B3.068 Big Case Hemophilia Flashcards
functional elements of hemostasis
vascular wall (endothelium and subendothelial collagen) platelets von Willebrand factor coagulation factors calcium
result of primary hemostasis
platelet plug
result of secondary hemostasis
fibrin meshwork stabilized by cross-linking
which clotting factors does thrombin stimulate in a positive feed back mechanism
11, 8a, 5a
PT factors
TF (thromboplastin) , 7, common
PTT factors
prekallikren, HMWK, 12, 11, 9, 8, common
common factors
10, 5, 2 (prothrombin), 1 (fibrinogen)
bleeding patterns associated with disorders of primary hemostasis
skin or mucosal bleeds
purpura, petechiae, ecchymosis
spontaneous bleeding
bleeding patterns associated with secondary hemostasis
bleeds into soft tissue, muscle, joints
hemarthrosis
bleeding with trauma
two classes of common acquired disorders of secondary hemostasis
acquired factor deficiencies
factor inhibitors
3 causes of acquired factor deficiencies
liver disease
DIC
vitamin K deficiency - includes warfarin therapy
why does liver disease cause factor deficiencies?
many coagulation factors are produced in the liver
which factor is one of the easiest to monitor for deficiencies?
factor 7
shortest half life
is the first to deplete and usually has the most significant depletion
goes up and down the most
which factors are vitamin K dependent?
2, 7, 9, 10
3 factor inhibitory conditions
lupus anticoagulant
heparin therapy
specific factor inhibitors
-associated with treatment of factor deficiencies
-associated with autoimmune or lymphoproliferative disorders
what is lupus anticoagulant and why is it a misnomer
autoantibody associated with increased PT, PTT
NOT associated with lupus directly
NOT associated with anticoagulant activity in vivo
which factors are inhibited by heparin
factor 10, 2
whats more common, acquired or inherited disorders of secondary hemostasis?
acquired more common
inherited super uncommon
most clinically relevant inherited disorder of secondary hemostasis
factor 8 or factor 9 deficiency
Hemophilia A and B respectively
what is interesting about factor 12, HMWK, and prekallikrein deficiencies?
no clinical relevance
discover through lab abnormalities, but have no legitimate risk for bleeding
patients just need to be aware to tell their clinicians
where is factor 8 made
liver
factor 8 half life
2.4 hours
12 hours if bound to vWF
how do you measure factor 8 function?
PTT- screen
F8 activity- based on clotting assay using F8 deficient reagent (mixing study)
where is vWf made
endothelial cells and platelets
how do you measure vWf?
PFA-100 - screen
vWf antigen- quantity
vWf activity (ristocetin cofactor activity)- quality
what is hemophilia
decreased factor 8 (A, 80%)
decreased factor 9 (B, 20%)
genetics of hemophilia
X-linked - males affected, females carriers
no family history in 30%- new mutations
>500 mutations
large gene deletions/insertions associated with most symptoms
clinical manifestations of hemophilia
spontaneous or traumatic bleeding into, soft tissue, muscle
life threatening bleeding (CNS, oropharyngeal space, retroperitoneal space)
self limited hematuria
contractures, joint deformities secondary to hemarthrosis
why is bleeding into the oropharyngeal space so dangerous
can quickly compromise airway
laboratory diagnosis of hemophilia
prolonged PTT (extent of prolongation doesn't correlate with factor level) decreased factor 8 or 9 level (only way to distinguish A from B)
discuss how disease severity varies with residual factor levels
severe <1%
moderate 1-5%
mild 6-30%
treatment of hemophilia
factor 8 or 9 concentrates -recombinant human (or bovine or porcine) supportive therapy -DDAVP -antifibrinolytic agents
what should you NEVER do to treat hemophilia?
use blood products like cryoprecipitate
can get HIV or HCV (leading cause of death in hemophilia patients)
what does DDAVP do
forces platelets and endothelial cells to release vWF
stabilizes more factor 8
why do antifibrinolytic agents help with hemophilia
stop breakdown of clots do you have more available fibrin to help with clot formation
factor 8 concentrate dose calculation
1 unit/kg body weight increases level by 2%
dose = (target level - baseline) * body weight * 0.5 (unit/kg)
dose twice daily
factor 9 concentrate dose calculation
1 unit/kg body weight increases level by 1%
dose = (target level - baseline) * body weight * 1 (unit/kg)
dose once daily
target factor levels for hemophilia treatment
primary prophylaxis - 1%
surgical prophylaxis - 100% for 7-10 days tapered based on likelihood of bleeding
mild bleeding- 30-50% for several days
severe bleeding- 100% for several days
why might your body develop antibodies to factor 8 or 9?
if you have hemophilia and get these factors transfused, your body might recognize them as foreign and attack them
incidence of Abs to F8 or F9
hemophilia A- 5-10% of all cases; 20% of severe cases
hemophilia B- 3-5% of all cases
risk factors for Abs to F8 or F9
severe deficiency (<1% factor level) family history of inhibitor African descent large deletions or rearrangements of gene intensive therapy
lab tests for detecting Abs to F8 or F9
PTT 1:1 mixing study
Bethesda assay- 1 BU = amount on inhibitor that neutralizes 50% factor activity at 2 h
discuss results of the Bethesda assay and their clinical implications
low responder <5 BU : treated by upping dose
high responder >10 BU : have to use bypass agents to treat
management of acute bleeding in people with Abs to F8 or F9
low responders - high dose recombinant human or porcine factor concentrate
high responders - bypass agents
how to reduce Abs to F8 or F9
immune tolerance induction
immunosuppression, anti-CD20 - variable effectiveness
