Young woman with a bleeding diathesis

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Young woman with a bleeding diathesis
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JM 24 y.o W/F with history of severe factor XII
deficiency HPI 1 day history of R upper back
pain, which feels like her typical hemorrhage
pain Denies trauma, muscle strain from activity,
or other current sites of hemorrhage PT 15.6,
PTT gt150 Received 2 units FFP overnight,
Dilaudid for pain C/O itching, swelling of
eyes, tongue, hives, chest tightness Epinephrine,
Benadryl PMH Easy bruising, gum bleeding with
tooth brushing, epistaxis, bleeding
following tooth extractions, prolonged bleeding
after cuts since childhood Multiple joint bleeds
(L knee, R knee, L wrist, L hip, L elbow) GI
bleed requiring 4 units PRBC L thigh hematoma 3
months PTA, most recent bleed Severe
metro-menorrhagia SHx Lives with parents,
tobacco FHx Adopted Meds DDAVP prn,
previous prophylactic FFP QWk 2001-2005
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PE BP 125/75, pulse 82, resp 18, temp
37o HEENT- esotropia Neck-supple Chest-
central catheter L anterior chest, lungs
clear Back- tenderness medial to right scapula,
no edema, no ecchymosis, full ROM R
shoulder Heart- HS normal, no murmur Abd- soft,
non-tender, no H/Smegally Ext- WNL Skin- small
bruises (lt 1 cm) right thigh and shin, 1.5 cm
ecchymosis about site of epinephrine injection
R upper arm No joint hypermobility, no
lax skin, no abnormal scars Neuro- WNL LAB Hct
34.9, Hgb 12.1, WBC 6.7, nl diff, MCV 91.3, RDW
12.3 Lytes nl, Bun 13, creat 0.6 Alkphos 89,
AST 24, ALT 20, Tprot 7.0, alb 4.3 PT 15.6 PTT
gt150 PT 14.0 PTT 36.3 15 hours later (after 2
units FFP)
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Hemostasis Evaluation Barnes (2002) SLU
(2005) PT 14.0 13.6 PTT
37-40 40 (corrects on mix) Fibrinogen
370, 367 Prothrombin 120
88 Factor V 74 Factor
VII 126 Factor VIII
87,124 135 Factor IX 98
74 Factor X 84 Factor XI
75 74 Factor XII 33, 64
66 Factor XIII nl x 2
nl vWFag 89, 133 110 RCoFactor
122 euglobulin lysis time gt120
min antiplasmin 97
112 PAI-1 antigen 38 (nl 3-40)
7.7 (nl 3-40) PAI-1 activity 16.9 (nl
3.2-29) Plasminogen 80 Lupus
Anticoagulant Neg
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Platelet Evaluation Barnes (2002) SLU
(2005) PFA ADP/Collagen nl x 3
nl Epi/Collagen long x 3
long Bleeding Time gt15
min Platelet Aggregation ADP
nl nl Collagen nl
mod abnl Epinephrine
mildly abnl ?
Arachidonic acid nl
marked abnl Thromboxane
nl Ristocetin mod
abnl Platelet Granule Content
Thromboglobulin nl Serotonin
nl
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DOES SHE HAVE A BLEEDING
DISORDER? aPTT 37-40 sec. 2001 (then started
on FFP qweek, d/cd 2005) Since 2004,
recurring picture of very long PTTs that return
toward normal after FFP (or time), has
happened more than once during a
single hospitalization Mixing studies showed
only partial correction in past x 2 No bleeding
as child Hemorrhagic symptoms started 2001 (L
hip pain, thigh bruises, menorrhagia) Joint
bleeds Based on pain, at times superficial
edema Joint hemorrhage never documented Orthop
edic surgeons have noted no evidence of bleeding
into joints by imaging or at time of
intervention (L patellar subluxation) X-rays
consistently negative for joint abnormalities GI
Bleed Upper/lower endoscopy normal No
documented blood transfusion L Thigh Hematoma
MRI showed no soft tissue swelling or mass at
site Severe Metro-menorrhagia No anemia, no
iron deficiency, no documentation Other Seizur
e disorder (2000) Following careful in-hospital
evaluation and monitoring--gtPseudoseizures Episodi
c Shortness of Breath (1999) Extensive
evaluation negative Episodic Chest-Left Arm Pain
(2000) Extensive cardiac evaluation
unremarkable Severe Abdominal Pain (2001)
Evaluation negative
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Impression 1. Despite subjective
symptoms, NO evidence for a major bleeding
diathesis Coagulation- Does not have
severe FXII deficiency, not associated with
bleeding anyway Markedly prolonged aPTTs on
admission most likely due to heparin Can
not exclude modest baseline aPTT prolongation
(36-40 sec) Borderline FXII deficiency may
contribute Platelets- Platelet
aggregation studies normal at Barnes (25 of
normals have minor dampening in epinephrine
response) Striking abnormalities at SLU
(esp. arachidonic acid response) not due to
congenital- inherited defect Probable
drug effect 2. Likely Munchausens
Syndrome- role of mother (a nurse) not
clear Recommend 1. Remove port-a-cath
2. Obtain blood from peripheral vein for
thrombin time (and anti-Xa if available) to
document heparin effect when aPTT very long
3. Refrain from using FFP, could use DDAVP if
patient insists 4. Test for high molecular
weight kininogen and prekallikrein 5. If
future testing confirms markedly prolonged aPTTs
due to heparin--gt Psychiatric Consultation
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Follow-up 9/23/06 R Back
Bleed 2 U FFP 12/5/06 L Knee Bleed 2 U
FFP 1/15/07 L Knee Bleed 3 U FFP 2/28/07 L
Hip Bleed 2 U FFP 3/9/07 ?
? 5/27/07 Headache, pyelonephritis, LP 2 U
FFP 9/14/07 L Knee Bleed 2 U FFP PT
16.4 aPTT gt150 Thrombin Time gt120
protamine 13.6 Anti-Xa 0.46
(therapeutic) 11/4/07 L Neck Bleed, pain down
left arm Wanted FFP, but did not receive
it 11/20/07 L Knee Bleed 2 U
FFP 2/26/08 Chin Contusion 2 U
FFP 3/12/08 Ophthalmology OR (? for esotropia)
Goes to other EDs/Hospitals as well
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• Role of Factor XII
• 1. Cascade Hypothesis MacFarland Nature, 1964
• (FXII activation of FXI) Davie,
  Ratnoff Science, 1964
• 2. Thrombin activation of FXI Naito,
  Davie JBC, 1991
• Gailani, Broze Science, 1991
• 3. Thrombin activation of FXI not detectable in
  plasma Gailani, Broze Blood, 1993
• 4. Thrombin activation of FXI occurs on platelet
  surface Baglia, Walsh Biochemistry, 1998
• Baglia, Walsh JBC, 2000
• 5. Thrombin activation of FXI not detectable in
  platelet rich plasma Pedicord et al PNAS, 2007
• 6. Retraction of platelet effect on FXI
  activation by thrombin Baglia,Walsh JBC, 2007

