Bleeding Diathesis

INTRODUCTION

Shirazi MH 1/12/2009

K&CH

Definition

• An unusual susceptibility to bleeding

Or

• A disruption of the haemostatic mechanism

Or

• Bleeding that is spontaneous or following tissue injury resulting from local, haematosis abnormalities or fibrinolysis

The Normal Clotting Cascade

The Normal Clotting Cascade Categorised

Cause – Bleeding Diathesis

Acquired • Anticoagulation with warfarin / heparin • Liver failure / Vitamin K deficiency / DIC• Snake venom e.g Rattle snake, viper• Viral hemorrhagic fever• Leukemia

Autoimmune• Acquired antibodies to coagulation factors• Inhibitor directed

– Against Factor VIII– Antiphospholipid

Genetic• Lack of coagulation factor protien producing genes

– Haemoplilia (VIIIA, IXB deficiency)

– Von willebrand (protein regured for platlet adhesion)

– Bernard souller (GpIb), the receptor for vWF) – Wiskott Aldrich (autoimmune haemolytic anaemia-defects in homeostasis)

– Glenzmann thromasthenia (platelets lack GP IIb/IIIa. Hence, no fibrinogen bridging

Clinical Diagnosis

– History • To identify presence of condition

» History of transfusion» Menorrhagia, Metrorrhagia (15-20 % vWD, immune thrombocytopenic purpura, platelet function defect)

» Anaemia» Response to trauma –(excellent screening for inherited hemorrhagic disorder)

• To identify possible cause– Inherited (Report little bleeding)

» Bleeding shortly after birth/During childhood» Positive family history (30-40% haemophilic a –Ve History)» Consistent genetic pattern

– Acquired (exaggerated tendency to bleed)» Dietary habits» Antibiotic use» Medication Aspirin (Beta lactamase antibiotics, NSAID,Clopidogrel,Ticloidine,Warfarin)» Thyroid, liver, and kidney disease

• To rationalise laboratory investigation

– Examination

Examination

Platelet DiseaseMucosal/cutaneous bleeding

Lack vessel protection by submucosal tissue Bleed immediately after vascular trauma

– Petechiae• From small capillary • In areas of increased venous

pressure (dependent parts of the body)

• Asymptomatic and not palpable• D/D small telangiectasias

(Angiomas, Vasculitic purpura, Wiskott-Aldrich Syndrome, Leukaemia, Vit K deficiency

– Purpura  • Characteristically purple in colour• Small, multiple, and superficial in

location• Develop without noticeable

trauma / not spread into deeper tissues

• Seen in – (Acute / Chronic leukaemia, Vitamin K deficiency)

ExaminationCoagulation Disorders

– Ecchymoses• Large palpable ecchymoses• Spreading into deep tissue -

haematomas – Hemarthrosis- severe coagulation disorder- haemophilia

• Coagulation disorder bleeding onset may be delayed after surgery

Laboratory Test

General screening tests1. Platelet count2. Bleeding time (BT)3. Prothrombin time (PT)4. Activated partial thromboplastin time (aPTT)5. Thrombin time (TT)

Other / Specific tests – Coagulation factor assays– Assessment of factor XIII activity via clot solubility testing. – Tests of fibrinolysis– Measurement of fibrin split - D-dimer levels– Alpha-2-antiplasmin activity– Euglobulin clot lyses time– Tissue Plasminogen activator– Plasminogen activator inhibitor-1 antigens– etc

Understanding The Screening Test

1 - Platelet Counting

– Detect quantitative/ qualitative (Uraemia) platelet abnormalities– Platelet function analyzer (PFZ-100)– Peripheral smear – Platelet release essays

2 - Bleeding Time

– Prolonged bleeding time

• Interaction of platelets with vessel wall

• Thrombocytopenia below 50,000/microL,

• von Willebrand disease (VWD)

• Vascular Purpura

• Severe fibrinogen deficiency

• Acquired –Aspirin/ Clopidogrel

3 - Prothrombin Time

– Production of fibrin via the extrinsic pathway and final common pathway

– Requires • Tissue thromboplastin (tissue

factor)• Factor VII (extrinsic pathway)• Factors X, V• Prothrombin (factor II)• Fibrinogen

– The test bypasses the intrinsic pathway• Thromboplastin : platelets• Factors VII, X, and II require

vitamin-K - altered by warfarin

4 - Activated Partial Thromboplastin Time

– Measures the intrinsic and common pathways of coagulation

• Deficiencies of all coagulation factors (Except VII and XIII)

• No Thromboplastin• Heparin assessment

5 - Thrombin Time

• Thrombin Time and Reptilase Time

•  

– Measure common pathway conversion of fibrinogen to fibrin

– The formation of initial clot by thrombin and reptilase

– Prolonged due to

» Hypofibrinogenemia

» Heparin

» structurally abnormal fibrinogens (dysfibrinogens)

