2. Case 1
• A 21 y.o. UNC student presented to the coagulation
clinic from the plastic surgery clinic. He had
undergone nipple piercing 11 days prior and had
prolonged bleeding, requiring 2 trips to the
emergency room, gelfoam application, pressure
dressing, stitching, re-stitching. He was still actively
bleeding.
• PMHx was notable for tongue laceration at age 7
following a fall, with persistent bleeding. Thumb
injury with persistent bleeding, ganglion cyst removal
without abnormal bleeding.
3. Case 1
• Family History - mother is on iron for
unknown reasons. Maternal grandmother
may have abnormal bleeding (pt unsure)
Sister alive and well without abnormal
bleeding.
• Meds - none
• SHx - senior at UNC, occasional alcohol, no
tobacco or drugs
• PEx - actively bleeding left nipple. No bruises
or petechiae.
5. Case 1 - questions
• Question 1: How do we evaluate
patients with an abnormal aPTT?
• Question 2: What does the patient
have?
• Question 3: How should the patient
be treated?
13. Coagulation made easy - the aPTT
VX
Prothrombin Thrombin
Fibrinogen Fibrin
XII
XI
IX
VIII
14. Coagulation made easy - the aPTT
Prothrombin Thrombin
Fibrinogen Fibrin
T
N
E
T VX
E
15. Coagulation made easy - the aPTT
Prothrombin Thrombin
Fibrinogen Fibrin
Twelve
Nine
Eight
Ten
VX
Eleven
16. • Deficiencies of factor XI,
IX, VIII, VII. X, V,
prothrombin and
fibrinogen are clinically
significant.
• Inhibitors of these factors
are clinically significant.
• Deficiency of Factor XII,
and the presence of the
lupus anticoagulant are
not clinically significant.
XII
XI
IX
VIII VII
X
V
Thrombin
Fibrinogen Fibrin
What matters clinically
17. Coagulation Made Easy- The Mixing Study
• Useful to differentiate etiologies of prolonged
clotting in a coagulation assay.
• Patient’’s plasma is mixed 50:50 with normal
plasma. Coagulation assay is repeated.
• If ““substantial”” correction is noted after mix,
suspect clotting factor deficiency.
• If no or minimal correction seen, suspect
inhibitor.
18. Case 1 - More Laboratory Data
• aPTT - 52.2 sec (22-32)
• aPTT mix - 31.5 sec
19. Case 1 - More Laboratory Data
• aPTT - 52.2 sec (22-32)
• aPTT mix - 31.5 sec
• Interpretation: Factor Deficiency
20. Case 1 - Which Factor(s) are deficient?
Prothrombin Thrombin
Fibrinogen Fibrin
Twelve
Nine
Eight
Ten
VX
Eleven
21. Case 1 - More Laboratory Data
Question 2: What does the patient have?
Factor II 104%
Factor V 111%
Factor VIII 128%
Factor IX 2%
Factor X 129%
Factor XI 78%
22. Hemophilia
• X-linked recessive disorder
• Hemophilia A - deficiency of Factor VIII
• Hemophilia B - deficiency of Factor IX
• Incidence 1/5000 live male births
• Estimated 20,000 cases in US; 1,000 in NC
• Racial groups affected with similar frequency
24. Hemophilia Treatment
• Replace Deficient Factor
• Many Products: Two general categories:
– Plasma derived
• Virally inactivated
• Generally reserved for individuals who are HIV/HepC
positive
– Recombinant
• More expensive
• Should be product of choice for all children and
previously untreated patients
• Inhibit Fibrinolysis - in mucosal bleeding
25. Hemophilia Treatment
• Clotting factor is dosed in UNITS
• One Unit = amount of factor present in 1 ml of
normal plasma
• Replacement Factor Dosing is based on 3
variables
– Volume of distribution
(extravascula/intravascular)
– Half-life
– Level of factor required for hemostasis
26. Hemophilia Treatment
Site of Bleeding Optimal Factor
Level
Duration in days
Joint or muscle 30-50 1-2
GI tract 40-60 7-10
Oral, nasal, GU
mucosa
30-50 Until healing
CNS 80-100 10-21
Retroperitoneal 80-100 7-14
Surgery/Trauma 80-100 7-21
27. Case 1 - Followup
• The patient was given a bolus dose of 4,000 units
of BeneFIX (recombinant Factor IX) calculated to
raise his Factor IX level to 50%. Pressure was re-applied,
and the bleeding stopped. This dose of
factor cost approximately $6,000. The patient is
uninsured.
