Hematologic Disorders

Front 1

ACUTE INTERMITTENT PORPHYRIA

a) Responsible gene and locus?
b) Protein?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 1

a) HMBS at 11q23.3
b) porphobilinogen deaminase
c) AD
d) Onset after puberty, acute attaks, abdominal pain, muscle weakness, neuropathy, hysteria, anxiety, hepatocellular carcinoma, NO CUTANEOUS FINDINGS
e) increased urine delta-amonolevulinic acid (ALA) and porphobilinogen (PBG) during acute attack
f) HMBS gene sequencing (>98%)
g) ?direct neurotoxicity of PBG. ? generation of reactive oxygen species or inhibition of GABA release at central synapses by ALA, ?loss of heme in the CNS
h) stop of treat precipitant (medication, infection, EtOH, dehydration, smoking, poor caloric intake); intubate if bulbar paralysis, IV dextrose, IV hemin (repress ALAS-N enzyme activity); pain control

Front 2

ALPHA THALASSEMIA

a) Responsible genes and loci?
b) Proteins?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment/Prognosis?

Back 2

a) HBA1, HBA2 at 16p13.3-pter
b) Hemoglobin subunit alpha 1 and 2
c) AR;
If one parents mutations are in cis: risk for HbH
If both parents' mutations are in cis: risk for HB Bart
d) HB Bart-- loss of dysfunction of all 4 alpha thal alleles, hydrops fetalis, severe hypochromic anemia, death in neonatal period
HbH-- Loss or dysfunction of 3 of 4 alpha thal alleles, microcytic hypochromic hemolytic anemia, HSM, jaundice
Alpha Trait-- loss or dysfunction of 2 alpha thal alleles, low MCV, low MCH, nl levels of Hbg A2 and F
Alpha "silent" carrier-- loss of dysfunction of 1 alpha thal allele, none or mild thalassemia-like effects
e) MCV, MCH, peripheral smear, reticulocyte count, hemoglobin electrophoresis, prenatal screen of at risk populations
f) targeted mutation analysis for common deletions (90%), gene sequencing (10%)
g) Inability to form normal Hb A (normally composed of 2 alpha and 2 beta chains)
h) No tx for HB Bart, rec termination due to maternal complications with hy

Front 3

BETA THALASSEMIA

a) Responsible gene and locus?
b) Protein?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 3

a) HBB at 11p15.5
b) Hemoglobin subunit beta
c) AR
d) severe anemia and HSM; Without Tx: severe FTT and shortened life expectancy,. Thal intermedia: present later, milder anemia, only rarely requires transfusion,; at risk for iron overload due to inc interstiinal absorption of iron. The clinical severity of the beta thal syndromes depends on the extent of globin alpha chain/non-globin alpha chain imbalance. at risk populations: Mediterranean, middle eastern, indian, thai, chiniese, african, african american
e) microcytic hypochromic anemia, an abnl peripheral blood smear with nucleated RBCs, and reduced amounts of hemoglobin A (HbA) on hemoglobin analysis. Carriers: reduced MCV, MCH, and RBC morphologic changes that are less severe than in affected individuals
f) Mutation scanning/sequencing
g) Absence of globin beta chains. The non assembled globin alpha chains that result form unbalances globin alpha chain/non-globin alpha chain synthesis precipitate in the form of inclusions which damage

Front 4

FACTOR V LEIDEN THROMBOPHILIA

a) Responsible gene and locus?
b) Protein?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 4

a) F5 at 1q23
b) Coagulation factor V
c) AD or AR
d) Inc risk for venous thromboembolism (VTE), most commonly deep venous thrombosis (DVT). Heterozygous: at most modest inc in VTE recurrence risk 2-3x in RR pregnancy loss/ Homozygous: inc chance VTE recurrence. Arterial thrombosis , MI, stroke NOT associated with factor V leiden
e) APC resistance assay, sensitivity and specificity for factor V leiden approaches 100%
f) F5 G to A substitution at nt 1691 (100%)
g) The G>A substitution affects an APC cleavage site and the mutant factor V Leiden is inactivated 10x more slowly and persists longer in circulation
h) Risk of VTE compounded by coexisting thromboembolic d/o, malignancy, travel, central venous catheters, pregnancy, OCP, HRT, advancing age, surgery, organ transplant. Heterozygotes with first VTE with no id'ed risk factor or a persistent risk factor require longer course of anticoagulation than those with transient risk factor (eg surgery). Long term anticoagulation with LMW Heparin o

