Blood Disorders Flashcards
What is the lifespan of an RBC?
120 days
What organ removes the RBC?
Spleen
Where is iron recycled?
Liver
What is Hematocrit?
Amount of red cells % by volume
What are the lower limits of Hemoglobin in men and women?
Lower limits: Men 13 g/dL, women 12 g/dL
What are the percentages of Hematocrit for men and women?
Men: 42%, Women 38%
What does a low and high MCV mean?
Microcytic – MCV is low
Macrocytic – MCV is high
What is Sideroblastic?
immature red cells with unused iron deposits
What is Hypochromic?
Cells with low hemoglobin appear pale
What produces bilirubin?
When hemoglobin breaks down
What is icterus?
Yellowing of eyes
What does increased bilirubin cause?
Gallstones and itching
What is one cause of babies having trouble clearing bilirubin?
Antibody mismatch with mother
What is fetal hemoglobin (HbF)?
Comprised of 2 alpha and two gamma globin chains
Higher affinity for oxygen (has to “steal” oxygen from mother
What is adult hemoglobin made of (HbA)?
2 alpha and 2 beta globin chains
What is HbA2 = variant hemoglobin?
2 alpha and 2 delta globin chains
What variant causes Sickle Cell Anemia?
p.Glu6Val in HBB
What hemoglobin chain is affected by Sickle Cell Anemia?
Mutation in Hemoglobin beta chain
What disorder leads to polymerization of hemoglobin under situations of low oxygen tension?
Sickle Cell Anemia
What is Vaso-occlusive crisis?
Sickle blood cells are more likely to be damaged and to block small blood vessels
What is the carrier rate of Sickle Cell Anemia in African Americans
10%
What is the occurrence of Sickle Cell Anemia in AA?
1:300-1:500 liveborn rate with sickle cell disease
What accounts for 60-70% of all sickle cell disease
Homozygous HbS accounts for 60-70% of all sickle cell disease
What are the compound het types of sickle cell disease?
Compound heterozygosity of other abnormal hemoglobins accounts for rest:
-HbS/HbC gives a milder disease phenotype with sickle cells
-HbS/β⁰-thalassemia gives severe phenotype
-HbC/C gives milder symptoms with hemolytic anemia
What are the presentations and complications of Sickle Cell Disease?
Acute pain crises
-Hand pain: Dactylitis
-Headaches
-Pain anywhere
-Often with infection
Acute chest
-Vasoocclusion in chest
Chronic hemolysis (jaundice
Gallstones (heme-based)
Splenic enlargement (sequestration)
Strokes and retinal arterial occlusion
Bacterial infections (pneumonia and meningitis)
What is the treatment in Sickle Cell Anemia?
Oxygen
Treatment of dehydration and fever
Pain control
Blood transfusion
Bone marrow transplant
Gene therapy in development
What medications prevent Sickle Cell Anemia symptoms?
Hydroxyurea reactivates fetal hemoglobin
Glutamine reduces oxidative stress
What is the genetic mechanism in Alpha-thalassemia?
Alleles are lost by deletions in alpha locus on Chr 16 (4 total copies)
What is the genotype of an asymptomatic Alpha-thal carrier?
Three normal copies
One deletion
What is the phenotype in an Alpha-thal minor person (asymptomatic with mild microcytic anemia)?
Deletion of two copies (either in cis or trans)
What is the genotype in an Alpha-thal Hb H person (symptomatic with mild microcytic anemia and splenomegaly)?
Three deletions
What is the presentation in an Alpha-thal Hb H person?
Symptomatic with mild microcytic anemia
Splenomegaly
What is the phenotype of someone with four missing copies of HBA1/HBA2 (BART)?
Incompatible with Life
Hydrops Fetalis
In what population is it more common to have two deleted HBA1/HBA2 loci on the same allele?
Southeast Asian
What ethnicities have a higher carrier frequency for Alph-thal?
Southeast Asia
Africa
Mediterranean variant
What are the genes involved in Alpha-thal?
HBA1 and HBA2
What type of globulin tetramer is seen in Bart’s?
Since this is a fetal onset disorder, gamma-globulin is seen instead of beta
What blood value are you looking at in alpha-thal?
