W5 LECT3

Question 1

Name 2 broad classes of platelet disoders

Answer 1

• Quantitative disoders
• Qualitative disoders

Question 2

Name 2 types of Platelet quantitative disoder

Answer 2

• ITP
• TTP

Question 3

Name 2 types of platelet qualitative disoders

Answer 3

• Glanzmann Thrombosthenia (Aggregation)
• Bernard-Soulier Syndrome (Adhesion)

Question 4

T/F:
All platelet disoders, no matter quantitative or qualitative, are either acquired or inherited

Answer 4

TRUE

Question 5

Increased platelet consumption through formation of thrombus lead to what qualitative platelet disoder?

Answer 5

Thrombotic thrombocytopenic pupura

Question 5

Increased platelet consumption due to antibody mediated destruction to platelet lead to what qualitative platelet disoder?

Answer 5

Immune thrombocytopenic Pupura (ITP)

Question 5

Discuss the pathogenesis of ITP

Answer 5

1951 – Antibodies directed against platelet glycoproteins
*Immune Thrombocytopenic Purpura excluded for the 1st time

• Antiplatelet antibodies directed against platelet specific glycoproteins»opsonised platelets destroyed in the spleen»_space;shortened platelet half-life
• 1980’s – In addition to increased platelet clearance, also decreased platelet production

Question 5

Name 3 causes of thrombocytopenia

Answer 5

• Decreased platelet production
• Increased platelet consumption
• Platelet sequestration by the spleen

Question 6

What are the clinical presentations of ITP?

Answer 6

• Primary
  *Children (1 – 5 years of age)
  *Platelet count <30 x 109/L
  *Generally preceding viral infection
• Secondary
  *Lymphoproliferative neoplasm
  *Infections: Viral (HIV, EBV, CMV, Hepatitis)
  *Autoimmune disorders
• Acute (newly diagnosed): ITP duration <3 months
• Persistent: ITP duration 3 – 12 months
• Chronic: ITP duration >12 months
• Mucocutaneous bleeding
  May 2024 NHLS-University of the Witwatersrand 8

Question 7

Discuss the management of ITP

Answer 7

1. First Line Therapy
   *Corticosteroids (CS)
   *IV Immunoglobulin (IVIG) – used with CS when a more rapid
   increase in platelet count is required
   *Either IVIG or Anti-D (in appropriate patients) if CS contra-
   indicated
2. Second Line Therapy
   *Rituximab (anti-CD 20 monoclonal antibody)
   *Thrombopoietin Receptor Agonists (TPO-RA)
   *Splenectomy

Question 8

How to carry out ITP investigations?

Answer 8

1. FBC
   -Thrombocytopenia (platelet count <30 109/L)
   -Platelet morphology: typically normal, with varying numbers of large platelets
2. Exclude secondary causes:
   * Liver function test
   * Thyroid function test
   * Haematinics: Vitamin B12 and folate
   * Infections
   * Viral screen: HIV, Hepatitis B/C, CMV, EBV
   * Bacterial: Cultures (if clinically appropriate)
   * Malaria screen
   * Mycobacterial (TB), etc
   * Coagulation screen: PT, aPTT, D-dimers
   * Autoimmune: ANA, Rheumatoid factor, ACLA, Lupus anticoagulant
   * Clinical examination and Imaging to assess spleen size
3. Bone Marrow investigation: exclude other causes, normal / increased megakaryocytes

Question 9

A qualitative platelet disoder that falls under the category of Thrombotic Microangiopathies (TMA)
* DIC, HUS, aHUS, HELLP

Answer 9

TTP

Question 10

Haematological Emergency

Answer 10

TTP

Question 10

Characterised by low platelets with micro-angiopathic
haemolytic anaemia

Answer 10

TTP

Question 10

To see o the peripheral blood picture of Thrombotic Microangiopathies

Answer 10

schistocytes- RED CELL FRAGMENTS

Question 11

Aetiology of TTP

Answer 11

1. Inherited / Congenital:
   * Very rare
   * Severe deficiency of ADAMTS13 (metalloprotease with
   thrombospondin repeats)
2. Acquired:
   * Idiopathic
   * HIV
   * Pregnancy
   * Transplant
   * Malignancy
   * Connective Tissue Disorders / Autoimmune
   * Drugs - Tacrolimus
   * Toxins

Question 12

Diagnoses of TTP

Answer 12

THE PENTAD:

A. LABORATORY:

1. Thrombocytopenia
   -Platelet count <20-30 x 109/L
2. Micro-angiopathic haemolytic anaemia (MAHA)
   -Schistocytes / red cell fragmentation on the peripheral blood smear (PBS)
   -Haemolytic screen: Elevated LDH, low haptoglobin, elevated reticulocyte production index (RPI), elevated unconjugated hyperbilirubinaemia,
   negative Coomb’s test
   -(Coagulation screen are typically normal)

B. CLINICAL:

3. Neurological deficits/abnormalities
4. Renal dysfunction/failure
5. Fever

C. Confirmation of the ADAMTS13 deficiency
*Deficiency of the ADAMTS13 activity level
* ADAMTS13 antigen levels vary

Question 12

Management of TTP

Answer 12

1. Supportive:
   *Avoid Platelet Transfusion
   *Aim for optimal haemoglobin (Hb)
   *Monitor for seizures, exclude acute coronary syndromes
   *Folic acid
   *Fluid resuscitation and maintenance
   *Find and Treat the cause (e.g. HIV = ART)
   *Consider Prednisone 1mg/kg/day (↓ circulating auto-antibodies)
   *Anticoagulation/antiplatelet when platelet count > 50 x 109/L
2. Specific:
   *Therapeutic Plasma Exchange (TPE)
   *Solvent Detergent (S/D) Fresh Frozen Plasma (FFP) may be used in the interim

Question 12

Characteristics of inherited qualitative platelet disoders

Answer 12

• Rare, described in few families
• Mild: presents later in life, with haemostatic challenge
• Severe: from early childhood or neonate
• Specialist management: haemophilia centre or
  specialised bleeding disorder centre

Question 13

Name all the characteristics of Glanzmann thrombasthenia as one of the qualitative platelet disoders

Answer 13

• Autosomal Recessive
• Platelet aggregation disoder
• Glycoprotein IIb/IIIa
• Severe mucocutaneous bleeding
• Normal platelet count with normal sized platelets
• No aggregation on addition of ADP, collagen, Adrenaline, Arachidonic acid
• Flow Cytometry: GPIIb(CD41)/IIIa(CD61) deficient

Question 14

Name all the characteristics of Bernard-Soulier Syndrome, as one of the qualitative platelet disoders

Answer 14

• Autosomal Recessive
• Platelet adhesion disoder
• Glycoprotein Ib/IX/V
• Mild-moderate mucocutaneous bleeding
• Thrombocytopenia (to normal) with large platelets
• Aggregation is absent with the addition of Ristocetin
• Flow Cytometry: GPIb(CD42b) deficient

Question 14

List 3 qualitative acquired platelet disoders

Answer 14

1. Systemic
   * Renal disease – Uremia → impaired vessel wall-platelet and platelet-platelet interaction
   * Liver disease – abnormal aggregation to ADP
2. Haematologic
   * Myelodysplasia (MDS) – impaired platelet aggregation
   * Myeloproliferative neoplasm (MPN) – leucocyte-platelet interaction, storage pool
   deficiency, impaired platelet aggregation, decreased glycoprotein expression and
   fibrinogen binding after platelet activation
   * Paraproteinaemia (Myeloma) – adsorption of abn. proteins onto platelet membranes
3. Drugs
   * Cyclo-oxygenase inhibitors: Salicylates (Aspirin), NSAIDs prevents platelet aggregation
   * Platelet Receptor Antagonists:
   *Glycoprotein IIb/IIIa inhibitors (abciximab)
   *Thienopyridines P2Y12 inhibitors (clopidogrel)
   * SSRIs (fluoxetine): diminished serotonin release on platelet activation → decreased
   platelet aggregation
   May 2024 NHLS-University of the Witwatersrand 22

Question 14

Name the 2 types of bleeding patterns

Answer 14

1. Platelet type
   -From defect in primary hemostasis
   -Characterized by mucosal cutenous bleeding
   -Petechiae
2. Clotting factor type
   -From defect in 2nday hemostasis
   -Characterized by bleeds into muscles, joints, internal organs
   -Ecchymoses

Question 14

Investigation of Platelet Disorders

Answer 14

1. Screening Tests
   *Full Blood Count (FBC) and Peripheral Blood Smear (PBS)
   *Bleeding Time
   * Platelet Function Assay
2. Diagnostic Tests
   *Platelet Aggregation Studies
   *Flow Cytometry
   *(Gene Sequencing