Thalassemias/ Hemolgobinopathies

Question 1

How is the dx of Hb Bart established in a fetus

Answer 1

RBC Indices: severe macrocytic hypochromic anemia, reticulocytosis (increase in immature RBCs) (>60%); large, hypochromic RBCs w severe anisopoikilocytosis (RBCs of different sizes and shapes) and numerous nucleated RBCs
hemoglobin analysis that reveals decreased amts or complete absence of HbA and increased amts of Hb Bart (80-90%; also have Hb Portland)

molecular analysis w biallelic PVs in HBA1 and HBA2 that results in deletion or inactivation of all 4 alpha globin genes

Question 2

How is the dx of Hb H dz established in a proband

Answer 2

RBC Indices: mild to moderate microcytic hypochromic hemolytic anemia, reticulocytosis (increase in immature RBCs) (3-6%); anisopoikilocytosis (RBCs of different sizes and shapes) and rarely nucleated RBCs
hemoglobin analysis that reveals presence of HbH (0.8-40%) and of HbA (60-90%)

molecular analysis w biallelic PVs in HBA1 and HBA2 that results in deletion or inactivation of 3 alpha globin genes

Question 3

Describe the predicated trends in MCV, MCH, and Hb for dx of Hb Barts and HbH dz

Answer 3

Hb Bart: extremely high MCV (~135), avg MCH (~32), extremely low Hb (3-8)

HbH: low MCV (~56 in children, 61 in adults), low MCH (~19), low Hb (~10-11)

Question 4

Describe the chemical make up of the following hemoglobin chains:
HbA, HbF, Hb Bart, HbH, HbA2, Hb Portland

Answer 4

HbA: two alpha globins and two beta globins
HbF: two alpha globins and two gamma globins
Hb Bart: four gamma globins
HbH: four beta globins
Hb A2: two alpha globins and two delta globins
Hb Portland: Two zeta globins and two gamma globins

Question 5

What molecular testing is ordered for alpha thal

Answer 5

targeted del analysis for common dels of HBA1 and HBA2, sequence analysis for HBA1/HBA2, del dup analysis, and the regulatory region multispecies conserved sequence 2 (MCS-R2) for uncommon dels

common dels of two alpha globins include: southeast Asian del (–SEA), Filipino del (–FIL), Mediterranean del (–MED)

other common dels including a 3.7kb del and a 4.2kb del

Question 6

What are the clinical features associated w Hb Bart

Answer 6

affected fetuses are either delivered stillborn at 30-40wks or die soon after birth
generalized edema, pleural and pericardial effusions as a result of congestive heart failure induced by severe anemia
RBCs have an extremely high oxygen affinity and are incapable of effective oxygen delivery
marked hepatosplenomegaly, massive placenta, brain growth delays, hydrocephalus, cardiovascular deformities, urogenital defects

Question 7

What maternal complications can occur in pregnancy w a fetus w Hb Bart

Answer 7

preeclampsia, polyhydramnios, oligohydramnios, antepartum hemorrhage, premature delivery

Question 8

What are the clinical features associated w Hb H dz

Answer 8

usually only dx during routine hematologic analysis in an asymptomatic individual
majority have splenomegaly and less commonly of the liver; mild jaundice, mild to moderate thalassemia-like skeletal changes (hypertrophy of maxilla, bossing of the skull, prominence of the malar eminences)
gallstones, acute episodes of hemolysis in response to oxidant drugs/infections
majority have minor disability but some have severe symptoms requiring regular blood transfusions

Question 9

What are the genotype phenotype correlations for alpha thal

Answer 9

Hb Bart: dels on both alleles; rarely can have a non del variant (–/aND-)
HbH: individuals homozygous for HBA2 PVs (aND-/aND-) may have dz; rarely, HbH is caused by compound heterozygosity for an MCS-R2 del and an additional alpha gene del ((aa)MCS-R2/-a)