• The patient was instructed to seek care at the
regional comprehensive hemophilia center after
graduation.
28. Teaching Points
• A prolonged PTT should be evaluated first by
mixing study, then with factor levels, if
appropriate.
• Hemophilia can be undiagnosed until
adulthood, especially if mild or moderate.
• Treating hemophilia is expensive and
complicated, and patients should be followed
in a comprehensive hemophilia center.
29. Case 2
• A 33 y.o. man presented with post-operative
bleeding after a tonsillectomy.
• 10/15/01 –– Hb/Hct = 15.3/42.7.
– PT/aPTT = 13/35.6 (22-33.4)
• 10/17/01 –– Tonsillectomy.
• 10/17-10/24, pt took ibuprofen for pain
• 10/24 early am –– Pt awoke with severe bleeding
– Hb/Hct in ER 14.1/38
30. Case 2
• Bleeding did not stop with ER cauterization.
• Pt given platelets, FFP, then taken to OR
• Notice made of persistent venous oozing and
bleeding. DDAVP given
• 10/25 –– Pt had persistent post-op bleeding
• H/H eventually reached 9.1/25
31. Case 2
• Bleeding History:
– Lifelong nosebleeds
– Gum bleeding with brushing teeth
– Prolonged bleeding with nicks
– Bleeding with multiple tooth extractions (characterized as
delayed)
– appy at age 19, wound dehisced and bled
• FHx - sister with easy bruising and abnormal
menstrual bleeding. Mother had hysterectomy in
early 30’’s.
32. Case 2 - Questions
• Question #1 - What is a reasonable screening
evaluation for patients pre-operatively?
• Question #2 - What is a reasonable screening
evaluation for patients with a positive bleeding
history?
• Question #3 - What does the patient have?
• Question #4 - How should the patient be
treated prior to future surgical interventions?
33. Case 2
• PT - 12.9 seconds. (11-14)
• aPTT - 33.9 seconds (22-33.4).
• Platelet function screen.
–col/epi closure time >300 sec (84-178)
–col/ADP closure time 136 sec (60-107)
34. The platelet function screen
• An in vitro method to test primary hemostasis
• Measures the length of time for whole citrated
blood taken up by microcapillary membranes
permeated with either collagen + epinephrine or
collagen + ADP to close off the microcapillaries.
• Designed to replace the bleeding time
36. The platelet function screen
• Prolonged in cases of platelet dysfunction
(acquired or congenital) or von Willebrand’s
disease.
• If hematocrit is <30 or if platelet count is <100,
this test will be abnormal.
• Assay must be run within 4 hours of sample draw.
• Sample is run on Whole Blood--NOT PLASMA!!
37. Case 2 - More laboratory data
• vWF antigen - 58%
• vWF activity - 50%
• Platelet aggregation studies: abnormal
aggregation in response to epinephrine, ADP,
arachidonic acid.
38. Case 2
Question #3: How should the patient be treated prior to
future invasive procedures?
Pre-DDAVP Post-DDAVP
Col/epi >300 sec 133 sec
Col/ADP 98 sec 56 sec
vWF antigen 67% 151%
vWF activity 78% 219%
39. Case 2
• The patient was told he had mild Type I von
Willebrand’s disease, coupled with a mild platelet
dysfunction. He subsequently suffered a left
ACL rupture and underwent surgical repair under
coverage with DDAVP.
• He did well and had no abnormal bleeding.
40. Teaching Points
• Take a bleeding history. Then, write it down.
• Not all bleeding diatheses show up with a
PT/PTT.
• Defects in primary hemostasis cause
mucocutaneous bleeding (““Oozing and
Bruising””) and are best screened for by using
the platelet function screen (PFA-100).
• DDAVP can improve primary hemostasis.
