1. CAUSES OF BLEEDING Defective clot formation Excessive fibrinolysis
Platelet plug
Fibrin clot
Excessive fibrinolysis
Vascular fragility

2. PLATELET DEFECTS Thrombocytopenia
Increased consumption (ITP, DIC)
Decreased production (marrow disease, chemo)
Defective platelet function (ASA, other drugs most common cause)
Von Willebrand disease (defective platelet adhesion)
Most common inherited bleeding disorder?

3. DEFECTS IN FIBRIN CLOT FORMATION
Inherited deficiency of single clotting factor (hemophilia A or B)
Acquired deficiency of multiple clotting factors
Liver disease
Vitamin K deficiency/warfarin
DIC
Circulating inhibitor
Antibody to factor VIII
Heparin
Defective fibrin crosslinking (factor XIII deficiency - very rare)

4. EXCESSIVE FIBRINOLYSIS
DIC
Thrombolytic drug administration
Inherited deficiency of fibrinolytic inhibitor (rare)

5. VASCULAR DISORDERS THAT CAN CAUSE BLEEDING
Inherited defect in collagen formation (Ehlers Danlos syndrome)
Acquired defect in collagen formation (scurvy) (mainly purpura)
Infiltrative disease (amyloidosis)
Vasculitis (purpura only)

6. ASSESSMENT OF BLEEDING RISK
History & physical exam*
Platelet count*
Assessment of platelet function
Bleeding time
Platelet Function Analysis
Assessment of fibrin clot formation
PT/INR*
aPTT
Thrombin time
Assessment of fibrinolytic system
*Part of routine pre-op screen

7. USEFULNESS OF THE HISTORY IN SCREENING FOR BLEEDING DISORDERS
Odds ratios for presence/absence of bleeding disorder by multivariate analysis
Symptom
Odds ratio
95% CI
Family members with proven bleeding disorder
50.5
Profuse bleeding from small wounds 30
Profuse bleeding with tonsillectomy
11.5
Easy bruising
9.9
Profuse bleeding after surgery
5.8
Muscle bleeding
4.8
Frequent nosebleeds
3.8
Profuse bleeding with tooth extraction
3.2
History of blood in stool
2.8
Family members with bleeding symptoms
2.5
History of joint bleeding
2.5
Menorrhagia
2.5
Profuse bleeding with childbirth
2.1
Frequent gum bleeding
0.7
History of hematuria
0.5
Arch Intern Med 1995;155:1409

8. FAMILY HISTORY IN BLEEDING DISORDERS
von Willebrand disease: dominant inheritance, variable penetrance
Hemophilia: sex linked inheritance, high penetrance
Other clotting factor deficiencies - recessive inheritance
Family tree in hemophilia

9. PATTERNS OF BLEEDING IN HEMOSTATIC DISORDERS
Platelet/vascular disorders
Coagulation factor deficiency
Onset
Immediate
Delayed
Skin, mucosal surfaces
Location
Deep tissue

10. PLATELET COUNT VS BLEEDING RISK
Bleeding risk rises as platelet count falls below 100K
Plts > 50K safe for many invasive procedures
Higher count may be needed if procedure is “blind” and it would be difficult to achieve hemostasis mechanically
Associated platelet function defects (eg, ASA), liver disease or DIC enhance risk
Lower bleeding risk at a given platelet count if thrombocytopenia due to consumption (eg, ITP) vs decreased production

11. ASSESSMENT OF PLATELET/VASCULAR FUNCTION: THE BLEEDING TIME
Advantages
In vivo test; measures vascular as well as platelet function
Disadvantages
Difficult to standardize
Sensitivity and specificity relatively poor
Does not predict bleeding risk

12. ASSESSMENT OF PLATELET/VASCULAR FUNCTION: PLATELET FUNCTION ANALYSIS
Advantages
In vitro test
Well-standardized
Better sensitivity and specificity
Disadvantages
Does not assess vascular function
No data re: ability to predict bleeding risk
Consider testing when clinical picture or family history suggest bleeding disorder, platelet count normal, AND no concurrent disease or drug known to affect platelet function

13. FIBRIN CLOT FORMATION ? IIa XIa TF VII(a) VIIIa IXa Xa VaPL
Ca++
VIIIa IXa
Xa Va
“Contact" system
XIa
XII, HMWK, PK ?
Not physiologically important
IIa
Fibrin

