BLEEDING DISORDERS

Hemostatic System

Blood vessels
Platelets
Plasma coagulation system
Proteolytic or Fibrinolytic system
How Bleeding Stops

Vasoconstriction
Platelet plug formation
Clotting cascade activated to form
fibrin clot
Haemostasis overview:
BV Injury
Contact/
Neural Tissue
Factor

Blood Vessel Platelet Coagulation

Constriction Aggregation Cascade
Primary hemostatic plug

Reduced Platelet
Activation Fibrin
Blood flow formation

Stable Hemostatic Plug

NORMAL HAEMOSTASIS

 formation of the platelet plug

 coagulation = fibrin formation
 clot retraction
 fibrinolysis
 RESOLUTION
Coagulation cascade
Coagulation factors
CLASSIFICATION

 PLATELET DISORDERS AND VASCULAR

COMPONENTS
 COAGULATION ABNORMALITIES
 OTHER
Vascular Disorders
 Vascular - hereditary
Hereditary hemorrhagic telangiectasia
Ehlers-Danlos syndrome
 - acquired
“senile purpura”
Henoch-Schonlein syndrome
Scurvy - Amyloid
Steroid purpura
Platelets disorders

Thrombocytopenia
Disorders of platelet function
(thrombastenia)
Inherited
Acquired
Acquired Coagulation Disorders

 Vitamin K deficiency
 Warfarin therapy
 Liver disease
 DIC
 Antibodies
Hereditery Coagulation Disorders

Hemophilias A & B
Von Willebrand’s disease
Types of Bleeding Disorders

Hemophilia A (factor VIII deficiency)

Hemophilia B (factor IX deficiency)

von Willebrand Disease (vWD)

 What is Hemophilia?

Hemophilia is an inherited bleeding

disorder in which there is a deficiency or
lack of factor VIII (hemophilia A) or
factor IX (hemophilia B)
Inheritance of Hemophilia

Hemophilia A and B are X-linked recessive

disorders
Hemophilia is typically expressed in males and
carried by females
Severity level is consistent between family
members
~30 % of cases of hemophilia are new mutations
Detection of Hemophilia
 Family history
 Symptoms
Bruising
Bleeding with circumcision
Muscle, joint, or soft tissue bleeding
 Hemostatic challenges
Surgery
Dental work
Trauma, accidents
 Laboratory testing
Degrees of Severity of Hemophilia
 Normal factor VIII or IX level = 50-150%
 Mild hemophilia
factor VIII or IX level = 6-50%
 Moderate hemophilia
factor VIII or IX level = 1-5%
 Severe hemophilia
factor VIII or IX level = <1%
Types of Bleeds

Joint bleeding - hemarthrosis

Muscle hemorrhage
Soft tissue
Life threatening-bleeding
Other
 Life-Threatening Bleeding

Head / Intracranial
 Nausea, vomiting, headache, drowsiness, confusion, visual changes,
loss of consciousness
Neck and Throat
 Pain, swelling, difficulty breathing/swallowing
Abdominal / GI
 Pain, tenderness, swelling, blood in the stools
Iliopsoas Muscle
 Back pain, abdominal pain, thigh tingling/numbness, decreased hip
range of motion
Other Bleeding Episodes

Mouth bleeding
Nose bleeding

Scrapes and/or minor cuts

Menorrhagia
Complications of Bleeding

Flexion contractures
Joint arthritis / arthropathy
Chronic pain
Muscle atrophy
Compartment syndrome
Neurologic impairment
Treatment of Hemophilia
 Replacement of missing clotting protein
On demand
Prophylaxis
 DDAVP : Desmopressin (a synthetic analogue of the
antidiuretic hormone vasopressin) , induces increase
levels of FVIII C, vasodilated agent
 Antifibrinolytic Agents
Amicar
 Supportive measures
Icing
Immobilization
Rest
Factor VIII Concentrate

