Coagulation Disorders Lecture Slides PDF

Coagulation disorders – Part I Platelet disorders Dr Caroline Kardeby Lecturer in Biosciences [email protected]  Aims and Objectives Introduce you to the platelet disorders Following this lecture you should be able to: 1. Describe the pathology of platelet dis...

Coagulation disorders – Part I Platelet disorders Dr Caroline Kardeby Lecturer in Biosciences [email protected]  Aims and Objectives Introduce you to the platelet disorders Following this lecture you should be able to: 1. Describe the pathology of platelet disorders 2. Describe what treatments that are available to the patients  Preparation For this lecture you’ll need… To have listened to lectures Caffeine! on: Haemostasis part I Haemostasis part II Haemostasis part III  Inherited and Acquired Platelet Disorders Inherited Acquired Glanzmann’s Thrombasthenia Immune thrombocytopenia (ITP) Thrombotic Thrombocytopenic Purpura (TTP) Bernard-Soulier Syndrome Disseminated intravascular coagulation (DIC) Storage Pool Diseases Drug-induced platelet dysfunction Myeloproliferative disorders (MPD) Chronic renal failure  Inherited Platelet Disorders Affect platelet numbers CDC42 MECOM IK2F5 KDSR RBM8A SLFN14 TRPM7 GNE ITGB3 TUBB1 FYB1 ADAMTS13 FLNA GF18 FL1 TPM4 RUNX1 MYH9 CD36 ANKRD26 THPO ETV6 RAP1B VWF WAS MPL GATA1 HOXA11 TUBB1 CYCS G6B PRKACG ACTN1 1980 1990 2000 2010 2020 ITGB3 GP9 AP3B1 HPS3 P2RY12 TBXAS1 ANO6 RASGRP2 ITGA2B HPS1 LYST HPS4 DTNBP1 BLOC1S3 PLA2G4A PLAU STIM1 F2RL3 GPIBA HPS6 HPS5 TBXA2E BLOC1S6 ABCC4 GPIBB VPS33B GP6 FREMT3 ACTB VIPAS39 AP3D1 PTGS1 Affect platelet function NBEA ISTH Gold Platelet Gene List www.isth.org/page/GinTh_GeneLists  Glanzmann’s Thrombasthenia Background Glanzmann’s Thrombasthenia was first identified in 1918 by Eduard Glanzmann, a Swiss paediatrician. One of the first patients was a 7-year-old girl with normal platelet count but very large bruises on her body. Affects 1 person in 1 million. Autosomal recessive disease caused by mutations in the genes ITGA2B and ITGB3. Leads to severe copy number reduction or reduced function of the fibrinogen receptor Integrin αIIbβ3 (aka GPIIbGPIIIa complex). Platelets will fail to bind to each other, and the platelet plug cannot be stabilised by fibrinogen.  Glanzmann’s Thrombasthenia Diagnosis and Treatment Most often identified in very young individuals. Severe bruising and bleeding. Platelet count: Normal Lumi-aggregometry test: No visible platelet aggregation. Flow cytometry test: Absence of Integrin αIIbβ3. Genetic test: Mutations in ITGA2B and ITGB3. Treatment: 1961 2014 2023 Platelet transfusions NovoSeven® reduce mortality during was approved for use in severe bleeding Glanzmann’s Thrombasthenia Other support: Hormonal treatment for women and iron supplements for blood loss.  Bernard-Soulier Syndrome Background Normal platelets Bernard-Soulier Syndrome was first identified in 1948 by Jean Bernard and Jean Pierre Soulier. The first patient was a male with episodes of bleeding throughout his life, died at the age of 28. Affects 1 person in 1 million. Autosomal recessive disease caused by Bernard-Soulier Syndrome mutations in the genes GPIBA, GPIBB and GP9. Leads to severe reduction or reduced function of the vWF (and thrombin) receptor aka. GPIb-IX-V complex. Leads to thrombocytopenia and giant platelets. Source: C. L. Balduini et al. 2013 JTH  Bernard-Soulier Syndrome Diagnosis and Treatment Most often identified in very young individuals, in mild disease forms the patient is older. Severe bruising and bleeding. Platelet count: 10-100 x 109/L (reference interval is 150-400 x 109/L) Lumi-aggregometry test: Low response to ristocetin, sometimes also thrombin. Flow cytometry test: Decreased levels of receptors in the GPIb-IX-V complex. Genetic test: Mutations in GPIBA, GPIBB or GP9. Treatment: Platelet transfusion (NovoSeven® not approved yet). Other support: Hormonal treatment in women and iron supplements for blood loss. Pressure on bleeding site if possible, use of antifibrinolytic substances applied topically.  What does severe bleeding mean? Large bruising from little or no damage. Some patients Spontaneous bleeding from the gums. report up to 10 Very heavy periods, can last a month (menorrhagia, >7 days). bleeding episodes Nosebleeds that can last for more than a day (epistaxis). per week. Potential death from trauma to the head (intracranial bleeding). Bleeding into joints that reduces mobility and causes pain. Major effects on everyday life! Not everyone cannot attend sports like most people, a small injury could become dangerous. Sometimes avoid social situations due to bleeds. Surgeries and giving birth has increased risks of severe bleeds. Source: Lecture at EUPLAN 2023 by Kate Kahir, Haemnet  Inherited and Acquired Platelet Disorders Inherited Acquired Glanzmann’s Thrombasthenia Immune thrombocytopenia (ITP) Thrombotic Thrombocytopenic Purpura (TTP) Bernard-Soulier Syndrome Disseminated intravascular coagulation (DIC) Storage Pool Diseases Drug-induced platelet dysfunction Myeloproliferative disorders (MPD) Chronic renal failure  Idiopathic Thrombocytopenic Purpura (ITP) Idiopathic Thrombocytopenic Purpura (ITP) is acquired thrombocytopenia, also known as Immune Thrombocytopenia. Platelets are destroyed by the body’s immune system Primary: Autoimmune anti-platelet antibodies. Secondary: Other autoimmune diseases or infections by bacteria or viruses. Top: Petechiae Affects 4 in 100.000 people per year. Bottom: Ecchymoses Source: https://www.msdmanuals.com Leads to a reduction in platelet count that results in bleeding. Requires