JC47 (Medicine) - Clotting disorders

Question 1

3 stages of blood clot

Answer 1

□ Vasoconstriction from loss of normal vasodilator secretion of intact endothelium (eg. PGI2, NO)

□ 1o haemostasis: collagen exposure and loss of endothelium → triggers platelet activation → formation of platelet plug (unstable)

□ 2o haemostasis: activation of coagulation cascade → culminating in fibrin production → cross-link with platelet plug → producs stable fibrin clot followed by clot retraction and fibrosis healing

Question 2

Agonists of platelet activation

Answer 2

Agonists:
→ Collagen from subendothelial structures
→ Thrombin from coagulation cascade
→ ADP, adrenaline, serotonin, calcium ionophore from platelet degranulation

Question 3

Phases of platelet activation

Answer 3

Phases of activation:
Trigger: platelet activation agonist → ↓cAMP → ↑intracellular [Ca]
Shape change in cytoskeleton → open canalicular system ‘flips outward’ to provide large SA for coagulative cascade
Platelet aggregation by surface glycoproteins
Platelet degranulation → further ↑activation → +ve feedback

Question 4

Function of degranulation and platelet aggregation

Answer 4

Granule contents:

Specific α-granules contain activators of coagulative cascade, eg. fibrinogen, factor V and XI, vWF, HMWK

Electron-dense (δ) granules contain platelet activation agonists, eg. ADP, ATP, serotonin, calcium

Question 5

Function of platelet surface glycoproteins

Answer 5

Surface glycoproteins (GP): act as receptors for platelet adhesion/aggregation

Glycoprotein Ia/IIb and VI → mediates direct adhesion to collagen

Glycoprotein Ib → mediates vWF-dependent adhesion to collagen

Glycoprotein IIb/IIIa → mediates vWF-dependent aggregation and association with fibrinogen

Question 6

Outline the in-vivo cascade of coagulation

Answer 6

Question 7

Two physiological phases of coagulation cascade in vivo

Answer 7

Initiation phase and Amplification phase

Question 8

2 metrics to measure coagulation cascade

Answer 8

Prothrombin time (PT)
→ Activates coagulation cascade via extrinsic pathway
→ Measures activity of factor 7, Tissue Factor

Activated partial thromboplastin time (aPTT):
→ Activates coagulation cascade via intrinsic pathway
→ Measures activity of factor 8,9

Factor 10 is the final common pathway

Question 9

Vascular defects causing bleeding disorder

Answer 9

Congenital vascular defects

• Hereditary haemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease)
• Ehler-Danlos syndrome

Acquired vascular defects

• Purpura simplex in young ladies
• Senile purpura in those >65y (UL>LL due to sunlight exposure)
• Scurvy due to vitamin C deficiency
• Steroid purpura
• Vasculitis, eg. Henoch-Schönlein purpura

Question 10

Congenital platelet defects

Answer 10

Qualitative, i.e. platelet dysfunction

• Defects of adhesion: *Bernard-Soulier syndrome (GPIb-IX defect)
• Defects of aggregation: Glanzmann’s thrombasthenia (GPIIb/IIIa defect)
• Defects of degranulation: Gray platelet syndrome (α-granule deficiency)
• Storage pool disease (δ-granule deficiency)

Quantitative, i.e. congenital thrombocytopenia

• Bernard-Soulier syndrome: thrombocytopenia with giant platelets
• Wiskott-Aldrich syndrome: cytoskeleton mutation with immunodeficiency
• May-Hegglin anomaly: giant platelets with Dohle body-like neutrophilic inclusions due to myosin heavy chain mutation
• Congenital BM failure syndromes

Question 11

Acquired platelet defects

Answer 11

Qualitative:

• Antiplatelet drugs: aspirin, P2Y12 inhibitors, GPIIb/IIIa inhibitors, NSAIDs
• Uraemia (common):
  (1) Uraemia → ↑NO production inhibit platelets
  (2) Anaemia → altered blood rheology → ↓platelet contact with endothelium
• MPN ± ↑PLT: platelet dysfunction due to platelet absorption of vWF

Quantitative:
↓production due to BM pathologies (e.g. Aplastic anaemia, Marrow infiltrative disease)

