, with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N92019D00018 for the National Gene Vector Biorepository Program. Dr. Komanduri acknowledges Stephanie Farnia (BCBS), Patricia Martin (Anthem), and Ronald Potts (INTERLINK and Kaiser Permanente) and members of the Massachusetts Institute of Technology Project on…

CAR 2.0: The Next Generation of Synthetic Receptor–Based Cellular Therapy for Cancer

Introduction The growing clinical experience with chimeric antigen receptor (CAR) T-cells targeting CD19 has indicated that this therapy can induce remission in a high percentage of relapsed and refractory patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) or B-cell non-Hodgkin's lymphoma (NHL) that is durable in some patients but has also highlighted a number of challenges. These include relapse of malignancy that retains expression of CD19…

CAR T-Cell Therapy for CNS Malignancies

Acknowledgment We would like to thank Ms. Catherine Gillespie for the professional editing and proofreading of the chapter. Introduction Central nervous system (CNS) tumors are a diverse group of neoplasms that have been classified by the World Health Organization (WHO) based on their cells of origin. Malignant gliomas arise from glial cells or their progenitors and account for around 80% of all malignant primary CNS tumors.…

Promising Chimeric Antigen Receptors for Non-B-Cell Hematological Malignancies, Pediatric Solid Tumors, and Carcinomas

Introduction The success of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory acute lymphoblastic leukemia and non-Hodgkin lymphoma has led to interest in developing CAR T-cell treatments for other malignancies. The modular nature of the CAR brought hope that simply replacing the FMC63 antigen-binding domain of CD19 CAR T-cells with other antigen-binding domains would rapidly yield new therapies, bringing cellular immunotherapy to myeloid leukemias, CD19-negative lymphoid…

Relapse Management and Role for Consolidative Hematopoietic Stem Cell Transplantation Following CAR T-Cell Therapy *

Disclaimer The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Introduction Treatment strategies for children and young adults with relapsed and/or refractory acute lymphoblastic leukemia (ALL) have evolved significantly, from a historical reliance on intensive combination antineoplastic therapy…

Response Assessment and Post–CAR T-Cell Therapy Management

Background CD19 chimeric antigen receptor-T (CAR T) cell therapy has dramatically improved the outcomes for pediatric and adult patients with short-term complete remission (CR) rates of approximately 90% in relapsed/refractory B-lineage acute lymphoblastic leukemia (ALL) and objective response rates (ORRs) of 50% in non-Hodgkin lymphoma (NHL). Long-term, sustained remissions lasting ≥1 year after CD19 CAR T-cell therapy were demonstrated in 50% of patients with ALL and NHL.…

Hematologic and Non-CRS Toxicities

Introduction Chimeric antigen receptor (CAR)–modified T-cell immunotherapy is highly effective for patients with relapsed and/or refractory B-cell malignancies, but significant adverse effects remain a concern. Systemic cytokine release syndrome (CRS) can occur in association with the inflammatory cytokine surge during in vivo CAR T-cell proliferation, and neurologic adverse effects commonly occur in this context. Significant progress has been made in CRS management, leading to a reduction in…