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

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?

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

How do blood clots form?

http://reddymed.com/hdbc_overview.htm

Parallel reading from textbook

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?

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

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)

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.

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

Clinical Classification

Classification

Severe Moderate Mild

FVIII or FIXactivity level

<1% 1%–5% 6%–30%

Pattern ofbleedingepisodes

2–4 permonth

4–6 per year Uncommon

Cause ofbleedingepisodes

Spontaneous Minortrauma

Majortrauma orSurgery

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

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

Acquired Risks

Obesity Advanced age Air travel Chronic diseases Hospitalization / surgery Trauma / Injury

What is Thalassemia?

Inherited disorder of hemoglobin synthesis that alters globin chain production • Mild to severe anemia • Alpha and Beta forms

Common Forms

Alpha thalassemia Number of alpha genes

Clinical significancealtered (of 4 genes)

a –Thalassemia silent carrier 1 No clinical significancecarrier

a–Thalassemia trait 2 Mild anemia, low RBC indices

a–Thalassemia intermedia (Hb H disease)Hgb H-Constant Spring

3 Mild to moderately severe anemia, splenomegaly,abnormal RBC indices

a –Thalassemia major 4 Fatal in utero

Common Forms, continued

Beta thalassemias Number of beta genes

Clinical significance

b–Thalassemia silent carrier 1 b+ No clinical significance

b–Thalassemia trait 1 b+ and b0 Mild anemia, low RBC indices

b–Thalassemia intermediaHb E/ b+ thalassemia

2 compoundheterozygoteb/variant

Anemia of intermediate severity,not transfusion-dependent, mildto severe

b–Thalassemia major (Cooley’s anemia)Hb E/bo thalassemia

2 Transfusion dependent anemia, massive splenomegaly, bonedeformities, growth retardation, fatal if not treated

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

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

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

Background

Thalassemia patients are the largest consumers of red blood cells in the United States

Increased risk for exposure to transfusion transmissible infections

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.

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

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.

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

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

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

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.

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.

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)

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).

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.

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