MCH and Hb
What is the genetic cause of Beta-thalassemia?
Autosomal recessive LoF mutations in HBB (beta-globin)
What are the symptoms of Beta-thalassemia?
Fatigue, lethargy
Anemia
Extramedullary hematopoeisis
Spleen, liver, flat bones
Iron overload
What are the blood levels measured in Beta-thalassemia?
Hb
MCV
MCH
What is a risk with anemia?
Iron overload
What are the complications of iron overload?
Toxic to the liver, heart and pancreas, hormonal dysfunction
Same problems with hemochromatosis, AKA “Bronze diabetes”
What is the treatment in thalassemia major?
Chelation therapy and limited transfusions
What is pancytopenia?
Deficiency of all three cellular components of the blood (red cells, white cells, and platelets).
What is the clinical triad of Fanconi Anemia?
- Physical findings
- Bone marrow failure
- Increased cancer risk
What are the three most common genes associated with Fanconi Anemia?
FANCA = most common 60-70%
FANCC = 14%
FANCG/XRCC9 = 10%
All three are AR
Everything else at 3% or less
What types of Fanconi Anemia are associated with an increased risk of breast and ovarian cancer?
FANCD1 = BRCA2
FANCS = BRCA1
FANCN = PALB2
What is the biological mechanism of Fanconi Anemia?
The body cannot properly produce a protein that protects DNA from damage
What are the physical findings in Fanconi Anemia?
75 % will show:
- Prenatal and/or postnatal short stature
-Abnormal skin pigmentation (e.g., café au lait macules, hypopigmentation)
-Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)
-Microcephaly
-Microophthalmia, cataract, other eye findings
-Genitourinary tract anomalies–horseshoe kidney, abnormal ureters, etc.
What are the initial laboratory findings in Fanconi Anemia?
Macrocytosis
Increased fetal hemoglobin (often precedes anemia)
Cytopenia (especially thrombocytopenia, leukopenia, and neutropenia)
What is the chance of developing bone marrow failure by age 50 in Fanconi Anemia?
70% by age 50
What are the cancer risks associated with Fanconi Anemia?
Acute Myelogenous Leukemia: 13% risk
Myelodysplastic syndrome: 50% by age 50
Solid tumors
-Head and neck squamous cell cancer
-Vulva, esophagus, brain cancer
-Nephroblastoma and neuroblastoma in children
-Higher risk for solid tumors after bone marrow transplant
Gene specific risks
-BRCA1 and BRCA2
What is the blood phenotype of Diamond-Blackfan?
Macrocytic anemia with onset prior to age one year
No other significant cytopenias
Reticulocytopenia (low response)
Normal marrow cellularity with a paucity of erythroid precursors
No evidence of another acquired or inherited disorder of bone marrow function.
(picture five fingers but no thumbs)
What is the general phenotype of Diamond-Blackfan?
Anemia (100%)
Craniofacial features (27%)
Upper limb anomalies (16%)
Genitourinary malformations (13%)
Heart defects (11%)
Growth deficiency (30%)
Malignancy (2-5%)
What is the most common gene associated with Diamond-Blackfan?
RPS19
Most cases are autosomal dominant
Multiple genes related to ribosomal function
What are the findings in Spherocytosis?
Anemia
Jaundice
Hemolytic crisis
Aplastic crisis (infection)
Pigment stones
Splenomegaly
The RBCs are more fragile than disc-shaped RBCs
What is the blood test performed with spherocytosis?
Osmotic fragility test
Hypotonic solutions will cause cells to lyse immediately
What is the therapy in spherocytosis?
Folic acid supplement
Monitor for iron overload
Abdominal ultrasound
-May need splenectomy
What are the genes associated with spherocytosis?
ANK1
SPTB
SPTA1
SLC4A1
EPB42
What is Elliptocytosis?
The RBCs assume an elliptical shape, rather than the typical round shape.
What are the genes associated with Elliptocytosis?
Genes affect the 4.1R complex:
SPTA1
SPTB
EBP41
GPC
What is the phenotype of Glucose 6 phosphate dehydrogenase deficiency (G6PD) in the newborn?
