B3.068 Big Case Hemophilia

Question 1

functional elements of hemostasis

Answer 1

vascular wall (endothelium and subendothelial collagen)
platelets
von Willebrand factor
coagulation factors
calcium

Question 2

result of primary hemostasis

Answer 2

platelet plug

Question 3

result of secondary hemostasis

Answer 3

fibrin meshwork stabilized by cross-linking

Question 4

which clotting factors does thrombin stimulate in a positive feed back mechanism

Answer 4

11, 8a, 5a

Question 5

PT factors

Answer 5

TF (thromboplastin) , 7, common

Question 6

PTT factors

Answer 6

prekallikren, HMWK, 12, 11, 9, 8, common

Question 7

common factors

Answer 7

10, 5, 2 (prothrombin), 1 (fibrinogen)

Question 8

bleeding patterns associated with disorders of primary hemostasis

Answer 8

skin or mucosal bleeds
purpura, petechiae, ecchymosis
spontaneous bleeding

Question 9

bleeding patterns associated with secondary hemostasis

Answer 9

bleeds into soft tissue, muscle, joints
hemarthrosis
bleeding with trauma

Question 10

two classes of common acquired disorders of secondary hemostasis

Answer 10

acquired factor deficiencies

factor inhibitors

Question 11

3 causes of acquired factor deficiencies

Answer 11

liver disease
DIC
vitamin K deficiency - includes warfarin therapy

Question 12

why does liver disease cause factor deficiencies?

Answer 12

many coagulation factors are produced in the liver

Question 13

which factor is one of the easiest to monitor for deficiencies?

Answer 13

factor 7
shortest half life
is the first to deplete and usually has the most significant depletion
goes up and down the most

Question 14

which factors are vitamin K dependent?

Answer 14

2, 7, 9, 10

Question 15

3 factor inhibitory conditions

Answer 15

lupus anticoagulant
heparin therapy
specific factor inhibitors
-associated with treatment of factor deficiencies
-associated with autoimmune or lymphoproliferative disorders

Question 16

what is lupus anticoagulant and why is it a misnomer

Answer 16

autoantibody associated with increased PT, PTT
NOT associated with lupus directly
NOT associated with anticoagulant activity in vivo

Question 17

which factors are inhibited by heparin

Answer 17

factor 10, 2

Question 18

whats more common, acquired or inherited disorders of secondary hemostasis?

Answer 18

acquired more common

inherited super uncommon

Question 19

most clinically relevant inherited disorder of secondary hemostasis

Answer 19

factor 8 or factor 9 deficiency

Hemophilia A and B respectively

Question 20

what is interesting about factor 12, HMWK, and prekallikrein deficiencies?

Answer 20

no clinical relevance
discover through lab abnormalities, but have no legitimate risk for bleeding
patients just need to be aware to tell their clinicians

Question 21

where is factor 8 made

Answer 21

liver

Question 22

factor 8 half life

Answer 22

2.4 hours

12 hours if bound to vWF

Question 23

how do you measure factor 8 function?

Answer 23

PTT- screen

F8 activity- based on clotting assay using F8 deficient reagent (mixing study)

Question 24

where is vWf made

Answer 24

endothelial cells and platelets

Question 25

how do you measure vWf?

Answer 25

PFA-100 - screen vWf antigen- quantity vWf activity (ristocetin cofactor activity)- quality

Question 26

what is hemophilia

Answer 26

decreased factor 8 (A, 80%) | decreased factor 9 (B, 20%)

Question 27

genetics of hemophilia

Answer 27

X-linked - males affected, females carriers no family history in 30%- new mutations >500 mutations large gene deletions/insertions associated with most symptoms

Question 28

clinical manifestations of hemophilia

Answer 28

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

Question 29

why is bleeding into the oropharyngeal space so dangerous

Answer 29

can quickly compromise airway

Question 30

laboratory diagnosis of hemophilia

Answer 30

``` prolonged PTT (extent of prolongation doesn't correlate with factor level) decreased factor 8 or 9 level (only way to distinguish A from B) ```

Question 31

discuss how disease severity varies with residual factor levels

Answer 31

severe <1% moderate 1-5% mild 6-30%

Question 32

treatment of hemophilia

Answer 32

``` factor 8 or 9 concentrates -recombinant human (or bovine or porcine) supportive therapy -DDAVP -antifibrinolytic agents ```

Question 33

what should you NEVER do to treat hemophilia?

Answer 33

use blood products like cryoprecipitate | can get HIV or HCV (leading cause of death in hemophilia patients)

Question 34

what does DDAVP do

Answer 34

forces platelets and endothelial cells to release vWF | stabilizes more factor 8

Question 35

why do antifibrinolytic agents help with hemophilia

Answer 35

stop breakdown of clots do you have more available fibrin to help with clot formation

Question 36

factor 8 concentrate dose calculation

Answer 36

1 unit/kg body weight increases level by 2% dose = (target level - baseline) * body weight * 0.5 (unit/kg) dose twice daily

Question 37

factor 9 concentrate dose calculation

Answer 37

1 unit/kg body weight increases level by 1% dose = (target level - baseline) * body weight * 1 (unit/kg) dose once daily

Question 38

target factor levels for hemophilia treatment

Answer 38

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

Question 39

why might your body develop antibodies to factor 8 or 9?

Answer 39

if you have hemophilia and get these factors transfused, your body might recognize them as foreign and attack them

Question 40

incidence of Abs to F8 or F9

Answer 40

hemophilia A- 5-10% of all cases; 20% of severe cases | hemophilia B- 3-5% of all cases

Question 41

risk factors for Abs to F8 or F9

Answer 41

``` severe deficiency (<1% factor level) family history of inhibitor African descent large deletions or rearrangements of gene intensive therapy ```

Question 42

lab tests for detecting Abs to F8 or F9

Answer 42

PTT 1:1 mixing study | Bethesda assay- 1 BU = amount on inhibitor that neutralizes 50% factor activity at 2 h

Question 43

discuss results of the Bethesda assay and their clinical implications

Answer 43

low responder <5 BU : treated by upping dose | high responder >10 BU : have to use bypass agents to treat

Question 44

management of acute bleeding in people with Abs to F8 or F9

Answer 44

low responders - high dose recombinant human or porcine factor concentrate high responders - bypass agents

Question 45

how to reduce Abs to F8 or F9

Answer 45

immune tolerance induction | immunosuppression, anti-CD20 - variable effectiveness