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BLEEDING DISORDERS

HEMOSTASIS
1. VASCULAR PHASE
2. PLATELET PHASE
3. COAGULATION PHASE
4. FIBRINOLYTIC PHASE

Lab Tests

Hemostasis
BV Injury
Tissue Factor

CBC-Plt
BT,(CT)
PT
PTT

Neural

Blood Vessel
Constriction

Platelet
Aggregation

Coagulation
Cascade

Primary hemostatic plug


Reduced

Platelet
Activation

Blood flow

Fibrin
formation

Plt Study
Stable Hemostatic Plug

Morphology
Function
Antibody

NORMAL CLOTTING
Response to vessle injury
1. Vasoconstriction to reduce blood flow
2. Platelet plug formation (von willebrand factor binds
damaged vessle and platelets)
3. Activation of clotting cascade with generation of fibrin
clot formation
4. Fibrinlysis (clot breakdown)

CLOTTING CASCADE
Normally the ingredients, called factors, act like a row of
dominoes toppling against each other to create a chain
reaction.
If one of the factors is missing this chain reaction cannot
proceed.

VASCULAR PHASE
WHEN A BLOOD VESSEL IS
DAMAGED, VASOCONSTRICTION
RESULTS.

PLATELET PHASE
PLATELETS ADHERE TO THE
DAMAGED SURFACE AND FORM A
TEMPORARY PLUG.

COAGULATION PHASE
THROUGH TWO SEPARATE
PATHWAYS THE CONVERSION OF
FIBRINOGEN TO FIBRIN IS
COMPLETE.

THE CLOTTING MECHANISM


INTRINSIC

EXTRINSIC

Collagen

Tissue Thromboplastin

XII
XI

VII

IX
VIII
X
FIBRINOGEN
(I)

V
PROTHROMBIN
(II)

THROMBIN
(III)

FIBRIN

FIBRINOLYTIC PHASE
ANTICLOTTING MECHANISMS ARE
ACTIVATED TO ALLOW CLOT
DISINTEGRATION AND REPAIR OF
THE DAMAGED VESSEL.

HEMOSTASIS
DEPENDENT UPON:
Vessel Wall Integrity

Adequate Numbers of Platelets


Proper Functioning Platelets
Adequate Levels of Clotting Factors
Proper Function of Fibrinolytic Pathway

LABORATORY EVALUATION
PLATELET COUNT
BLEEDING TIME (BT)
PROTHROMBIN TIME (PT)
PARTIAL THROMBOPLASTIN TIME (PTT)
THROMBIN TIME (TT)

PLATELET COUNT
NORMAL

100,000 - 400,000 CELLS/MM3

< 100,000

Thrombocytopenia

50,000 - 100,000

Mild Thrombocytopenia

< 50,000

Sev Thrombocytopenia

BLEEDING TIME
PROVIDES ASSESSMENT OF PLATELET
COUNT AND FUNCTION

NORMAL VALUE
2-8 MINUTES

PROTHROMBIN TIME
Measures Effectiveness of the Extrinsic
Pathway
Mnemonic - PET

NORMAL VALUE
10-15 SECS

PARTIAL THROMBOPLASTIN TIME


Measures Effectiveness of the Intrinsic
Pathway
Mnemonic - PITT

NORMAL VALUE
25-40 SECS

THROMBIN TIME
Time for Thrombin To Convert
Fibrinogen
Fibrin
A Measure of Fibrinolytic Pathway

NORMAL VALUE
9-13 SECS

So What Causes Bleeding


Disorders?
VESSEL DEFECTS
PLATELET DISORDERS
FACTOR DEFICIENCIES
OTHER DISORDERS

VESSEL DEFECTS
VITAMIN C DEFICIENCY

BACTERIAL & VIRAL INFECTIONS


ACQUIRED &
HEREDITARY CONDITIONS

Vascular defect - cont.

Infectious and hypersensitivity vasculitides


- Rickettsial and meningococcal infections
- Henoch-Schonlein purpura (immune)

PLATELET DISORDERS
THROMBOCYTOPENIA
THROMBOCYTOPATHY

THROMBOCYTOPENIA
INADEQUATE NUMBER
OF PLATELETS

THROMBOCYTOPATHY
ADEQUATE NUMBER BUT
ABNORMAL FUNCTION

THROMBOCYTOPENIA
DRUG INDUCED
BONE MARROW FAILURE
HYPERSPLENISM
OTHER CAUSES

OTHER CAUSES
Lymphoma
HIV Virus
Idiopathic Thrombocytopenia Purpura (ITP)