Question 10

Describe the features of someone who is an alpha thal silent carrier and someone who has alpha thal trait

Answer 10

alpha thal silent carrier: -a/aa; some globin production on one chromosome 16
alpha thal trait (null): cis (–/aa); zero alpha globin protein is produced from one chrom 16
alpha thal trait (+): trans (-a/-a); some alpha globin protein is produced from each of 2 chromosomes 16

Question 11

What is the standard genotype nomenclature for alpha thal

Answer 11

in the expression of aa/aa, the first alpha in each pair typically refers to HBA2 and the second alpha in each pair to HBA1
HBA2 encodes two to three times more globin than HBA1

Question 12

Describe the prevalence of alpha thal in the African, Mediterranean, Arabian Peninsula, Indian, and Southeast Asian

Answer 12

Africa: alpha 3.7kb del is common
Mediterranean: alpha 3.7kb del is common; Hb Bart rarely reported; High heterogeneity of variants, particularly the non del variants
Arabian: alpha 3.7kb del
India: both 3.7 and 4.2kb del are common
SE Asian: null alleles (cis) and alpha thal trait (+) are very common, causing a major public health burden

Question 13

What are the recommended txs for Hb Bart

Answer 13

40-50% of survivors had growth restriction and 20% had neurodevelopmental delay, congenital anomalies were common
in utero transfusions associated w earlier resolution of hydrops, delivery closer to term, and better neuro outcomes
do not stay alive long, need lifelong blood transfusions

Question 14

What are the recommended txs for HbH dz

Answer 14

most are clinically well and survive w out any tx
those w non-deletional HbH who have biallelic PVs in HBA2 may be more severely affected, ie, transfusion dependent

may need occasional blood transfusions if the Hb level suddenly drops bc of hemolytic or aplastic crises
iron chelation therapy may be needed in those w iron loading caused by regular blood transfusion, inappropriate iron therapy, or abnormal iron absorption (only one approved is deferasirox)
splenectomy for those w massive splenomegaly or hypersplenism (antimicrobial prophylaxis is usually given until at least 5yo to prevent sepsis

regular folic acid supplementation

Question 15

What is the recommended surveillance for those w HbH dz

Answer 15

hematologic eval q6-12mo to determine levels of Hb
in children, assessment of growth q6-12mo
monitor for iron overload w serum ferritin

Question 16

What is the molecular pathogenesis for alpha thal

Answer 16

inactivation of HBA1 or HBA2 reduces production of alpha globin chains; thus the more alpha globin genes inactivated, the fewer alpha globin chains are synthesized, leading to an increasing imbalance between alpha globin and beta globin chains
The expression of HBA1 and HBA2 is regulated through the MCS-R2 region located ~40kb upstream from the alpha globin cluster. Del of MCS-R2 results in alpha thal phenotype in spite of the structural integrity of both alpha globin genes

Question 17

How is the dx of beta thal established in a proband younger than 12mo

Answer 17

Complete absence of HbA on NBS
Biallelic PVs in HBB
reduction of HbA levels in infants w B+ thal overlaps w the normal range in healthy infants; therefore, genetic testing is REQUIRED to dx infants younger than 12mo

Question 18

How is the dx of beta thal established in probands older than 12mo

Answer 18

identification of microcytic hypochromic anemia, absence of iron deficiency, anisopoikilocytosis w nucleated RBCs, and decreased or complete absence of HbA and increased HbA2 w or w/out increased HbF on hemoglobin analysis

Question 19

What are the expected RBC indices for a pt w beta thal

Answer 19

major: low MCV, low MCH, very low Hb
intermedia: low MCV, slightly low MCH, very low Hb
minor: minorly low MCV, low MCH, minorly low Hb

microcytosis, hypochromia, anisocytosis, poikilocytosis, nucleated RBCs (# of nucleated RBCs is related to the degree of anemia)
beta thal minor: microcytosis, hypochromia, and target cells