Front 5

HEMOPHILIA A

a) Responsible gene and locus?
b) Protein?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 5

a) F8 at Xq28
b) Coagulation factor VIII
c) X Linked Recessive
d) hemarthrosis or intracranial bleed with mild or no trauma; deep muscle hematomas, prolonged or renewed bleeding after trauma, surgery, tooth extraction, nose bleeds, mouth injury, or circumcision, excessive bruising
e) prolonged PTT, severe hemophilia: >1%, moderate: 1-5%, mild: 6-35% Factor VIII activity.
f) Severe: F8 intron 22-A gene inversion (45%), F8 intron 1 gene inversion (3%), F8 gene del or rearrangement, frameshift, splice junction, or nonsense mutations (40%), missense mutation (10%). Mild-moderate: missense mutation (97%).
g) Normal Factor VIII circulates as an inactivated clotting cofactor activated by thrombin. Severe mutations lead to absent protein, mild-mod mutations to abnormal protein.
h) IV Factor VII prophylactically 3x/wk in severe cases and after trauma, aboid IM injection, consider testing for HIV, Hep A, B, and C if hx of receiving blood products

Front 6

HEMOPHILIA B

a) Responsible gene and locus?
b) Protein?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 6

a) F9 at Xq27.1-q27.2
b) Coagulation factor IX
c) X linked recessive
d) hemarthrosis or intracranial bleed with mild to no trauma, deep muscle hematomas, prolonged or renewed bleeding after trauma, surgery, tooth extraction, nose bleeds, mouth injury, or circumcision, excessive bruising
e) prolonged PTT, severe: <1%, moderate: 1-5%, mild: 6-30% factor IX activity.
f) F9 sequence analysis (99%). Large gene deletions, nonsense mutations and most frameshift mutations cause severe disease
g) Factor IX activates factor X, which is a critical early step that can regulate the overall rate of thrombin generation in coagulation
h) Recombinant factor IX concentrate 2-3x/wk for severe deficiency and within one hour of trauma. Avoid IM injection. Consider testing for HIV, Hep A, B, C if hx of receiving blood products

Front 7

HFE-ASSOCIATED HEREDITARY HEMOCHROMATOSIS (HFE-HHC)

a) Responsible gene and locus?
b) Protein?
c) Inheritance?
d) Clinical Features and Diagnostic Criteria?
e) Clinical Tests?
f) Molecular Tests?
g) Disease Mechanism?
h) Treatment?

Back 7

a) HFE at 6p21.3
b) Hereditary hemochromatosis protein
c) AR (penetrance is low)
d) Inappropriately high iron absorption by the GI mucosa leads to excessibe iron storage in the liver, skin, pancreas, heart, joints, and testes. Early sx: abdominal pain, weakness, lethargy, and weight loss
e) Inc fasting transferrin-iron saturation (men >60%, women 50%, some use >45% as cutoff for both men and women) on at least 2 occasions, inc serum ferritin concentration (nonspecific for HHC), quantitative phlebotomy to determine iron quantity, liver biopsy, hepatic MRI
f) targeted mutation testing (60-90% C282Y/C282y; 3-8% C282Y/H63D)
g) HFE protein binds transferrin receptor 1 and is thought to reduce cellular iron uptake - mutation leads to inc iron uptake
h) if untreated: hepatic fibrosis or cirrhosis, increased skin pigmentation, DM, CHF, and/or arrhythmias, cardiomyopathy, arthritis, or hypogonadism. Treat with phlebotomy if symptomatic, aim for ferritin and transferrin iron saturation both <50%.