THROMBOCYTOPATHY

UREMIA
INHERITED DISORDERS
MYELOPROLIFERATIVE DISORDERS
DRUG INDUCED

FACTOR DEFICIENCIES
(CONGENITAL)

HEMOPHILIA A
HEMOPHILIA B
von WILLEBRANDS DISEASE

FACTOR DEFICIENCIES
HEMOPHILIA A (Classic Hemophilia)
80-85% of all Hemophiliacs
Deficiency of Factor VIII
Lab Results - Prolonged PTT

HEMOPHILIA B (Christmas Disease)


10-15% of all Hemophiliacs
Deficiency of Factor IX
Lab Test - Prolonged PTT

FACTOR DEFICIENCIES
VON WILLEBRANDS DISEASE
Deficiency of VWF & amount of Factor VIII
Lab Results - Prolonged BT, PTT

OTHER DISORDERS
(ACQUIRED)

ORAL ANTICOAGULANTS
COUMARIN

HEPARIN

LIVER DISEASE
MALABSORPTION
BROAD-SPECTRUM ANTIBIOTICS

INHIBITORS
30% of people with haemophilia develop an antibody to the
clotting factor they are receiving for treatment. These
antibodies are known as inhibitors.
These patients are treated with high does of FVIIa for bleeds or
surgery. This overrides defect in FVIII or FIX deficiency.
Longterm management involves attempting to eradicate
inhibitors by administering high dose FVIII (or FIX) in a
process called immune tolerance

Bleeding Disorders

Clinical Features of Bleeding Disorders


Platelet

Coagulation
disorders

factor disorders
Site of bleeding

Skin
Mucous membranes
(epistaxis, gum,
vaginal, GI tract)

Deep in soft tissues


(joints, muscles)

Petechiae

Yes

No

Ecchymoses (bruises)

Small, superficial

Large, deep

Hemarthrosis / muscle bleeding

Extremely rare

Common

Bleeding after cuts & scratches

Yes

No

Bleeding after surgery or trauma

Immediate,
usually mild

Delayed (1-2 days),


often severe

Platelet

Petechiae, Purpura

Coagulation

Hematoma, Joint bl.

Petechiae
(typical of platelet disorders)

Do not blanch with pressure


(cf. angiomas)
Not palpable
(cf. vasculitis)

Hemarthrosis

Hematoma

Petechiae

Purpura

Ecchymosis

Senile Purpura

Petechiae in patient
with Rocky Mountain
Spotted Fever

Henoch-Schonlein purpura

Ecchymoses
(typical of coagulation
factor disorders)

CT scan showing large hematoma


of right psoas muscle

Coagulation factor disorders

Inherited bleeding
disorders
Hemophilia

A and B
vonWillebrands disease
Other factor deficiencies

Acquired bleeding
disorders
Liver

disease
Vitamin K
deficiency/warfarin
overdose
DIC

Hemophilia A and B
Coagulation factor deficiency
Inheritance

Incidence
Severity

Complications

Hemophilia A

Hemophilia B

Factor VIII

Factor IX

X-linked
recessive

X-linked
recessive

1/10,000 males

1/50,000 males

Related to factor level


<1% - Severe - spontaneous bleeding
1-5% - Moderate - bleeding with mild injury
5-25% - Mild - bleeding with surgery or trauma
Soft tissue bleeding

Hemophilia
Clinical manifestations (hemophilia A & B are
indistinguishable)
Hemarthrosis (most common)
Fixed joints

Soft tissue hematomas (e.g., muscle)


Muscle atrophy
Shortened tendons

Other sites of bleeding


Urinary tract
CNS, neck (may be life-threatening)

Prolonged bleeding after surgery or dental extractions

Hemarthrosis (acute)

Treatment of hemophilia A

Intermediate purity plasma products


Virucidally

treated
May contain von Willebrand factor

High purity (monoclonal) plasma products


Virucidally

treated
No functional von Willebrand factor

Recombinant factor VIII


Virus

free/No apparent risk


No functional von Willebrand factor

Dosing guidelines for hemophilia A

Mild bleeding
Target:

Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria

Major bleeding
Target:

30% dosing q8-12h; 1-2 days (15U/kg)

80-100% q8-12h; 7-14 days (50U/kg)

CNS trauma, hemorrhage, lumbar puncture


Surgery
Retroperitoneal hemorrhage
GI bleeding

Adjunctive therapy
-aminocaproic acid (Amicar) or DDAVP (for mild disease only)

Complications of therapy

Formation of inhibitors (antibodies)


