1. Management of the Bleeding Patient Dr
Management of the Bleeding Patient Dr. Alan Tinmouth, MD, MSc University of Ottawa Centre for Transfusion Research Director, Adult Regional Hemophilia and Bleeding Disorders Clinic

2. Outline Overview of hemostasis Review common coagulation tests
“Coagulopathy Poker”

3. Breakdown of Hemostasis Processes
Primary hemostasis
Platelets form temporary hemostatic plug at site of injury
Secondary hemostasis
Coagulation proteins form insoluble fibrin clot at site of initial platelet plug
III. Fibrinolysis
Fibrinolytic proteins breakdown fibrin clot after endothelial repair is completed

4. Overview of Hemostasis

5. Primary Hemostasis: Platelets
Adhesion
Platelet glycoprotein Ib/V/IX adheres to subendothelium  binding is primarily to vWF
Activation
Shape change  formation of pseudopods
Anionic phospholipids (phospatidylserine and phosphoethanolamine) exposed on external membrane
Glycoprotein IIb/IIIa exposed on surface
Secretion of platelet granules
Aggregation
Platelets bind to each other via Gp IIb/IIIa receptor and soluble fibrinogen and vWF
 FORMATION OF HEMOSTATIC PLUG

6. Platelet Adhesion and Activation

7. Platelet Aggregation

8. Current Model of Coagulation Cascade
Initiation Phase
Exposure of factor VIIa to tissue factor (TF) on subendothelial cell starts coagulation cascade and leads to initial thrombin generation (thrombin “burst”)
Amplification Phase
Small amount of thrombin then activates platelets and other coagulation factors (factor V, VIII and XI)
Propagation Phase
Large amounts of thrombin produced on surface of platelets
Thrombin converts fibrinogen to fibrin (fibrin deposition) which is cross-linked to form stable thrombus (clot)
 Formation of stable thrombus allows for endothelial repair

9. Initiation Phase
Tissue factor is spark initiating coagulation factor cascade
Exposed TF activates factor VII
Factor VIIa:TF activates (i) Factor VII*  VIIa
(ii) Factor X*  Xa
(iii) Factor IX*  IXa
Factor Xa with Va generates a small amount of thrombin II
IIa X Xa TF
VIIa Va
TF-Bearing Cell TF
VIIa IX
IXa
* Vitamin K dependent clotting factors

10. Amplification Phase II
Factor VIIa:TF inactivated by Tissue Factor Pathway Inhibitor (TFPI):Factor Xa complex
Thrombin* (II) generated on TF-bearing cell activates platelets and coagulation factors (V, VIII*, XI) II
IIa
VIII/vWF
TFPI Xa Xa TF
VIIa
VIIIa Va
TF-Bearing Cell XI
XIa V Va
Platelet
VIIIa Va
XIa
Activated Platelet
* Vitamin K dependent clotting factors

11. Propagation Phase
Activated platelets serve as phospholipid platform for generation of large amounts of thrombin
Factor IXa with VIIIa (+ Ca2+) forms tenase which activates factor X*
Factor Xa with Va (+ Ca2+) forms prothrombinase which produces large thrombin burst
Thrombin then generates fibrin and fibrin clot
TF-Bearing Cell TF
VIIa IX II
IXa X Xa
IIa
IXa
VIIIa Va
XIa
Activated Platelet IX

12. Formation of Fibrin Clot: Fibrin Deposition
Thrombin binds to fibrinogen and forms fibrin
Cleaves fibrinopeptide A and B to leave fibrin monomer
Thrombin activates factor XIII to XIIIa,
Factor XIIIa catalyzes cross-linking of fibrin monomers to produce stable clot
IIa
IIa

13. Fibrinolysis
Fibrin clots are temporary scaffolding that allow for cellular wound healing
Dissolution of clots needed to maintain vessel patency
Plasmin (converted from plasminogen) is primary agent of fibrinolysis
Fibrinolysis is controlled by
t-PA - Activator of plasminogen
PAI-1 - Inhibitor of plasminogen activation
α2 antiplasmin - Inhibitors of plasmin

14. Fibrinolytic System

15. Principle of Coagulation Tests
Screening tests are based on the addition of thrombogenic stimuli to ex vivo plasma
 time to clot generation is used as the end point
Other tests of specific coagulation factors can also be performed
Screening Tests:
Prothrombin time (PT)
Commonly reported as International Normalized Ratio (INR)
Activated partial thromboplastin time (aPTT)
Thrombin Time (TT)

