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

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 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 ClassificationSevereModerateMild FVIII or FIX activity level <1%1%–5%6%–30% Pattern of bleeding episodes 2–4 per month 4–6 per yearUncommon Cause of bleeding episodes SpontaneousMinor trauma Major trauma or Surgery

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 Alpha thalassemia Number of alpha genes Clinical significance altered (of 4 genes) a –Thalassemia silent carrier1No clinical significance carrier a–Thalassemia trait2Mild anemia, low RBC indices a–Thalassemia intermedia (Hb H disease) Hgb H-Constant Spring 3Mild to moderately severe anemia, splenomegaly, abnormal RBC indices a –Thalassemia major4Fatal in utero

16. Common Forms, continued Beta thalassemias Number of beta genes Clinical significance b–Thalassemia silent carrier1 b + No clinical significance b–Thalassemia trait1 b + and b 0 Mild anemia, low RBC indices b–Thalassemia intermedia Hb E/ b + thalassemia 2 compound heterozygote b/variant Anemia of intermediate severity, not transfusion- dependent, mild to severe b–Thalassemia major (Cooley’s anemia) Hb E/b o thalassemia 2Transfusion dependent anemia, massive splenomegaly, bone deformities, growth retardation, fatal if not treated

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