10-15%

of severe hemophilia A patients


1-2% of severe hemophilia B patients

Viral infections
Hepatitis

B
Hepatitis C
HIV

Human parvovirus
Hepatitis A
Other

Viral infections in hemophiliacs

Hepatitis serology
Negative
Hepatitis B virus only
Hepatitis C virus only
Hepatitis B and C
Blood 1993:81;412-418

HIV -positive
(n=382)
53%
% positive

HIV-negative
(n=345)
47%
% negative

1
1
24
74

20
1
45
34

Treatment of hemophilia B

Agent
High

purity factor IX
Recombinant human factor IX

Dose
Initial

dose: 100U/kg
Subsequent: 50U/kg every 24 hours

von Willebrand Disease: Clinical Features

von Willebrand factor


Synthesis

in endothelium and megakaryocytes


Forms large multimer
Carrier of factor VIII
Anchors platelets to subendothelium
Bridge between platelets

Inheritance - autosomal dominant

Incidence - 1/10,000

Clinical features - mucocutaneous bleeding

Laboratory evaluation of
von Willebrand disease

Classification
Type 1
Type 2
Type 3

Partial quantitative deficiency


Qualitative deficiency
Total quantitative deficiency

Diagnostic tests:
Assay
vWF antigen
vWF activity
Multimer analysis

Normal

vonWillebrand type
2
Normal

Normal

Absent

Treatment of von Willebrand Disease

Cryoprecipitate
Source

of fibrinogen, factor VIII and VWF


Only plasma fraction that consistently contains VWF multimers

DDAVP (deamino-8-arginine vasopressin)

plasma VWF levels by stimulating secretion from endothelium


Duration of response is variable
Not generally used in type 2 disease
Dosage 0.3 g/kg q 12 hr IV

Factor VIII concentrate (Intermediate purity)


Virally

inactivated product

Vitamin K deficiency

Source of vitamin K

Green vegetables
Synthesized by intestinal flora

Required for synthesis

Factors II, VII, IX ,X


Protein C and S

Causes of deficiency

Malnutrition
Biliary obstruction
Malabsorption
Antibiotic therapy

Treatment

Vitamin K
Fresh frozen plasma

Common clinical conditions associated with


Disseminated Intravascular Coagulation
Activation of both coagulation and fibrinolysis
Triggered by

Sepsis

Obstetrical complications

Trauma

Head injury
Fat embolism

Malignancy

Amniotic fluid embolism


Abruptio placentae

Vascular disorders

Reaction to toxin (e.g.


snake venom, drugs)

Immunologic disorders

Severe allergic reaction


Transplant rejection

Disseminated Intravascular Coagulation (DIC)


Mechanism
Systemic activation
of coagulation

Intravascular
deposition of fibrin

Thrombosis of small
and midsize vessels
with organ failure

Depletion of platelets
and coagulation factors

Bleeding

Pathogenesis of DIC
Release of
thromboplastic
material into
circulation

Coagulation

Fibrinolysis
Fibrinogen
Plasmin

Thrombin

Fibrin
Monomers

Fibrin
Clot
(intravascular)

Consumption of
coagulation factors;
presence of FDPs
aPTT
PT
TT
Fibrinogen

Presence of plasmin
FDP
Fibrin(ogen)
Degradation
Products

Plasmin

Intravascular clot
Platelets
Schistocytes

Disseminated Intravascular Coagulation


Treatment approaches

Treatment of underlying disorder

Anticoagulation with heparin

Platelet transfusion

Fresh frozen plasma

Coagulation inhibitor concentrate (ATIII)

Classification of platelet disorders

Quantitative disorders
distribution
Dilution effect
Decreased production

Qualitative disorders

Abnormal

Inherited

disorders (rare)
Acquired disorders
Medications
Chronic renal failure
Cardiopulmonary bypass

Increased

destruction

Thrombocytopenia
Immune-mediated
Idioapthic
Drug-induced
Collagen vascular disease
Lymphoproliferative disease
Sarcoidosis
Non-immune mediated
DIC
Microangiopathic hemolytic anemia

Liver Disease and Hemostasis


1.

Decreased synthesis of II, VII, IX, X, XI, and


fibrinogen

2.

Dietary Vitamin K deficiency (Inadequate


intake or malabsortion)

3.

Dysfibrinogenemia

4.

Enhanced fibrinolysis (Decreased alpha-2antiplasmin)

5.

DIC

6.

