CAUSES OF BLEEDING
• Defective clot formation


Platelet plug
Fibrin clot
• Excessive fibrinolysis
• Vascular fragility
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?
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)
EXCESSIVE FIBRINOLYSIS
• DIC
• Thrombolytic drug administration
• Inherited deficiency of fibrinolytic inhibitor
(rare)
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)
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
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
Profuse bleeding from small wounds
Profuse bleeding with tonsillectomy
Easy bruising
Profuse bleeding after surgery
Muscle bleeding
Frequent nosebleeds
Profuse bleeding with tooth extraction
History of blood in stool
Family members with bleeding symptoms
History of joint bleeding
Menorrhagia
Profuse bleeding with childbirth
Frequent gum bleeding
History of hematuria
50.5
30
11.5
9.9
5.8
4.8
3.8
3.2
2.8
2.5
2.5
2.5
2.1
0.7
0.5
Arch Intern Med 1995;155:1409
12.5-202.9
8.1-111.1
1.2-111.9
3.0-32.3
1.3-26.4
0.7-31.4
0.9-15.7
0.9-11.3
0.7-11.7
0.7-9.4
0.6-10.2
0.6-9.9
0.3-13.5
0.3-2.0
0.1-2.3
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
PATTERNS OF BLEEDING IN HEMOSTATIC
DISORDERS
Platelet/vascular
disorders
Coagulation
factor deficiency
Onset
Immediate
Delayed
Location
Skin, mucosal
surfaces
Deep tissue
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
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
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
FIBRIN CLOT FORMATION
TF
VII(a)
PL
Ca++
VIIIa
IXa
Xa
“Contact" system
XII, HMWK, PK
Va
XIa
?
Not physiologically important
IIa
Fibrin
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
Prothrombin time
VII(a)
PL
Ca++
VIIIa
XII, HMWK, PK
IXa
Xa
Va
XIa
IIa
Fibrin
Patient
PT
INR =
Mean Normal PT
(
ISI
)
ISI (International Sensitivity Index) is reagent- and method-specific; higher
number indicates lower sensitivity to changes in clotting factor levels
Reagent A: ISI = 1.24, mean normal = 12.6 sec
PT = 22 sec
22.0
INR =
12.6
(
1.24
)
= 2.0
Reagent B: ISI = 2.46, mean normal = 12.2 sec
PT = 16.2 sec
16.2
INR =
12.2
(
2.46
)
= 2.0
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
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
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
TF
aPTT
VII(a)
PL
Ca++
VIIIa
XII, HMWK, PK
IXa
Xa
Va
XIa
IIa
Fibrin
RESULTS OF 1025 CONSECUTIVE aPTT MEASUREMENTS
(excluding those ordered for monitoring heparin)
# abnormal: 143 (14%)
Abnormal result
On anticoagulant
Liver disease
No cause found, no bleeding
Normal on repeat testing
Known hemophilia
History of intestinal bypass
Other malabsorption (CF)
# TESTS
143
64
41
15
9
5
5
2
# PATIENTS
97
37
27
14
9
4
4
1
Technical problem with test
1
1
Newly dx'd bleeding disorder
0
0
Robbins and Rose, Ann Intern Med 1979;90:796
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
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?
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
XII, HMWK, PK
IXa
Xa
Va
XIa
IIa
Fibrin
FIBRINOLYSIS
Platelets
Endothelial cell
PAI-1
Plasminogen
Fibroblasts
TPA
UK
Macrophage
Liver
Fibrin
2 PI
Plasmin
FDP
2 PI
Fibrinogen
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
Bleeding severity vs antiplasmin activity
patients with platelets > 30,000
100
% of patients
80
0-2+ bleeding
60
3-4+ bleeding
40
20
0
< 50%
50-75%
Antiplasmin activity
> 75%
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)
VARIABILITY IN VON WILLEBRAND FACTOR LEVELS OVER TIME
Abildgaard et al, Blood 1980;56:712
NORMALS
TYPE I VWD
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
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
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
Muscle
40-50%
20-40 U/kg/day
Risk of compartment
syndrome or neuro
compromise
Oral mucosa
50% initially
25 U/kg x 1
Follow with
antifibrinolytic therapy
Epistaxis
Initially 80-100%, then 30%
until healed
40-50 U/kg then 30-40
U/kg daily
Pressure, packing,
cautery
Initially 100%, then 30%
until healed
Initially100%, then 30%
until healed
40-50 U/kg then 30-40
U/kg daily
40-50 U/kg then 30-40
U/kg daily
CNS
Initially100%, then 50%
until healed
50 U/kg then 25 U/kg q
12h infusion
Trauma or surgery
Initially100%, then 50%
until healed
50 U/kg then 25 U/kg q
12h infusion
GI
GU
Endoscopy to find lesion
R/O stones, UTI
Test for inhibitor before
surgery!
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
Bleeding events/100 patient-yr
200
150
100
50
0
<2
2.0-2.9
3-4.4
INR
• Treatment: vitamin K (oral or parenteral); FFP
4.5-6.9
>7
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
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
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)
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
DISSEMINATED INTRAVASCULAR
COAGULATION
DIAGNOSIS
ASSESS
SEVERITY
GUIDE
TREATMENT
D-Dimer
Antithrombin
Prothrombin time
Fibrinogen
Plasminogen
Fibrinogen
Prothrombin time
Alpha2-antiplasmin
Platelet count
Platelet count
Protein C
Alpha2-antiplasmin
Fibrin monomer
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 < 50-100)
 Platelets (if count < 30-50K)
• Pharmacologic inhibitors (selected pts)
 Heparin
 Antifibrinolytics
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)
FRESH FROZEN PLASMA
Contains: all clotting factors and inhibitors
UWHC/VA transfusion indications
adult dose = 10-15 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
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
DDAVP
(Desmopressin)
• Vasopressin analog; stimulates VWF release from endothelium
• Intravenous administration (0.3 mcg/kg); intranasal (Stimate)
• Increased plasma VWF levels for 18-24 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)
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
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
REVERSAL OF WARFARIN
ANTICOAGULATION
INR
ACTION
< 6, no bleeding
Withhold warfarin until INR therapeutic,
restart at lower dose
< 6, rapid reversal needed for surgery,
etc.
Vitamin K 1-2 mg po
6-10 or significant bleeding
Vitamin K 1-2 mg iv or 2.5-5 mg po; give
additional 0.5-1.0 mg if INR still
supratherapeutic at 24 hours
10-20
Vitamin K 3 mg slow iv, recheck INR q 6h
and repeat as needed
> 20
Vitamin K 10 mg slow iv; repeat q 6-12
hours as needed
Add FFP for major bleeding if INR > 2
Avoid subcutaneous Vit K (unreliable absorption)