↑destruction: (e.g. Immune thrombocytopenic purpura (ITP), Drug-induced thrombocytopenia, Post-transfusion purpura, DIC and thrombotic microangiopathies (mixed)), Hypersplenism

Question 12

Congenital coagulation defect

Answer 12

• Von Willebrand disease (vWD)
• Haemophilia A due to factor VIII deficiency
• Haemophilia B due to factor IX deficiency

Other very rare diseases (majority AR inheritance)
Factor VII deficiency → isolated ↑PT
Factor X deficiency → ↑PT + ↑aPTT
Fibrinogen deficiency → ↑PT, aPTT, TT
(Factor XII deficiency → isolated ↑aPTT)

Question 13

Acquired coagulation defects

Answer 13

Vitamin K deficiency
- Cholestasis
- Hospitalized patients with malnutrition, malabsorption and Abx use (↓intestinal flora vitamin K production)
- Haemorrhagic disease of the newborn - HDN

Anticoagulant use
- Warfarin, DOAC, Heparin, LMWH

Liver disease with ↓production of clotting factors

DIC and thrombotic microangiopathies

Massive transfusion

Acquired inhibitors of coagulation: Acquired haemophilia A due to anti-factor VIII Ab; Acquired von Willebrand syndrome (aVWS)

Question 14

How to differentiate between platelet disorder and coagulation disorder?

Answer 14

Platelet type: mucocutaneous bleeding (petechiae/purpura, epistaxis, tongue haematoma, GI bleed, menorrhagia) or continuous oozing after trauma

Coagulation type: deep-seated bleeding (muscle haematoma, haemarthrosis, ICH, retroperitoneal haematoma) or rebleeding after initial cessation

Question 15

Compare between platelet disorder and coagulation disorders:

Presence of subcutaneous bleed, mucosal bleed, intracranial bleed, retinal bleed and intra-muscular bleed

Answer 15

Specific to Platelet: Petechiae, purpura, mucosal and retinal bleed

Specific to Coagulation: Intramuscular bleed and intra-articular bleed

Both: Ecchymosis, Intracranial bleed

Question 15

3 types of subcutaneous bleed with size cut-offs

Answer 15

Question 16

Key questions in bleeding history

Answer 16

Pattern of current bleeding:
→ Platelet type: mucocutaneous bleeding (petechiae/purpura, epistaxis, tongue haematoma, GI bleed, menorrhagia) or continuous oozing after trauma
→ Coagulation type: deep-seated bleeding (muscle haematoma, haemarthrosis, ICH, retroperitoneal haematoma) or rebleeding after initial cessation

Prior/other bleeding:
→ Age of onset: congenital vs acquired, previous blood screening results
→ Previous bleeding challenges, eg. labour, surgery, dental procedures, injury
→ Other bleeding: head-to-toe bleeding history → ICH, epistaxis, gum bleeding, easy bruising or cutaneous petechiae/purpura, joint/muscle haematoma, GI bleeding, menstrual Hx

Systemic illnesses, eg. liver disease, kidney disease, connective tissue disease

Drug history esp on oral anticoagulant, fibrinolytic and antiplatelet use

Family history of clotting disorders: inherited vs sporadic/acquired

Question 17

Outline physical examinations for abnormal bleeding

Answer 17

Physical examination: look for features of suspected conditions
Cutaneous: initially red/purple and later becoming yellow as haemoglobin is degraded
→ Bleeding: petechiae (<2mm, esp dependent areas), purpura (2-10mm), ecchymosis (>10mm)
→ Telangiectasiae around lips/fingertips → indicate HHT
→ Hyperelasticity → indicate Ehler-Danlos syndrome

Fundoscopy: retinal bleeding indicates ↑risk for CNS bleeding

Mouth: for gum bleeding and macroglossia (classical for amyloidosis)

Joints: for joint effusion (haemarthrosis) and deformities (chronic haemarthrosis)

LNs: for haematological malignancies

Abdomen:
→ Hepatosplenomegaly in liver disease, lymphoma, myeloproliferative neoplasm
→ Flank/abdominal mass may be retroperitoneal or abdominal haematoma respectively

