CAUSES OF BLEEDING

1
CAUSES OF BLEEDING

• Defective clot formation
• 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
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 19951551409
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
Deep tissue
Location
10
PLATELET COUNT VS BLEEDING RISK

• Bleeding risk rises as platelet count falls below
  100K
• Plts gt 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
TF VII(a)
PL 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
XIa
XII, HMWK, PK
IIa
Fibrin
15
ISI
(
)
Patient PT Mean Normal PT
INR
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
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 199471727
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
Fibrin
IIa
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
0
0
Newly dx'd bleeding disorder
Robbins and Rose, Ann Intern Med 197990796
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 199289691
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
XIa
XII, HMWK, PK
IIa
Fibrin
24
FIBRINOLYSIS
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 gt 30,000
100
80
0-2 bleeding
60
of patients
3-4 bleeding
40
20
0
lt 50
50-75
gt 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 198056712
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
• lt1 severe frequent "spontaneous" bleeds
• 1-5 moderate spontaneous bleeding less common
• gt 5 mild bleeding mainly after
  trauma/surgery may go undiagnosed until adulthood

30
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 80-100, then 30 until healed
40-50 U/kg then 30-40 U/kg daily
Pressure, packing, cautery
Epistaxis
Initially 100, then 30 until healed
40-50 U/kg then 30-40 U/kg daily
Endoscopy to find lesion
GI
Initially100, then 30 until healed
40-50 U/kg then 30-40 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
100
Bleeding events/100 patient-yr
50
0
lt2
2.0-2.9
3-4.4
4.5-6.9
gt7
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 gt 1.6)
• Cryoprecipitate (if fibrinogen lt 50-100)
• Platelets (if count lt 30-50K)
• Pharmacologic inhibitors (selected pts)
• Heparin
• Antifibrinolytics

39
PLATELET TRANSFUSION
UWHC/VA TRANSFUSION INDICATIONS
standard adult dose 5 units

• Plts lt 20K (except ITP, TTP)
• Most beneficial in marrow failure states
• 10K trigger safe for most patients
• Plts lt 50K AND significant bleeding OR invasive
  procedure/surgery planned within six hours
• Plts lt 100K AND major CNS or eye surgery (up to
  48 hours postop)

40
FRESH FROZEN PLASMA
Contains all clotting factors and inhibitors
UWHC/VA transfusion indications
adult dose 10-15 ml/kg

• Active bleeding and INR gt 1.6
• Invasive procedure planned within 6 hours and INR
  gt 1.6
• Immediate reversal of warfarin effect for
  emergency surgery or active bleeding
• Surgery with massive transfusion (gt 10 units
  RBC/24 hours)
• Replacement during plasmapheresis
• TTP

41
CRYOPRECIPITATE
Contains fibrinogen, factor VIII, von Willebrand
factor
UWHC/VA transfusion indications

• Fibrinogen deficiency (lt100 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 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)

43
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
lt 6, no bleeding
lt 6, rapid reversal needed for surgery, etc.
Vitamin K 1-2 mg po
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
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
gt 20
Add FFP for major bleeding if INR gt 2 Avoid
subcutaneous Vit K (unreliable absorption)