14. ASSESSMENT OF FIBRIN CLOT FORMATION
The prothrombin time
Sensitive to changes in factors VII, V, X, II, fibrinogen
Best global test of clotting system integrity
Magnitude of test abnormality proportional to severity of coagulopathy
Abnormal in most acquired coagulopathies (liver disease, vitamin K deficiency, DIC)
Will not detect deficiencies of factors VIII, IX, XI
TF VII(a)
Prothrombin time PL
Ca++
VIIIa IXa
Xa Va
XII, HMWK, PK
XIa
IIa
Fibrin

15. ( ) ISI Patient PT INR = Mean Normal PT
ISI (International Sensitivity Index) is reagent- and method-specific; higher number indicates lower sensitivity to changes in clotting factor levels

16. Reagent A: ISI = 1.24, mean normal = 12.6 sec
PT = 22 sec
1.24 ( )
22.0
12.6
INR =
= 2.0
Reagent B: ISI = 2.46, mean normal = 12.2 sec
PT = 16.2 sec
2.46 ( )
16.2
12.2
INR =
= 2.0

17. 10 patients on stable warfarin therapy
INR COMPARISON
10 patients on stable warfarin therapy
REAGENT E (ISI 2.98)
REAGENT B (ISI 0.96)
PATIENT #
INR
INR 1
3.4
2.7 2
2.8
2.5 3
3.5
2.3 4
2.6 2 5
2.2
1.2 6
2.3
2.4 7
1.9
1.7 8 3
2.8 9
2.2
2.7 10 4 4

18. DOES THE INR SYSTEM WORK IN LIVER DISEASE?
Comparison of three reagents
Reagent (ISI)
A (0.86)
B (1.09)
C (2.53)
Mean INR (warfarin pts)
2.63
2.75
2.67
Mean INR (liver disease)
1.88
2.17
2.63
Thrombosis and Haemostasis 1994;71:727

19. ASSESSMENT OF FIBRIN CLOT FORMATION
The partial thromboplastin time
Sensitive to changes in factors XI, VIII, IX,, V, X, II, fibrinogen
Very sensitive to contact factor levels (XII, etc) - not clinically important
Magnitude of test abnormality often not proportional to severity of coagulopathy
Used to screen for hemophilia, monitor heparin, detect circulating anticoagulants
aPTT
TF VII(a) PL
Ca++
VIIIa IXa
Xa Va
XII, HMWK, PK
XIa
IIa
Fibrin

20. RESULTS OF 1025 CONSECUTIVE aPTT MEASUREMENTS
(excluding those ordered for monitoring heparin)
# abnormal: 143 (14%)
# TESTS
# PATIENTS
Abnormal result
143 97
On anticoagulant 64 37
Liver disease 41 27
No cause found, no bleeding 15 14
Normal on repeat testing 9 9
Known hemophilia 5 4
History of intestinal bypass 5 4
Other malabsorption (CF) 2 1
Technical problem with test 1 1
Newly dx'd bleeding disorder
Robbins and Rose, Ann Intern Med 1979;90:796

21. RESULTS OF PREOPERATIVE SCREENING IN 1603 CHILDREN
PT, aPTT, BT, history
# with abnormal labs on repeat testing 13
# of those in whom bleeding disorder diagnosed (1 mild hemophilia, 1 VWD) 2
# in which bleeding disorder not apparent from history alone (mild hemophilia A) 1
Burk et al, Pediatrics 1992;89:691

22. The aPTT can help us decide why a patient is bleeding, but is much less useful in predicting whether a patient will bleed
To bleed or not to bleed? is that the question for the PTT?

23. ASSESSMENT OF FIBRIN CLOT FORMATION
The thrombin time
Measures only conversion of fibrinogen to fibrin, fibrin polymerization
Very sensitive to heparin; normal or near-normal result essentially rules out heparin as cause of prolonged clotting times
Thrombin time
TF VII(a) PL
Ca++
VIIIa IXa
Xa Va
XII, HMWK, PK
XIa
IIa
Fibrin

24. FIBRINOLYSIS Plasminogen PAI-1 TPA UK Plasmin PI PI Fibrin FDP
Platelets
Plasminogen
Endothelial cell
Fibroblasts
PAI-1
TPA UK
Macrophage
Plasmin
Liver PI PI 2 2
Fibrin
FDP
Fibrinogen

25. ASSESSMENT OF THE FIBRINOLYTIC SYSTEM
Euglobulin lysis time (not well standardized)
Alpha2-antiplasmin level* (depletion implies poor fibrinolytic control)
PAI-1 activity
Available at UW

26. Bleeding severity vs antiplasmin activity
patients with platelets > 30,000
100 80 60
0-2+ bleeding
% of patients
3-4+ bleeding 40 20
< 50%
50-75%
> 75%
Antiplasmin activity