Question 20

What are the expected hemoglobin elec results for beta thal

Answer 20

major: HbA (near 0), HbF (up to 95%), HbA2 (>5%)
intermedia: HbA (10-50%), HbF (10-50%), HbA2 (>4%)
minor: HbA (>88%), HbF (<5%), HbA2 (>4%)

Question 21

What molecular testing would you order for beta thal

Answer 21

single gene testing; sequence then del dup (rare)
analysis is complicated by the presence of highly homologous gene family members AND a pseudogene

targeted analysis can be performed first in individuals of specific at-risk pops

Question 22

What are the clinical features associated w beta thal major

Answer 22

occurs between 6-24mo
progressive pallor, poor weight gain, stunted growth, feeding problems, diarrhea, irritability, recurrent fever, hepatosplenomegaly causing enlargement of abdomen (if dx before 24mo and blood transfusions started, growth and development will progress normally until at least 10-11yo)

after 10-11yo, affected individuals are at risk for severe complications related to iron overload –> stunted growth, failure of sexual maturation, heart involvement (arrhythmias, DCM), liver cirrhosis/fibrosis, endocrinopathies

complications of iron chelation: ocular toxicity, hearing loss, liver injury, proteinuria, impaired renal filtration, agranulocytosis, injection site rxn

if untx: poor musculature, leg ulcers, skeletal changes from bone marrow expansion (deformities of the long bones in the legs, craniofacial changes, osteoporosis)

Question 23

What is the prognosis of beta thal major

Answer 23

life expectancy greatly diminished in low resource settings, w more than half dying before 30yo compared to more than half living to 60yo in high resource settings

Question 24

What are the clinical features associated w beta thal minor

Answer 24

pallor, jaundice, cardiac dz, cholelithiasis, hepatosplenomegaly, moderate to severe skeletal changes, leg ulcers, pulmonary HTN, thrombotic complications
RBC transfusions may become regularly needed over time or due to complications
iron overload mainly from increased intestinal absorption of iron caused by hepcidin deficiency; complications of iron overload present later in individuals but can be as severe as those in the major form

Question 25

What are genotype/phenotype correlations in beta thal

Answer 25

B0 variants: absent hemoglobin subunit beta production; nonsense, frameshift, and some splice variants; biallelic variants typically result in beta thal major

B+ variants: reduced hemoglobin subunit beta production; intronic, promoter, poly A signal, 5’ and 3’ untranslated region as well as some splicing variants; biallelic variants can be associated w intermedia or minor; B+ and B0 can cause beta thal major; B+ silent variants and B0 can cause a mild phenotype

HBB Pvs can be associated w AD Beta thal intermedia: results in hyper unstable hemoglobins; most are in exon 3

double heterozygosity for beta and alpha thal dup increases imbalance in the ration of alpha/non-alpha globin chains which cause beta thal intermedia in heterozygotes

Question 26

In what populations is beta thal prevalent

Answer 26

Mediterranean, Middle East, Central and Southeast Asia, Indian subcontinent, African decent

Question 27

What are the tx recommendations for beta thal major

Answer 27

HSCT is an alternate to RBC transfusions and iron chelation; if successful, iron overload may be reduced by repeated phlebotomy and therefore iron chelation is no longer necessary
gene therapy for curative therapy: gene editing can either introduce a functional beta globin chain or silence BCL11A to induce gamma globin chain production; betibelogene autotemcel yields transfusion independence in 91% who are NOT homozygous for B0 alleles; exagamglogene autotemcel: success in more than 95% of individuals

Supportive therapy
RBC transfusions: q2-4wks
Chelation therapy to prevent transfusional iron overload: deferoxamine B, deferiprone, deferasirox

VTE at an increased rate, even in spleen intact individuals but splenectomy is an additional significant risk factor, need indefinite anticoagulation
cholecystectomy in those w biliary colic
osteoporosis tx w HRT, RBC transfusions and iron chelation, vitamin D supplementation