Question 18

Standard investigations for abnormal bleeding

Answer 18

CBC ± PBS for platelet count and platelet morphology

Clotting profile including PT and INR, aPTT (± TT)

Additional tests:
→ Platelet function tests and vWF function assay (Normal initial tests)
→ Specific clotting factor assays and mixing tests (haemophilia)
→ Fibrinogen, D-dimer (DIC or thrombotic microangiopathies)

Question 19

Causes of thrombocytopenia with pancytopenia

Answer 19

Marrow hypoplasia*

• Congenital BM failure syndromes, eg. Fanconi anaemia, dyskeratosis congenita
• Aplastic anaemia (idiopathic and secondary)
• Transfusion-associated GvHD

Marrow infiltration*

• Myelofibrosis (primary, secondary)
• Malignant infiltration (haematological, non-haematological)
• Lysosomal storage disease, eg. Gaucher’s disease

Megaloblastic anaemia*

Infections
Sepsis-related haemophagocytosis (HLH) and BM suppression

Hypersplenism*

Question 20

Platelet counts and bleeding risk

• Surgical bleeding
• Spontaneous bleeding
• Life-threatening bleeding

Answer 20

<100×109/L → risk of surgical bleeding for high-risk operations, eg. major cardiac or orthopaedic surgery, neurosurgery

<50×109/L → risk of surgical bleeding for usual operations

<20×109/L → risk of spontaneous bleeding

<10×109/L → risk of life-threatening bleeding, eg. ICH

Question 21

Investigations for thrombocytopenia

Answer 21

1. Repeat CBC (± use citrate tubes) to r/o platelet clumping
   → Pseudothrombocytopenia may occur esp with EDTA tubes
2. PBS: r/o platelet clumping, morphological abnormalities
   → Giant platelet in peripheral destruction (eg. ITP) or congenital megathrombocytopenia (eg. Bernard-Soulier)
   → Large, agranular platelets in grey platelet syndrome (no α-granules)
   → RBC/WBC morphology, eg. schistocyte in MAHA, megaloblastic anemia
3. Consider BM failure if pancytopenia
   → Bone marrow exams
4. Consider peripheral destruction if isolated thrombocytopenia
   → Hypersplenism with chronic liver disease → LFT
   → ITP or drug-induced thrombocytopenia → PBS + r/o alternative causes by HIV, HCV
5. Assess bleeding risk → PLT count + fundus for risk of Intra-cranial hemorrhage

Question 22

Treatment of thrombocytopenia (Non-ITP)

various level of treatment e.g. actively bleeding vs prevention of spontaneous bleeding

Answer 22

Platelet concentrate transfusion
for Active bleeding:
- <50×109/L if diffuse microvascular/mucosal bleeding, major bleeding
- <100×109/L if retinal/CNS bleeding or post-cardiopulmonary bypass bleeding

for Prevention of spontaneous bleeding: <10×109/L if stable, <20×109/L if fever/sepsis

for Preparation of invasive procedure:
- <20×109/L for minor procedures, eg. diagnostic endoscopy, central line, BM aspiration
- <50×109/L for major procedures
- <100×109/L for neurosurgery or ocular surgery

Question 23

Contraindications of Platelet concentrate transfusion

Answer 23

ITP
TTP/ HIT
Antiplatelet drug use

Question 24

Investigations for suspected hereditary platelet dysfunctions

Answer 24

**Platelet aggregometry**: measure response to agonists by aggregometry **PFA-100: platelet function analyzer** **Electron microscopy studies**: can detect granulation disorders **Flow cytometry**: can detect **glycoprotein defects** **Genetic studies** as indicated

Question 25

ITP | - Types and definition

Answer 25

**Primary ITP**: acquired immune-mediated thrombocytopenia (platelet <100×109/L) that is **not triggered by apparent associated condition** **Secondary ITP**: acquired immune-mediated thrombocytopenia **a/w underlying condition** **Drug-induced** immune thrombocytopenia (DITP): thrombocytopenia due to drug-dependent platelet antibodies that cause platelet destruction