27. VON WILLEBRAND DISEASE
Inherited deficiency or dysfunction of von Willebrand factor
Type I = partial quantitative deficiency
Type II = partial qualitative deficiency
Type III = severe deficiency
Defective platelet adhesion, (slightly) decreased factor VIII activity
Mild or moderate bleeding tendency in most type I and type II pts
Diagnosis: von Willebrand antigen, factor VIII, ristocetin cofactor activity, platelet function analysis
Treatment: DDAVP (type I); intermediate purity factor VIII concentrate (types II, III)

28. VARIABILITY IN VON WILLEBRAND FACTOR LEVELS OVER TIME
Abildgaard et al, Blood 1980;56:712
NORMALS
TYPE I VWD

29. HEMOPHILIA
Inherited deficiency of factor VIII (Hemophilia A) or IX (Hemophilia B)
Sex-linked inheritance: almost all patients male
Bleeding into joints, soft tissues; mucosal/skin/CNS bleeding rare
Severity inversely proportional to factor level:
<1% = severe: frequent "spontaneous" bleeds
1-5% = moderate: spontaneous bleeding less common
> 5% = mild: bleeding mainly after trauma/surgery; may go undiagnosed until adulthood

30. Treatment of bleeding episodes
HEMOPHILIA
Treatment of bleeding episodes
Unexplained pain in a hemophiliac should be considered a bleed until proven otherwise
External signs of bleeding may be absent, particularly early in course
Treatment: factor replacement, pain control
1 U/kg factor VIII should increase plasma level by about 2%
Test for inhibitor if unexpectedly low response to factor replacement

31. HEMOPHILIA Factor replacement in severe hemophilia A Site of bleed
Desired factor level
Dose
Other
Joint
40-50%
20-40 U/kg/day
Rest, immobilization, PT
Risk of compartment syndrome or neuro compromise
Muscle
40-50%
20-40 U/kg/day
Follow with antifibrinolytic therapy
Oral mucosa
50% initially
25 U/kg x 1
Initially %, then 30% until healed
40-50 U/kg then U/kg daily
Pressure, packing, cautery
Epistaxis
Initially 100%, then 30% until healed
40-50 U/kg then U/kg daily
Endoscopy to find lesion GI
Initially100%, then 30% until healed
40-50 U/kg then U/kg daily GU
R/O stones, UTI
Initially100%, then 50% until healed
50 U/kg then 25 U/kg q 12h infusion
CNS
Initially100%, then 50% until healed
50 U/kg then 25 U/kg q 12h infusion
Test for inhibitor before surgery!
Trauma or surgery

32. VITAMIN K DEFICIENCY
Deficiency of factors II, VII, IX, X, protein C, protein S
Causes:
Decreased vitamin K intake
Decreased production of vitamin by gut flora (antibiotics)
Poor absorption - sprue, biliary obstruction, etc
Inhibition of vitamn K action (warfarin, certain antibiotics)
Bleeding tendency roughly correlated to INR
Treatment: vitamin K (oral or parenteral); FFP
200
150
Bleeding events/100 patient-yr
100 50
<2
3-4.4
>7
INR

33. LIVER DISEASE Pathophysiology:
Diminished synthesis of most clotting proteins and inhibitors
platelet sequestration
low grade intravascular coagulation?
Bleeding due to impaired fibrin formation and (in some cases) increased fibrinolytic activity
INR, platelet count, antiplasmin level help predict bleeding risk
Treatment: FFP, platelets, Amicar

34. COAGULATION INHIBITORS
Heparin: prolongs thrombin time, aPTT, high levels prolong PT/INR
Factor VIII antibodies: prolong aPTT only
Bovine thrombin antibodies: prolong all clotting times, minimal bleeding
Lupus anticoagulant (does not cause bleeding)
Diagnosis: prolonged clotting time that does not correct after mixing with normal plasma
Treatment depends on type of inhibitor

35. THROMBOLYTIC DRUGS t-PA, streptokinase, urokinase, etc
Activate plasminogen, initiate fibrinolysis
Depletion of plasminogen may limit efficacy
Most lysis initially at surface of clot; antiplasmin inhibits plasmin in blood
Depletion of antiplasmin increases risk for systemic fibrinolysis
Life-threatening bleeding may occur despite normal fibrinogen, clotting times
Risk of bleeding greater with higher dose, longer duration of therapy
Antidote: antifibrinolytic drug (Amicar)

36. DISSEMINATED INTRAVASCULAR COAGULATION
Rapid formation and lysis of intravascular fibrin
Consumption of clotting factors, platelets, inhibitors
Lifethreatening underlying disease in most pts
Bleeding due to uncontrolled fibrinolysis, thrombocytopenia, etc
Large vessel thrombosis unusual
Tissue necrosis due to microvascular occlusion, hypotension, endothelial damage, direct effects of cytokines
Most deaths due to underlying disease

