JC47 (Medicine) - Clotting disorders Flashcards
3 stages of blood clot
□ 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
Agonists of platelet activation
Agonists:
→ Collagen from subendothelial structures
→ Thrombin from coagulation cascade
→ ADP, adrenaline, serotonin, calcium ionophore from platelet degranulation
Phases of platelet activation
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
Function of degranulation and platelet aggregation
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
Function of platelet surface glycoproteins
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
Outline the in-vivo cascade of coagulation
Two physiological phases of coagulation cascade in vivo
Initiation phase and Amplification phase
2 metrics to measure coagulation cascade
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
Vascular defects causing bleeding disorder
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
Congenital platelet defects
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
Acquired platelet defects
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
Congenital coagulation defect
- 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)
Acquired coagulation defects
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)
How to differentiate between platelet disorder and coagulation disorder?
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
Compare between platelet disorder and coagulation disorders:
Presence of subcutaneous bleed, mucosal bleed, intracranial bleed, retinal bleed and intra-muscular bleed
Specific to Platelet: Petechiae, purpura, mucosal and retinal bleed
Specific to Coagulation: Intramuscular bleed and intra-articular bleed
Both: Ecchymosis, Intracranial bleed
3 types of subcutaneous bleed with size cut-offs
Key questions in bleeding history
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
Outline physical examinations for abnormal bleeding
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
Standard investigations for abnormal bleeding
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)
Causes of thrombocytopenia with pancytopenia
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*
Platelet counts and bleeding risk
- Surgical bleeding
- Spontaneous bleeding
- Life-threatening bleeding
<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
Investigations for thrombocytopenia
-
Repeat CBC (± use citrate tubes) to r/o platelet clumping
→ Pseudothrombocytopenia may occur esp with EDTA tubes -
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 - Consider BM failure if pancytopenia
→ Bone marrow exams - 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 - Assess bleeding risk → PLT count + fundus for risk of Intra-cranial hemorrhage
Treatment of thrombocytopenia (Non-ITP)
various level of treatment e.g. actively bleeding vs prevention of spontaneous bleeding
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
Contraindications of Platelet concentrate transfusion
ITP
TTP/ HIT
Antiplatelet drug use
Investigations for suspected hereditary platelet dysfunctions
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
ITP
- Types and definition
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
Pathogenesis of ITP
anti-platelet antibodies leading to platelet destruction
-
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 -
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 - Consequence: ↓platelet lifespan from ~7-10d to ~1-2d
Platelet sensitization → premature removal by RES
Inhibition on TPO stimulation of platelet production in BM
Clinical features of ITP
- Preceding events: e.g. viral infection
- Platelet-type bleeding: petechiae and purpura on skin and mucosa
- Thrombocytopenia: <100×109/L, ↑risk of bleeding if platelet <20×109/L
- Fatigue
± anaemic S/S: usu due to bleeding (IDA)
± hemolysis: Evans syndrome = AIHA + ITP; Thrombotic microangiopathies (TMA): MAHA or TTP
Diagnostic criteria of Primary ITP
Diagnosis by EXCLUSION:
- isolated thrombocytopaenia (<100×109/L) w/o anaemia, leukopenia or apparent cause of thrombocytopenia
- 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
Investigations for suspected ITP
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
Causes of drug-induced thrombocytopenia by BM suppression
Causes of drug-induced thrombocytopenia by immune reactions
Management of ITP General Indication for observation only Indications for standard therapy: 1st line and 2nd line Emergency treatment options
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
Heparin-induced thrombocytopenia
Types and definition, causes of each type
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»_space; Immune-mediated platelet activation»_space; paradoxical thrombosis with thrombocytopenia
Clinical manifestation of Heparin-induced Thrombocytopenia (HIT)
Onset
Platelet levels
Complications
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)
Diagnostic criteria of Heparin-induced Thrombocytopenia
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
Management of Heparin-induced Thrombocytopenia
- Stop heparin immediately to halt platelet activation
- Hold and reverse warfarin: initial warfarin administration depletes functional protein C/S»_space; 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
List all metrics in typical clotting profile
Prothrombin time (PT)
International normalized ratio (INR)
Activated partial thromboplastin time (aPTT)
Thrombin time (TT)
Fibrinogen
D-dimer
Prothrombin time
- Function
- Method
- Normal range
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
INR
- Function
- Method
- Use
- Range
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
aPTT
- Function
- Method
- Use
- Normal range
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
Thrombin time
- Function
- Method
- Normal range
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
Fibrinogen level
- Function
- Use
- Normal range
- Limitation
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
D-dimer
- Function
- Use
- Normal range
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
Mixing test for abnormal bleeding
- Indication
- Rationale
- Method
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
Causes of clotting factor inhibition
- 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
Specific Tests for haemophilia and vWD
□ Specific factor assay for factor deficiencies, eg. haemophilia A/B, factor XI deficiency
□ vWF assay for suspected von Willebrand disease (vWD)
Causes of isolated prolonged PT*****
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)
Causes of isolated prolonged aPTT
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)
Causes of prolonged PT and aPTT *****
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)
Causes of bleeding with normal clotting times
Platelet disorders*
Mild von Willebrand disease
Mild coagulation factor deficiency
Factor XIII deficiency (just for fibrin cross-linking
Approach to isolated prolonged PT
□ 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
Approach to isolated prolonged aPTT
□ 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
Approach to concurrent prolonged PT + aPTT
□ 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)
Haemophilia A, B, C and acquired factor deficiencies
Define underlying factor deficiencies and inheritance patterns
□ 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)
acquired factor deficiency
- Patient demographic
- Typical presentation
Postpartum
Autoimmune diseases
Old and poorly mobilized
Classical presentation is retroperitoneal haematoma due to poor mobilization
presents with back pain + profound anaemia
Clinical presentation of haemophilia
Age of diagnosis for mild, moderate and severe haemophilia
Age of diagnosis: average 1mo, 8mo and 36mo for severe, moderate, mild haemophilia
Presentations:
1. Neonatal Cephalhaematoma and ICH
- Haemarthrosis (80%) at weiight-bearing joints: stiffness, pain, swelling
-
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 -
Mucosal bleed:
- Oropharyngeal, GI bleed, bowel wall haematoma
- Haematuria
Complications of severe haemophilia
Haemophilic arthropathy and joint deformation
Bloodborne infections, eg. HIV, HBV, HCV
Inhibitor development: develop alloAb vs exogenous factor/ treatment resistance
Typical lab tests for suspected haemophilia
□ 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
Management of Haemophilia
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
Von Willebrand Disease
Major Types and definition
Von Willebrand disease
Physiological function of vWF
Pathogenesis of vWD
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
Clinical features of vWD
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
Typical investigations and results in vWD
Screening assays
Basics: isolated ↑aPTT ± thrombocytopenia in type 2B
vWD screening assays:
- vWF antigen (vWF:Ag) titre
-
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)
Management of vWD
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
Approach to low platelet
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