Question 26

Pathogenesis of ITP

Answer 26

**anti-platelet antibodies** leading to platelet destruction 1. **Inciting event**: occurs in some cases **Viral infection**: Ab vs viral Ag cross-react with normal platelet antigens → molecular mimicry **Immune diseases**: A/I disease or low-grade lymphoproliferative neoplasm or immunodeficiency → loss of peripheral tolerance → produce autoAb 2. **Antibody production**: Driven by CD4+ helper T cells reacting to platelet surface glycoproteins Results in production of **autoAb (usu IgG) vs platelet surface components** esp GPIIb/IIIa and GPIb/IX 3. Consequence: ↓platelet lifespan from ~7-10d to ~1-2d Platelet sensitization → **premature removal by RES** **Inhibition on TPO stimulation** of platelet production in BM

Question 27

Clinical features of ITP

Answer 27

1. Preceding events: e.g. viral infection 2. **Platelet-type bleeding**: petechiae and purpura on skin and mucosa 3. **Thrombocytopenia**: <100×109/L, ↑risk of bleeding if platelet <20×109/L 4. Fatigue **± anaemic S/S**: usu due to bleeding (IDA) **± hemolysis**: Evans syndrome = AIHA + ITP; Thrombotic microangiopathies (TMA): MAHA or TTP

Question 28

Diagnostic criteria of Primary ITP

Answer 28

**Diagnosis by EXCLUSION**: 1. **isolated thrombocytopaenia** (<100×109/L) w/o anaemia, leukopenia or apparent cause of thrombocytopenia 2. Occasional **large platelets w/o morphological abnormalities** → indicates active thrombocytogenesis Exclude following: - **secondary causes of ITP**: recent viral infection (esp HCV, HIV), A/I diseases, lymphoproliferative disease - **causes of peripheral consumption**: liver disease and hypersplenism, MAHA, recent transfusion - **drug use**

Question 29

Investigations for suspected ITP

Answer 29

**CBC**: isolated thrombocytopaenia **PBS**: occasional large platelets *w/o morphological abnormalities* **Anti-HIV, HCV** if appropriate (inciting viral infection) **Autoimmune profile** and aPTT for underlying A/I diseases **Antiplatelet Ab** (MAIPA test) (Poor sensitivity) **Bone marrow exam**: Rule out MDS

