Thrombophilias Flashcards
Hem A, Hem B, Protein C deficiency, Protein S deficiency, and Factor V Leiden
What lab features are seen in Hemophilia A
normal platelet count
prolonged activated partial thromboplastin time
normal prothrombin time
What lab features are seen in Hemophilia B
normal platelet count
prolonged activated partial thromboplastin time in those w severe/moderate dz; normal or mildly prolonged in pts w mild dz
normal prothrombin time
How is the dx of Hemophilia B established in a male proband? Female?
male w decreased factor 9 clotting activity
Severe: <1% F9 clotting activity
Moderate: 1-5% clotting activity
Mild: 6-40% clotting activity
identification of a hemizygous PV in F9 which can help to predict clinical phenotype
female w bleeding symptoms, decreased F9 clotting activity; and/or identification of a heterozygous PV clotting activity alone cannot identify heterozygous females since only 30% that are heterozygous have clotting levels lower than 40%
What molecular testing should be ordered for Hemophilia B
sequence analysis of F9 followed by del dup if the previous tests are negative
What are the clinical features associated with severe Hemophilia B
Usually dx in the neonatal period or within one yr of life
Hemarthrosis, especially with mild or no antecedent trauma (the most frequent manifestation)
Deep-muscle hematomas (causing pain)
Intracranial bleeding in the absence of major trauma
Neonatal cephalohematoma or intracranial bleeding
Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *
Prolonged or delayed bleeding or poor wound healing following surgery or trauma *
Unexplained gastrointestinal bleeding or hematuria *
Heavy menstrual bleeding, especially with onset at menarche
Prolonged nosebleeds, especially recurrent and bilateral *
Excessive bruising, especially with firm, subcutaneous hematomas
2-5 bleeding episodes per month
leading cause of death related to bleeding is intracranial hemorrhage; major cause of disability is joint pain
What are the clinical features associated with moderate hemophilia B
seldom have spontaneous bleeding, have prolonged or delayed oozing after relatively minor trauma and are usually dx before 5-6yo
bleeding episodes once a month to once a year
What are the clinical features associated with mild hemophilia B
do NOT have spontaneous bleeding
abnormal bleeding w sx, tooth extractions, and major injuries
bleeding episodes a few times a yr to once q10yrs
often not dx until later in life when they undergo sx or tooth excision or experience major trauma
What are the clinical features associated w hemophilia B in females
at risk for bleeding that is comparable to that seen in males with a similar severity of hemophilia
more subtle, abnormal bleeding may occur w baseline factor 9 clotting activity levels between 30-60%
What variants are directly correlated w disease severity in hemophilia B
alloimmune inhibitors occur much less frequently than in hemophilia A; occur with the greatest frequency (40-60%) in individuals w large partial (>50bp) dels, whole gene dels, or early termination variants; missense variants rarely associated
large dels, nonsense variants, and most frameshifts cause severe dz
missense variants can cause severe, moderate, or mild dz dependent on location and specific substitutions involved unlike hem A, severe hem B is often caused by a missense variant
What are the tx recommendations for pts w hemophilia B
Tx should be coordinated through a hemophilia treatment center
IV infusion of plasma-derived or recombinant factor IX to tx acute bleeding or prevent bleeding on a long term basis or prior to/following procedures.
peds issues: males w a FH of hemophilia B should NOT be circumcised unless hemophilia A is excluded or is tx w factor IX; immunizations should be given subcutaneously (not intramuscular if feasible)
for alloimmune tolerance against the first tx, gave use immune tolerance therapy
PT: use of musculoskeletal u/s aids in the eval of bleeding and helps to guide tx
gene therapy also exists and can achieve therapeutic levels in many individuals
PROPHYLACTIC TX IS CONSIDERED THE STANDARD OF CARE; greatest benefit is seen in those who start therapy before 2.5-3yo
How can you test for hemophilia B in pregnancy (in an unconventional way)
assay of factor 9 clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein; factor IX clotting activity in cord blood in a normal term newborn is lower than in adults; therefore, the dx of hemophilia B can be established in those w <1% activity but is not confirmed in those with moderately low activity
women w hemophilia B are NOT protected in pregnancy since factor 9 levels do not rise; they are more likely to need factor 9 infusion support for delivery and/or to tx or prevent postpartum hemorrhage
How is the dx of Hemophilia A established in a male proband? Female?
