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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)

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causes of bleeding
CAUSES OF BLEEDING
  • Defective clot formation
    • Platelet plug
    • Fibrin clot
  • Excessive fibrinolysis
  • Vascular fragility
platelet defects
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
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
EXCESSIVE FIBRINOLYSIS

DIC

Thrombolytic drug administration

Inherited deficiency of fibrinolytic inhibitor (rare)

vascular disorders that can cause bleeding
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
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
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 1995;155:1409

family history in bleeding disorders
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
PATTERNS OF BLEEDING IN HEMOSTATIC DISORDERS

Platelet/vascular disorders

Coagulation factor deficiency

Onset

Immediate

Delayed

Skin, mucosal surfaces

Location

Deep tissue

platelet count vs bleeding risk
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
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
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
FIBRIN CLOT FORMATION

TF VII(a)

PL

Ca++

VIIIa IXa

Xa Va

“Contact" system

XIa

XII, HMWK, PK

?

Not physiologically important

IIa

Fibrin

assessment of fibrin clot formation

The prothrombin time

ASSESSMENT OF FIBRIN CLOT FORMATION

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

slide15

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

slide16

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

inr comparison
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
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 formation1

The partial thromboplastin time

ASSESSMENT OF FIBRIN CLOT FORMATION

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

results of 1025 consecutive aptt measurements
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 1979;90:796

results of preoperative screening in 1603 children
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

slide22

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 formation2

The thrombin time

ASSESSMENT OF FIBRIN CLOT FORMATION

Thrombin time

TF VII(a)

PL

Ca++

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

VIIIa IXa

Xa Va

XIa

XII, HMWK, PK

IIa

Fibrin

fibrinolysis
FIBRINOLYSIS

Platelets

Plasminogen

Endothelial cell

Fibroblasts

PAI-1

TPA

UK

Macrophage

Plasmin

Liver

PI

PI

2

2

Fibrin

FDP

Fibrinogen

assessment of the fibrinolytic system
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
Bleeding severity vs antiplasmin activity

patients with platelets > 30,000

100

80

0-2+ bleeding

60

% of patients

3-4+ bleeding

40

20

0

< 50%

50-75%

> 75%

Antiplasmin activity

von willebrand disease
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)

slide28

NORMALS

TYPE I VWD

VARIABILITY IN VON WILLEBRAND FACTOR LEVELS OVER TIME

Abildgaard et al, Blood 1980;56:712

hemophilia
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

hemophilia1

Treatment of bleeding episodes

HEMOPHILIA

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

hemophilia2
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

vitamin k deficiency
VITAMIN K DEFICIENCY

200

150

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

Bleeding events/100 patient-yr

100

50

0

<2

2.0-2.9

3-4.4

4.5-6.9

>7

INR

liver disease
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
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
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
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 coagulation1
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

treatment of dic
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

PLATELET TRANSFUSION

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

FRESH FROZEN PLASMA

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

CRYOPRECIPITATE

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)

DDAVP

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)

AMICAR

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
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
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 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

> 20

Add FFP for major bleeding if INR > 2

Avoid subcutaneous Vit K (unreliable absorption)