 Intravenous infusion
IV push
Continuous infusion
 Dose varies depending on type of bleeding
Ranges from 20-50+ units/kg. body weight
 Half-life 8-12 hours
 Each unit infused raises serum factor VIII level by 2 %
 Factor IX Concentrate

 Intravenous infusion
IV push
Continuous infusion
 Dose varies depending on type of bleeding
Ranges from 20-100+ units/kg. body weight
 Half-life 12-24 hours
 Each unit infused raises serum factor IX level by 1%
Prophylaxis

 Scheduled infusions of factor concentrates to prevent

most bleeding
 Frequency: 2 to 3 times weekly to keep trough factor VIII
or IX levels at 2-3%
 Types
primary prophylaxis
secondary prophylaxis
DDAVP (Desmopressin acetate)

Synthetic vasopressin
Method of action -
 release of stores from endothelial cells raising factor VIII and vWD serum
levels

Administration -
 Intravenous
 Subcutaneously
 Nasally (Stimate)
Amicar
(epsilon amino caproic acid)

Antifibrinolytic
Uses
 Mucocutaneous bleeding

Dosing: 50 - 100 mg./kg. q. 6 hours

Contraindications
 Hematuria
Complications of Treatment

Inhibitors/Antibody development
Hepatitis A
Hepatitis B
Hepatitis C
HIV
Inhibitors

Definition
 IgG antibody to infused factor VIII or IX concentrates, which occurs after
exposure to the extraneous VIII or IX protein.

Prevalence
 20-30% of patients with severe hemophilia A
 1-4% of patients with severe hemophilia B
 von Willebrand Disease

Marked heterogeneity in phenotype, autosomal

Dominant or Recessive Inheritance
Deletion in chromosome 12
Incidence Man = Women
patients range from asymptomatic to spontaneous
bleeding similar to a severe hemophiliac
characterized by mucocutaneous bleeding
 Function of vWF

 Serves as the carrier protein for factor VIII (probably factor VIII
and vWF are brought together in storage granules).
 Serves as the ligand that binds to glycoptrotein Ib receptor
on platelets to initiate platelet adhesion to damaged blood
vessel walls.
 vWF needs to be activated to be able to bind to GP 1b
receptor on platelets (Ristocetin, high shear force, collagen,
etc)
Classification

A- Quantitative deficiency of VWF

Type 1: Partial quantitative deficiency of vWF
Type 3: Virtually complete deficiency of vWF

B- Qualitative deficiency of VWF

Type 2A: Qualitative variants with decreased platelet dependent function
associated with the absence of high and intermediate molecular
weight vWF multimers

Type 2B: Qualitative variants with increased affinity for platelet GPIb
Type 2M: Qualitative variants with decreased platelet dependent function
not caused by the absence of high-molecular weight vWF
multimers

Type 2N: Qualitative variants with markedly decreased affinity for

factor VIII
 Differential Diagnosis
Hemophilia A & von Willebrand Disease
 von Willebrand’s Disease - Treatment

 DDAVP (Stimate)
 0.3 micrograms/kg IV in 50cc NS over 30 minutes
 intranasally 2 puffs for adults, 1 puff for children
 Factor VIII product containing Vwf
 Humate P
 Koate HP
 Alphanate
 Cryoprecipitate ONLY IF VWF/VIII PRODUCT NOT AVAILABLE!
 1 bag/10 kg q 12 to 24 hours depending upon the
bleeding
 epsilon amino caproic acid (Amicar)
Other defects
 Other Factor deficiencies
 Vitamin K deficiency
 drug-induced/malabsorption
 rarely nutritional in an outpatient
 Liver Disease
 long PT +/- aPTT
 poor clearance of coagulation products
 DIC
 Bone Marrow disease
 TTP
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 200

antibiotics) 150

Bleeding events/100 patient-yr

• Bleeding tendency roughly correlated to INR 100

• Treatment: vitamin K (oral or parenteral); FFP 50

0
<2 2.0-2.9 3-4.4 4.5-6.9 >7
INR
 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
 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
 Thrombotic Thrombocytopenic Purpura

 Diagnosis is made by finding 3 of 5 features.