Question 28

What are the tx recommendations for beta thal intermedia

Answer 28

splenectomy should be discussed w a clinician bc of risk factors (VTE/ pulmonary HTN)
folic acid supplementation
cardiac dz: MRI to assess myocardial iron deposition and assessment of cardiac function is vital; iron chelation should be initiated or increased when cardiac iron deposition is identified

VTE at an increased rate, even in spleen intact individuals but splenectomy is an additional significant risk factor, need indefinite anticoagulation
cholecystectomy in those w biliary colic
osteoporosis tx w HRT, RBC transfusions and iron chelation, vitamin D supplementation

Question 29

What should be done for newborn sibs of those w beta thal

Answer 29

HBB molecular testing can allow for the dx without having to wait for the hemoglobin shift
initial screening for those older than 12mo can including CBC since the absence of microcytosis rules out all beta thals

Question 30

What testing should be offered to suspected carriers of beta thal and what will the results be

Answer 30

red cell indices
microcytosis (low MCV) and reduced content of Hb per blood (MCH) w normal iron studies
hemoglobin elec
show hemoglobin A2 >3.5%

alpha thal carriers are easily distinguishable since they have normal HbA2 levels; remember that coinheritance of alpha thal may normalize blood indices although HbA2 concentration will stay in heterozygote range

B+ silent carriers are associated w consistent residual output of beta globin chains, normal RBC indices, and normal/borderline HA2

Question 31

What is the molecular pathogenesis of beta thal

Answer 31

HBB spans 1.6kb containing 3 exons, 5’ and 3’ UTRs; is regulated by an adjacent 5’ promoter and an upstream regulatory element called the locus control region (LCR)

complex beta thal result from various contiguous dels within the HBB gene cluster; beta thal can also be caused by the del of LCR

Question 32

What is the etiology for Hemoglobin C? How can it present?

Answer 32

lysine is substituted for glutamate in the sixth position of the beta globin chain making it less soluble than Hb A

in people who are homozygous, can present w mild chronic hemolysis, splenomegaly, and jaundice; typically though does not develop into serious complications

Question 33

Where is hemoglobin C most prevalent

Answer 33

in Atlantic W Africa and SE Asia due to the protective effect against Malaria infections

Question 34

What are the clinical features associated with HbCC?
HbSC?

Answer 34

HbCC: mild, most do not have symptoms; some may have mild hemolytic anemia and complain of fatigue, tiredness, weakness, paleness of the skin; mild to moderate splenomegaly, occasionally jaundice; some can have cholelithiasis
HbSC: symptoms that are generally similar but more mild than hemoglobin SS dz (SCA); can have acute vaso-occlusive crises but less frequently; most often present w vascular retinopathy and avascular necrosis of the femoral head

Question 35

What evals should be done for pts with hemoglobin CC?

Answer 35

CC: evals should be done for pts w a moderate to severe clinical course; induces red cell dehydration causing them to have a high MCH; mostly show HbC, HbA is absent and HbF is slightly increased; presence of hexagonal or tetragonal crystals due to decreased solubility of HbC

Question 36

What is the tx for a pt w hemoglobin C?

Answer 36

no tx is required except for folic acid, which can be depleted from body stores due to chronic hemolysis

Question 37

What is the etiology of G6PD?

Answer 37

plays a vital role in preventing cellular damage from reactive oxygen species
inherited deficiencies of G6PD can result in acute hemolytic anemia during increased ROS production caused by stress or exposure to foods containing high amounts of oxidative substances, such as fava beans or certain meds
most are point mutations; none of the mutation patterns seen in humans cause complete inactivation of G6PD since this would be lethal to a developing embryo

G6PD is the most common human enzyme defect affecting over 400 million people worldwide