41. Bleeding History
• Nosebleeds
• Gum bleeding
• Bleeding with (wisdom) tooth extraction
• Easy bruisability
• Bleeding with surgeries (including circumcision)
– Include timing of bleeding
• Menstrual bleeding
• Transfusion requirements
• Family history of bleeding
– Hysterectomies at an early age
– Bleeding with surgeries
42. Case 3
• A 72 y.o. man suffered complications of an MVA
with multiple fractures and splenic rupture 7 days
prior. He is now thought to be septic and all
wounds are bleeding.
• Labs show H/H 7/21, Plts 14, PT 33, PTT 60
Fibrinogen 81
• After transfusion of 4 units PRBC, H/H only 8/23
43. Case 3 - Questions
• Q1. What blood products should be given to the
patient?
• Q2. What are the indications for use of Novo-
Seven in the bleeding surgical patient?
44. What blood products to give?
• H/H 7/21, Plts 14, PT 33, PTT 60 Fibrinogen 81
• Platelets - With active hemorrhage, try to keep platelets >
50. If no bleeding, keep platelets >10
• Cryoprecipitate - With active bleeding, keep fibrinogen
>100. Cryo also contains FVIII, VWF, FXIII
• RBCs - With active bleeding and thrombocytopenia, plts
will work better if Hgb >10
45. Review Cascade model of hemostasis
IInnttrriinnssiicc ppaatthhwwaayy
XXII,, IIXX,, VVIIIIII
EExxttrriinnssiicc ppaatthhwwaayy
TTFF,, VVIIII
XXaa ggeenneerraattiioonn
TThhrroommbbiinn GGeenneerraattiioonn
46. A Cell-Based Model of Hemostasis
• Initiation
• Amplification
• Propagation
54. NovoSeven in Surgery/Trauma
• This is an Off-Label Use
• Pts are at significant risk for thrombosis,
especially if they have activated platelets in
circulation (ie vasculopaths, DIC)
• Remember that rVIIa requires platelets, Factor X,
prothrombin, and fibrinogen to work, so
• Fix the Plts, PT, PTT, Fibrinogen.
• If pt still bleeding, can then give rVIIa
55. Case 4
• A patient presents with a perforated diverticular
abscess. He has alcoholic cirrhosis and poor
nutrition.
• His PT and PTT are prolonged at baseline to 18
and 48 sec, respectively. DIC screen shows
fibrinogen of 300, Ddimers of 800
• How can we use factor levels to determine the
cause of his coagulopathy?
56. Case 4
Vitamin K
Deficiency
Liver Disease DIC
Factor V ¬ ¯ ¯¯
Factor VII ¯¯ ¯¯ ¯¯
Factor VIII ¬ ¬ /¯
57. Case 5
• A 65 y.o. female smoker with a h/o peripheral
vascular disease presented to the ER with
unstable angina. She was admitted to the hospital
and placed on heparin. Platelet count on
admission was 450. Cardiac catheterization
showed severe 3-vessel coronary disease, and the
patient was scheduled for CABG which occurred
on hospital day #7. Pre-op platelet count was
200. Post-op platelet count was 90.
58. Case 5
• On hospital day #12, the patient developed acute
left leg swelling and a DVT was diagnosed by
ultrasound. Platelet count was 150. The patient
was started on IV heparin. The next day, she
developed a pulseless left leg and had a platelet
count of 30. While in vascular radiology, he
developed acute chest pain and suffered a cardiac
arrest and subsequently died. Autopsy showed
occlusion of all of her bypass grafts
59. HIT
• Seen in 1-3% of patients treated with heparin
• Usually, 7-10 d after heparin started, platelets fall by at
least 1/3 to 1/2.
– Patients do not have to be thrombocytopenic.
– Can occur earlier in patients who have been previously exposed
to heparin, even as SQ injections.
• Caused by antibodies against the complex of heparin and
PF4. These antibodies activate platelets.
• Can lead, paradoxically, to THROMBOSIS, in up to half
of patients.
• More common in patients with vascular disease
60. Alternate Presentations of HIT/T
• Small drop in platelet count (especially with
skin necrosis)
• Earlier onset thrombocytopenia with heparin re-exposure
• Delayed-onset thrombocytopenia/ thrombosis
after stopping heparin
• Thrombosis after heparin exposure
61. HIT/T treatment
1. IF PLATELETS FALL ON HEPARIN, STOP
HEPARIN IMMEDIATELY.