Microangiopathic hemolytic anemia
Thrombocytopenic purpura
Fever
Neurologic abnormalities
Renal failure
TTP Treatment

Plasma infusion in large amounts. This almost

always means plasmapheresis, using plasma to
replace volume for volume.
Other treatment with pheresis includes:
Persantine (platelet agregasi inhibitor)
Prednisone
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
 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
 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,
• Lupus anticoagulant
• 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
• Activate plasminogen, initiate fibrinolysis
• Most lysis initially at surface of clot; antiplasmin inhibits
plasmin in blood
• 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)
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
Laboratory Investigation of
Bleeding Disorders
Assessment of Primary Hemostasis
Platelet
Complete blood count (CBC)
Bleeding time/ PFA-100
Platelet aggregation study
Blood vessel
Bleeding time
von Willebrand factor (vWF)
Bleeding time
vWF Antigen, vWF: RCO, vWF multimer, FVIII
Bleeding Time

Principle
The bleeding time test is a useful tool to test for platelet
plug formation and capillary integrity
The bleeding time is dependent upon
 The efficiency of tissue fluid in accelerating the
coagulation process
 Capillary function and
 The number of blood platelets present and their
ability to form a platelet plug.
 Prolonged bleeding times are generally found when
 The platelet count is below 50,000/µL
 When there is platelet dysfunction.

 Four procedures are currently in use for determining

the bleeding time:
I. The Duke method.
II. The Ivy Method.
III. The Mielke Method.
IV. The Simplate or Surgicutt Method.
I. Duke Method
With the Duke method, the patient is pricked with a
special needle or lancet, preferably on the earlobe
or fingertip, after having been swabbed with
alcohol.
 The prick is about 3–4 mm deep. The technician
then wipes the blood every 30 seconds with a
filter paper.
 The test ceases when bleeding ceases.
 The usual time is about 1–3 minutes.
 No repeat testing is allowed due to space.
 The test causes nervousness in the patient.
 This test method is the easiest to perform, but is
the least standardized and has the less precision
and accuracy.
II. Ivy Method
In the Ivy method, a blood pressure cuff is placed on the upper
arm and inflated to 40 mmHg to control capillary tone and to
improve the sensitivity and reproducibility– this will maintain
constant pressure within the capillaries and help standardize
the procedure.
 A sterile, disposable blood lancet is used to make a shallow incision that is 1
millimeter deep on the underside of the forearm.
 Every 30 seconds, filter paper is used to draw off the blood.
 The time from when the incision is made until all bleeding has stopped is
measured.
Ivy Method

 The test is finished when bleeding has stopped

completely.
 A prolonged bleeding time may be a result from
decreased number of thrombocytes or impaired
blood vessels. However, it should also be noted that
the depth of the puncture or incision may be the
source of error.
 Normal values fall between 2 – 7 minutes depending
on the method used.
 The greatest source of variation in this test is largely
due to difficulty in performing a standardized
puncture. This usually leads to erroneously low
results.
Bleeding Time
Platelet Function Analysis
LTA – Principle

Agonist
Arachidonate
Platelet Rich
Plasma
(PRP)
+ ADP
TRAP
Aggregate
Clumping

Collagen
Epinenphrine

Baseline Light Transmission – Light transmission

the unaggregated platelets in increases as platelets
plasma creates a turbid aggregate and fall to the
solution that absorbs light bottom of the tube.
 Epinephrine ADP Collagen Ristocetin Arachidonic
acid
Normal +++ +++ +++ +++ +++
Glanzmann’s - - - +++ -
Thrombasthenia
Bernard-Soulier +++ +++ +++ - +++
Syndrome
Storage Pool + +* +* +++ ++
Disease (no secondary wave)
Aspirin + ++ + ++ -
Effect
Assessment of Secondary Hemostasis

Screening tests: Additional Tests

Fibrinogen
PT
Thrombin Time
aPTT Reptilase time
Mixing study Coagulation factor
assays
D-dimer
Fibrin Degradation
Product
Euglobulin lysis time
Prothrombin Time (PT)

