AN APPROACH TO AN APPROACH TO PATIENT WITH PATIENT WITH

BLEEDING BLEEDING DISORDERDISORDER

Dr. Salma AfroseAssociate ProfessorDepartment of Hematology

Haemostasis Definition

Spontaneous arrest of bleeding when a small vessel is cut or ruptured

Function • To prevent blood loss from intact vessel • Arrest of bleeding from injured vessel

Mechanism of Normal Haemostasis

Trauma

Vessel Constriction + Shed blood

Coagulation Platelet Adhesion & release of ADP

ThrombinFibrin Platelet aggregation

(unstable plug)

Stable Haemostatic Plug

Haemostatic system is a complex mosaic of activating inhibitory feedback or feed-forward pathways, integrating it’s 5 major components

Vessel Wall Vessel Wall Platelets Platelet Inhibitors Coagulation Fibrinolysis

Blood flow

Production of local Prevention of Haemostasis uncontrolled thrombosis

Damaged Endothelium

Role of Platelet in Haemostasis

vWF

1.Adhesion through vWF

2. Release of ADP, etc

3. Aggregation

4. Clot retraction

Platelet

Endothelial cell

FUNCTIONS OF vWF:

1. vWF mediates platelet adhesion at site of injury 2. Stabilizes FVIII in circulation

Pathways of Haemostasis

XII XIIa

XI XIa

IX IXa

VIIIa Ca2+Phospholipid

VII

Ca2+ Tissue factor

VIIa

X Xa

VIIIa, Ca2+, Phospholipid

Prothrombin (IIa)

Fibrinogen

Fibrinolytic Pathways Plasminogen

Intrinsic Extrinsic XIIa-pa u - pa

t - pa

PAI PAI

PlasminAP

Fibrin FDP

Protease action on Fibrinogen

& FibrinFIBRINOGEN PLASMIN Fibrinogen

degradation products

X,Y,D,E THROMBIN Fibrin monomer Fibrinopeptide A & B FIBRIN PLASMIN Fibrin

degradation[NON CROSS LINKED] products

X,Y,D,E

FACTOR XIII

FIBRIN PLASMIN D dimer[CROSS LINKED] X,Y,D,E

PRIMARY HYPER FIBRINOGENOLYSIS

BLOOD

FREE PLASMIN FIBRINOGEN FDP

ENDOGENOUS ACTIVATOR +PLASMINOGEN

FIBRINOGENOLYSIS

Clinical Distinction Between Disorders of Coagulation & Platelets or Vessel

Finding Disorder of Coagulation

Disorder of Platelets or

Vessels

Petechiae Rare Characteristic

Deep dissecting hematomas

Characteristic Rare

Superficial ecchymoses

Common usually large & solitary

Characteristic usually small & multiple

Hemarthrosis Characteristic Rare

Delayed Bleeding Common Rare

Clinical Distinction Between Disorders of Coagulation & Platelets or Vessel

FindingDisorder of Coagulation

Disorder of Platelets or

vesselBleeding from

superficial cuts & scratches

Minimal Persistent often profuse

Sex of patient80-90% of hereditary forms occur only in

Male

Relatively more common in females

Positive family history Common Rare

HAEMORRHAGIC DISORDER

Definition:These are a group of disorder of widely differing aetiology which have in common tendency to bleed due to defect in the mechanism of haemostasis.

Clinical Features:

1.Spontaneous bleeding in to the skin, mucous membranes & internal tissues.

2.Excessive or prolonged bleeding following trauma or surgery.

3.Bleeding from more than one site.

Classification: Due to Vascular Defects

• Acquired– Simple easy bruising – Senile purpura – Symptomatic vascular

purpura• Henoch-Scholein Purpura • Scurvy • Dysproteinaemia

– Miscellaneous – Orthostatic purpura – Mechanical purpura

• Congenital – Hereditary haemorrhagic

telangiectasia– Ehlar Danlos disease

ClassificationAbnormal Platelet Production • Acquired

– Idiopathic thrombocytopenic purpura

– Drugs & chemicals – Leukemias– Aplastic anaemia– Hypersplenism – Disseminated lupus

erythematosus– Dengue fever

Abnormal Platelet Production • Neonatal & Congenital

– Auto-immune – mothers with chronic ITP

– Drug administration to mother

Classification

• Congenital – Membrane receptor defects – Glanzmann’s Thrombasthenia– Enzyme defect – Phospholipase deficiency – Cycle-oxygenase deficiency – Granuels defects – Storage pool deficiency

