Bachelor of Chinese Medicine, The University of Hong Kong Bleeding disorders Dr. Edmond S. K. Ma...

Bachelor of Chinese Medicine, The University of Hong Kong

Bleeding disorders

Dr. Edmond S. K. Ma

Division of Haematology

Department of Pathology

The University of Hong Kong


Components of normal haemostasis• Blood vessels

– Endothelial cells– Sub-endothelial surface

• Platelets: primary haemostasis– Platelet membrane– Platelet granules

• Coagulation factors• Fibrinolytic pathway• Naturally occurring inhibitors of coagulation


The endothelial cell


Haemostatic response to vessel injury


Conventional model of coagulation


New model of coagulation


The fibrinolytic pathway


Naturally occurring inhibitors: e.g. Protein C pathway


Coagulation tests• Prothrombin time• Activate partial thromboplastin time• Thrombin time• Fibrinogen level• Tests for platelet disorders

– Platelet count– Platelet aggregation test– Skin bleeding time


Conventional model of coagulation


Prothrombin time

• Tests the extrinsic and final common pathways

• Prolongation in:– Liver disease– vitamin K antagonism (i.e. warfarin) and

deficiency– Disseminated intravascular coagulation– Factor VII, X, V, II and fibrinogen defect


Activated partial thromboplastin time

• Tests the intrinsic and common pathways

• Prolongation in:– Liver disease– Disseminated intravascular coagulation– Heparin therapy– Vitamin K antagonism or deficiency– Factor XII, XI, IX, VIII, X, V, II, and

fibrinogen defect


Thrombin time

• Evaluate fibrinogen and for inhibition of thrombin action

• Prolongation in:– Hypofibrinogenaemia– Dysfibrinogenaemia

(http://www.fmshk.com.hk/hkabth) – Heparin therapy– Disseminated intravascular coagulation


Platelet aggregometry: testing for platelet dysfunction


Clinical features of bleeding disorders

• History– Personal (age of onset)– Family

• Pattern of bleeding– Platelet / vessel type– Coagulation type

• Drugs• Associated systemic illnesses


Platelet



Platelet disorders

• Bleeding due to low platelet count

• Bleeding due to platelet dysfunction


Bruises


Petechiae


Causes of Thrombocytopenia (N.B. analogous to anaemia)

• Production failure– Isolated thrombocytopenia

– Pancytopenia

• Increased peripheral destruction– immune

– non-immune

• Splenic pooling (sequestration)– Hypersplenism

• Dilutional– Massive blood transfusion


Peripheral destruction: immune thrombocytopenia

• Autoimmue– ITP

• acute

• chronic

• Alloimmune– Neonatal alloimmune thrombocytopenia– Post-transfusion purpura


Peripheral destruction: microangiopathic syndromes


Inherited platelet disorders• Glycoprotein defect

– GP IIb/IIIa: Glanzmann’s thrombasthenia– GP Ib/IX/V complex: Bernard-Soulier syndrome

• Granule defect– Storage pool disease– Grey platelet syndrome

• Hereditary thrombocytopenia– Bernard-Soulier syndrome – Wiskott-Aldrich syndrome (small platelets, eczema,

immunodeficiency)– May-Hegglin anomaly


Bernard-Soulier Syndrome


May-Hegglin Anomaly


Approach to platelet disorders

• Low platelet count– Bone marrow

examination

– Platelet antibodies

– Screening tests for DIC

• Normal platelet count– Bleeding time

– Platelet aggregation study

– Special platelet function tests (e.g. nucleotide pool assay)

– von Willebrand disease study


Haemophilia

• Insufficient activity of the tenase complex

Factor VIII deficiencyHaemophilia A

Factor IX deficiencyHaemophilia B


Haemophilia

• Haemophilia A Factor VIII deficiency

• Haemophilia B Factor IX deficiency

• Clinical presentation: haemarthrosis

• Coagulation screening test: isolated prolongation of APTT

• Diagnostic test: Factor assay


Haemophilia: clinical problems• Recurrent joint bleeds Progressive joint

deformity• Factor inhibitors• Viral agents transmitted by blood products• Diagnosis of carrier status in females

– family history– phenotype– mutation detection


Haemarthrosis


Haemophilia A showing severe disability


Genomic organization of the human FVIII gene


Intron 22 inversion of the FVIII gene


Intron 22 inversion of FVIII

• Seen in 40 - 50% of severe haemophilia A

• Error of DNA replication during spermatogenesis

• In males, absence of a second X favours intrachromosomal alignment

• Maternal grandfather

• Distal inversion more common


Platelet adhesion


Von Willebrand Disease

• Defect of Von Willebrand Factor– quantitative– qualitative

• Autosomal dominant

• Normal function of VWF– Mediate platelet adhesion – Stabilize factor VIII in circulation– Localize factor VIII to site of vessel injury


Von Willebrand Disease

• Pattern of bleeding– Usually platelet type– Coagulation type if severe

• Diagnostic tests– Factor VIII activity– VWF antigen assay– VWF function, e.g. ristocetin cofactor assay


Multimer analysis in vWD


Comparison between haemophilia and vWD


Reference

• Chapters 18 - 20, Essential Haematology by AV Hoffbrand, JE Pettit and PAH Moss, 4th Edition 2001, Blackwell Science

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Bachelor of Chinese Medicine, The University of Hong Kong Bleeding disorders Dr. Edmond S. K. Ma...

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