16. Coagulation in a test tube
aPTT
XII
XIIa PT XI
XIa
VIIa
VII IX
IXa
+VIIIa X Xa
+Va II
IIa
Fibrinogen
Fibrin TT

17. Coagulopathy Poker

18. One of Kind Prolonged aPTT Factor Deficiency (VIII, IX, XI, XII)
Inhibitor (factor VIII)
Heparin
Lupus anticoagulant / Antiphospholipid antibody
von Willebrand Disease

19. Three cases of an elevated aPTT
68 year old male lower GI bleed & coagulation factor deficiency
INR 0.93
aPTT 46 sec
Case 2:
70 year old with SOB and hemoptysis
INR 1.02
aPTT 65
Case 3:
51 year old with no bleeding
INR 1.1
aPTT 120 secs
Mild factor VIII deficiency – 5%
Antiphospholipid antibody
Factor XII deficiency – 1%

20. Evaluation of Prolonged aPTT
Repeat aPTT (peripheral)
ANTIPHOSPHOLIPID ANTIBODY
positive
Mixing Study
(50:50 mix with normal plasma)
correction
> 3 secs of normal
Antiphoslipid
Antibody Testing
INHIBITOR
negative
corrects
SPECIFIC INHIBITOR
FACTOR DEFICIENCY
Individual Factor Levels
Factor VIII, IX, XI, XII, vWF
Specific Factor Levels and Inhibitor Testing

21. One of Kind Prolonged INR(PT) Factor Deficiency (VII) Warfarin
Liver Disease

22. Fresh Frozen Plasma or Frozen Plasma
FFP frozen within 8 hrs of collection
FP frozen within 24 hrs of collection
Contains all coagulation factors
FFP has minimum factor VIII level of 0.7 IU/ml
FP has factor VIII > 0.5 IU/ml
mls / unit
Effect may only last 4 hrs (t1/2 of factor VII)
Indications:
INR / PTT > 1.5 x normal
and
Bleeding or
Emergency procedure or operation

23. Fresh Frozen Plasma / Frozen Plasma
Dose:
10-15 ml/kg for bleeding patients
Sufficient to increase all individual coagulation factors by 30% (minimum hemostatic level)
Alternatives
Vitamin K
2 mg will correct INR in hrs
No effect on PTT (factors VIII, IX, XI)
Oral dose more effective than subcutaneous
Intravenous associated with anaphylactic reactions

24. One of Kind Thrombocytopenia Decreased production
Increased Destruction
► physiologic consumption
► immune mediated clearance
Hypersplenism
► 1/3 of platelets normally in spleen
► minimum platelet count ~ 50 x 109/l

25. Indications for Platelet Transfusions
Thrombocytopenia
Platelet Dysfunction
Congenital
Acquired
Therapeutic
Plat ct < 50x109/L
Plat dysfunction
Prophylactic
Prior to invasive procedures
Plat ct < x109/L
Prevent spontaneous bleeding
Plat ct  10x109/L

26. Platelet Dysfunction Congenital Bernard-Soulier Syndrome (GP Ib/IX)
► abnormal adhesion
Glanzmann Thrombasthenia (GP IIb/IIIa)
► abnormal aggregation
Gray Platelet Syndrome (α granule deficiency)
► abnormal secondary aggregation
δ storage pool density

27. Platelet Dysfunction Acquired Renal Failure Cardiopulmonary Bypass
Myoproliferative Disorders
Drugs
► ASA
► NSAIDs
► Ticlopidine

28. Immune Thrombocytopenic Purpura (ITP)
Contraindications to Platelet Transfusions in Thrombocytopenic Patients
Immune Thrombocytopenic Purpura (ITP)
► Poor platelet recovery
► Only for patients with ongoing bleeding
► IVIG and steroids should be give concurrently
Thrombotic Thrombocytopenic Purpura (TTP / HUS)
► Platelet transfusions may aggravate thrombosis
► Only in life threatening bleeding
Heparin Induced Thrombocytopenia

29. 167 surgical or invasive procedure in 95 patients with acute leukemia
Prophylactic Platelet Transfusion Threshold: Surgical / Invasive Procedures
167 surgical or invasive procedure in 95 patients with acute leukemia
29 major surgeries
52 Hickman line insertions
Results:
Transfused of pre-op platelet count < 50 x 109/l
93% no bleeding or minor bleeding
All bleeding episodes easily controlled with further transfusion or pressure dressing
Conclusion:
Minimum platelet count of 40 – 50 x 109/l safe
Bishop. Am J Hematology 1987; 26: 147

