Plot The Clot

1. Day Two: Understanding the Role of Blood Clots in Inheritable Blood Disorders Plot The Clot

2. Inquiry Lab Review • What were your findings from our lab in the previous class? • What do you think caused the “clots” to form in the blood/milk? • What effect would the formation of these clots have on the human body? • What would happen if blood clots did not form in the human body?

3. Today’s Objectives • To develop an understanding of how blood clots in the human body • To learn about specific blood disorders and their effect on an individual’s health • To learn how public health efforts are used to help people with inherited blood disorders

4. How do blood clots form? • http://reddymed.com/hdbc_overview.htm • Parallel reading from textbook

5. Back to some of our previous questions • What effect would the formation of these clots have on the human body? • What would happen if blood clots did not form in the human body? • How would/could people live who had these kinds of conditions?

6. Two Types of Blood Disorders • Malignant - used to describe a severe and progressively worsening disease. This term is most familiar as a description of cancer • Non-Malignant - does not spread or "metastasize" to other parts of the body

7. Non-Malignant Blood Disorders • Bleeding Disorders ( Hemophilia, von Willebrand) • Clotting Disorders – (Thrombosis, Thrombophilia) • Hemoglobinopathies – (Thalassemia, Sickle Cell disease) • Red Cell Disorders – (Diamond Blackfan Anemia) • Iron Disorders – ( Hemochromatosis)

8. Hemophilia • Inherited disease that prevents the blood from clotting properly. • Caused by a deficiency of a blood protein, also called a “clotting factor.” • 18 to 20 thousand people in U.S. – 400 babies born each year in U.S.

9. Hemophilia • X-linked recessive bleeding disorder • Males affected, females carriers • 1 out of every 5000 live male births • Decreased levels of • FVIII in hemophilia A (90%) • FIX in hemophilia B (10%) • Lack of factor results in a weak blood clot

10. Clinical Classification

11. Venous Thromboembolism (VTE) • Includes Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) • Estimates range from 300,000 to 900,000 annually • 30 % of people with VTE die within one month of diagnosis • 25% of those with PE present with sudden death

12. Public Health Burden of VTE • PE is the leading cause of maternal mortality in the U.S • PE is second leading cause of maternal mortality (behind post-partum hemorrhage) internationally • Fortunately, much of the morbidity and mortality may be preventable

13. Acquired Risks • Obesity • Advanced age • Air travel • Chronic diseases • Hospitalization / surgery • Trauma / Injury

14. What is Thalassemia? • Inherited disorder of hemoglobin synthesis that alters globin chain production • • Mild to severe anemia • • Alpha and Beta forms

15. Common Forms

16. Common Forms, continued

17. Who Does Thalassemia Affect? • Sex • Both sexes equally affected • Age • age at onset of symptoms varies significantly depending on severity of disease • Ancestry • Alpha thalassemias • Most common among Southeast Asian, Indian, Chinese, or Filipino. • Beta thalassemias • Most common among people of Mediterranean (Greek, Italian, and Middle Eastern), Asian, or African

18. Global and Domestic Burden • Worldwide • Most common blood inherited blood disorder • In all race/ethnic groups • 15 million people with clinically significant thalassemic disorders • India: 30 million carriers • Cyprus – 1 in 7 carriers, 1 in 158 with beta Thalassemia • US • Exact prevalence unknown • Beta thalassemia major (Cooley’s anemia) : 1000 individuals • Increasing due to demographic changes and longer life expectancy

19. Treatment • Blood transfusions • Frequency depends on severity • Every 2-4 weeks for those with b thalassemia • major • Iron chelation therapies • Fetal hemoglobin inducers • Blood and marrow stem cell transplant

20. Background • Thalassemia patients are the largest consumers of red blood cells in the United States • Increased risk for exposure to transfusion transmissible infections

21. Sickle Cell Disease • Inherited blood disorder that affects red blood cells. • Occurs when a defective hemoglobin gene is inherited from both parents • Can cause anemia and obstruct blood vessels, causing major complications.

22. Sickle Cell Disease • Most common inherited blood disorder in the U.S. • Estimated 100K Americans affected • Most of those affected with SCD are those whose ancestors come from Africa, an increasing number of Hispanics also have the disease

23. Sickle Cell Trait • Occurs when a person carries only one copy of the defective hemoglobin gene. • Individuals have a 50% chance of passing the defective hemoglobin gene to each of their children • Estimated 2 million Americans that have the sickle cell trait in the U.S. • About 1 in 12 African Americans has sickle cell trait.

24. What is DBA? • Diamond Blackfan Anemia: • Red blood cell anemia resulting from failure of bone marrow to produce sufficient red blood cells. • Diagnostic criteria: increase in a specific red cell enzyme called erythrocyte adenosine deaminase (eADA) and mutation analysis (genetic testing) • Named after the two doctors that discovered it in the 1930’s; Dr Diamond and Dr Blackfan

25. What is DBA? • Treatment • Corticosteroids and blood transfusions • Chelation therapy • Hope for a cure? • Stem cell transplantation (SCT), also known as bone marrow or cord blood transplantation is curative in DBA • SCT remains complex and controversial

26. DBA: Truly Rare Disease • Diamond Blackfan Anemia: • True prevalence unknown • Estimated 25 – 35 cases per year in US and Canada (7 in a million!) • Suspect 500 – 1000 patients in the US • Occurs equally in males and females and among all ethnic groups • Usually diagnosed before age 2

27. Genetic Discovery • DBA is usually a dominant or sporadic mutation • DBA is the first human disease due to mutations in a ribosomal structural protein • At least six different genetic mutations to DBA have been discovered • Most common: RPS 19 (About 25%) • Others: RPS 24, RPS 17, RPL 5, RPL 11, and RPL 35a • A genetic mutation has not yet been found for half of all patients with DBA.

28. Birth Defects and DBA • Congenital Anomalies (Birth Defects) 47% of the patients in the DBAR have physical abnormalities (not including short stature). • Common locations: • 50% face and head (including cleft lip and palate), neck and shoulders • 20% hands (triphylangeal thumb) • 20% urogenital tract • 15% heart • Over 20% of patients have more than one abnormality.

29. Cancer and DBA • Studies are ongoing by NCI to determine the extent of DBA and the development of cancers: • Leukemia (cancer of the blood and bone marrow) • Sarcomas (cancer arising in bone, fat, cartilage, tendons or connective tissue)

30. Hemochromatosis(HHC) • Is an inherited condition of abnormal iron metabolism (iron overload) • Iron cannot be excreted therefore the metal can reach toxic levels in tissues of major organs such as the liver, heart, pituitary, thyroid, pancreas, and synovium (joints).

31. Hemochromatosis • Hard to detect • Estimated 37 million "silent carriers" in U.S. • Another 2 to 3 million Americans who are at high risk for having HHC.

32. Acknowledgements: • Presentation adapted from • Christopher S. Parker, Ph.D., MPH • Division of Blood Disorders (DBD) • National Center on Birth Defects and Developmental Disabilities (NCBDDD) • Centers for Disease Control and Prevention (CDC) • Web Video • Dr. Usha M Reddy, MD • Reddy Medical Communications, LLC