Hematologic disorders Flashcards
ACUTE INTERMITTENT PORPHYRIA
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Responsible gene: HMBS
Protein: Porphobilinogen deaminase
Cytogenetic locus: 11q23.3
Inheritance: AD
Clinical Features and Diagnostic Criteria: Onset after puberty, acute attacks, abdominal pain, muscle weakness, neuropathy, hysteria, anxiety, hepatocellular carcinoma, NO CUTANEOUS FINDINGS
Clinical Tests: increased urine delta-amonolevulinicacid (ALA) and porphobilinogen (PBG) during acute attack
Molecular Tests:HMBS gene sequencing (>98%)
Disease Mechanism: toxicity of ALA
Treatment: Stop or 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; liver transplantation
ALPHA THALASSEMIA
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Responsible genes: HBA1, HBA2
Protein names: Hemoglobin subunit alpha 1 and 2Cytogenetic locus (loci): 16pter-p13.3
Inheritance: AR; if parents Alpha Thaltrait, risk for HbHdisease if one parent’s mutations are in cis, at risk for HB Bart if both parents in cis
Clinical Features and Diagnostic Criteria: HB Bart: loss or dysfunction of all 4 alpha thalalleles, hydrops fetalis, severe hypochromic anemia, death in neonatal period; HbH: loss or dysfunction of 3 of 4 alpha thalalleles, microcytic hypochromic hemolytic anemia, HSM, jaundice Alpha Trait:lossor dysfunction of 2 alpha thalalleles, low MCV, low MCH, nllevels HgbA2 and F; Alpha “silent” carrier: loss or dysfunction of one alpha thalallele, none or mild thalassemia-like effect
Clinical Tests: MCV, MCH, peripheral smear, reticulocyte count, hemoglobin electrophoresis. Prenatal screen at risk populations!
Molecular Tests:Targeted mutation analysis for common deletions (90%); gene sequencing (10%)
Disease Mechanism: Inability to form normal HbA (normally composed of two alpha and two beta chains)
Treatment/Prognosis: No txfor HB Bart, rec termination due to maternal complications with hydrops; intrauterine blood transfusions, hematopoietic stem cell transplant emerging. HbH: prbctransfusions during hemolytic crisis, anemia causing cardiac sx, or severe bony changes; splenectomy with abxprophylaxis (if <5y) for splenomegaly
BETA-THALASSEMIA
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Responsible gene:HBB
Protein:Hemoglobin subunit beta
Cytogenetic locus: 11p15.5
Inheritance:AR
Clinical Features and Diagnostic Criteria: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 incintestinal absorption of iron. The clinical severity of the beta-thalsyndromes depends on the extent of globin alpha chain/non-globin alpha chain imbalance. At risk pop’s: Mediterranean, middle eastern, Indian, Thai, Chinese, African, African American.
Clinical Tests:microcytic hypochromic anemia, an abnlperipheral 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.
Molecular Tests:Mutation scanning/sequencing.In each at-risk population, 4-10 mutations account for the large majority of HBB disease. Compound heterozygosity for a mild/silent mutation and a severe mutation produces a variable phenotype, ranging from thalassemia intermedia to thalassemia major.
Disease Mechanism:Absence of globin beta chains. The non-assembled globin alpha chains that result from unbalanced globin alpha chain/non-globin alpha chain synthesis precipitate in the form of inclusions which damage the erythroid precursors in the bone marrow and spleen, causing ineffective erythropoiesis.
Treatment/Prognosis:Treat with a regular transfusion program and chelation therapy (to reduce transfusion iron overload), allows for normal growth and development and extends life expectancy into the third to fifth decade; bone marrow transplantation is curative
FACTOR V LEIDEN THROMBOPHILIA
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Responsible gene: F5Protein: Coagulation factor V
Cytogenetic locus: 1q23
Inheritance: AD (moderately inc.risk VTE), AR (significantly inc.risk VTE)
Clinical Features and Diagnostic Criteria: inc.risk venous thromboembolism (VTE), most commonly deep venous thrombosis (DVT). Heterozygous: at most modest inc.in VTE recurrence risk, 2-3x incRR pregnancy loss. Homozygous: Inc. chance VTE recurrence. Arterial thrombosis, MI, and stroke notassociated with factor V Leiden.