37. DISSEMINATED INTRAVASCULAR COAGULATION
ASSESS SEVERITY
GUIDE TREATMENT
DIAGNOSIS
D-Dimer
Antithrombin
Prothrombin time
Fibrinogen
Plasminogen
Fibrinogen
Prothrombin time
Alpha2-antiplasmin
Platelet count
Platelet count
Protein C
Alpha2-antiplasmin
Fibrin monomer

38. TREATMENT OF DIC TREAT UNDERLYING DISEASE!
Clotting factor & inhibitor replacement IF patient bleeding or at high risk
Fresh frozen plasma (if INR > 1.6)
Cryoprecipitate (if fibrinogen < )
Platelets (if count < 30-50K)
Pharmacologic inhibitors (selected pts)
Heparin
Antifibrinolytics

39. UWHC/VA TRANSFUSION INDICATIONS
PLATELET TRANSFUSION
UWHC/VA TRANSFUSION INDICATIONS
standard adult dose = 5 units
Plts < 20K (except ITP, TTP)
Most beneficial in marrow failure states
10K trigger safe for most patients
Plts < 50K AND significant bleeding OR invasive procedure/surgery planned within six hours
Plts < 100K AND major CNS or eye surgery (up to 48 hours postop)

40. UWHC/VA transfusion indications
FRESH FROZEN PLASMA
Contains: all clotting factors and inhibitors
UWHC/VA transfusion indications
adult dose = ml/kg
Active bleeding and INR > 1.6
Invasive procedure planned within 6 hours and INR > 1.6
Immediate reversal of warfarin effect for emergency surgery or active bleeding
Surgery with massive transfusion (> 10 units RBC/24 hours)
Replacement during plasmapheresis
TTP

41. UWHC/VA transfusion indications
CRYOPRECIPITATE
Contains: fibrinogen, factor VIII, von Willebrand factor
UWHC/VA transfusion indications
Fibrinogen deficiency (<100 mg/dl)
For DIC: give 1 bag/2-3 Units FFP
Factor VIII or VWF deficiency
Rarely used for this indication; factor concentrates preferable
Fibrin glue

42. DDAVP
(Desmopressin)
Vasopressin analog; stimulates VWF release from endothelium
Intravenous administration (0.3 mcg/kg); intranasal (Stimate)
Increased plasma VWF levels for hours, enhanced platelet adhesiveness
Effective in
Type I von Willebrand disease
Mild hemophilia A (some cases)
Other disorders of primary hemostasis (variable efficacy)
Reducing surgical blood loss (conflicting data)
Can give q 24 hours with little tachyphylaxis
Few side effects in adults (flushing, occasional hyponatremia, rare thromboembolism)

43. (Epsilon-aminocaproic acid)
AMICAR
(Epsilon-aminocaproic acid)
Antifibrinolytic: Inhibits plasmin activation by tPA, fibrin degradation by plasmin
Short plasma half-life; need frequent dosing, up to 24 gm/day
Oral, intravenous, or topical (mouthwash)
Uses:
Treatment of bleeding due to hyperfibrinolytic states: DIC, thrombolytic drugs, post cardiac bypass, liver disease
Prophylaxis in severely thrombocytopenic patients
Treatment of GI or urinary tract bleeding
Treatment of menorrhagia
Prophylaxis after dental extractions in hemophilia (mouthwash)
Risks & side effects: GI symptoms, orthostatic hypotension, rhabdomyolysis, rarely thrombosis

44. VITAMIN K
Oral, subcutaneous, or iv administration (potential for anaphylaxis with iv form)
Indications:
Correction of vitamin K deficiency
Treatment of warfarin or superwarfarin overdose
Treatment of warfarin-induced skin necrosis
Prophylactic use in patients on TNA or at high risk for vitamin K deficiency

45. REVERSAL OF WARFARIN ANTICOAGULATION
INR
ACTION
Withhold warfarin until INR therapeutic, restart at lower dose
< 6, no bleeding
< 6, rapid reversal needed for surgery, etc.
Vitamin K 1-2 mg po
Vitamin K 1-2 mg iv or mg po; give additional mg if INR still supratherapeutic at 24 hours
6-10 or significant bleeding
Vitamin K 3 mg slow iv, recheck INR q 6h and repeat as needed
10-20
Vitamin K 10 mg slow iv; repeat q 6-12 hours as needed
> 20
Add FFP for major bleeding if INR > 2
Avoid subcutaneous Vit K (unreliable absorption)