2. Stop heparin
3. Stop heparin
4. Use a different anticoagulant
1. Lepirudin
2. Argatroban
3. Bivalirudin (off label)
4. Fondaparinux (off-label)
62. HIT Testing
Test Advantages Disadvantages
HIPA Specificity: high Sensitivity: low
Rapid turn around time Technique-dependent
ELISA Sensitivity: high Specificity: low (false-positives
Technically easy high for some populations)
Poor concordance with SRA
There is no Gold Standard in diagnostic
testing;
HIT is a clinical diagnosis
Pts Must Be off heparin for 16 hours prior
to testing
63. Lepirudin
• Recombinant protein, irreversibly binds to and
inactivates thrombin
• Associated with increased bleeding, compared to
heparin.
• Short t 1/2.
• Renally excreted.
• Antibody formation is common
– decrease clearance and potentiate anticoagulation
effect.
– Allergic reactions may occur
• Monitor by using aPTT (aim for 50-70 sec)
64. Argatroban
• Synthetic direct thrombin inhibitor
• Reversibly binds to thrombin’’s catalytic site
• Associated with increased bleeding compared to heparin
• Short t 1/2 - must give as continuous infusion - no loading
dose
• Dose is 0.2 mcg/kg/min (maximum dose is 10 mcg/kg/min)
• Monitor using the aPTT (aim for aPTT 50-80)
• Hepatically cleared - reduce dose by 75% in liver failure.
• Prolongs the PT.
65. Fondaparinux
• Derived from AT-binding moiety of heparin.
• Leads to indirect inhibition of Xa.
• Once daily SQ therapy
• Renally cleared
• Approved for treatment of VTE and prophylaxis of
patients at high risk for VTE (hip, knee surgery,
abdominal surgery)
• Not approved for use in HIT
66. Case 6
• A 72 y.o. woman requires red cell transfusion for
symptomatic anemia. Red cells are delivered to
the bedside. The patient verbally confirms her
name and date of birth, which correlate with the
label on the red cell bag. Which of the following
is the most appropriate course of action to take at
this time?
67. Case 6
A. Proceed with the transfusion.
B. Have another health care professional witness the
patient’s confirmation of her ID, then proceed with the
transfusion.
C. Check the patient’s wrist ID band against the red cell
bag tag, along with another health care professional
witness, then proceed with the transfusion.
D. Check the patient’s wrist ID band against the red cell
bag tag, along with another health care professional
witness, confirm that the consent for transfusion form
has been signed, then proceed with the transfusion.
68. Case 7
• A patient in the SICU is in the process of
receiving a transfusion of platelets for a platelet
count of 8. Midway through the transfusion, the
patient’s temperature rises from a baseline of 36.8
to 38. The blood pressure is stable, and the pulse
has risen from 88 to 102. There are no hives,
stridor, back pain, or rash. The patient is already
on broad spectrum antibiotics. What is the most
apropriate course of action to take at this time?
69. Case 7
A. Draw blood cultures, administer acetominophen, then proceed
with the transfusion before the unit of platelets expire.
B. Draw blood cultures, administer acetominophen, then proceed
with the transfusion when the temperature reaches baseline.
C. Draw blood cultures, change antibiotics, administer
acetominophen, then proceed with the transfusion when the
temperature reaches baseline.
D. Stop transfusion, draw workup for possible transfusion reaction,
send workup and remainder of platelets to blood bank, and do
not give further blood products until workup is negative.
70. Case 8
• A patient with aplastic anemia is scheduled to
undergo breast biopsy in the morning. Her
platelet count is 4. What is the most appropriate
course of action at this point?
71. Case 8
A. Order 2 doses of platelets for transfusion.
B. Order 2 doses of platelets for transfusion, then check
platelet count in the morning before procedure.
C. Order 1 dose of platelets for transfusion , then check
platelet count in the morning before procedure.
D. Order 1 dose of platelets for transfusion , then check
platelet count before ordering another dose of platelets.
