Introduction
Over the past century, scientists have made significant strides in understanding how platelets play a crucial role in stopping bleeding and how they are produced by large cells called megakaryocytes. Having too few platelets is a condition called thrombocytopenia, which can lead to bleeding disorders. Some cases are inherited, like Bernard-Soulier syndrome, discovered in 1948, showing how genetic factors can affect platelet levels and function. Thrombocytopenia often involves a low platelet count and varying platelet sizes, which can worsen bleeding tendencies. Most cases stem from problems in how megakaryocytes develop, influenced by genes that control cell function and signaling. Recent advancements in gene sequencing technologies have revolutionized the human ability to identify genetic causes behind platelet disorders, paving the way for better diagnosis and treatment strategies. Moving forward, the focus lies on integrating next-generation sequencing into initial screening processes and improving understanding of bleeding risks and treatment options.
How Is Platelet Production Related to Their Lifespan?
The number of platelets in the blood is determined by a balance between the number made, the length of time they last, and the speed at which they are used up. It all starts with special cells called CD34 hematopoietic stem cells, which mature into megakaryocyte-erythrocyte progenitors. Some progenitors become colonies, growing into mature megakaryocytes with lots of DNA. Various factors, including certain proteins and chemicals, control this transformation.
Thrombopoietin, produced mainly in the liver, is a key player in regulating the number of platelets in the blood. Mature megakaryocytes release platelets into the bloodstream through long extensions called proplatelets, with the help of proteins like myosin IIA and actin filaments. Collagen in the body can slow down this process to prevent too many platelets from being made too quickly. Interestingly, recent studies have shown that platelets can also be produced directly in the lungs, providing an extra source when needed urgently.
What Are the Common Types of Inherited Thrombocytopenia Included?
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MYH9-Related Disease: MYH9-related disorder is a condition that can show various signs and symptoms, such as bleeding issues, hearing impairment, kidney problems, and clouding of the eye's lens (cataracts). The bleeding problems in individuals with MYH9-related disorders are due to thrombocytopenia, which means there is a low level of platelets in the blood. Platelets are small cells that help with blood clotting. People with this disorder often experience easy bruising, and women may have heavy menstrual bleeding. The platelets in these individuals are larger than usual, making it hard for them to move into small blood vessels like capillaries. This further reduces the platelet level in these vessels, making clotting more difficult.
Some people with MYH9-related disorders experience hearing loss caused by inner ear abnormalities. This hearing loss can be present from birth or develop later in life. Around 30 to 70 percent of individuals with MYH9-related disorders develop kidney disease, usually starting in early adulthood. The first sign of kidney disease is protein or blood in the urine. The kidneys' filtering structures, called glomeruli, are particularly affected, leading to kidney failure and end-stage renal disease (ESRD).
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Bernard-Soulier Syndrome: Bernard-Soulier syndrome is a rare inherited bleeding disorder marked by a deficiency or dysfunction of the glycoprotein complex GPIb-IX-V on the surface of platelets. This deficiency impaired platelet adhesion to the blood vessel wall, leading to prolonged bleeding and easy bruising. Individuals with Bernard-Soulier syndrome often present with mucocutaneous bleeding, such as nosebleeds, gum bleeding, and heavy menstrual periods in women. Additionally, they may experience excessive bleeding after injury or surgery. Diagnosis typically involves blood tests assessing platelet function and specific genetic testing. Treatment options include platelet transfusions to manage bleeding episodes and medications that promote clot formation.
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ETV6-Related Thrombocytopenia: ETV6-related thrombocytopenia is a rare genetic disorder with a marked decrease of platelet levels in the blood, known as thrombocytopenia. Mutations in the ETV6 gene cause it. Platelets are crucial for blood clotting, and their reduced levels can lead to increased bleeding tendencies. Common symptoms include easy bruising, nosebleeds, and prolonged bleeding from minor injuries. This disorder primarily affects platelet production and function, often resulting in chronic thrombocytopenia throughout life. ETV6-related thrombocytopenia is inherited in an autosomal dominant pattern, meaning a mutation in one copy of the ETV6 gene is sufficient to cause the disorder.
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Jacobsen Syndrome: Jacobsen syndrome, also known as 11q deletion disorder, is a rare chromosomal disorder caused by a deletion on the long arm of chromosome 11. Individuals with Jacobsen syndrome typically have distinctive facial features, intellectual disabilities, delayed development, and heart defects. Other common features may include feeding difficulties, skeletal abnormalities, and bleeding disorders due to thrombocytopenia (low platelet count). Additionally, individuals with Jacobsen syndrome may have eye abnormalities, such as ptosis (droopy eyelids) or coloboma (a gap or hole in the structures of the eye). Treatment typically involves addressing the specific symptoms and complications associated with the disorder through a multidisciplinary approach involving various medical specialists.
What Is the Diagnosis of Inherited Thrombocytopenia?
Diagnosing inherited thrombocytopenias can be challenging, especially without a clear family history of bleeding. Diagnostic algorithms based on clinical data and lab tests help manage patients effectively. Modern techniques like whole blood electronic counters helps in assessing platelet count and function. Advances in gene sequencing, like next-generation sequencing (NGS), have significantly expanded the understanding of the genetic basis of these disorders. However, prioritizing and filtering genetic variants remains crucial. Despite these advancements, a systematic approach to diagnosis and management remains essential, as outlined in expert consensus reports. This includes a thorough assessment of clinical information and appropriate referrals to specialist centers when needed.
What Is the Treatment for Inherited Thrombocytopenia?
Inherited platelet disorders can lead to various types of bleeding, including nosebleeds, gum bleeding, and easy bruising, characterized by tiny red skin spots known as petechiae. Severe cases may involve bleeding in the digestive tract, and bleeding can be prolonged after injuries or surgeries. Women with these disorders may also experience heavy menstrual bleeding, and face added risks during childbirth. Although platelet count significantly determines bleeding risk, other factors, such as platelet function defects, contribute. Interestingly, platelets have roles beyond blood clotting, such as maintaining the integrity of blood vessels.
Treating bleeding in these disorders often involves transfusions of platelets and red blood cells. In some cases, medications like recombinant activated factor VII or tranexamic acid may be used to control bleeding. Emerging treatments, such as stem cell transplants and gene therapy, offer potential avenues, particularly for severe cases like Wiskott-Aldrich syndrome. Thrombopoietin-mimetic drugs can also help raise platelet levels, providing a temporary solution in certain situations. A thorough diagnosis is crucial for effective management, ensuring appropriate treatment for each patient's needs while avoiding unnecessary interventions for those with lower bleeding risks.
Conclusion
Inherited thrombocytopenia, genetic conditions resulting in low platelet counts, and heightened bleeding risks continue to pose challenges for diagnosis and treatment. Progress in gene sequencing brings hope for personalized care strategies. The focus should be on integrating these advancements into routine screening processes and customizing treatments based on individual bleeding tendencies. By doing so, we can enhance patient care and improve outcomes for those affected by inherited thrombocytopenia.
