Bleeding disorders

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
 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 • Normal platelet count
– Bone marrow
examination
– Platelet antibodies
– Screening tests for DIC
– 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 deficiency

Haemophilia A

Factor IX deficiency
Haemophilia 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
 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