Question 38

What are the clinical features associated with G6PD deficiency

Answer 38

although most are asymptomatic, some may manifest depending on their age
serious risk factor for the development of neonatal hyperbilirubinemia- can include lethargy, extreme sleepiness, and poor muscle tone

in adults: common symptoms and exam findings of G6PD include hemolytic anemia, pallor, jaundice, fatigue, splenomegaly, and dark urine

Question 39

What tx is recommended for pts w G6PD deficiency

Answer 39

in neonatal pts, tx focuses on managing jaundice and preventing kernicterus including phototherapy and in severe cases, an exchange transfusion may be necessary

less severe presentations may be managed w supportive care, discontinuation, and avoidance of the offending agents

Question 40

How is the dx of SCD established on NBS

Answer 40

identifies the relative quantification of hemoglobins using isoelectric and/or high performance liquid chromatography on an elute of dried blood spots
normal NBS result is “FA”= HbF> HbA
infants w HbS identified on NBS require additional confirmatory testing of a separate blood sample within four weeks

Question 41

How can the dx of SCD be established

Answer 41

identification of significant quantities of HbS w or without an additional abnormal and pathogenic beta globin chain variant by hemoglobin assay and/or identification of biallelic HBB PVs including AT LEAST one p.Glu6Val

Question 42

What on hemoglobin assay is indicative of SCD

Answer 42

identifies adult hemoglobins and fetal hemoglobin which decreases over the first yr of life
identification of HbS as the sole adult beta chain on Hb assay indicates either Hb S/S (normal MCV and low HbA2) or Hb S/B0- (low MCV and high HbA2) thalassemia (hemolysis and anemia by 6-12mo)
HbS/B0 thal and Hb S/B+ thalassemia are distinguished by the presence of HbA in individuals w S/B+ thal, but HbA is below that observed in sickle cell trait (low MCV, high HbA2)
Identification of HbS and an additional beta chain variant on Hb assay can establish the dx in individuals who are compound heterozygous for specific HBB PVs (ex: HbC; milder anemia and hemolysis; normal to low MCV, low HbA2)

Question 43

What hemoglobins would be identified in a newborn at 6 wks w SCD: S/S, S/B0, S/B+, S/C

Answer 43

SS: HbF, HbS
SB0: HbF, HbS
SB+: HbF, HbS, HbA
SC: HbF, HbS, HbC

Question 44

What molecular testing should be ordered for SCD

Answer 44

Sequence analysis (100%) of HBB then del dup

targeted analysis (allele-specific PCR) can be performed to detect HBB PV p.Glu6Val and to distinguish individuals w Hb S/S from those w sickle trait (Hb A/S)

Question 45

What clinical features are associated w SCD

Answer 45

vaso-occlusive events: ischemia/reperfusion damage to tissues that lead to pain and acute or chronic injury affecting any organ system; most frequent cause of recurrent morbidity; results from multicellular aggregates that block blood flow in small blood vessels, depriving downstream tissues of nutrients and oxygen causing excruciating, chronic pain
chronic hemolysis: associated w chronic anemia; increased risk of developing pulmonary artery HTN, priapism, gallstones, leg ulcers, nephropathy
dactylitis (pain and/or swelling of the hands or feet)
splenic sequestration (10-30%): between 6mo-3yrs; acutely enlarging spleen w very low hemoglobin; abdominal pain, nausea, vomiting, lethargy, irritability; contributes to the increased risk of sepsis and infection
infection: increased risk for osteomyelitis, acute chest syndrome, parvovirus an important cause of aplastic crisis
ACS: major cause of mortality; develops in the setting of vaso-occlusive episode; can progress rapidly (hrs or days) requiring intubation and mechanical ventilatory support
neuro: 50% by 14yo; ischemic stroke: most catastrophic symptoms; hemiparesis, monoparesis, seizures, aphasia/dysphagia, cranial nerve palsies, mental status changes; silent cerebral infarcts w/out known focal neurologic symptoms but associated w neurocognitive deficits
aplastic crises: temporary interruption of RBC production resulting in potentially life threatening anemia (sickles only last 7-12ds compared to normal lifespan of 100-120ds)
PAH in 6-35%
priapism (painful, unwarranted erections) is very common
kidney dz: accumulation of multiple renal insults; >50% w SCD were shown to have elevated glomerular filtration rates; acute kidney injury, hematuria, UTIs, pyelonephritis, renal medullary carcinoma
Other: retinopathy, cardiomyopathy, delayed growth and sexual maturation; those w HbC are at particularly high risk for retinopathy and avascular necrosis