Prolonged hyperbilirubinemia
-20% of kernicterus assoc. with G6PD
-Kernicterus = bilirubin deposition in the brain, esp. basal ganglia
-Lethargy, poor muscle tone, progressing to brain damage
What is the phenotype of Glucose 6 phosphate dehydrogenase deficiency (G6PD) in the adult?
Hemolytic anemia
Splenomegaly
Anemia and fatigue
Jaundice
What triggers Glucose 6 phosphate dehydrogenase deficiency (G6PD)?
Fava beans!
Medications
Anti-malarial drugs
Infections
Which ethnicities have a higher occurrence of G6PD?
African, Mediterranean, and Asian descent
What is the mode of inheritance for G6PD and what type of mutations?
X-linked
Point mutations
LoF presumed to be lethal
What is the gene associated with Pyruvate Kinase Deficiency and what is the mode of inheritance?
PKLR gene
Autosomal recessive
What is the phenotype of Pyruvate Kinase Deficiency?
Chronic hemolytic anemia (unlike G6PD, which is triggered)
Leads to…
Kernicterus
Anemia
Jaundice
Splenomegaly
Gallstones
Iron overload
What is Thrombocytopenia?
Platelet count of less than 150K per microliter
What are the signs of Thrombocytopenia?
Frequent bruising
Nose bleeds
Heavy periods
What does TAR stand for?
Thrombocytopenia absent radius syndrome
What are the findings in TAR syndrome?
Absent radius, but thumbs are PRESENT
Thrombocytopenia
-Platelet count below 50 at birth or within first few weeks
-Platelets<50 = risk of brain hemorrhage
-Improves with time—hooray!
Cow’s milk allergy common and makes bleeding worse
Skeletal findings variable
Heart, GU findings at <20%,
Normal IQ and height
What is the genetic cause of TAR syndrome?
RBM8A
-One null allele (recurrent 200kb deletion which is inherited 75% of time)
-One hypomorphic allele
(Hypomorphic: a mutation that causes a partial loss of gene function)
What are the findings in Wiskott-Aldrich syndrome?
Congenital thrombocytopenia
Platelet count <70, with low MPV
Immune disorder:
Eczema
Recurrent bacterial or viral infection
Autoimmune disease (including vasculitis)
Malignancy/Lymphoma
What is the gene and mechanism associated with Wiskott-Aldrich syndrome?
WAS gene
X-linked
Females unaffected
What is the genetic cause of Hemophilia A?
Deficiency of Factor VIII (1/5000)
X-linked
What is the genetic cause of Hemophilia B?
Deficiency of Factor IX (1/15000)
X-linked
What is the phenotype of Hemophilia A and B?
Severe:
Bleeding from mouth injuries
Large hematomas from minor injuries
Spontaneous bleeding into joints and muscle
Moderate:
Prolonged bleeding/oozing after minor trauma
Mild:
Abnormal bleeding with surgery
What is the treatment for Hemophilia A and B?
Frozen plasma or cryoprecipitate
Replacement therapy: Clotting factor concentrates
What are the symptoms in Von Willebrand Disease?
Recurrent and prolonged nosebleeds
Bleeding from the gums
Increased menstrual flow
Excessive bleeding from a cut
What are the modes of inheritance in Von Willebrand Disease Types I, II, and III
Type 1: AD
(Partial quantitative deficiency of essentially normal VWF)
Type 2: AD or AR
(Qualitative deficiency of defective VWF)
-Domain specific (exon 28)
Type 3: AR
(Complete quantitative deficiency of (virtually absent) VWF)
-LoF and deletions
What is the treatment in Von Willebrand Disease type I?
DDAVP (desmopressin)
What are the Porphyrias?
A group of conditions in which heme synthesis is impaired
What are the symptoms of Porphyrias?
Acute types with neurovisceral crises (psychosis, neuropathy, and abdominal pain)
Cutaneous types with photosensitivity, painful rashes and blisters
What triggers Porphyrias?
Starvation
Drugs
Worse with menstrual cycles
What is the treatment for Porphyrias?
Acute therapy is IV glucose and hematin (synthetic heme) which shuts down the cycle
What are the complications of Porphyria?
Liver disease
Cancer
Kidney failure
What are the tests for porphyria?
Delta-ALA
Porphobilinogens
Urobilinogens (urine test)