male w decreased factor 8 clotting activity and a normal, functional von Willebrand factor level
Severe: <1% F8 clotting activity
Moderate: 1-5% clotting activity
Mild: 6-40% clotting activity
identification of a hemizygous PV in F8 which can help to predict clinical phenotype
female w bleeding symptoms, decreased F8 clotting activity, and a normal functional von Willebrand factor level; and/or identification of a heterozygous PV clotting activity alone cannot identify heterozygous females since only 30% that are heterozygous have clotting levels lower than 40%
What molecular testing should be ordered for Hemophilia A
targeted analysis for intron 22 and intron 1 (45% of PVs in severe type) for those with (1) severe hemophilia, (2) females w a FH of hemophilia, (3) females w a FH of Hemophilia A of unknown severity and a PV is not known
sequence analysis of F8 followed by del dup if the previous tests are negative
What are the clinical features associated with severe Hemophilia A
Usually dx in the neonatal period or within one yr of life
Hemarthrosis, especially with mild or no antecedent trauma (the most frequent manifestation)
Deep-muscle hematomas (causing pain)
Intracranial bleeding in the absence of major trauma
Neonatal cephalohematoma or intracranial bleeding
Prolonged bleeding or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *
Prolonged or delayed bleeding or poor wound healing following surgery or trauma *
Unexplained gastrointestinal bleeding or hematuria *
Heavy menstrual bleeding, especially with onset at menarche
Prolonged nosebleeds, especially recurrent and bilateral *
Excessive bruising, especially with firm, subcutaneous hematomas
leading cause of death related to bleeding is intracranial hemorrhage; major cause of disability is joint pain
What are the clinical features associated with moderate hemophilia A
seldom have spontaneous bleeding, have prolonged or delayed bleeding after relatively minor trauma and are usually dx before 5-6yo
bleeding episodes once a month to once a year
What are the clinical features associated with mild hemophilia A
do NOT have spontaneous bleeding
abnormal bleeding w sx, tooth extractions, and major injuries
bleeding episodes a few times a yr to once q10yrs
often not dx until later in life when they undergo sx or tooth excision or experience major trauma
What are the clinical features associated w hemophilia A in females
at risk for bleeding that is comparable to that seen in males with a similar severity of hemophilia
25% of females w normal factor 8 clotting activity have a phenotype
What variants are directly correlated w disease severity in hemophilia A
F8 Intron 22 inversions are associated w severe hemophilia A and account for 45% of individuals w severe form
an inversion between 1kb sequence in intron 1 (3%) and an inverted repeat 5- to F8 is also associated w severe form
SNVs leading to stop codons are all associated w severe form, additionally frameshift variants
splice site variants often result in severe dz
missense variants are found in nearly all those w a dx of moderate/mild dz
What are the tx recommendations for pts w hemophilia A
Tx should be coordinated through a hemophilia treatment center
IV infusion of plasma-derived or recombinant factor VIII for bleeding episodes within an hour of noticing symptoms (individuals on emicizumab w bleeding or requiring major sx will need F8 supplementation; emicizumab therapy may be chosen in young children to provide hemostatic protection while avoiding IV infusions)
peds issues: males w a FH of hemophilia A should NOT be circumcised unless hemophilia A is excluded or is tx w factor VIII; immunizations should be given subcutaneously (not intramuscular if feasible)
for those w mild dz, and respond well, can give DDAVP (desmopressin acetate) which often doubles to triples F8 clotting activity
for alloimmune tolerance against the first tx, gave use immune tolerance therapy
PT: use of musculoskeletal u/s aids in the eval of bleeding and helps to guide tx
gene therapy also exists but is not curative, in the mild hemophilia range w tx
PROPHYLACTIC TX IS CONSIDERED THE STANDARD OF CARE; greatest benefit is seen in those who start therapy before 2.5-3yo
How can you test for hemophilia A in pregnancy (in an unconventional way)
assay of factor 8 clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein
women w hemophilia A are protected in pregnancy due to the natural rise of factor 8, but may experience post-partum hemorrhage
What is the de novo rate for hemophilia A? Likelihood mom is a carrier?
de novo: 30%
mom of a male proband who is a simplex case= 80% chance of being a carrier
if proband has an intron 22 inversion, mom has a 98% chance of being heterozygous, bc most intron 22 inversions occur in spermatogenesis
studies have shown varying frequencies of mosaicism ranging from 13-23% of mothers in apparent simplex cases
What test should NOT be ordered for carrier testing in hemophilia A
factor VIII clotting activity, or its ratio to von Willebrand factor level, is not a reliable test for determining genetic status; it can only be suggestive if low
What is the molecular pathogenesis for hemophilia A
synthesized primarily in the liver, is stabilized by binding to von Willebrand factor
LOF; abnormal gene products vary from deficiency caused by absence of detectable protein to those w normal levels of a dysfunctional protein
What is the prevalence of hemophilia B in relation to hemophilia A
hem B is about 1/5 as prevalent as hemophilia A
expect about the same severity as all other affected males in the family