Question 46

What laboratory findings are consistent w a vaso-occlusive crisis

Answer 46

high WBC count
low fetal hemoglobin level
co-existing alpha thal trait
vessel flow resistance related to deoxygenation

Question 47

What lab findings are consistent w chronic hemolysis in pts w SCD

Answer 47

Elevated plasma levels of lactate dehydrogenase
low hemoglobin level
high reticulocyte count
elevated LDH
leg ulcers, priapism, PAH, systemic HTN, platelet activation, chronic anemia, jaundice, predisposition to aplastic crises, cholelithiasis
co-existing alpha thal trait is protective against this phenotype

Question 48

What is the prognosis for pts w SCD

Answer 48

Median survival around 43yo
main causes of death are infection, ACS, PAH, and cerebrovascular events

children w high rates of death from infection and sequestration crises, whereas adult mortality is secondary to chronic end-organ dysfunction, thrombotic dz, and tx-related complications

Question 49

What are the clinical features associated with sickle cell trait

Answer 49

not anemic and have normal RBC indices, HbS % near 40, survival advantage in children who contract malaria (usually asymptomatic)
extremes of physical exertion, dehydration, and/or altitude can induce sickle cell vaso-occlusive events
renal medullary carcinoma is an extremely rare form of kidney cancer almost exclusively in those w sickle cell trait
NOT associated w avascular necrosis, stroke, leg ulcers, or cholelithiasis

Question 50

What is a genotype/phenotype correlation associated with SCD

Answer 50

Individuals w Hb SS and SB0 thal are more severely affected than individuals w Hb S/C or S/B+ thal

presence of alpha thal may modify SCD severity by improving RBC survival and decreasing hemolysis

Question 51

What are the tx recommendations for those w SCD

Answer 51

Disease Modulating Pharmacotherapy
hydroxyurea: decreased pain, decreased hospitalizations, decreased episodes of ACS, decreased need for transfusion, primary stroke prevention, increased life span; is safe in children @6mo
L-glutamine: involved in many pathways that affect SCD, decreasing acute events by 25%
Voxelotor: oral agent that binds hemoglobin and increases its affinity for oxygen, decreasing hemolysis whether on hydroxyurea or not

Transplantation
HSCT: from a healthy donor w no HBB PV or a donor w sickle cell trait can be CURATIVE; chance of cure must be weighed against the consequences: chronic GVHD, cardiac abnormalities, infertility

Gene therapy: Exagamglogene; Lovotibeglogene
individuals w SCD have been cured w an increase in myeloid malignancy; should be considered for those w severe dz who do not have a matched sib donor

Question 52

What are supportive txs needed for pts w SCD

Answer 52

Lifelong comprehensive care
penicillin prophylaxis prevents 84% of sepsis if started by age 2mo
timely administration of vaccines
folic acid supplementation to support increased RBCs synthesis
chronic RBC transfusion therapy can decreased the # of RBCs at risk to sickle, significantly reducing the risk of pain, stroke, ACS, and other complications. May be warranted for the following:
primary prevention of stroke and recurrence, tx of chronic pain, pulmonary HTN, chronic kidney failure, recurrent episodes of ACS, severe end-organ damage

