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Cardiorespiratory 2 > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

Define haemostasis

A

The cellular and biochemical processes that enables both the specific and regulated cessation of bleeding in response to vascular insult

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2
Q

What is haemostasis?

A

Prevention of blood loss from intact vessels
Arrest bleeding from injured vessels
Enable tissue repair

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3
Q

Describe mechanism of haemostasis

A
  1. Vessel constriction - Vascular smooth muscle cells contract locally, Limits blood flow to injured vessel
  2. Primary haemostasis - Formation of an unstable platelet plug - platelet adhesion, platelet aggregation. Limits blood loss + provides surface for coagulation.
  3. Secondary haemostasis - Stabilisation of the plug with fibrin. Blood coagulation stops blood loss.
  4. Fibrinolysis - Vessel repair and dissolution of clot. Cell migration/proliferation & fibrinolysis. Restores vessel integrity.
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4
Q

Why do we need to understand haemostatic mechanisms?

A
  1. Diagnose and treat bleeding disorders
  2. Control bleeding in individuals who do not have an underlying bleeding disorder
  3. Identify risk factors for thrombosis
  4. Treat thrombotic disorders
  5. Monitor the drugs that are used to treat bleeding and thrombotic disorders
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5
Q

What can cause a decrease in thrombotic factors?

A
  1. Lack of a specific factor - Failure of production: congenital and acquired, Increased consumption/clearance
  2. Defective function of a specific factor - Genetic, Acquired: drugs, synthetic defect, inhibition
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6
Q

Describe platelet adhesion and aggregation

A

Damage to endothelial wall means platelets can bind directly to the exposed collagen via the GP1a receptor or can bind to VWF via the GP1b receptor. Platelets release granular contents and together with generation of thromboxane from arachidonic acid results in platelet activation. Activation of GP2b/3a receptors on platelets.

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7
Q

What can cause thrombocytopenia?

A

Bone marrow failure eg: leukaemia, B12 deficiency
Accelerated clearance eg: immune (ITP), Disseminated Intravascular Coagulation (DIC)
Pooling and destruction in an enlarged spleen

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8
Q

What is immune thrombocytopenia purpura?

A

Autoantibodies bind to platelets causing macrophages to clear them.

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9
Q

What can cause impaired function of platelets?

A

Hereditary absence of glycoproteins or storage granules

Acquired due to drugs: aspirin, NSAIDs, clopidogrel (common)

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10
Q

What are 3 hereditary conditions causing impaired platelet function?

A

Glanzmann’s thrombasthenia - autosomal recessive disease
Bernard Soulier syndrome
Storage Pool disease

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11
Q

When is antiplatelet therapy used and what is it?

A

Widely used in the prevention and treatment of cardiovascular & cerebrovascular disease. The prostaglandin Thromboxane A2 is produced by platelets from Arachidonic acid. Aspirin irreversibly blocks COX preventing thromboxane formation. Clopidogrel irreversibly blocks the ADP receptor P2Y12 on platelets, preventing platelet shape change response and aggregation.

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12
Q

What is the function of VWF in haemostasis?

A

Binding to collagen and capturing platelets

Stabilising Factor VIII

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13
Q

What causes von Willebrand disease?

A

VWD is usually hereditary (autosomal inheritance pattern):
Deficiency of VWF (Type 1 or 3)
VWF with abnormal function (Type 2)

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14
Q

What are potential disorders of primary haemostasis?

A

Platelets
Von Willebrand Factor
The vessel wall
Inherited (rare) Hereditary haemorrhagic telangiectasia Ehlers-Danlos syndrome and other connective tissue disorders

Acquired (common): Steroid therapy, Ageing (‘senile’ purpura), Vasculitis, Scurvy (Vitamin C deficiency)

Long term steroids: can develop atrophy of collagen fibres supporting blood vessels in the skin
Senile purpura: come on with age, dark purple with well-defined edges, most commonly distributed on extensor surfaces of forearms and dorsal aspects of hands

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15
Q

What is typical primary haemostasis bleeding?

A

Immediate
Prolonged bleeding from cuts
Nose bleeds (epistaxis): prolonged > 20 mins
Gum bleeding: prolonged
Heavy menstrual bleeding (menorrhagia)
Bruising (ecchymosis), may be spontaneous/easy
Prolonged bleeding after trauma or surgery

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16
Q

What are petechiae and purpura signs of?