Thrombocytoepnia due to hypersplenism

Management of Hemostatic
Defects in Liver Disease
Treatment

for prolonged PT/PTT

Vitamin K 10 mg SQ x 3 days - usually


ineffective

Fresh-frozen plasma infusion


25-30% of plasma volume (1200-1500 ml)
immediate but temporary effect

Treatment

for low fibrinogen

Cryoprecipitate (1 unit/10kg body weight)

Treatment

for DIC (Elevated D-dimer, low factor


VIII, thrombocytopenia

Replacement therapy

Vitamin K deficiency due to warfarin overdose


Managing high INR values
Clinical situation

Guidelines

INR therapeutic-5

Lower or omit next dose;


Resume therapy when INR is therapeutic

INR 5-9; no bleeding

Lower or omit next dose;


Resume therapy when INR is therapeutic
Omit dose and give vitamin K (1-2.5 mg po)
Rapid reversal: vitamin K 2-4 mg po (repeat)

INR >9; no bleeding

Omit dose; vitamin K 3-5 mg po; repeat as necessary


Resume therapy at lower dose when INR therapeutic

Chest 2001:119;22-38s (supplement)

Vitamin K deficiency due to warfarin overdose


Managing high INR values in bleeding patients
Clinical situation

Guidelines

INR > 20; serious bleeding

Omit warfarin
Vitamin K 10 mg slow IV infusion
FFP or PCC (depending on urgency)
Repeat vitamin K injections every 12 hrs as needed

Any life-threatening bleeding

Omit warfarin
Vitamin K 10 mg slow IV infusion
PCC ( or recombinant human factor VIIa)
Repeat vitamin K injections every 12 hrs as needed

Chest 2001:119;22-38s (supplement)

Approach to Post-operative bleeding


1. Is the bleeding local or due to a hemostatic failure?
1.
2.

Local: Single site of bleeding usually rapid with minimal


coagulation test abnormalities
Hemostatic failure: Multiple site or unusual pattern with
abnormal coagulation tests

2. Evaluate for causes of peri-operative hemostatic failure


1.
2.

Preexisting abnormality
Special cases (e.g. Cardiopulmonmary bypass)

3. Diagnosis of hemostatic failure


1.
2.

Review pre-operative testing


Obtain updated testing

Laboratory Evaluation of Bleeding


Overview
CBC and smear

Platelet count
RBC and platelet morphology

Thrombocytopenia
TTP, DIC, etc.

Coagulation

Prothrombin time
Partial thromboplastin time
Coagulation factor assays
50:50 mix
Fibrinogen assay
Thrombin time

Extrinsic/common pathways
Intrinsic/common pathways
Specific factor deficiencies
Inhibitors (e.g., antibodies)
Decreased fibrinogen
Qualitative/quantitative
fibrinogen defects
Fibrinolysis (DIC)

FDPs or D-dimer
Platelet function

von Willebrand factor


vWD
Bleeding time
In vivo test (non-specific)
Platelet function analyzer (PFA) Qualitative platelet disorders
and vWD
Platelet function tests
Qualitative platelet disorders

Laboratory Evaluation of the


Coagulation Pathways
Partial thromboplastin time
(PTT)

Prothrombin time
(PT)

Surface activating agent


(Ellagic acid, kaolin)
Phospholipid
Calcium

Thromboplastin
Tissue factor
Phospholipid
Calcium

Intrinsic pathway

Extrinsic pathway

Thrombin time

Common pathway

Thrombin

Fibrin clot

Coagulation factor deficiencies


Summary
Sex-linked recessive
Factors VIII and IX deficiencies cause bleeding
Prolonged PTT; PT normal

Autosomal recessive (rare)


Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding
Prolonged PT and/or PTT
Factor XIII deficiency is associated with bleeding and
impaired wound healing
PT/ PTT normal; clot solubility abnormal
Factor XII, prekallikrein, HMWK deficiencies
do not cause bleeding

Thrombin Time

Bypasses factors II-XII

Measures rate of fibrinogen conversion to fibrin

Procedure:
Add

thrombin with patient plasma


Measure time to clot

Variables:
Source

and quantity of thrombin

Causes of prolonged Thrombin Time

Heparin
Hypofibrinogenemia
Dysfibrinogenemia
Elevated FDPs or paraprotein
Thrombin inhibitors (Hirudin)
Thrombin antibodies

Classification of thrombocytopenia

Associated with thrombosis


Thrombotic

thrombocytopenic

purpura
Heparin-associated
thrombocytopenia
Trousseaus syndrome
DIC

Associated with bleeding


Immune-mediated

thrombocytopenia (ITP)
Most others

Bleeding time and bleeding

5-10% of patients have a prolonged bleeding time

Most of the prolonged bleeding times are due to


aspirin or drug ingestion

Prolonged bleeding time does not predict excess


surgical blood loss

Not recommended for routine testing in


preoperative patients

Drugs

and blood products used for


bleeding

Treatment Approaches to
the Bleeding Patient

Red blood cells


Platelet transfusions
Fresh frozen plasma
Cryoprecipitate
Amicar
DDAVP
Recombinant Human factor VIIa

