1. Hematologic/Coagulation Cases in Critical Care
Alice Ma, M.D.
University of North Carolina-Chapel Hill
Division of Hematology

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.

4. Case 1- Initial Laboratory Studies
PT 13.9 sec (11-14)
aPTT 52.2 sec (22-32)

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?

6. Obligatory Confusing Coag Cascade

7. Coagulation made easy
The PTT Pathway
The PT Pathway

8. Coagulation made easy
The PTT Pathway
The PT Pathway X

9. Coagulation made easy
The PTT Pathway
The PT Pathway V X

10. X Coagulation made easy Prothrombin Thrombin The PTT Pathway
The PT Pathway V X
Prothrombin
Thrombin

11. X Coagulation made easy Prothrombin Thrombin Fibrinogen Fibrin
The PTT Pathway
The PT Pathway V X
Prothrombin
Thrombin
Fibrinogen
Fibrin

12. Coagulation made easy - the PT7 V X
Prothrombin
Thrombin
Fibrinogen
Fibrin

13. Coagulation made easy - the aPTT
XII XI IX V X
VIII
Prothrombin
Thrombin
Fibrinogen
Fibrin

14. Coagulation made easy - the aPTTV X T
Prothrombin
Thrombin
Fibrinogen
Fibrin

15. Coagulation made easy - the aPTT
Twelve
Eleven
Nine
Eight V X
Ten
Prothrombin
Thrombin
Fibrinogen
Fibrin

16. What matters clinically
XII XI
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. IX
VIII
VII X V
Thrombin
Fibrinogen Fibrin

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 sec (22-32)
aPTT mix sec

19. Case 1 - More Laboratory Data
aPTT sec (22-32)
aPTT mix sec
Interpretation: Factor Deficiency

20. Case 1 - Which Factor(s) are deficient?
Twelve
Eleven
Nine
Eight V X
Ten
Prothrombin
Thrombin
Fibrinogen
Fibrin

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

23. Clinical Classification of Hemophilia
Type
FVIII/IX activity
Clinical picture
Severe < 1%
Moderate 1% - 5%
Mild 5% - 25%
Severe hemarthrosis
Spontaneous bleeding
Serious bleeding after
minor trauma
Bleeding after surgery
or trauma
Moderate bleeding after
trauma or surgery
Subclinical 25% - 50%

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
Until healing
CNS
80-100
10-21
Retroperitoneal
7-14
Surgery/Trauma
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 ( )
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

35. The platelet function screen

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 Pre-DDAVP Post-DDAVP Col/epi >300 sec 133 sec Col/ADP 98 sec
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
Intrinsic pathway
XI, IX, VIII
Extrinsic pathway
TF, VII
Xa generation
Thrombin Generation

46. A Cell-Based Model of Hemostasis
Initiation
Amplification
Propagation

47. Initiation

48. Amplification

49. Propagation

50. Hemostasis

51. Hemophilia is a Defect in Plateetl Surface Thrombin Generation

52. NovoSeven can Ameliorate the Defect in Hemophilia

53. NovoSeven Augments Thrombin Generation on the Platelet Surface in Non-Hemophilics

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 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 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 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
IF PLATELETS FALL ON HEPARIN, STOP HEPARIN IMMEDIATELY.
Stop heparin
Use a different anticoagulant
Lepirudin
Argatroban
Bivalirudin (off label)
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 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 Proceed with the transfusion.
Have another health care professional witness the patient’s confirmation of her ID, then proceed with the transfusion.
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.
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 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
Draw blood cultures, administer acetominophen, then proceed with the transfusion before the unit of platelets expire.
Draw blood cultures, administer acetominophen, then proceed with the transfusion when the temperature reaches baseline.
Draw blood cultures, change antibiotics, administer acetominophen, then proceed with the transfusion when the temperature reaches baseline.
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 Order 2 doses of platelets for transfusion.
Order 2 doses of platelets for transfusion, then check platelet count in the morning before procedure.
Order 1 dose of platelets for transfusion , then check platelet count in the morning before procedure.
Order 1 dose of platelets for transfusion , then check platelet count before ordering another dose of platelets.