CAUSES OF BLEEDING

• Defective clot formation

 Platelet plug
 Fibrin clot
• Excessive fibrinolysis
• Vascular fragility
• 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?
• 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)
• DIC
• Thrombolytic drug administration
• Inherited deficiency of fibrinolytic inhibitor (rare)
• Inherited defect in collagen formation (Ehlers
Danlos syndrome)
• Acquired defect in collagen formation (scurvy)
(mainly purpura)
• Infiltrative disease (amyloidosis)
• Vasculitis (purpura only)
 • 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

 Odds ratios for presence/absence of bleeding
disorder by multivariate analysis
Symptom Odds ratio 95% CI
Family members with proven bleeding disorder 50.5 12.5-202.9
Profuse bleeding from small wounds 30 8.1-111.1
Profuse bleeding with tonsillectomy 11.5 1.2-111.9
Easy bruising 9.9 3.0-32.3
Profuse bleeding after surgery 5.8 1.3-26.4
Muscle bleeding 4.8 0.7-31.4
Frequent nosebleeds 3.8 0.9-15.7
Profuse bleeding with tooth extraction 3.2 0.9-11.3
History of blood in stool 2.8 0.7-11.7
Family members with bleeding symptoms 2.5 0.7-9.4
History of joint bleeding 2.5 0.6-10.2
Menorrhagia 2.5 0.6-9.9
Profuse bleeding with childbirth 2.1 0.3-13.5
Frequent gum bleeding 0.7 0.3-2.0
History of hematuria 0.5 0.1-2.3

Arch Intern Med 1995;155:1409

 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

 Platelet/vascular Coagulation
disorders factor deficiency

Onset Immediate Delayed

Skin, mucosal
Location Deep tissue
surfaces
• 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
• 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
• 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
 TF VII(a)

PL
Ca++

VIIIa IXa Xa Va
“Contact" system

XII, HMWK, PK XIa

?
Not physiologically important
IIa Fibrin
• Sensitive to changes in factors VII, V, X, II, fibrinogen
• Best global test The
of clotting system time
prothrombin 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
 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
Reagent A: ISI = 1.24, mean normal = 12.6 sec
PT = 22 sec
1.24
22.0
INR = (
12.6 ) = 2.0

Reagent B: ISI = 2.46, mean normal = 12.2 sec

PT = 16.2 sec
2.46
16.2
INR = (
12.2 ) = 2.0
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
 Comparison of three reagents
Reagent (ISI) A (0.86) B (1.09) C (2.53)

Mean INR
2.63 2.75 2.67
(warfarin pts)

Mean INR
1.88 2.17 2.63
(liver disease)

Thrombosis and Haemostasis 1994;71:727

• Sensitive to changes in factors XI, VIII, IX,, V, X, II, fibrinogen
• Very sensitive to partial
The contactthromboplastin
factor levels (XII,time
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 VII(a)
aPTT
PL
Ca++

VIIIa IXa Xa Va

XII, HMWK, PK XIa

IIa Fibrin
 (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 0 0

Robbins and Rose, Ann Intern Med 1979;90:796

 PT, aPTT, BT, history

# with abnormal labs on repeat

13
testing
# of those in whom bleeding disorder
diagnosed (1 mild hemophilia, 1 2
VWD)
# in which bleeding disorder not
apparent from history alone (mild 1
hemophilia A)

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
To bleed or not to bleed? is that the question for the PTT?

patient will bleed

• Measures only conversion of fibrinogen to fibrin, fibrin
polymerization The thrombin time
• 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
Platelets

Plasminogen
Endothelial cell
Fibroblasts

PAI-1 TPA UK
Macrophage

Liver Plasmin
2 PI 2 PI

Fibrin FDP Fibrinogen

• 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

80
% of patients

60 0-2+ bleeding

3-4+ bleeding
40

20

0
< 50% 50-75% > 75%
Antiplasmin activity
• 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

• 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"
 • Unexplained pain in
a hemophiliac
Treatment of bleeding
should be episodes
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
 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
Muscle 40-50% 20-40 U/kg/day syndrome or neuro
compromise
Follow with
Oral mucosa 50% initially 25 U/kg x 1
antifibrinolytic therapy
Initially 80-100%, then 30% 40-50 U/kg then 30-40 Pressure, packing,
Epistaxis
until healed U/kg daily cautery
Initially 100%, then 30% 40-50 U/kg then 30-40
GI Endoscopy to find lesion
until healed U/kg daily
Initially100%, then 30% 40-50 U/kg then 30-40
GU R/O stones, UTI
until healed U/kg daily
Initially100%, then 50% 50 U/kg then 25 U/kg q
CNS
until healed 12h infusion
Initially100%, then 50% 50 U/kg then 25 U/kg q Test for inhibitor before
Trauma or surgery
until healed 12h infusion surgery!
• 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

200

• Treatment: vitamin K (oral or parenteral); FFP

Bleeding events/100 patient-yr

150

100

50

0
<2 2.0-2.9 3-4.4 4.5-6.9 >7
INR
• 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
• 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
• 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)
• 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
 ASSESS GUIDE
DIAGNOSIS
SEVERITY 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
• Plts < 20K (except ITP, TTP)
 Most beneficial in marrow failure states
 10K
UWHC/VA TRANSFUSION
trigger safe for most patientsINDICATIONS
• Plts < 50K AND significant bleeding OR invasive
standard adult dose = 5 units
procedure/surgery planned within six hours
• Plts < 100K AND major CNS or eye surgery (up to 48 hours
postop)
• Active bleeding and INR > 1.6
• Invasive procedure planned within 6 hours and INR > 1.6
• Immediate reversal
Contains: allofclotting
warfarin effect for
factors andemergency
inhibitorssurgery or
active bleeding
UWHC/VA
• Surgery with transfusion
massive transfusion indications
(> 10 units RBC/24 hours)
• Replacement during plasmapheresis
adult dose = 10-15 ml/kg
• TTP
• Fibrinogen deficiency (<100 mg/dl)
 For DIC: give 1 bag/2-3 Units FFP
• Contains:
Factor VIII or VWF deficiency
fibrinogen, factor VIII, von Willebrand factor
 Rarely used for this indication; factor concentrates
preferable
UWHC/VA transfusion indications
• Fibrin glue
• Vasopressin analog; stimulates VWF release from endothelium
• Intravenous administration (0.3 mcg/kg); intranasal (Stimate)
• Increased plasma VWF (Desmopressin)
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)
• Antifibrinolytic: Inhibits plasmin activation by tPA, fibrin degradation by
plasmin
(Epsilon-aminocaproic
• Short plasma half-life; need frequent dosing, upacid)
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
• 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
 INR ACTION
Withhold warfarin until INR therapeutic,
< 6, no bleeding
restart at lower dose
< 6, rapid reversal needed for surgery,
Vitamin K 1-2 mg po
etc.

Vitamin K 1-2 mg iv or 2.5-5 mg po; give

6-10 or significant bleeding additional 0.5-1.0 mg if INR still
supratherapeutic at 24 hours

Vitamin K 3 mg slow iv, recheck INR q 6h

10-20
and repeat as needed

Vitamin K 10 mg slow iv; repeat q 6-12

> 20
hours as needed

Add FFP for major bleeding if INR > 2

Avoid subcutaneous Vit K (unreliable absorption)