30. Platelet Transfusions - Products
Random Donor Platelets
Separated from whole blood donations
Dose = 5 units ( mls)
ABO matched preferable but not mandatory
Increases platelet ct by 5-10 x 109/L per unit
Single Donor Platelets
Collected from 1 donor by apheresis
Equivalent to 5-6 random donor platelets
Decrease donor exposure
Can be matched if patient has identified antibodies to platelets (alloimmune platelet refractoriness)

31. Pair 45 year old male (105 kg) with recurrent nose bleeds INR 4.8
aPTT 120 secs
Diagnosis:
Factor Deficiency (II, V, X)
Warfarin overdose
Liver Disease

32. Coagulation in a Test Tube
XII
XIIa XI
XIa
VIIa
VII IX
IXa
+TF
INTRINSIC
+VIIIa
EXTRINSIC X Xa
+Va II
IIa
Fibrinogen
Fibrin
COMMON

33. Three of a kind Increased INR, aPTT and decreased Fibrinogen Diagnosis
Fibrinogen deficiency
Liver disease

34. Cryoprecipitate Precipitate collected from plasma thawed at 40C
10-15 mls/unit
Contains specific clotting factors from plasma
Factor VIII & von Willebrand’s Factor
Fibrinogen
Factor XIII
Indications
Fibrinogen < 1.0 g/L
Dysfibrinogenemia
Dose
1 unit / 5-10 kg body weight (total 8-10 units)
t ½ of 3-5 days

35. Four of a kind Increased INR and PTT
Decreased Fibrinogen and Platelets
Diagnosis:
Liver Disease
Massive Transfusion

36. Massive Transfusion
Replacement of blood volume or transfusion 10+ units of RBCs in less than 24 hrs
Complications
Thrombocytopenia
Replacement > 1.5 plasma volume*
Coagulopathy
Hypothermia
Hypocalcemia/citrate toxicity
Hyperkalemia
* May occur earlier in trauma patients

38. Recombinant Factor VIIa
Initiates coagulation by interaction with TF
Only approved for treatment of hemophilia with inhibitors
Treat/prevent bleeding in other patient groups?
Efficacy not proven
Risk of thrombosis?
Primary use is bleeding patients refractory to other treatments
Dose for hemophilia 90 ug/kg q2-3h
Lower dose often effective in other patients ug/kg
Vials of 1.2 mg, 2.4mg, 4.8mg
Cost ~ $1000/mg

39. Multicentre RCT of rVIIa in Trauma
280 pts with blunt or penetrating trauma
All patients receive 3 doses
200 ug/kg followed by 100ug/kg 1h and 3h later
Arrive at ER
rVIIa
48h
30d
trauma
randomize 6 8
placebo
Units of RBCs
48h
30d
Transfusion
ICU/Hosp LOS
Survival
Adverse Events

40. Multicentre RCT of rVIIa in Trauma
287 patients with blunt and penetrating trauma
Non significant reduction in RBC units transfused
Significant only in blunt trauma if early deaths excluded (within 48h)
Similar overall survival - 25% vs 30%
Composite outcome incl organ dysfunction showed increased trend favouring rVIIa (29 vs. 43%)
No difference in adverse events

41. Bleeding with normal tests
Von Willebrand’s Disease
Mild Hemophilia A or B
Mild Factor XI deficiency
Platelet Function Disorder
Factor XIII deficiency
Alpha 2 antiplasmin deficiency
Plasminogen Activator Inhibitor deficiency

42. DDAVP Synthetic vasopressin Release of VIII and vWF from endothelium
May also help with platelet dysfunction
2-3 fold rise in levels
Dose – 0.3 ug/kg q hours
Tachyphylaxis may occur after 2-3 doses
Uses
Mild hemophilia A
Von Willebrand Disease
Platelet dysfunction

43. Antifibrinolytics Tranexamic acid (Cyclokapron)
20-25 mg/kg po or 10 mg/kg IV q8h
Epsilon aminocaproic acid (Amicar)
50-60 mg/kg po q6h
Competitive inhibition with plaminogen activator (t-PA)
Prevents fibrinolysis (clot breakdown)
Promotes thrombosis
Relative contraindication in renal bleeding
Uses
Mucosal bleeding
Fibrinolytic disorders