PT : test extrinsic and common pathway

 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
Activated Partial Thromboplastin Time
(aPTT)

aPTT : test intrinsic and common

pathway
The partial thromboplastin time

• Sensitive to changes in factors XI, VIII, IX,, V, X, II, fibrinogen

• Very sensitive to contact factor levels (XII)
• Magnitude of test abnormality often not proportional to
severity of coagulopathy
• Used to screen for hemophilia, monitor heparin, detect
circulating anticoagulants
Other Tests for Secondary Hemostasis

Fibrinogen
D-dimer
Fibrin(ogen) degradtion product
Thrombin time
Reptilase time
Euglobulin lysis time
Fibrinogen
Functional level (200-400 mg/dl)
↓ Fibrinogen (esp. < 100 )
DIC
Fibrinolytic therapy
Primary fibrinolytic state
Congenital afibrinogenemia
Acquired/congenital dysfibrinogenemia
↑ Fibrinogen
Inflammatory states/acute illness
May associated with shortened PT/aPTT
D-Dimer
Measured cross-linked fibrin degradation product by
plasmin
More sensitive and specific for fibrinolysis than
Fibrin(ogen) Degradatioin Product (FDP)
↑ D-dimer:
DIC
Acute thromboembolic episodes
Post-trauma or surgery
Malignancy
Fibrin(ogen) Degradation Product

↑ levels in
Primary fibrinolytic syndromes
DIC
After lytic therapy
Acute thromboembolic episodes
After injury/surgery
Thrombin Time

Thrombin Time (TT)

Assess the ability to convert fibrinogen  fibrin by adding
thrombin to plasma

Prolonged TT:
Inhibitor of thrombin: heparin, anti-thrombin antibody
Hypofibrinogenemia or dysfibrinogenemia
Inhibitor of fibrin polymerization: fibrin degradation
product, paraprotein
Euglobulin Lysis Time

Euglobulin fraction of plasma is precipitated by acetic

acid and thrombin added.
Lysis of clot is observed.
Normal : > 120 min
Shortened ELT:
DIC
Liver disease
Primary fibrinogenolysis: malignancy, e.g. prostate
carcinoma
 Clotting time or Coagulation time

 The time required for blood to clot in a glass tube.

 The normal range for the test described below is 5 to 15 min. but each
laboratory should determine its own normal values.

 Reagent & equipment

1. water bath, 37C.
2. Glass test tube.
3. Stopwatch.
4. Plastic syringe and 20-gauge needle.

 Specimen: fresh whole blood , 4 ml .

 Procedure
1. Label 3 glass test tube with patient name and number
them, #1, #2, and #3.
2. Add 1 ml of blood in each tube. The last 1 mL of blood
may be discarded.
3. Start the stopwatch as soon as the blood is placed in
tube #3.
4. Place the three test tubes in a 37°C water bath.
5. At exactly 5 min., title test tube #1 gently to a 45°
angle. Repeat this procedure every 30 seconds, until
the test tube can be completely inverted without
spilling the contents (that is, until the blood is
completely clotted).
6. Record the time it took the blood in test tube #1 to
clot.
7. 30 sec. after the blood in test tube #1 is clotted.
Proceed with tube #2, and repeat the preceding
procedure, tilting the test tube every 30 seconds, until
a clot is formed. Record the results. Repeat this
procedure for test tube #3.
 Clotting time - capillary method

 Material

1. Sterile disposable pricking needle or lancet.

2. Stop watch
3. Dry glass capillary tube (narrow diameter 1 top 2 mm,
minimum 10 cm long.)
4. Cotton Swab of absorbent cotton.
5. Spirit wetted, cotton swab.
6. 70 % v/v ethyl alcohol
 Clotting Time - Slide Method
 The surface of the glass tube initiates
the clotting process. This test is
sensitive to the factors involved in the
intrinsic pathway
 The expected range for clotting time is
4-10 min.
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