Approach to

Bleeding Disorder

Prof Dr Smriti Karki

Head, Department Of Pathology
 OBJECTIVES
• CAUSES OF BLEEDING

• CLINICAL FEATURES

• DIAGNOSIS
 Hemostasis
Repair injured vessels from bleeding through a mechanism

[Link] HEMOSTASIS [Link] HEMOSTASIS

 BLEEDING

CAUSES

1. Primary Hemostatic Disorder

2. Secondary Hemostatic Disorder
3. Vessel wall abnormalities

CLINICAL FEATURES
 BLEEDING
1. PRIMARY HEMOSTATIC DISORDERS

• LOW PLATELET COUNT

• PLATELET FUNCTION DEFECT

SUPERFICIAL BLEEDING MUCOCUTANEOUS BLEED MOUTH, NOSE & GIT

Petechiae
• Small, pinpoint (1-3 mm) red non blanching
Purpura
macular (flat) lesions
• Larger, raised, rash like lesions caused by
• Intradermal capillary bleed
bleeding within skin
• eg: infections, drug reactions
 BLEEDING
2. SECONDARY HEMOSTATIC DISORDERS
DEEP BLEEDS
• PROBLEMS IN CLOTTING FACTORS ECCHYMOSIS, BRUISING,
CLOTTING FACTOR DEFICIENCY OR BLEEDING INTO JOINTS,
CLOTTING FACTOR INHIBITORS SOFT TISSUE - HEMATOMA

Ecchymoses:

Blood in subcutaneous tissue, blunt force injury Hemarthrosis

Coagulation Disorders palpable ecchymoses Severe coagulation disorder: Haemophilia

Spreading into deep tissue - haematoma

I. Decreased Production of Platelets
1. Generalized disease of bone marrow
Aplastic anemia: congenital and acquired
Marrow infiltration: leukemia, disseminated cancer

2. Selective impairment of platelet production

Drug-induced: alcohol, thiazides, cytotoxic drugs
Infections: measles, HIV infection

3. Ineffective megakaryopoiesis
Megaloblastic anemia
Paroxysmal nocturnal hemoglobinuria
II. Decreased Platelet Survival
1. Immunologic destruction
Autoimmune: immune thrombocytopenic
purpura, systemic lupus erythematous
Isoimmune: post-transfusion and neonatal
Drug-associated: quinidine, heparin, sulfa
compounds
Infections: infectious mononucleosis, HIV
infection, cytomegalovirus infection

2. Nonimmunologic destruction
Disseminated intravascular coagulation
Thrombotic thrombocytopenic purpura
Giant hemangiomas
III. Sequestration

Hypersplenism

IV. Dilutional
 Thrombocytopenia
Distinction Between Reduced Production Vs Destruction

**Examination of bone marrow is of utmost importance.

Decreased
NORMAL

production
Increased destruction

BONE MARROW Very few

ASPIRATION SMEAR
megakaryocytes. Increased number of
megakaryocytes
including many young forms.
 Immune Thrombocytopenia
Idiopathic Thrombocytopenic Purpura)
- ITP

ts become coated with antibodies and destroyed by the reticulo-endothel

• Two types : Acute ITP & Chronic ITP

Features of Acute and Chronic ITP

Features Acute (<6m) Chronic (>6m)

Peak age Children (2-6 yrs) Adults (20-40 yrs)

Female:male 1:1 3:1

Antecedent infection (viral) Common -

Onset of symptoms Abrupt Indolent

Platelet count at presentation <20,000

<50,000

Duration 2-6 weeks Long-term

Spontaneous remission Common Uncommon

Features of Acute and Chronic ITP
Features Acute Chronic

Pathogenesis Antiplatelet IgMAbs IgG against Platelet GP

Peripheral smear Thrombocytopenia Same

& Giant PLTS

Bone marrow Not indicated Normal or ↑ Megakaryocytes

Tests —————— Antiplatelet antibodies

GPIIa/IIIa
is characterized by small vessel disease with thrombotic les
Thrombotic Thrombocytopenic Purpura
(TTP)

Rare disease
Young adults
PENTAD
Thrombocytopenia,
red cell fragmentation,
fever,
transient neurologic deficit
kidney failure
HEMOLYTIC UREMIC SYNDROME (HUS)