vasco-occlusive crises: oral hydration and oral analgesics including NSAIDs and opiates; severe episodes require hospitalization and adjunctive txs like massage and PT; transfusion and hydroxyurea are NOT helpful
splenic sequestration: may progress rapidly to cardiovascular collapse and death; emergency RBC transfusion is indicated when signs of cardiovascular instability are present
fever/suspected infection: urgent CBC w differential and reticulocyte count, blood culture and chest radiograph for sepsis and ACS; broad spectrum antibiotics
ACS: chest radiograph, aggressive tx w oxygen, analgesics, antibiotics; simple RBC transfusion may be required for those who are critically ill
stroke: any hx of neurologic symptom requires emergent eval w CBC and reticulocyte count and brain CT exam
silent cerebral infarcts: chronic transfusion, MRI surveillance q12-24mo to assess for progression
aplastic crises: monitor hematocrit, reticulocyte, and cardiovascular status are required
priapism: require urgent eval and tx, including hydration and analgesia, may require aspiration and irrigation
kidney dz: ACE inhibitors or angiotensin II receptor blockers are recommended

Question 53

If the PV in a family w SCD is unknown, what is the gold standard to test relatives at risk

Answer 53

combination of high performance liquid chromatography or isoelectric focusing combined w CBC and reticulocyte count

as microcytosis helps guide interpretation of results, a measure of iron status such as zinc protoporphyrin test or serum iron and total iron-binding capacity is of benefit

Question 54

What is the recommended pregnancy management for those w SCD

Answer 54

Increased risk for thrombosis, infectious complications, acute painful episodes, ACS, preeclampsia, maternal death; stop hydroxyurea, generally not advised to do chelation therapy

fetus: preterm birth, IUGR, stillbirth, perinatal mortality

Question 55

What is the molecular pathogenesis for SCD

Answer 55

HBB encodes hemoglobin beta chain; Sickle hemoglobin results specifically from the p.Glu6Val variant
GOF
if sickle beta thal dz is suspected, consider HBB sequence analysis and del analysis as dels, frameshift, nonsense, and missense variants have been reported, including the 5’ and 3’ UTR and deep intronic regions

Question 56

How is the dx of von Willebrand dz established

Answer 56

in a proband w excessive mucocutaneous bleeding and characteristic results of assays of hemostasis factors specific for VWD and/or heterozygous, homozygous, or compound heterozygous PV(s) in VWF on molecular testing

the dx requires a positive FH but FH may not be positive because of incomplete penetrance and variable expressivity

Question 57

What are the different types of von Willebrand dz

Answer 57

Type 1: partial quantitative deficiency of essentially normal VWF
Type 2: qualitative deficiency of defective VWF
Type 3: complete quantitative deficiency (virtually absent) VWF

Question 58

What clinical laboratory testing should support the dx of von Willebrand dz

Answer 58

normal CBC or could show microcytic anemia or a low platelet count (thrombocytopenia, may be in T2)
normal activated partial thromboplastin time (aPTT)
normal prothrombin time

hemostasis factor assays: give guidance on the measurement of von Willebrand factor activity; if abnormalities are identified, specialized coagulation labs may also perform more assays to determine the subtype of VWD

Question 59

What molecular testing should be ordered for von Willebrand dz

Answer 59

sequence of VWF followed by del dup
analysis of exons 23-34 is complicated by the presence of a partial pseudogene, VWFP1

Question 60

What are the clinical features associated with von Willebrand dz

Answer 60

congenital bleeding disorder but features may become apparent w increasing age; do NOT tend to have musculoskeletal bleeding
Bruising without recognized trauma
Prolonged, recurrent nosebleeds
Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions
Menorrhagia, particularly if occurring since menarche
Prolonged bleeding following surgery, trauma, or childbirth
Gastrointestinal bleeding

there is an inverse relationship between the VWF level and the severity of bleeding

Question 61

Describe the clinical features associated with the different forms of von Willebrand dz (Type 1, 2A, 2B, 2M, 2N, 3)