RBC transfusion therapy


Indications

Improve oxygen carrying capacity of blood


Bleeding
Chronic

anemia that is symptomatic

Peri-operative

management

Red blood cell transfusions


Special preparation
CMV-negative

CMV-negative patients

Prevent CMV
transmission

Irradiated RBCs

Immune deficient recipient


or direct donor

Prevent GVHD

Leukopoor

Previous non-hemolytic
transfusion reaction
CMV negative patients

Prevents reaction

PNH patients
IgA deficient recipient

Prevents hemolysis
Prevents anaphylaxis

Washed RBC

Prevents transmission

Red blood cell transfusions


Adverse reactions
Immunologic reactions
Hemolysis
Anaphylaxis
Febrile reaction
Urticaria
Non-cardiogenic
pulmonary edema

RBC incompatibility
Usually unknown; rarely against IgA
Antibody to neutrophils
Antibody to donor plasma proteins
Donor antibody to leukocytes

Red blood cell transfusions


Adverse reactions
Non-immunologic reactions
Congestive heart failure

Volume overload

Fever and shock

Bacterial contamination

Hypocalcemia

Massive transfusion

Transfusion-transmitted disease
Infectious agent

Risk

HIV
Hepatitis C
Hepatitis B
Hepatitis A
HTLV I/II
CMV
Bacteria
Creutzfeld-Jakob disease
Others

~1/500,000
1/600,000
1/500,000
<1/1,000,000
1/640,000
50% donors are sero-positive
1/250 in platelet transfusions
Unknown
Unknown

Platelet transfusions

Source
Platelet

concentrate (Random donor)


Pheresis platelets (Single donor)

Target level
Bone

marrow suppressed patient (>10-20,000/l)


Bleeding/surgical patient (>50,000/l)

Platelet transfusions - complications

Transfusion reactions
Higher

incidence than in RBC transfusions


Related to length of storage/leukocytes/RBC mismatch
Bacterial contamination

Platelet transfusion refractoriness


Alloimmune

destruction of platelets (HLA antigens)


Non-immune refractoriness
Microangiopathic hemolytic anemia
Coagulopathy
Splenic sequestration
Fever and infection
Medications (Amphotericin, vancomycin, ATG, Interferons)

Fresh frozen plasma

Content - plasma (decreased factor V and VIII)


Indications
Multiple

coagulation deficiencies (liver disease, trauma)

DIC
Warfarin

reversal
Coagulation deficiency (factor XI or VII)

Dose (225 ml/unit)


10-15

ml/kg

Note
Viral

screened product
ABO compatible

Cryoprecipitate

Prepared from FFP


Content
Factor

VIII, von Willebrand factor, fibrinogen

Indications
Fibrinogen

deficiency

Uremia
von

Willebrand disease

Dose (1 unit = 1 bag)


1-2

units/10 kg body weight

Hemostatic drugs
Aminocaproic acid (Amicar)

Mechanism

Dose

50mg/kg po or IV q 4 hr

Uses

Prevent activation plaminogen -> plasmin

Primary menorrhagia
Oral bleeding
Bleeding in patients with thrombocytopenia
Blood loss during cardiac surgery

Side effects

GI toxicity
Thrombi formation

Hemostatic drugs
Desmopressin (DDAVP)

Mechanism

Dose

0.3g/kg IV q12 hrs


150mg intranasal q12hrs

Uses

Increased release of VWF from endothelium

Most patients with von Willebrand disease


Mild hemophilia A

Side effects

Facial flushing and headache


Water retention and hyponatremia

Recombinant human factor VIIa (rhVIIa; Novoseven)

Mechanism

Direct activation of common pathway

Use

Factor VIII inhibitors


Bleeding with other clotting disorders
Warfarin overdose with bleeding

CNS bleeding with or without warfarin

Dose

90

g/kg IV q 2 hr
Adjust as clinically indicated

Cost (70 kg person) - $1 per g

~$5,000/dose or $60,000/day

Approach to bleeding disorders


Summary

Identify and correct any specific defect of


hemostasis

Laboratory testing is almost always needed to establish the cause of


bleeding

Screening tests (PT,PTT, platelet count) will often allow placement


into one of the broad categories

Specialized testing is usually necessary to establish a specific


diagnosis

Use non-transfusional drugs whenever possible

RBC transfusions for surgical procedures or large


blood loss