Bleeding Disorders

Question 1

The three roles of Von Willebrand’s Factor

Answer 1

1. Bring platelets into contact with exposed sub-endothelium
2. Make platelets bind to each other
3. Binds to factor VIII, protecting it from destruction in circulation

Question 2

Symptoms of Von Willebrand’s Disease (VWD)

Answer 2

Behaves like a platelet disorder:

○ Epistaxis
○ Menorrhagia
○ Bruising
○ Increased bleeding post tooth extraction

Question 3

Describe VWD Type 1

Answer 3

○ Autosomal Dominant
○ Most common type ~80%
○ Decreased levels of vWF

Question 4

Describe VWD Type 2

Answer 4

○ Abnormal vWF, lacks high molecular weight multimers

Question 5

Describe VWD Type 2A

Answer 5

○ Defective platelet adhesion due to decreased high molecular weight vWF multimers (vWF protein too small)

Question 6

Describe VWD Type 2B

Answer 6

○ Pathological increase of vWF-platelet interaction

Question 7

Describe VWD Type 2M

Answer 7

○ Decreased vWF-platelet interaction

Question 8

Describe VWD Type 2N

Answer 8

○ Type ‘‘Normandy’”

○ Abnormal binding of vWF to Factor VIII

Question 9

Describe VWD Type 3

Answer 9

○ Autosomal Recessive
○ Most severe
○ Complete absence of vWF

Question 10

Investigations of VWD

Answer 10

○ Bleeding time (prolonged)
○ APTT (may be prolonged)
○ Factor VIII Level (may be reduced)
○ Defective platelet aggregation with ‘risocetin’

Question 11

Management of VWD

Answer 11

○ Tranexamic Acid: for mild bleeding
○ Desmopressin (DDAVP): raises levels of vWF by inducing release of vWF from Weibel-Palade Bodies in endothelial cells
○ Factor VIII concentrate: surgery and major bleeds
○ Avoid aspirin and NSAIDs

Question 12

Four causes of Thrombocytopaenia

Answer 12

1. Reduced Platelet Production
2. Increased Platelet Consumption
3. Abnormal Distribution of Platelets
4. Dilutional

Question 13

Differential Diagnosis of Reduced Platelet Production

Answer 13

○ Abnormal Megakaryocyte Development
▫ Congenital mutation of c-MPL thrombopoietin receptor
▫ May-Hegglin syndrome
▫ Wiskott-Aldrich syndrome
▫ Drugs, Chemicals
▫ Viral Infections

○ Generalised Bone Marrow Failure
▫ Haematological Malignancy (Leukaemia, Myeloma, Aplastic Anaemia, Myelodysplasia, Myelofibrosis)
▫ Secondary to cytotoxic drugs and radiotherapy
▫ Infection: HIV, CMV, Hepatitis B and C
▫ Alcohol Excess
▫ Megaloblastic Anaemia

Question 14

Differential Diagnosis of Platelet Consumption/Destruction

Answer 14

○ Immune Mediated
▫ Idiopathic / Primary Autoimmune (Immune Thrombocytopaenia)

○ Other
▫ Secondary: SLE, CLL, Lymphoma
▫ Infections: HIV, Hepatitis B and C, Malaria
▫ Drug Induced: Rifampicin, Penicillins, Sulphonamides, Heparin, Quinine
▫ Post-Transfusion Purpura
▫ Thrombotic Thrombocytopenic Purpura
▫ Disseminated Intravascular Haemolysis

Question 15

Differential Diagnosis of Abnormal Distribution of Platelets

Answer 15

○ Splenomegaly

Question 16

Differential Diagnosis of Dilution Thrombocytopaenia

Answer 16

○ Massive Transfusion

○ IVT

Question 17

Symptoms of Thrombocytopaenia

Answer 17

○ Petechiae (small pinprick red dots) on skin
○ Increased bruises
○ Mucosal bleeding in mouth
○ Nose Bleeds
○ Blood in Urine or Stools
○ Rarely ICH (fatal in 25% of cases)

Question 18

Potential Blood Film Findings in Thrombocytopania

Answer 18

○ Uniformly large platelets, due to inherited causes: Bernard - Soulier syndrome

○ Very small platelets in male infants (esp. w/eczema): Wiskott - Aldrich syndrome, or X-linked thrombocytopaenia

○ ITP: can have large and small platelets

○ Abnormality of morphology of red cells may suggest alternative diagnosis
▫ Red Cell Fragments: Thrombotic Thrombocytopenic Purpura (TTP), DIC

○ Platelet clumping: pseudo-thrombocytopaenia; an ethylenediaminetetraacetic acid (EDTA) artifact

Question 19

Describe Immune Thrombocytopaenia (ITP)

Answer 19

○ Acquired immune disorder
○ Isolated thrombocytopaenia (all other blood parameters normal)
○ Platelet count < 100 x 104
○ Incidence 1:10 000
○ Incidence equal across sexes, except 3rd and 4th decade of life, F > M
○ Cause: unknown, can be proceeded by infection or vaccination

Question 20

Describe the THREE stages of ITP

Answer 20

○ Newly Diagnosed: 0 -3 months
○ Persistent: 3-12 months
○ Chronic: > 12 months

Question 21

Describe the pathophysiology of ITP

Answer 21

○ Anti-platelet antibodies directed against both platelets and megakaryocytes
▫ Antibody coated platelets are targeted for destruction by macrophages in spleen, sometimes in liver, and by direct platelet-lysis
▫ Antibodies that target megakaryocytes reduce platelet production

○ Regulatory T cells are reduced in patients with ITP

○ Skewing towards T helper 1 and 17 autoimmune phenotypes

○ Cytotoxic T cells also directly lyse platelets

Question 22

Describe the management of “newly diagnosed” ITP

Answer 22

○ Newly Diagnosed ITP (0 - 3 months)

▫ Steroids (prednisolone, dexamethasone, methylprednisolone)

▫ Intravenous Immunoglobulin (IVIG)

Question 23

Describe the management of “persistent” ITP

Answer 23

○ Persistent ITP (3 - 12 months) = immunosuppression

▫ Mycophenolate mofetil (MMF)

▫ Thrombopoietin receptor agonists (TRAs - eltrombopag, romiplostim). New agents that stimulate bone marrow to produce platelets. Good for sparing corticosteroids and immunosuppressants. May increase risk of thrombosis; use with caution in patients with other thrombosis or cardiac risk factors

▫ Rituximab

▫ Azathioprine

Question 24

Describe the management of “chronic” ITP

Answer 24

○ Chronic ITP (> 12 months)

▫ Continuous TRAs

▫ Repeated Rituximab (+/- dexamethasone)

▫ Continuous MMF

▫ Others: (danazol, dapsone, hydroxychloroquine)

▫ Splenectomy; before splenectomy, platelet disruption scan is performed to see whether platelets are predominately removed by spleen.

Question 25

Describe the principles of treatment of ITP

Answer 25

○ Platelet count > 30 x 104 rarely need treatment, unless bleeding risk (taking anticoagulant) or about to undergo surgery

○ Adults with platelet count > 10 x 104 are routinely treated

○ Adults with platelet count between 10 - 30 x 104 are treated depending on; age, risk factors, bleeding and others symptoms (i.e. fatigue), lifestyle ‘risk’ factors

○ Patient with infections: H Pylori, HIV, Hepatitis, should be treated accordingly