– Heparin prolongs the TT not the RT (helps determining if heparin is the cause of prolonged TT)

Other/Specific Tests

1. Coagulation Factor Tests (How Identified)– Deficiency / Inhibitor of a coagulation factor

– Correctable by addition of normal plasma to patient plasma for tested (1:1)– Immunologic assays also used to measure factor levels– Antibodies suspected when test does not or partially corrects

2. Fibrinogen – Levels are measured by immunologic assays – dysfibrinogenemia

3. Urea clot solubility – initial fibrin clot is non-covalent bonded and soluble in urea– Factor XIII creates covalently cross links fibrin - resistant to solubilisation with urea

4. Tests for fibrinolysis– Fibrin / fibrinogen degradation products (FDP)- plasmin - fibrin or fibrinogen– Do not differentiate between fibrin / fibrinogen degradation products- Possible ELISA– Quantitative FDP levels - more sensitive than D-dimer levels as indicator of degree of

fibrinolytic activity

5. More specific tests of the fibrinolytic system– Tissue plasminogen activator (t-PA)– Alpha-2 antiplasmin– Plasminogen activator inhibitor-1 (PAI-1)– Thrombin-activatable fibrinolysis inhibitor (TAFI).

Diagnostic Approach

Diagnosing Bleeding Diathesis

– Mostly apparent from history and physical examination

– Confirmed with the appropriate specific tests

– When not apparent• Screen with

– Platelet Count

– PT and aPTT

Interpreting Screening Results

1. Low platelets -<50,000/micrL(Thrombocytopenia most common acquired Diathesis)

2. Normal Platelet Count and PT, aPTT + mucocutaneous bleeds• Platelet dysfunction

– Qualitative disorders– Morphology – Aggregation/Function

– Common acquired causes of dysfunction» Aspirin, NSAID, Beta-lactam antibiotics» Uraemia» myeloproliferative and myelodysplastic syndromes.

– Uncommon causes of dysfunction

» Bernard-Soulier syndrome» Glanzmann's thrombasthenia

• Platelet aggregation» Wiskott-Aldrich syndrome

• von Willebrand's disease (vWD) –XIII

• Other disorders– Factor XIII deficiency (Bleeding delayed by 24-36hr)– alpha-2 antiplasmin deficiency - plasminogen activator inhibitor-1 deficiency

Interpreting Screening Results

• Normal PT and APTT +Prolonged BT– Vascular purpura – Screening tests are usually normal

in bleeding disorders of vascular tissue abnormalities

– Include • Hereditary hemorrhagic

telangiectasia• Ehlers-Danlos disease• Osteogenesis imperfecta• Scurvy• Steroid-induced purpura• Small vessel vasculitis• Purpura associated with the

presence of paraproteins

Interpreting Screening Results

Normal PT and Prolonged aPTT• Disorders intrinsic pathway of

coagulation– Inherited disorders hemophilia A,

von Willebrand disease, IX (hemophilia B), and XI. Hemophilia A and B

– Life-long recurrent soft tissue and joint bleeding

– Frequent replacement therapy– Factor XI deficiency presents with

a variable and unpredictable bleeding commonly seen following surgery

– Disorders prolonging aPTT not associated with excessive bleeding

• Factor XII deficiency• Prekallikrein • High molecular weight

kininogen

– rheumatologic disorders

Diagnostic Approach Screening Results

Prolonged PT and Normal aPTT 

– An indicative of an abnormality in the extrinsic pathway –(factor VII deficiency)

• Manifestations - no excessive bleeding to a severe hemorrhagic tendency

• Acquired inhibitors of factor VII

– Warfarin therapy– Early liver disease– Vitamin K deficiency– Early cases of DIC.

Interpreting Screening Results• Prolonged PT and aPTT

– Disorder Inherent common pathway• Mucocutaneous bleeding - Abate

with age• Low fibrinogen level• Deficiency factor X, factor V,

Prothrombin– Treatable with fibrinogen

replacement

– Disorder Acquired common pathway• Supratherapeutic warfarin / heparin-

thromboembolic disease• Vitamin K deficiency (Factor II,

VII,IX and X)– Liver disease– DIC, Fibrinolysis

• Evaluation prolonged PT and aPTT – Exclude or identify

abnormality of fibrinogen – Deficiencies of factor V, factor

X, and prothrombin (specific factor assays).

– Acquired inhibitors to prothrombin and factor X

Diagnostic Approach screening TestUnknown cause

• Some patients are encountered with a significant bleeding history for which there is no explanation

– self-inflicted

– some disorders of haemostasis escape detection with currently available methods

– Psychogenic purpura may be among these disorders• Gardener Diamond Syndrom

– Other acquired antibodies• Antiphospholipid antibodies

• Autoerythrocyte sensitization, painful bruising syndrome

• Antibodies to factor VIII (acquired hemophilia), IX, and XI• Malignancy• Clonal lympho-proliferative disorders• Pregnancy

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