Question 30

Causes of drug-induced thrombocytopenia by BM suppression

Answer 30

Question 31

Causes of drug-induced thrombocytopenia by immune reactions

Answer 31

Question 32

``` Management of ITP General Indication for observation only Indications for standard therapy: 1st line and 2nd line Emergency treatment options ```

Answer 32

General: for secondary ITP - **Remove inciting drug ** - **Treat underlying infection** (e.g. HCV, HIV, H. pylori) - **Avoid aspirin and antiplatelet agents**, IM injections For **asymptomatic/ minor mucocutaneous bleed**: **Active Observation**: platelet ≥30×109/L 1st line therapy/ **significant bleeding**: platelet <30×109/L - **Glucocorticoids: Prednisolone ** - **Azathioprine** for refractory pt. or prolonged use 2nd line treatment: **Steroid-dependent** or **unresponsive ITP** - **Splenectomy** - **Rituximab** - **TPO receptor agonist**: eg. eltrombopag, romiplostim **Emergency therapy** - **IVIg** (MoA: saturates phagocyte Fc receptors in RES → ↓platelet degradation) - **Pulse IV steroids** (methylprednisolone) or **oral steroids** (pulse dexamethasone) - **IV anti-Rh(D)** - **Platelet transfusion**

Question 33

Heparin-induced thrombocytopenia | Types and definition, causes of each type

Answer 33

HIT type I (10-20%): mild, transient thrombocytopenia occurring in 1-4d after starting heparin >> Non-immune platelet aggregation, clinically insignificant HIT type II (1-3%): significant thrombocytopenia occurring 5-10d after starting heparin >> Antibody vs platelet factor 4 complexed to heparin >> Immune-mediated platelet activation >> paradoxical thrombosis with thrombocytopenia

Question 34

Clinical manifestation of Heparin-induced Thrombocytopenia (HIT) Onset Platelet levels Complications

Answer 34

thrombocytopenia + paradoxical A/V thrombosis - Onset: generally 5-10d - Thrombocytopenia (75-90%): mean PLT at 60×10^9/L - Thrombosis (up to 50%): → VTE and death → Skin necrosis esp at site of heparin injection (classical) → Acute limb ischaemia → Organ ischaemia: stroke, MI, mesenteric, renal - Anaphylactoid reaction (rare)

Question 35

Diagnostic criteria of Heparin-induced Thrombocytopenia

Answer 35

Clinical: as in 4T score - Thrombocytopenia score - Timing of platelet count score - Thrombosis or other sequalae - Other causes of thrombocytopenia Anti-PF4-heparin antibody demonstrated in serum

Question 36

Management of Heparin-induced Thrombocytopenia

Answer 36

- Stop heparin immediately to halt platelet activation - Hold and reverse warfarin: initial warfarin administration depletes functional protein C/S >> transient hypercoagulable state Therapeutic anticoagulation: prevent thrombosis: - Parenteral direct thrombin inhibitors, eg. argatroban, bivalirudin - Heparinoid anticoagulants, eg. danaparoid, fondaparinux (no interaction with PF4) - NOACs, eg. dabigatran, apixaban, edoxaban, rivaroxaban bridge to warfarin when PLT >150×109/L

Question 37

List all metrics in typical clotting profile

Answer 37

Prothrombin time (PT) International normalized ratio (INR) Activated partial thromboplastin time (aPTT) Thrombin time (TT) Fibrinogen D-dimer

Question 38

Prothrombin time - Function - Method - Normal range

Answer 38

Prothrombin time (PT): clinically used to measure **factor VII activity** → Method: measures time for plasma to clot when exposed to tissue factor → Normal range: 11.3-13.5s

Question 39

INR - Function - Method - Use - Range

Answer 39

International normalized ratio (INR): used to **standardize PT assay** for therapeutic monitoring → Method: calculated from comparison to PT of control serum and ISI (specified in lab assay) Use: - therapeutic monitoring of warfarin - surrogate for PT esp in liver failure **healthy people: INR of 1.1 or below** is normal **Warfarin use** for prophylaxis against thrombosis: **INR range of 2.0 to 3.0**

Question 40

aPTT - Function - Method - Use - Normal range

Answer 40

**Activated partial thromboplastin time (aPTT)**: clinically used to measure **factor VIII, IX activity** → Method: measures time for plasma to clot when **exposed to thromboplastic material** without tissue factor activity (i.e. partial thromboplastin) and negatively charged substance resulting in **factor XII activation** → Note: also used for **heparin monitoring** as heparin interferes with PT assay → Normal range: **25.9-33.7s**

Question 41

Thrombin time - Function - Method - Normal range

Answer 41

Thrombin time (TT): clinically used as a surrogate for **fibrinogen activity** → Method: measures time for plasma to clot when exposed to thrombin → Normal range: 14-19s

