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I sit with my 52-year-old patient with sickle cell disease and newly diagnosed pulmonary hypertension, discussing his recent decision to discontinue hydroxyurea. A pulmonary fellow in our PH clinic listens closely.

I prepare to ask him, "You know your organs will progressively fail and you will die if you do not take your hydroxyurea every day?"

I catch myself and ask, "How many times have you been told in your life that you will die?"

His expression softens and he answers, "Doc, I was told so many times as a kid that I would not live to 18, but I proved them all wrong!"

I follow up, "Did you have a brother or sister that died of sickle cell disease?"

"My older brother died of sickle cell when I was 7."

After we leave the room, I ask the fellow to reflect for a minute upon the patient's answers to these simple questions and what they explained about this person's resilience, suffering, and perhaps cynical reactions to physicians and therapeutic urgency.

This poignant exchange with a patient with sickle cell disease illustrates an important point: as physicians and scientists, it is almost impossible to understand the physical and psychological trauma of sporadic random attacks of 11-point pain on a 10-point scale ("worse than having my first child"; "like an ice pick hitting over and over on my shin bone"), missed school, headaches, strokes, fatigue, weight loss, and the traumatic loss of a sibling or loved one, that all limit sports participation, degrade school performance, and drive physical and spiritual pain. All of this is compounded by economic disparity, healthcare inequities, systemic racism, a commercially driven opioid epidemic, and in many US states an abrupt loss of comprehensive healthcare at age 18 years, when sickle cell disease becomes a "pre-existing condition."

It is impossible for most of us to understand how socioeconomic inequality compounds the already unfathomable burden of illness due to sickle cell disease. Ironically, one friend and one-time patient, who is now a chief executive in a large organization, shared his unique experience that all of his brothers who did not have sickle cell disease had either died or were incarcerated. He sincerely credits sickle cell disease with his own survival and success, as his inability to "run the streets" focused him on school and surrounded him in a protective cocoon from the violence that consumed his brothers. We can only try to imagine his resilience in the life he was given.

This book leverages the motivation from such stories to compile the collective clinical expertise of world experts and summarize the innovative, transformative, and discovery science of the field of sickle cell disease. In many ways, this book reflects a triumph of humanity over an ancient disease—cruel collateral damage in our molecular code cut by the unsparing and uncaring genetic adaptation to endemic malaria. It is a triumph, albeit far from complete, for people with sickle cell disease who as individuals, patients, participants, and partners, with families, friends, and healthcare workers, withstand this assault and partner with us to advance knowledge, science, and medicine.

This book chronicles the groundbreaking discoveries of the 20th century and almost three decades of scientific progress since the last textbook on sickle cell disease was published in 1994. The three editors share more than 80 years of collective experience working with sickle cell disease as clinicians and scientists, yet experience a sense of awe in absorbing the text, figures, and clinical images within this book, which details a remarkable collaborative journey to understand and tame this disease. More than 90 dedicated experts in the field present their combined clinical knowledge of basic mechanisms, screening, diagnosis, management, and treatment of myriad complex complications of a single base point mutation in the human genome over 34 chapters. The text covers the dizzying pace of basic and clinical discovery over 100 years from the biophysics of hemoglobin S polymerization, the transcriptional regulation of globin synthesis, the characterization of vascular inflammation and impaired redox signaling, advances in small molecule and antibody-based therapeutics, and the emergence of curative stem cell and gene editing technologies. Individual chapters have been dedicated to specific organ pathology, and the book concludes with four enlightening perspectives that exemplify the added challenges of facing sickle cell disease in resource-poor countries. The editors believe that readers will especially appreciate the case studies with "How I Treat" authoritative insights that root the text into clinical practice by providing overviews of common and rare complications by world experts in sickle cell disease, and the Key Facts, which provide at-a-glance high yield information. The text is complemented by memorable images, high-quality figures, and many original diagrams.

The editors sincerely hope that the shared clinical knowledge, cases, and expert discussions of specific complication management will support care providers and advance best practices for the many individuals living with sickle cell disease worldwide. We also hope that the gripping story of clinical and scientific discovery presented in these pages inspires new physicians, advanced practice providers, scientists, and those from every other walk of life to join this field and, together, move us closer to a world without suffering from sickle cell disease.

Mark T. Gladwin, MD

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