Genetics of Cardiovascular and Hematologic Disease Flashcards
What are the two pathways associated with the coagulation cascade?
- intrinsic pathway
- extrinsic pathway
The activation of what factor initiates the first step of the common pathway of the coagulation cascade?
factor X
What allows you to stop bleeding by forming clots?
fibrin
What is a bleeding disorder that has a combined incidence of 1 in 5000 males?
hemophilia
Hemophilia is caused by a mutation of what?
on the F8 or F9 genes on the X chromosome
Hemophilia A and B are what type of disorders?
X-linked recessive disorders
1/3 of hemophilia patients do not have a family history of this disease, so they are what type of mutations?
do novo mutations
Who is usually affected in hemophilia?
males
Will affected fathers with hemophilia ever pass the disease to their sons?
No
Hemophilia A is a disorder due to mutations on which gene?
F8 (factor 8)
Hemophilia A has a deficiency with which clotting factor?
Factor VIII
What type of hemophilia is considered the “classic” hemophilia and is the most common?
Hemophilia A
Which Hemophilia is also named the “Christmas disease”?
Hemophilia B
Hemophilia B is associated with mutations on which gene?
F9 gene (factor 9)
Hemophilia B has a deficiency with which clotting factor?
factor IX
Which hemophilia is considered the “Christmas disease” and is less common than the other?
Hemophilia B
Hemophilia A and B are clinically indistinguishable, what does this mean?
both will present the same way
Who can manifest mild symptoms of Hemophilia or may have more classic symptoms?
female carriers
What are some possible explanations as to why female carriers of hemophilia may manifest mild symptoms or have more classic symptoms?
- X-chromosome inactivation during embryogenesis
- mating between an affected male and carrier female
- an abnormal karyotype resulting in loss of all or part of one chromosome (turner syndrome)
Most children with hemophilia become symptomatic by age (1) and are typically diagnosed by age (2)?
- 2
- 6
If there is so trauma or witnessed bleeding at birth, what can be missed with newborns?
hemophilia diagnosis
Newborns with what disease can present with:
- intracranial hemorrhage
- seizures
- increased bleeding with circumcision
Hemophilia
What are these manifestations associated with:
- excessive bleeding as result of injury or surgical procedure
- excessive bruising
- skin hematomas
- joint hemarthrosis
- knees, ankles, and elbows commonly affected
hemophilia
What are these ENT manifestations associated with:
- nose epistaxis (bloody nose)
- bleeding from posterior pharynx after coughing
- hematochezia
- hematuria
- menorrhagia
Hemophilia
What is the term for blood in stool?
hematochezia
What is the term for blood in urine?
hematuria
What is the term for a heavier menstrual cycle?
menorrhagia
What can be used to diagnose hemophilia A and B?
specific coagulation factor assays and genetic testing
What is a bleeding disorder associated with hemophilia?
hemophilia C
Hemophilia C is a disease with a deficiency with what clotting factor?
factor XI
What is the inheritance pattern for hemophilia C?
autosomal recessive
What is a large glycoprotein with several functions and is involved in platelet adhesion to the sub-endothelium?
Von Willebrand factor
What acts as a “bridge” between platelets and the injured sub-endothelium (brings them together)?
Von Willebrand factor
What binds to the Von Willebrand factor?
receptors in platelets
Von Willebrand factor acts as a carrier for which factor in circulation?
factor VIII
Von Willebrand factor increases factor 8’s half-life by?
five-fold
Factor VIII levels are low in Von Willebrand factor which results in what?
reduced clotting potential
What is the most common inherited bleeding disorder?
Von Willebrand disease
What gene is associated with Von Willebrand disease?
VWF gene
Most people with Von Willebrand disease are what?
asymptomatic
What is the inheritance pattern associated with Von Willebrand Disease?
mostly autosomal dominant with variable penetrance
What can follow an autosomal recessive pattern but is less common and causes more severe symptoms in this form?
Von Willebrand Disease
How many types of Von Willebrand disease classifications are there?
3:
- type 1, 2 and 3
What is the defect associated with type 1 Von Willebrand disease?
quantitative defect; not enough VWF
What is the defect associated with type 2 Von Willebrand disease?
qualitative disease; dysfunctional VWF
What is the defect associated with type 3 Von Willebrand disease?
profound quantitative defect; total or near absence of VWF
What is the inheritance of type 1 Von Willebrand disease?
autosomal dominant
What is the inheritance of type 2 Von Willebrand disease?
autosomal dominant (common)
autosomal recessive (uncommon)
What is the inheritance of type 3 Von Willebrand disease?
autosomal recessive
What type of Von Willebrand disease is associated with barely any bleeding and is the most mild?
type 1
What type of Von Willebrand disease is associated with moderate to severe bleeding?
type 2
What type of Von Willebrand disease is associated with severe bleeding and is clinically similar to hemophilia A?
type 3
What are some clinical bleeding symptoms associated with type 1 Von Willebrand disease?
- epistaxis
- postoperative bleeding
- gastrointestinal bleeding
- ecchymosis and hematomas (brusing)
- joint bleeding
- menorrhagia, hematuria, postpartum bleeding
Sickle cell anemia is more common with ancestry connected to?
sub-Saharan Africa (african americans)
Sickle cell anemia is associated with mutations on what gene?
HBB gene for hemoglobin
Sickle cell anemia is what type of substitution at the 6th codon?
single substitution
The single substitution on the 6th codon in sickle cell anemia results in what?
sickled hemoglobin
Who requires newborn screening for sickle cell anemia?
all states
Normal hemoglobin in adults is comprised of what?
- two alpha polypeptide chains
- two beta polypeptide chains
Within each chain of hemoglobin, what is there?
a heme group which contains iron
Hemoglobin is responsible for what?
oxygen transport
When you lose hemoglobin, what else do you lose?
iron
If an older individual is suddenly anemic, what should you check for?
colorectal cancer; they’re suddenly losing hemoglobin and iron
Normal hemoglobin is very (1) and (2), but HgbS (sickle) is not
- pliable
- deformable
How do sickled cells flow?
they do not flow freely and lead to pain and vaso-occlusive infarction of organs
Sickled cells get what?
stuck places
How is sickle cell anemia inherited?
autosomal recessive pattern
Heterozygous individuals are carriers of sickle cell anemia and are referred to as having what?
the sickle cell trait
What has been found to provide a 60% protection against malaria?
- most of the benefit occurs before age 16
- higher frequency of carries are in malaria regions
Sickle cell anemia
Mice that were genetically engineered to be sickle cell carriers were protected against what?
cerebral malaria