Question 42

Fibrinogen level - Function - Use - Normal range - Limitation

Answer 42

Fibrinogen: precursor to fibrin Decreased due to **↓synthesis (liver disease) or ↑consumption (widespread thrombosis, eg. DIC, TTP)** Normal range: 1.46-3.38g/L *also an acute phase reactant (APR) → can be falsely -ve*

Question 43

D-dimer - Function - Use - Normal range

Answer 43

D-dimer: one of the **major fibrin degradation products** after cleavage by plasmin, also APR Increased in **significant thrombosis, eg. DIC, PE, DVT** Normal range: <0.5mg/L

Question 44

Mixing test for abnormal bleeding - Indication - Rationale - Method

Answer 44

Mixing test to differentiate between **factor deficiency and factor inhibitor** Indication: in unexplained abnormal clotting time Rationale: 50% clotting factor activity sufficient for normal clotting Method: repeat the abnormal test with **1:1 mix with normal plasma** (immediate + 1-2h incubation) → **clotting time normalized in factor deficiency vs abnormal in inhibitor**

Question 45

Causes of clotting factor inhibition

Answer 45

- **Anticoagulant use**, eg. heparin, NOAC (NOT warfarin → ↓synthesis) - **Lupus anticoagulant**: dRVVT/aPTT fails to correct after mixing, but **corrected after addition of excess phospholipids** → only interferes with the test, not in vivo clotting → a/w thrombosis not bleeding - **Acquired Ab** vs clotting factors: common in **haemophilia**

Question 46

Specific Tests for haemophilia and vWD

Answer 46

□ **Specific factor assay** for factor deficiencies, eg. haemophilia A/B, factor XI deficiency □ **vWF assay** for suspected von Willebrand disease (vWD)

Question 47

Causes of isolated prolonged PT*****

Answer 47

Think extrinsic pathway - TF and F7, F7a activate F10, F10a activate thrombin Factor deficiency or inhibition - **Warfarin** (factor II, VII, IX, X) - **Liver disease** (↓synthesis) - Inherited **factor VII deficiency** (rare) Vitamin K: - Causes of **cholestasis** (↓vitamin K absorption) - **Vitamin K deficiency** (factor II, VII, IX, X)

Question 48

Causes of isolated prolonged aPTT

Answer 48

Think about intrinsic pathway - aPTT measure F8 and F9 activity, activate F10a/F5a cascade in amplification phase Factor inhibition: - **Heparin contamination** (most common in in-pt) - **Lupus anticoagulant** (a/w thrombosis) - **Acquired haemophilia A** (rare, due to F8 inhibitor) Factor deficiency: - **Congenital haemophilia A/B** (usually in men) - **Von Willebrand disease** - **Factor XII deficiency** (10% normal population, NOT a/w bleeding)

Question 49

Causes of prolonged PT and aPTT *****

Answer 49

F7,8,9 across intrinsic and extrinsic pathway: Consumption: - Diffuse intravascular coagulation (**DIC**) Production/inhibition: - **Warfarin** and **Vitamin K deficiency** (factor II, VII, IX, X) - **Liver disease** (↓synthesis) and **cholestasis** - **Factor X and fibrinogen deficiency** (rare)

Question 50

Causes of bleeding with normal clotting times

Answer 50

Platelet disorders* Mild von Willebrand disease Mild coagulation factor deficiency Factor XIII deficiency (just for fibrin cross-linking

Question 51

Approach to isolated prolonged PT

Answer 51

□ Repeat and confirm □ Look for features of **cholestasis** and LIVER DISEASE*** and their causes □ Hx of **WARFARIN use** Isolated PT Treatment: □ **Parenteral vitamin K** □ **VitK + FFP + PCC if warfarin overdose**

Question 52

Approach to isolated prolonged aPTT

Answer 52

□ Repeat and confirm □ Most commonly **HEPARIN and LUPUS COAGULANT** → perform **mixing test** to r/o □ Check **HEMOPHILIA A/B** in men (XLR) and **vWD** in both genders (AD) → perform **specific factor assay and vWF assay** □ Management: → **FACTOR CONCENTRATES** for haemophilia A/B → **DDAVP** for mild haemophilia and vWD

Question 53

Approach to concurrent prolonged PT + aPTT

Answer 53

□ Repeat and confirm □ Consider **DIC** → Measure **fibrinogen, D-dimer, platelet** + look for underlying cause → Classical result: ↑PT, ↑aPTT, ↓fibrinogen, ↓platelet + fragmented RBCs □ Management: → **FFP** to replenish consumed coagulation factors in active bleeding → **Treat underlying cause** only if no bleeding (prophylactic FFP may ↑risk of thrombosis)

Question 54

Haemophilia A, B, C and acquired factor deficiencies Define underlying factor deficiencies and inheritance patterns

Answer 54