Essential Lesions are:

•Microangiopathy of kidney - glomerular
capillaries & arterioles
•Microangiopathic hemolytic anemia
•Thrombocytopenia due to platelet consumption
microangiopathic hemolytic anemia (MAHA) in Hemolytic Ur

Bacterial toxins damage glomerular capillary endothelium

MICROTHROMBI activation of
IN GLOMERULAR Platelets adhere to collagen
CAPILLARIES coagulation pathway

Platelet aggregation in capillaries

Impaired kidney function

Red cells try to pass
through loose fibrin network
with partial penetration

Red cells get fragmented - schistocytes

Blood urea
Thrombocytopenia Hemolytic anemia (MAHA)
S. Creatinine
coagulation
defect Poor platelet plug
 I. HEREDITARY

1. Defects of platelet adhesion

i. Bernard-Soulier Disease

(Def. of GP Ib-IX)

2. Defects of platelet secretion

i. Storage Pool Disease

ii. Grey-platelet Disease

3. Defects of platelet aggregation

• Glanzmann’s Disease (Def.

of GP IIb-IIIa)
II. ACQUIRED

Aspirin :
Permanently blocks cyclooxygenase
by acetylating it, preventing production of
Thromboxane A2 (Potent vasoconstrictor and
activates plt. agg).

NSAID : Temporarily blocks

cyclooxygenase.

Uremia: Platelet vessel wall

interaction dysfunction
 LABORATORY EVALUATION

1. Platelet Count

2. Bleeding Time (obsolete)

3. Platelet function test: tests degree of platelet aggregation in

response to ADP,

4. thrombin, collagen, serotonin, catecholamines, ristocetin,

thromboxane A2.

5. Peripheral smear
 PLATELET COUNT
Normal values
1,50,000-4,50,000 cells/mm3

Platelet count /mm3 Severity of bleeding

>50,000 No spontaneous bleed
10,000 to 50,000 Spontaneous bleeding in skin
& mucous membrane
(purpura,petechiae)
Post traumatic bleeding
<10,000 Serious genitourinary / [Link]

These are obtained on anticoagulated blood by using an

automated cell counter.

Counts outside this range must be confirmed by a visual

inspection of a PERIPHERAL BLOOD SMEAR.
 BLEEDING TIME

l The time taken for a standardized skin puncture to stop bleeding.

l Measured in minutes
l PROVIDES ASSESSMENT OF PLATELET COUNT AND FUNCTION.
Provides an in vivo assessment of platelet response to limited vascular injury
l Variability and poor reproducibility.

NORMAL VALUE
3-8 MINUTES
Prolonged bleeding time

Thrombocytopenia
<50,000,
von Willebrand disease
(VWD)
Vascular Purpura
Severe fibrinogen deficiency
Acquired –Aspirin/
Clopidogrel
Thrombocytopenia - Intepretation

LABORATORY INVESTIGATIONS:

Platelet Count : < 100,000

BT :
PT : Normal
APTT : Normal
 BLEEDING

CAUSES

1. Primary Hemostatic Disorder

2. Secondary Hemostatic Disorder
3. Vessel wall abnormalities
THE COAGULATION CASCADE

Common Pathway
Coagulation studies

VENIPUNCTURE
BLOOD

TRISODIUM
CITRATE 0.5 ML
+
4.5ML BLOOD
PROTHROMBIN TIME (PT)
l It represents the time needed

for plasma to clot in the

presence of an exogenously

added source of tissue

thromboplastin (TF) and Ca2+

ions.

l A prolonged PT: Deficiency of

factors V, VII, or X,

prothrombin, or fibrinogen, in

liver disease, coumarin therapy.

ACTIVATED PARTIAL THROMBOPLASTIN
TIME
(APPT)
l Measures
Effectiveness of
the Intrinsic
Pathway and
common clotting
pathways.

NORMAL VALUE
25-40 SECS
 THROMBIN TIME
l Time for Thrombin To
Convert
Fibrinogen Fibrin
l A Measure of Fibrinolytic
Pathway:
l Prolonged due to:
Hypofibrinogenemia
l Heparin
l Dysfibrinogens

NORMAL VALUE
9-13 SECS
Fibrinolytic System
Fibrinolytic System

Fibrin Degradation Products (FDP) :

Elevated levels indicates ongoing fibrinolysis by plasmin eg in

DIC / large thrombi.