• Acquired – Leukemias – Myelodysplasia– Myeloproliferative

disorders – Uraemia – DIC

Due to Disorder of Platelet Function

Classification

• Hereditary – X-linked recessive trait

• Haemophilia-A • Haemophilia-B

– Autosomal recessive trait• Afibrinogenemia• Factor XIII deficiency

– Autosomal Dominant trait • Von-Willbrand Disease

• Acquired – Haemorrhagic disease

of new born – Biliary obstruction – Malabsorption of Vitamin K– Drugs – Liver disease – DIC

Due to Disorder of Coagulation

THROMBOCYTOPENIA

Definition: Thrombocytopenia is defined as a reduction

in peripheral blood platelet count below the normal lower limit of 150 x 109/Liter .

There is no absolute relation between platelet count & occurrence & rate of bleeding.

Bleeding is common –<30000/L but not invariable<10000/L bleeding is usual & often severe

Thrombocytopenia is accompanied by positive tourniquet test & prolonged bleeding time.

Clinical Evaluation • History Purpuric

Coagulation disorder • Hereditary: Onset, positive family history• Acquired: Drug, Viral infection • Drug History• Family History• Clinical feature • Physical examination

Lab Investigation • Hemoglobin percentage • ESR • Total count & Differential count of WBC • Platelet count • Blood film – leukemia, platelet morphology• Bleeding time (BT)• Clotting time (CT)• Prothrombin time (PT)• Activated partial thromboplastin time (APTT)

Special Investigation • Platelet function test • Coagulation factor assay • Fibrinogen Degradation Product (FDP) • Fibrinogen assay • VWF

Immune Thrombocytopenic Purpura

Types of ITP• Primary (Idiopathic)• Secondary

Definition The term idiopathic thrombocytopenic purpura usually refers to thrombocytopenia in which apparent exogenous etiologic factors are lacking & in which diseases known to be associated with secondary thrombocytopenia have been excluded.

Classification

1. Acute Idiopathic Thrombocytopenic Purpura

2. Chronic Idiopathic Thrombocytopenic Purpura

Difference Between Acute & Chronic ITP

Feature Acute ITP Chronic ITPPeak of Age Children of 2-

6 years Adults 20-40 years

Sex predilection

None 3:1 female to male

Antecedent infection

Common 1-3 weeks before

Unusual

Onset of bleeding

Abrupt Insidious

Difference Between Acute & Chronic ITP

Feature Acute ITP Chronic ITP

Hemorrhagic bullae in mouth

Present in severe cases

Usually absent

Platelet count <20,000/ microL 30,000 – 80,000 / microL

Eosinophilia & lymphocytosis

Common Rare

Duration 2-6 weeks rarely longer

> 6 months

Spontaneous remissions

Occur in 80% cases

uncommon

Patho-physiology ITP is caused by platelet specific antibody that bind to patient’s own platelet which are then rapidly cleared from circulation by the mononuclear phagocytic system via macrophage Fc receptor.The auto antibodies formed against platelet gp-IIb/IIIa & gp-Ib/IX.Splenic sequestration account for the shortest survival of platelet in most patients but the liver & RE cells of the bone marrow can play a major role. The Spleen has also been implicated as site of antibody production.

PATHOGENESIS

PLATELET

PLASMA CELL

ANTIBODYCOATEDPLATELET MACROPHAGE

REMOVAL OF ANTIBODYCOATED PLATELETS

Clinical Features • Haemorrhagic manifestation of ITP are of

purpuric type• Severity of bleeding depends on platelet

count • Patient Usually present with cutaneous

purpura, petechiae, echymoses & easy bruising (dry purpura)

On Examination The outstanding feature is absence of physical findings other than those due to anemia:

• Anemia proportionate to the blood loss • Purpuric rashes • Splenomegaly in <10% cases

Lab Investigations: • Hemoglobin percentage – Reduced • CBC:

– WBC count normal / increased during bleeding episodes

–Platelet count reduced • Peripheral Blood film:

–Normocytic normochromic / microcytic anemia

–Platelets are morphologically abnormal; large, small & atypical forms

Lab Investigation• Bleeding time: Raised• Bone Marrow Examination: (in special

circumstances)– Megakaryocyte & their precurosors are

present in normal / increased number & shift to the left

– Other findings are normal – Sometime there is erythroid hyperplasia

if anemia is severe enough

• Special Cases: 1. Not responding to treatment or relapse 2. Patients above 60 years3. Before splenectomy

Diagnosis

• Bleeding manifestation without any physical sign except signs of hemorrhage

• Isolated thrombocytopenia

Differential Diagnosis

• Aplastic anemia• Acute leukemia• Drug induced thrombocytopenia

Treatment• Specific treatment

– Corticosteroid – Immunosuppressive therapy

o Azathioprineo Dexamethasoneo Methylprednisoloneo Ciclosporino Dapsoneo Vincristine

– Splenectomy

Treatment (Contd.)

• Supportive treatment – Blood transfusion– If emergency, platelet transfusion

Thrombotic Thrombocytopenic Purpura

It is a rare disease which is characterized by –– Fever – Thrombocytopenic purpura– Hemolytic anemia – Fluctuating neurological disturbances of

variable nature – Renal failure

It occurs in all age & have the Lab finding like HUS

Hemolytic Uremic Syndrome

DefinitionHemolytic uremic syndrome is a triad of microangiopathic hemolytic anameia, thrombocytopenia & acute renal insufficiency.

Aetiology E.coli 0156:H7 Shigella dysentery serotype-I

(less frequently)

Types

PathogenesisToxin Absorption from Gut in to blood

Attachment to the receptor membrane

Endocytosed Cytolysis Endothelial swelling & desquamation

Platelet & Coagulation activation

Symptoms• Bloody diarrhoea• Severe abdominal pain• Vomiting• Passage of dark red urine which may lead

to Oliguria or anuria

Signs• Anemia • Jaundice • Bleeding manifestation

Lab Findings • Hemoglobin – Decreased• Platelet count – Decreased • Peripheral Blood film - Evidence of hemolysis

present• Serum bilirubin – Increased• Blood urea – Increased• Hemoglobinaemia - Present • Hemoglobinurea – Present• Stool Culture

Treatment• Fluid & electrolyte balance• Dialysis if required • Medication, such as anti-biotic if

indicated • Blood / blood product transfusion if

necessary

Clinical Features • Patient may present with mucosal

bleeding –Epistaxis–Haematuria –Menorrhagia–Melaena

• Intracranial Haemorrhage (rare)

Hemophilia

DefinitionIt is an inherited & X-linked recessive disease

Classification Haemophilia A – Factor VIII

deficiency Haemophilia B – Factor IX deficiency

The daughters of affected males are obligate carriers but the sons are normal.

Clinical FeaturesBleeding tendency usually appear in

infancy In mild cases it may not become

apparent until adolescent or adult life Coagulation factor <1% is severe Coagulation factor 1-5% is moderate Coagulation factor 6-40% is mild

Clinical Feature (contd.) Hemarthrosis Bleeding from skin Tissue bleeding EpistaxisBleeding from central nervous systemUrogenic & gastro-intestinal bleeding

Signs

Anemia Chronic arthritic changes in joints Haematoma

Diagnosis History

Age Sex

History of maternal side Physical findings Clinical findings

InvestigationBleeding time – Normal Platelet count – NormalClotting time – Raised Prothrombin time – Normal APTT – Raised Factor VIII / IX assay - Deficient

Management General Supportive treatment

Rest Local haemostatic measure Replacement therapy

FFP Factor VIII or IX concentrate Blood transfusion

Fibrinolytic inhibitors Aminocapric acid Tranexamic acid

Disseminated Intravascular Coagulation

Definition DIC is an acquired syndrome occurs as a result of inappropriate & excessive activation of haemostatic system that leads to the formation of micro-thrombi throughout the circulation of the body & consumption of platelet, fibrin & coagulation factors

Investigations CBC – Bleeding Time - Raised Platelet Count – DecreasedProthrombin Time – Raised APTT – Raised Fibrinogen Level – Reduced Fibrin Degradation Product – Raised Blood film -

PERIPHERAL BLOOD SMEAR IN DIC

MICROSPHEROCYTE

SCHISTOCYTE

Treatment Treatment of the cause Replacement of coagulation factors &

plateletAnti-coagulant therapy