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haematology > Introduction to Haemostasis and Platelets > Flashcards

Introduction to Haemostasis and Platelets Flashcards

1
Q

Haemostasis

A

The process whereby
haemorrhage following vascular
injury is stopped

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2
Q

List the Major Role players in Haemostasis

A

Blood vessel endothelium

Blood Coagulation factors

Blood platelets

Inhibitors of coagulation

Fibrinolysis

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3
Q

Blood Vessel Wall/Endothelium

A

Injury to the vessel wall:

  • causes vasoconstriction
  • activates membrane bound tissue factor which initiates coagulation
  • exposes subendothelial connective tissue which allows binding of platelets to subendothelial collagen via von Willebrand factor (vWF)
  • vWF mediates platelet adhesion to sub-endothelium and carries coagulation factor VIII in plasma
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4
Q

Phases in Haemostasis

A
  1. Vascular Phase
  2. Platelet Phase
  3. Coagulation Phase
  4. Fibrinolytic Phase
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5
Q

Haemostasis is dependent on which factors:

A

Vessel Wall

Adequate Platelet Numbers

Proper Platelet Function

Adequate Coagulation Factor Levels

Proper Coagulation Factor Function

Proper Function of Fibrinolytic Pathway

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6
Q

Platelets:

A

Produced by megakaryocytes in bone
marrow

Circulate in blood as disclike spheres, 1-2 μm in
diameter

Normal count:150-400 X 10 /l

Mean platelet lifespan is 10-12 days

Third of total platelet mass is pooled in the spleen

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7
Q

Platelets:

Formation

A

Megakaryocyte:
–One of largest cells in body
–Produces platelets by fragmentation of the cytoplasm
– +- 2000-3000 platelets per megakaryocyte

Production is regulated by the cytokine thrombopoietin (TPO)

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8
Q

Platelets:

Structure

A

Anucleate, small & discoid

Surface receptors for binding to:
– Vessel wall
– vWF
– Fibrinogen

Storage granules:
– Dense granules: calcium
– α-granules: vWF, fibrinogen, some coagulation factors
– Lysosomes: enzymes

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9
Q

Platelet:

Morphology

A

Peripheral zone:
– site of platelet adhesion and aggregation
– surface contains receptors for thrombin, collagen, ADP,
adrenalin, serotonin and others: platelet agonists
– many plasma proteins and coagulation factors V, XI and
fibrinogen are bound to the surface

Sol-gel zone:
-Composed of fibrous elements, some of which are
arranged along the greatest circumference of the
platelet
– these elements contain a contractile protein,
thrombastenin which is responsible for platelet
contraction and clot retraction

Organelle zone:
– contains dense bodies, granules, glycogen particles and mitochondria
– dense bodies and granules release their contents into the plasma during the release reaction through a system of tortuous channels

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10
Q

Platelet Functions

A

Formation of plug to arrest bleeding
– Platelet-vessel wall binding (adhesion)
– Platelet-platelet binding (aggregation)

Platelet provides negatively charged phospholipid
membrane
– Activates & promotes coagulation

Initiate haemostasis - (temporary plug)
– adhere to exposed subendothelium
– aggregate to form a plug

Localise the coagulation process
– provide a phospholipid surface for the clotting factors to attach

End result: stabilisation of the platelet plug

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11
Q

Phase of Plate Function

A

Adhesion

Secretion

Aggregation

Contraction

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12
Q

Phases of Platelet Function:

Adhesion

A

Circulating vWF binds to exposed sub-endothelial collagen
• vWF undergoes a conformational change, allowing it to
now bind to Glycoprotein (GP)Ibα on platelet membrane
• Platelet therefore binds to subendothelium via vWF
• GPIbα-vWF interaction particularly important in areas of
high fluid shear stress, where it is the primary initiator of
haemostasis
• Other GPs (e.g. GPIa/IIa and GPVI) bind directly to
collagen at low shear stress areas
• GPIbα-vWF interaction induces intracellular signalling that
activates membrane GPIIb/IIIa
• GP IIb/IIIa is a receptor for fibrinogen and is important in
platelet-platelet adhesion

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13
Q

Phases of Platelet Function:

Secretion

A

• After initial stimulation, platelets release their granule
contents, e.g. ADP, thrombin, fibrinogen, vWF, etc.
• Platelet prostaglandin synthesis is activated to form
thromboxane A2, a potent stimulator of further platelet
activation

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14
Q

Phase of Platelet Function:

Aggregation

A

Additional platelets accumulate, become activated, and adhere to one another

Active metabolic process: agonist binding initiates
signalling pathways that convert GPIIb/IIIa to its activated state

GPIIb/IIIa on platelets now able to bind to fibrinogen and vWF in plasma, leading to aggregation of activated platelets at site of vessel damage

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15
Q

Platelet Function:

Coagulation Cascade

A

• Platelets also participate in the coagulation cascade
– secrete coagulation factors such as fibrinogen, and
factors V and XIII
– provide a negatively charged surface that binds the
vitamin K dependent coagulation factors to localise the
coagulation process

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16
Q

Phases of Platelet Function:

Contraction

A

• After formation of stable secondary platelet-fibrin
haemostatic plug, the clot is reduced in volume and
becomes more compact through process of clot retraction
• Forces responsible for clot retraction are generated by
platelet actin-myosin cytoskeleton
• Actin filaments are anchored to membrane GPIIb/IIIa
receptors, which in turn are linked to fibrin strands outside
platelet
• As clot contracts serum is extruded from the fibrin mesh
with reduction in clot volume

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17
Q

Clinical Manifestations of Bleeding Tendencies

A

PETECCHIAE
– Red to purple spots smaller than 3 mm in diameter
– Prominent on extremities due to increased venous
pressure
• ECCHYMOSES
– Blue to purple subcutaneous haemorrhages larger than
3 mm
• PURPURA
– Purple appearance of the skin due to petecchiae or
ecchymoses
• HAEMATOMA
– Large collection of clotted blood in tissues
• HAEMARTHROSES
– Joint bleeds

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18
Q

Thrombocytopenia/Platelet Function Abnormality

A 
Mucocutaneous bleeding:
– Excessive bleeding after dental extraction & gingival bleeding
– Petechiae & ecchymoses
– Menorrhagia, often worse at menarche
– Epistaxis
19
Q

Platelet Abnormalities

A

Qualitative(Numbers)-Thrombocytopenia and Thrombocytosis

Quantitative(Functional Abnormality)-Inherited and Acquired

20
Q

Thrombocytopenia:

Causes

A

Decreased Production

Increased peripheral destruction/consumption/Loss

21
Q

Thrombocytopenia:

Decreased Production

A 
Generalised bone marrow failure:
– Drugs
– Aplastic anaemia
– Leukaemia
– HIV
– MDS

Affecting only megakaryocytes:
– Drugs, viruses
– Rare congenital disorders

Inherited

22
Q

Thrombocytopenia:

Increased peripheral destruction/consumption/Loss

A

Immune:
– ITP
– Infections: viruses (HIV), malaria
– Drugs

TTP

DIC

Massive splenomegaly (↑ pooling)

Extracorporeal circulation (platelet loss)

23
Q

Immune Thrombocytopenia:

Def

Clinical Variant

Clinical Features

Treatment

A

Thrombocytopenia due to an immunologic destruction of circulating platelets

Megakaryocytes present in BM

CLINICAL VARIANTS
• Acute self-limiting (children, infections)
• Chronic (adults)

HAEMATOLOGICAL AND CLINICAL FEATURES
• Thrombocytopenic haemorrhages (mucocutaneous)
• Platelet lifespan shortened
• Platelets are destroyed in the RES
• Platelet antibodies

TREATMENT
• General: Treat patient and not platelet count.
• Children: Conservative, > 90% spontaneous cure
• Adults:
– Steroids - remission in 75%
– Splenectomy - remission in 75% of those not responding to steroids
– Chemotherapy/other immunosuppressive
therapy/thrombopoietin receptor agonists, for pts not
responding to splenectomy
– Exclude SLE

24
Q

Value of a Peripheral Blood Smear

A

Normal

Bernard Soulier Syndrome(BBS)

Gray Platelet Syndrome(GPS)

NB: Thrombocytopenia + RBC  fragments = haematological emergency!!
•TTP
•DIC
•HELLP syndrome
•Severe sepsis
25
Q

Inherited Thrombocytopenia:

Peripheral Blood Smear

A

Bernard-Soulier Syndrome-Large Platelets

May-Hegglin anomaly:

  • Large Platelets
  • Inclusions-Dohl-like bodies

Exclude Pseudothrombocytopenia

26
Q

Thrombocytopenia-Treatment Principles

Types

A

Normal

  • > 50 x 109/l - safe to undergo operation
  • > 20 x 109/l - low danger of severe spontaneous bleeding

Stress Platelets:
->5 x 109/l - prevent spontaneous bleeding

ASSOCIATED DYSFUNCTION (uraemia, drugs, sepsis)
-Do Bleeding Time to determine platelet function

Types:
General Measures
RCC Transfusions
Platelet Transfusions

27
Q

Thrombocytopenia: Treatment Principles

General Measures

A 
Reduce risk of intracranial haemorrhage
– bed rest
– ensure soft stools
– cough suppression
– control hypertension

Avoid aspirin containing drugs

Avoid intramuscular injections

Suppress menses

28
Q

Thrombocytopenia: Treatment Principles

RCC Transfusions

A

Maintain normal Hb level

29
Q

Thrombocytopenia: Treatment Principles

Platelet Transfusions:

A

Standard treatment for bleeding associated with
thrombocytopenia and /or defective platelet function in conditions such as:
– Bone marrow failure e.g. aplastic anaemia, acute
leukaemia
– Massive transfusion with dilutional thrombocytopenia
– Acute DIC
– Congenital disorders of platelet function

Role of prophylactic platelet transfusions less well defined

Spontaneous bleeding unusual at counts >5x109/l

Widely accepted transfusion triggers:

  1. Threshold of 10x109 /l for adult stable patients
  2. Threshold of 20x109 /l for patients at increased bleeding risk:

-Anatomic lesions e.g. peptic ulcer
-Fever/sepsis
-Recent severe haemorrhage/bleeding from mucous
membranes
-Anticoagulant therapy
-On drugs affecting platelet function
-Severe anaemia
Threshold of 50 x109 /l for most surgical procedures e.g. laparotomy, liver biopsy

100 x109 /l for CNS surgery, ocular surgery

Massive transfusion: maintain platelet count at >50x 109 /l

Multiple trauma and head injury, maintain platelet count at > 100x109 /l

Cardiopulmonary bypass - transfuse only in the presence of microvascular bleeding and platelet count < 100 x109 /l

Chronic stable thrombocytopenia e.g. aplastic anaemia, prophylactic transfusions are generally not indicated

Not required for BM aspirate/biopsy. Application of local pressure is sufficient.

30
Q

Thrombocytosis:

Causes

A
  1. Myeloproliferative Disorders
  2. Reactive
  3. Post-splenectomy
31
Q

Thrombocytosis: Causes

Myeloproliferative Disorders

A

Essential thrombocythaemia (ET)

Polycythaemia vera (PV)

Chronic myelogenous leukaemia (CML)

Myelofibrosis

32
Q

Thrombocytosis: Causes

Reactive

A

Infection, inflammation

Bleeding

Surgery, trauma

Iron deficiency

Malignancy

33
Q

Thrombocytosis: Causes

Post-Splenectomy

A

Large platelets,Howell-Jolly bodies)

34
Q

Platelet Function Abnormalities

A

Inherited

Acquired:

  • Drugs
  • Uraemia-Renal Failure
35
Q

Von Willebrand Disease

A

Deficiency of VWF amount or function

Lab Results - Prolonged BT, abnormal
Von Willebrand Factor testing

36
Q

Von Willebrand Disease:

Etiology

A 
Von Willebrand Factor
– Synthesis in endothelium and megakaryocytes
– Forms large multimeres
– Carrier of factor VIII
– Anchors platelets to sub-endothelium
– Bridge between platelets

Incidence - 1/10,000

Clinical features - mucocutaneous bleeding
le is controversial

37
Q

Von Willebrand Disease:

Laboratory Evalutation

A

Based on [VWF Ag], functional assays and multimere
pattern

Classification
– Type 1 Partial quantitative deficiency
– Type 2 Qualitative deficiency
– Type 3 Total quantitative deficiency

38
Q

Blood Vessel Abnormalities

A

INFECTIONS
– Typhoid fever, meningococcal septicaemia

SCURVY

CUSHING’S DISEASE AND STEROID THERAPY

PURPURA SIMPLEX

SENILE PURPURA

ALLERGIC PURPURA
– Henoch-Schönlein-purpura

DRUGS

39
Q

Von Willebrand Disease:

Diagnosis

A
  1. Clinical History
  2. FBC and Peripheral Smear
    - Often Normal
    - Morphology can give a clue
40
Q

Von Willebrand Disease:

Diagnosis-Bleeding Time

A

µL)Hereditary and acquired platelet dysfunctionsVon Willebrand Disease (VWD)Afibrinogenaemia, severe hypofibrinogenaemiaSome vascular bleeding disorders e.g. hereditarycollagen abnormalities

41
Q

Von Willebrand Disease:

Diagnosis-Platelet Function Analyser(PFA-100)

A

Whole blood

Measures platelet function under high shear
conditions similar to the environment of a partially occluded blood vessel

•

42
Q

Von Willebrand Disease:

Diagnosis-Platelet Aggregometry

A

Platelet rich plasma, whole blood

43
Q

Von Willebrand Disease:

Diagnosis-Flow Cytometry

A

Tests for specific platelet receptors:

CD41 (GPIIb/IIIa)

CD42b (GPIb)

CD61 (GPIIIa)

44
Q

Anti-Platelet Drugs

A

Aspirin (Disprin®): irreversibly inhibits cyclo-oxygenase

Clopidogrel (Plavix®), prasugrel (Efient®): irreversibly
inhibits platelet’s ADP receptor (P2Y12 receptor)

Abciximab (ReoPro®), Eptifibatide (Integrilin®), Tirofiban
(Aggrastet®): Glycoprotein IIb/IIIa antagonists

Dipyridamole (Persantin®): ↑ platelet [c-AMP] thereby
inhibiting platelet function, but role is controversial

haematology (10 decks)

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