Answer 61

Type 1: ~30% of all cases, mild mucocutaneous bleeding; epistaxis and bruising are common symptoms among children. Menorrhagia is the most common finding in women of reproductive age
Type 2: ~60% of all cases, frequency is 2A> 2M > 2N > 2B
A: mild to moderate mucocutaneous bleeding
M: mild to moderate mucocutaneous bleeding but bleeding episodes can be severe
N: same symptoms as those seen in hemophilia A, excessive bleeding at the time of sx or procedures since both conditions result from reduced FVIII activity
B: mild to moderate mucocutaneous bleeding; thrombocytopenia may be present, worsening of thrombocytopenia during stressful situations
Type 3: ~10% of all cases; severe bleeding including both excessive mucocutaneous bleeding and musculoskeletal bleeding; can have gastrointestinal angiodysplasia (also seen in 2A) affecting the colon, small intestine, and stomach

Question 62

What is the penetrance for von Willebrand dz

Answer 62

TYPE 1
PVs resulting in low VWF levels (<25) are mostly fully penetrant. Those w higher levels are often incompletely penetrant
Individuals w non O blood groups have higher VWF levels than those w O blood group; those w group AB have the highest
OTHER AD TYPES (2B, 2A, 2M): often fully penetrant

Question 63

What txs are available for someone w von Willebrand dz

Answer 63

desmopressin: promotes release of stored VWF and raises levels 3-4fold; contraindicated in those w arteriovascular dz and in those older than 70yo
IV infusion of VWF/FVIII clotting factor concentrates: for those who are non-responsive to desmopressin and for those in whom desmopressin is contraindicated, bleeding episodes can be prevented or controlled (called VWF Vonvendi)

indirect txs: fibrinolytic inhibitors: for tx or prevention of bleeding episodes; hormonal txs: combined oral contraceptive pill for the tx of menorrhagia

Question 64

What txs of von Willebrand dz are useful for each type of the dz?

Answer 64

Type 1: desmopressin or VWF/FVIII clotting factor concentrates are usually only needed for the tx or prevention of severe bleeding; indirect txs are often effectives
Type 2A: tx w clotting factor concentrates usually only required for the tx or prevention of severe bleeding episodes; responsiveness to desmopressin is variable, indirect tx can be beneficial
Type 2B: Clotting factor concentrates are usually required to treat severe bleeding or at the time of surgery. Treatment with desmopressin should be undertaken cautiously as it can precipitate a worsening of any thrombocytopenia. Indirect tx can be useful
Type 2M: desmopressin response is poor, use VWF/FVIII concentrates as tx
Type 2N: desmopressin can be used for minor bleeding but FVIII level will drop rapidly so concentrate containing VWF AND FVIII is required for sx procedures
Type 3: repeated infusion of VWF/FVIII clotting factor concentrates; desmopressin not effective, indirect txs may also be beneficial

Question 65

What are some pediatric issues in von Willebrand dz

Answer 65

infant males should be circumcised only after consultation w pediatric hemostasis specialist
VWF levels are higher in the neonatal period; thus phenotypic testing for milder forms of VWD should be delayed until later in childhood
meds that affect platelet formation (NSAIDs) should be avoided as they can worsen bleeding symptoms

Question 66

What are the pregnancy recommendations for someone with von Willebrand dz

Answer 66

VWF levels will increase throughout pregnancy with the peak occurring 4hrs after delivery
pregnant ppl w VWD are at increased risk for bleeding complications and care should be provided in centers
delayed, secondary postpartum bleeding may be a problem. VWF levels rapidly return to pre-pregnancy level following delivery

Question 67

How is von Willebrand dz inherited

Answer 67

types 2B and 2M are AD
types 1 and 2A are AD but may also be inherited as AR
types 2N and 3 are AR

Question 68

Do heterozygotes of von Willebrand dz have clinical features

Answer 68

those that are carriers of type 3 are often asymptomatic but between 15-50% may show some mild bleeding symptoms and may be dx w type 1