A

Petechiae and Purpura are caused by bleeding under the skin
Purpura do not blanch when pressure is applied

Thrombocytopenia – Petechiae
Purpura – platelet (thrombocytopenic purpura) or vascular disorders
Severe VWD – haemophilia-like bleeding (due to low FVIII)

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17
Q

What are tests for disorders of primary haemostasis?

A

Platelet count, platelet morphology
Bleeding time (PFA100 in lab)
Assays of von Willebrand Factor
Clinical observation

Note –coagulation screen (PT, APTT) is normal (except more severe VWD cases where FVIII is low)

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18
Q

What are principles of treating disorders of primary haemostasis?

A
  1. Failure of production/function:
    Replace missing factor/platelets e.g. VWF containing concentrates - can be prophylactic or therapeutic
    Stop drugs e.g. aspirin/NSAIDs
  2. Immune destruction
    Immunosuppression (e.g. prednisolone)
    Splenectomy for ITP
  3. Increased consumption
    Treat cause
    Replace as necessary
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19
Q

What are additional haemostatic treatments?

A 
Desmopressin (DDAVP)
	Vasopressin analogue 
	2-5 fold increase in VWF (and FVIII)
	releases endogenous stores (so only useful in mild disorders)
Tranexamic acid
	Antifibrinolytic
Fibrin glue/spray
Other approaches e.g hormonal (oral contraceptive pill for menorrhagia)
20
Q

What characterises disorders of secondary haemostasis?

A

The role of coagulation is to generate thrombin (IIa), which will convert fibrinogen to fibrin. Deficiency of any coagulation factor results in a failure of thrombin generation and hence fibrin formation.

21
Q

What are disorders of coagulation?

A
  1. Deficiency of coagulation factor production
    Hereditary: Factor VIII/IX: haemophilia A/B
    Acquired: Liver disease, Anticoagulant drugs (Warfarin, Direct Oral Anticoagulants (DOACs))
  2. Dilution
    Acquired: Blood transfusion
  3. Increased consumption
    Acquired: Disseminated intravascular coagulation (DIC) – common
    (Immune – autoantibodies – rare)
22
Q

What are hereditary coagulation disorders?

A 
Haemophilia A (Factor VIII deficiency) 
Haemophilia B (Factor IX deficiency) - sex linked, 1 in 104 births
Others are very rare (autosomal recessive)
23
Q

What is haemophilia and what is a hallmark of it?

A

Failure to generate fibrin to stabilise platelet plug. Haemarthrosis is a hallmark - spontaneous joint bleeding that occurs when factors 8/9 are low. In long term, leads to significant joint deformity and muscle wasting. Intramuscular injections should be avoided.

24
Q

What is the consequence of different coagulation factor deficiencies?

A

Factor VIII and IX (Haemophilia) - Severe but compatible with life, Spontaneous joint and muscle bleeding
Prothrombin (Factor II) - Lethal
Factor XI - Bleed after trauma but not spontaneously
Factor XII - No bleeding at all

25
Q

How can coagulation disorders be acquired?

A
  1. Liver failure – decreased production
    Most coagulation factors are synthesised in the liver
  2. Anticoagulant drugs*
  3. Dilution
    Red cell transfusions no longer contain plasma
    Major haemorrhage requires transfusion of plasma as well as red cells and platelets
26
Q

What happens in disseminated intravascular coagulopathy?

A

Generalised activation of coagulation – Tissue factor
Associated with sepsis, major tissue damage, inflammation
Consumes and depletes coagulation factors
Platelets consumed - thrombocytopenia
Activation of fibrinolysis depletes fibrinogen – raised D-dimer (a breakdown product of fibrin)
Deposition of fibrin in vessels causes organ failure

27
Q

What are clinical features of coagulation disorders?

A
  1. Superficial cuts do not bleed (platelets)
  2. Bruising is common, nosebleeds are rare
  3. Spontaneous bleeding is deep, into muscles and joints
  4. Bleeding after trauma may be delayed and is prolonged
  5. Bleeding frequently restarts after stopping
28
Q

What is the clinical distinction between bleeding due to platelet and coagulation defects?

A

Platelet/Vascular defect:
Superficial bleeding into skin, mucosal membranes
Bleeding immediate after injury

Coagulation defect:
Bleeding into deep tissues, muscles, joints
Delayed, but severe bleeding after injury.
Bleeding often prolonged

29
Q

What are tests for coagulation disorders?

