Download Inherited and acquired bleeding disorders

Bleeding disorders
Dr. Edmond S. K. Ma
Division of Haematology
Department of Pathology
The University of Hong Kong
Bachelor of Chinese Medicine, 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
Bachelor of Chinese Medicine, The
University of Hong Kong
The endothelial cell
Bachelor of Chinese Medicine, The
University of Hong Kong
Haemostatic response to vessel injury
Bachelor of Chinese Medicine, The
University of Hong Kong
Conventional model of coagulation
Bachelor of Chinese Medicine, The
University of Hong Kong
New model of coagulation
Bachelor of Chinese Medicine, The
University of Hong Kong
The fibrinolytic pathway
Bachelor of Chinese Medicine, The
University of Hong Kong
Naturally occurring inhibitors:
e.g. Protein C pathway
Bachelor of Chinese Medicine, The
University of Hong Kong
Coagulation tests
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Prothrombin time
Activate partial thromboplastin time
Thrombin time
Fibrinogen level
Tests for platelet disorders
– Platelet count
– Platelet aggregation test
– Skin bleeding time
Bachelor of Chinese Medicine, The
University of Hong Kong
Conventional model of coagulation
Bachelor of Chinese Medicine, The
University of Hong Kong
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
Bachelor of Chinese Medicine, The
University of Hong Kong
Activated partial thromboplastin time
• Tests the intrinsic and common pathways
• Prolongation in:
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Liver disease
Disseminated intravascular coagulation
Heparin therapy
Vitamin K antagonism or deficiency
Factor XII, XI, IX, VIII, X, V, II, and
fibrinogen defect
Bachelor of Chinese Medicine, The
University of Hong Kong
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
Bachelor of Chinese Medicine, The
University of Hong Kong
Platelet aggregometry: testing for
platelet dysfunction
Bachelor of Chinese Medicine, The
University of Hong Kong
Clinical features of bleeding disorders
• History
– Personal (age of onset)
– Family
• Pattern of bleeding
– Platelet / vessel type
– Coagulation type
• Drugs
• Associated systemic illnesses
Bachelor of Chinese Medicine, The
University of Hong Kong
Platelet
Bachelor of Chinese Medicine, The
University of Hong Kong
Bachelor of Chinese Medicine, The
University of Hong Kong
Platelet disorders
• Bleeding due to low platelet count
• Bleeding due to platelet dysfunction
Bachelor of Chinese Medicine, The
University of Hong Kong
Bruises
Bachelor of Chinese Medicine, The
University of Hong Kong
Petechiae
Bachelor of Chinese Medicine, The
University of Hong Kong
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
Bachelor of Chinese Medicine, The
University of Hong Kong
Peripheral destruction: immune thrombocytopenia
• Autoimmue
– ITP
• acute
• chronic
• Alloimmune
– Neonatal alloimmune thrombocytopenia
– Post-transfusion purpura
Bachelor of Chinese Medicine, The
University of Hong Kong
Peripheral destruction:
microangiopathic syndromes
Bachelor of Chinese Medicine, The
University of Hong Kong
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
Bachelor of Chinese Medicine, The
University of Hong Kong
Bernard-Soulier Syndrome
Bachelor of Chinese Medicine, The
University of Hong Kong
May-Hegglin Anomaly
Bachelor of Chinese Medicine, The
University of Hong Kong
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
Bachelor of Chinese Medicine, The
University of Hong Kong
Haemophilia
• Insufficient activity of
the tenase complex
Factor VIII deficiency
Haemophilia A
Factor IX deficiency
Haemophilia B
Bachelor of Chinese Medicine, The
University of Hong Kong
Haemophilia
• Haemophilia A
• Haemophilia B
Factor VIII deficiency
Factor IX deficiency
• Clinical presentation: haemarthrosis
• Coagulation screening test: isolated
prolongation of APTT
• Diagnostic test: Factor assay
Bachelor of Chinese Medicine, The
University of Hong Kong
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
Bachelor of Chinese Medicine, The
University of Hong Kong
Haemarthrosis
Bachelor of Chinese Medicine, The
University of Hong Kong
Haemophilia A showing severe disability
Bachelor of Chinese Medicine, The
University of Hong Kong
Genomic organization of the
human FVIII gene
Bachelor of Chinese Medicine, The
University of Hong Kong
Intron 22 inversion of the FVIII gene
Bachelor of Chinese Medicine, The
University of Hong Kong
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
Bachelor of Chinese Medicine, The
University of Hong Kong
Platelet adhesion
Bachelor of Chinese Medicine, The
University of Hong Kong
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
Bachelor of Chinese Medicine, The
University of Hong Kong
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
Bachelor of Chinese Medicine, The
University of Hong Kong
Multimer analysis in vWD
Bachelor of Chinese Medicine, The
University of Hong Kong
Comparison between
haemophilia and vWD
Bachelor of Chinese Medicine, The
University of Hong Kong
Reference
• Chapters 18 - 20, Essential Haematology by
AV Hoffbrand, JE Pettit and PAH Moss, 4th
Edition 2001, Blackwell Science
Bachelor of Chinese Medicine, The
University of Hong Kong