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• Role of Factor XII
• 1. Cascade Hypothesis MacFarland Nature, 1964
• (FXII activation of FXI) Davie,
  Ratnoff Science, 1964
• 2. Thrombin activation of FXI Naito,
  Davie JBC, 1991
• Gailani, Broze Science, 1991
• 3. Thrombin activation of FXI not detectable in
  plasma Gailani, Broze Blood, 1993
• 4. Thrombin activation of FXI occurs on platelet
  surface Baglia, Walsh Biochemistry, 1998
• Baglia, Walsh JBC, 2000
• 5. Thrombin activation of FXI not detectable in
  platelet rich plasma Pedicord et al PNAS, 2007
• 6. Retraction of platelet effect on FXI
  activation by thrombin Baglia,Walsh JBC, 2007

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XIIa
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• Role of Factor XII
• 1. Cascade Hypothesis MacFarland Nature, 1964
• (FXII activation of FXI) Davie,
  Ratnoff Science, 1964
• 2. Thrombin activation of FXI Naito,
  Davie JBC, 1991
• Gailani, Broze Science, 1991
• 3. Thrombin activation of FXI not detectable in
  plasma Gailani, Broze Blood, 1993
• 4. Thrombin activation of FXI occurs on platelet
  surface Baglia, Walsh Biochemistry, 1998
• Baglia, Walsh JBC, 2000
• 5. Thrombin activation of FXI not detectable in
  platelet rich plasma Pedicord et al PNAS, 2007
• 6. Retraction of platelet effect on FXI
  activation by thrombin Baglia,Walsh JBC, 2007

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Will FXII(a) inhibition reduce thrombosis
without causing bleeding in
humans? Absence of an effect of FXII
deficiency in mouse Rose Bengal/Laser stroke
model Multiple previous reports suggesting FXII
deficiency associated with venous/arterial
thrombosis and fetal wastage (largely
unconfirmed)
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Will FXII(a) inhibition reduce thrombosis
without causing bleeding in
humans? Absence of an effect of FXII
deficiency in mouse Rose Bengal/Laser stroke
model Multiple previous reports suggesting FXII
deficiency associated with venous/arterial
thrombosis and fetal wastage (largely
unconfirmed)
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