□ Haemophilia A due to inherited deficiency of factor VIII (XLR) □ Haemophilia B (Christmas disease) due to inherited deficiency of factor IX (XLR) □ Haemophilia C (Rosenthal syndrome due to inherited deficiency of factor XI (AR) □ Acquired factor deficiencies due to autoAb vs clotting factors (most commonly VIII)

Question 55

acquired factor deficiency - Patient demographic - Typical presentation

Answer 55

Postpartum Autoimmune diseases Old and poorly mobilized Classical presentation is **retroperitoneal haematoma due to poor mobilization** presents with **back pain + profound anaemia**

Question 56

Clinical presentation of haemophilia Age of diagnosis for mild, moderate and severe haemophilia

Answer 56

Age of diagnosis: average 1mo, 8mo and 36mo for severe, moderate, mild haemophilia Presentations: 1. **Neonatal Cephalhaematoma and ICH** 2. **Haemarthrosis (80%) at weiight-bearing joints**: stiffness, pain, swelling 3. **Soft tissue haematoma**: - **Muscle haematoma**, commonly in **calf and psoas muscles**: Lead to compartment syndrome (acute bleed into calf) and Femoral nerve compression in psoas bleed - **Acute abdomen** - **Haemophilic pseudotumor** in pelvis/ bone 4. **Mucosal bleed**: - Oropharyngeal, GI bleed, bowel wall haematoma - Haematuria

Question 57

Complications of severe haemophilia

Answer 57

**Haemophilic arthropathy** and joint deformation **Bloodborne infections**, eg. HIV, HBV, HCV **Inhibitor development**: develop alloAb vs exogenous factor/ treatment resistance

Question 58

Typical lab tests for suspected haemophilia

Answer 58

□ **Prenatal diagnosis**: often presumed based on sex on USG (XLR) □ Clotting profile: **isolated prolonged aPTT that is corrected in mixing studies** □ **Specific factor assay**: ↓activity (<40%) in factor VIII (haemophilia A), IX (haemophilia B) □ **Genetic testing**: appropriate → identify the mutation that can be used for relative screening

Question 59

Management of Haemophilia

Answer 59

General measures: - Avoid invasive procedures - Dental hygiene - Exercise - Avoid antiplatelet/ anticoagulants **DDAVP for mild haemophilia A** - MoA: promote **release of factor VII and vWF** (F8 carrier) from storage pools in platelet granules and endothelial cells **Recombinant factor replacement** Specific complications: **Haemarthrosis: analgesics** (eg. COX-2, Panadol → avoid NSAID), **RICE** as needed **Muscle haematoma: surgical decompression** **Haematuria: forced diuresis** **Mucosal bleeding: add antifibrinolytic agents**, eg. tranexamic acid, aminocaproic acid

Question 60

Von Willebrand Disease Major Types and definition

Answer 60

Question 61

Von Willebrand disease Physiological function of vWF Pathogenesis of vWD

Answer 61

Pathogenesis: due to **qualitative or quantitative defect** in von Willebrand factor (vWF) Physiology: a large multimeric glycoprotein **secreted by endothelium** as ultra-large multimers → eventually **cleaved by ADAMTS13** into smaller polymers (less active) → **degraded by other proteases** in plasma Main functions: → **Carrier protein for factor VIII** → prevent rapid degradation in plasma → Mediates **platelet adhesion from GPIb to collagen** in sub-endothelial matrix Pathology: genetic **defect in VWF gene** (ch12) → **defective platelet adhesion + ↓factor VIII level**

Question 62

Clinical features of vWD

Answer 62

vWF affects both platelet adhesion to collagen AND factor 8 function: **Mucocutaneous** bleeding (deep-seated bleeding in Type 3 vWD only) **Deep-seated bleeding/ Joint and tissue bleeding**: usually only seen in **types 2N and 3** **Heavy menstrual bleed** (60-90%) in women **Post-partum bleeding** (62%) in women

Question 63

Typical investigations and results in vWD Screening assays

Answer 63

Basics: **isolated ↑aPTT** ± thrombocytopenia in type 2B **vWD screening assays**: 1. **vWF antigen (vWF:Ag)** titre 2. **vWF activity (vWF:Act)**: measures binding activity of vWF - **Ristocetin cofactor assay** (vWF:RiCof) - **Collagen binding assay** - **Factor VIII activity** **vWF Act:Ag ratio** **Multimer analysis** **Ristocetin-induced platelet aggregation (RIPA)**

Question 64

Management of vWD

Answer 64

Trial of **DDAVP** (in all non-type 3 patients) **vWF concentrates** in major bleeding/surgery; refractory to DDAVP **Antifibrinolytic agents**: alone or with DDAVP/vWF in mucosal bleeds

Question 65

Approach to low platelet

Answer 65

Repeat and confirm:**Citrate blood** **Thrombocytopenia with Pancytopenia**:**BM exam** for failure/ suppression **Isolated thrombocytopenia**:**Liver disease, ITP, DRUG** Assess **bleeding risk: Bleeding history + P/E + Clotting profile + Fundoscopy**