D-dimer :

Product of broken-down clots that have been crosslinked –

elevated in DIC / large thrombi.
 DISORDERS OF COAGULATION

INHERITED

Hemophilia A
Hemophilia B
von Willibrand’s Disease

ACQUIRED

Disseminated Intravascular Coagulation

Vitamin K deficiency
Liver Disease
 DISORDERS OF COAGULATION
INHERITED

Hemophilia A Hemophilia B von Willibrand’s Disease

X-linked recessive disease Deficiency FIX Autosomal co-dominant (recessive+x-linked)

X-linked recessive Gene of vWF located on chr 12.

Clinical features milder Defective Platelet function : adhesion (GpIb)

than HA
Coagulation defect: vWF IS A CARRIER OF VIIIc
Males affected as
Hemarthrosis :5-15 yrs
Mild : easy bruising, Severe: hemarthrosis
only 1x chromosome
Hemarthrosis

LAB TESTS LAB TESTS LAB TESTS

Bleeding time: prolonged

Platelet count - normal PT: Normal
APTT: INCREASED
PT: normal APTT: INCREASED
APTT: Increased vWF assay: reduced
F IX: reduced
Factor VIII assay: reduced Platelet count: normal
Disseminated Intravascular Coagulation (DIC)

DIC is a syndrome in which either extrinsic or

intrinsic or both pathways are activated to
produce multiple fibrin clots in small blood
vessels.

A paradoxical situation both thrombosis &

hemorrhage (thrombo hemorrhagic disorder)
occurs – due reduction of coagulation factors &
platelets.
Disseminated Intravascular Coagulation (DIC)
Release of thromboplastin into the bloodstream

Obstetrical catastrophe : thromboplastin from placenta or amniotic fluid

embolism
Major tissue injury : burns, surgery, trauma
Acute promyelocytic leukemia : thrombo-plastin from the granules of the
leukemic cells
Sepsis : thromboplastin from PMNs
Snakebite:

Endothelial damage
Vasculitis : eg. Meningococcemia, rickettsial disease, malignant
hypertension
 DIC
LAB INTERPRETATION
 P.S: Fragmented rbcs
Platelet Count : reduced
 BT : increased
 PT : prolonged
 APTT : increased
 TT: raised (decrease
fibrinogen)
 FDP / D-Dimer : positive
 BLEEDING

CAUSES

1. Primary Hemostatic Disorder

2. Secondary Hemostatic Disorder
3. Vessel wall abnormalities
 BLEEDING
3. VESSEL WALL ABNORMALITIES
 How to investigate a case of bleeding diathesis?

1. HISTORY 2. PHYSICAL EXAMINATION 3. BLOOD EXAMINATION

Site: Skin/mucous membrane

Age of onset
/intramuscular Complete blood count
Family history
Platelet disorder: Petechiae/epistaxis/ Peripheral Smear Examination:
Spontaneous/ induced/
gingival bleeds Acute/Chronic Leukemia
traumatic
Coagulation disorder: Hematomas, Macrocytic anemias
Severity & duration
haemarthrosis, Other carses of thrombocytopenia
Drug intake [Link] PROFILE
echymosis, + bleeding in G.I.T,
Dental extraction/
Raised PT: Vit K def, Obstructive
Genitourinary system
surgery/ menstrual jaundice,
liver disease, anti-coagulant
history
therapy
[Link] COUNT [Link] Function Tests
Raised APTT: DIC,Hemophilia A / B,
If all secondary causes of Platelet aggregation studies vWD
thrombocytopenia to rule out vWD,
should be ruled out - ITP storage pool disorder, Raised TT: DIC, FIBRINOGEN DEF
Giant platelets - Bernard Bernard Soulier syndrome
Soulier Syndrome Test for detection of Hemophilia A/B
FDP-D-DIMER: +VE DIC
work hard, mama

THANK YOU!
 DEPARTMENT OF PATHOLOGY WISHES YOU ALL

A HAPPY DASHAIN!!