Clinical Tests: APC resistance assay, sensitivity and specificity for factor V Leiden approaches 100%
Molecular Tests:F5 G to A substitution at nt1691 (100%)
Disease Mechanism: 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-> inc.thrombin generation
Treatment/Prognosis: 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’edrisk factor or a persistent risk factor require longer course of anticoagulation than those with a transient risk factor (egsurgery). Long term anticoagulation with LMW Heparin or Warfarin if recurrent VTE, multiple thrombophilicd/o, coexistent circumstantial risk factors, and factor V Leiden homozygotes
HEMOPHILIA A
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Responsible gene: F8
Protein: Coagulation Factor VIII
Cytogenetic locus: Xq28
Inheritance: XLR
Clinical Features and Diagnostic Criteria: hemarthrosisor 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.
Clinical Tests: Prolonged PTT, severe hemophilia: <1%, moderate: 1-5%, and mild hemophilia 6-35% Factor VIII activity. 10% of carrier females have Factor VIII activity <35%.
Molecular Tests:Severe: F8 intron 22-A gene inversion (45%), F8intron 1 gene inversion (3%), F8 gene del or rearrangement, frameshift, splice junction, or nonsense mutations (40%), missense mutation (10%). Mild-moderate: missense mutation (97%)
Disease Mechanism: Normal Factor VIII circulates as an inactivated clotting cofactor activated by thrombin. Severe mutations lead to absent protein, mild-mod mutations to abnormal protein.
Treatment/Prognosis: IV Factor VIII prophylactically 3x/wkin severe cases and after trauma, avoid IM injection. Consider HIV, Hep A, B, and C testing if history of receiving blood products; DDAVP in mild cases
HEMOPHILIA B
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Responsible gene: F9
Protein: Coagulation factor IX
Cytogenetic locus: Xq27.1-q27.2
Inheritance: XLR
Clinical Features and Diagnostic Criteria: hemarthrosisor 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.
Clinical Tests: Prolonged PTT, severe hemophilia: <1%, moderate: 1-5%, and mild hemophilia 6-30% Factor IX activity. 10% of carrier females have Factor VIII activity <30%.
Molecular Tests:F9sequence analysis (99%). Large gene deletions, nonsense mutations, and most frameshift mutations cause severe disease.
Disease Mechanism: Factor IX activates Factor X which is a critical early step that can regulate the overall rate of thrombin generation in coagulation.
Treatment/Prognosis: Recombinant factor IX concentrate 2-3x/wkfor severe deficiency and within one hour of trauma. Avoid IM injection. Consider HIV, Hep A, B, and C testing if history of receiving blood products.
HFE-ASSOCIATED HEREDITARY HEMOCHROMATOSIS
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Responsible gene: HFEProtein: Hereditaryhemochromatosis protein
Cytogenetic locus: 6p21.3
Inheritance: AR (penetrance is low, a large fraction of homozygotes never develop symptoms.
Clinical Features and Diagnostic Criteria: Inappropriately high iron absorption by the GI mucosa leads to excessive iron storage in the liver, skin, pancreas, heart, joints, and testes. Early Sx: abdominal pain, weakness, lethargy, and weight loss.
Clinical Tests: 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
Molecular Tests:Targeted mutation testing (60-90% C282Y/C282Y; 3-8% C282Y/H63D.
Disease Mechanism: HFE protein binds transferrin receptor 1 and is thought to reduce cellular iron uptake-mutation leads to inc.iron uptake
Treatment/Prognosis: 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 <50, transferrin-iron saturation <50%