A
  1. Screening tests (‘clotting screen’)
    Prothrombin time (PT)
    Activated partial thromboplastin time (APTT)
    Full blood count (platelets)
  2. Coagulation factor assays (for Factor VIII etc)
  3. Tests for inhibitors
30
Q

What can cause prolonged APTT with normal PT?

A

Haemophilia A
Haemophilia B
Factor XI deficiency
Factor XII deficiency

31
Q

What can cause prolonged PT with normal APTT?

A

Factor VII deficiency

32
Q

What can cause prolonged PT and APTT?

A

Liver disease
Anticoagulant drugs e.g. warfarin
DIC (platelets and D dimer)
Dilution following red cell transfusion

33
Q

What is factor replacement therapy?

A
  1. Plasma (fresh frozen plasma FFP) - Contains all coagulation factors
  2. Cryoprecipitate - Rich in Fibrinogen, FVIII, VWF, Factor XIII
  3. Factor concentrates - Concentrates available for all factors except factor V. Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X
  4. Recombinant forms of FVIII and FIX are available
    ‘On Demand’ to treat bleeds
    Prophylaxis to prevent bleeds
34
Q

Describe evolution of haemophilia treatment

A
  1. Plasma-Derived Clotting Factors used - widespread viral contamination occured
  2. Currently Approved Recombinant Clotting Factors - Eliminated potential for transmission of blood borne pathogens
  3. Novel treatments for haemophilia
35
Q

What are novel treatments for haemophilia?

A
  1. Gene therapy (Haem A and B)
  2. Bispecific antibodies (Haem A)
    Emicizumab - Binds to FIXa and FX and mimics procoagulant function of FVIII
  3. RNA silencing (Haem A and B)
    Targets natural anticoagulant - antithrombin
36
Q

What are additional treatment of abnormal haemostasis?

A

Desmopressin (DDAVP)
Vasopressin analogue
2-5 fold increase in VWF (and FVIII)
releases endogenous stores (so only useful in mild disorders)
Tranexamic acid - Antifibrinolytic
Fibrin glue/spray
Other approaches e.g hormonal (oral contraceptive pill for menorrhagia)

37
Q

What are characteristics of pulmonary embolism?

A 
Tachycardia
Hypoxia
Shortness of breath
Chest pain
Haemopysis
Sudden death
38
Q

What are characteristics of deep vein thrombosis?

A 
Painful leg
Swelling
Red
Warm
May embolise to lungs
Post thrombotic syndrome
39
Q

What are characteristics of thrombosis?

A 
Intravascular coagulation
Inappropriate coagulation
Can be venous (or arterial)
Obstructs flow
May embolise to lungs
40
Q

What is Virchow’s Triad?

A

Details three contributory factors for thrombosis:
Blood: dominant in venous thrombosis
Vessel wall: dominant in arterial thrombosis
Blood flow: contributes to both arterial and venous thrombosis

41
Q

How can thrombophilia present?

A

Thrombosis at young age
‘spontaneous thrombosis’
Multiple thromboses
Thrombosis whilst anticoagulated

42
Q

What factors make venous thrombosis more likely?

A
  1. A decrease in anticoagulant proteins such as antithrombin, protein C and S
  2. An increase in platelets and coagulant factors - Factor VIII, Factor II, Factor V Leiden (increase activity due to activated protein C resistance) or myeloproliferative disorders causing excess of platelets.
43
Q

How do vessel wall and blood flow contribute to risk of thrombosis?

A

Little known about role of vessel wall in venous thrombosis. Many proteins active in coagulation are expressed on the surface of endothelial cells and their expression altered in inflammation (TM, EPCR, TF).

Blood flow contributes to both arterial and venous thrombosis. Stasis increases risk of thrombosis - surgery, pregnancy, long haul flight.

44
Q

How do acquired factors affect risk of venous thrombosis?

A

Genetic risk factors create a baseline elevated level of risk. An acquired risk factor can then push the cumulative risk above thrombotic threshold producing symptoms.

45
Q

How can venous thrombosis be prevented?

A
  1. Assess and prevent risks

2. Prophylactic anticoagulant therapy

46
Q

How can risk of recurrence of thrombosis be reduced?

A
  1. lower procoagulant factors e.g.: warfarin, DOACs

2. Increase anticoagulant activity e.g: heparin

Cardiorespiratory 2 (13 decks)

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