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Yr2 Lily BRS CardioResp > haemostasis - bleeding > Flashcards

haemostasis - bleeding Flashcards

1
Q

what is haemostasis and what is it for?

A

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

use:
Prevention of blood loss from intact vessels

Arrest bleeding from injured vessels

enable tissue repair

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2
Q

what are the main parts of haemostasis?

A

in response to injury to the endothelial lining

vessel constriction

primary haemostasis (unstable platelet plug)

secondary haemostasis (stabilisation with fibrin)

fibrinolysis

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3
Q

what is the mechanism of vessel constriction ofter injury?

A

Vascular smooth muscle cells contract locally

purpose:
Limits blood flow to injured vessel

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4
Q

what is the mechanism of primary haemostasis?

A

Formation of an unstable
platelet plug

process:
platelet adhesion

platelet aggregation

purpose:
Limits blood loss +
provides surface for coagulation

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5
Q

what is the mechanism of secondary haemostasis?

A

Stabilisation of the plug with fibrin

process:
blood coagulation

purpose:
Stops blood loss

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6
Q

what is the mechanism of fibrinolysis?

A

Vessel repair and dissolution of clot

process:
Cell migration/proliferation & fibrinolysis

purpose:
Restores vessel integrity

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7
Q

Why do we need to understand haemostatic mechanisms?

A

Diagnose and treat bleeding disorders

Control bleeding in individuals who do not have an underlying bleeding disorder

Identify risk factors for thrombosis

Treat thrombotic disorders

Monitor the drugs that are used to treat bleeding and thrombotic disorders

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8
Q

what is the balance involved in haemostasis?

A

between fibrinolytic factors, such as anticoagulant proteins, and coagulant factors, such as platelets

too much fibrinolysis leads to bleeting

too much coagulation leads to thrombosis

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9
Q

how can the haemostatic balance be tipped towards bleeding?

A
  1. decrease in coagulant factors (eg. platelets)

Lack of a specific factor:
Failure of production (congenital and acquired)
Increased consumption/clearance

Defective function of a specific factor:
Genetic
Acquired - drugs, synthetic defect, inhibition

  1. increase in Fibrinolytic factors
    Anticoagulant proteins
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10
Q

quick overview of primary haemostasis?

A

adhesion:
platelets bind to VWF
via Gp1b
or directly yo the endothelial wall collagen via Gp1a

this stimulates release of ADP and thromboxane (from arachadonic acid) .these are the contents of platelet’s alpha and dense granules
it activates them

aggregation:
activates GpIIb/IIIa receptors on platelets
allows them to stick together with fibrinogen in between
this is the unstable platelet plug

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11
Q

what are the main components that can be effected in primary haemostasis?

A

platelets:
number
function

von willebrand factor:
Von Willebrand disease -
Hereditary decrease of quantity +/ function (common)
Acquired due to antibody (rare)

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),

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12
Q

how can platelet number be effected?

A

low number:
thrombocytopenia
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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13
Q

what is immune thrombocytopenia purpura (ITP)?

A

when there are antiplatelet autoantibodies present in the blood

these stick to sensitised platelets that have been produced by the bone marrow

this complex is then cleared by immune system macrophages

it is a common cause of thrombocytopenia

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14
Q

how can platelet function be affected?

A

Impaired function:

Hereditary absence of glycoproteins or storage granules (rare)

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

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15
Q

what hereditary platelet defects may effect their function?

A

missing surface glycoproteins:
GpIIb/IIIa (Glanzmann’s thrombasthenia)
GpIb (Bernard Soulier syndrome)

missing dense granules:
so no ADP required for aggregation
storage pool disease

Glanzmann’s thrombasthenia
Bernard Soulier syndrome
Storage Pool disease

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16
Q

how can aspirin and clopidogrel impair platelet function?

A

Antiplatelet therapy: widely used in the prevention and treatment of cardiovascular & cerebrovascular disease

aspirin and clopidogrel are the most commonly used antiplatelet drugs

aspirin revesibly blocks COX

this stops production of the prostaglandin Thromboxane A2 (from arachadonic acid)
this persists for about 7 days

clopidogrel irreversibly blocks the ADP receptor on platelets (P2Y12), so the ADP Induced conformational change in the GPIIb/IIIa can’t occur and fibrin can’t bind

these both prevent platelet aggregation

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17
Q

what is the role of VWF in haemostasis?

A

VWF has two functions in haemostasis:

Binding to collagen and capturing platelets

Stabilising Factor VIII
(Factor VIII may be low if VWF is very low)

VWD (disease) is usually hereditary (autosomal inheritance pattern):

Deficiency of VWF (Type 1 or 3)

VWF with abnormal function (Type 2)

without VWF the platelet plug cannot form

18
Q

what is a summary of possible causes of disorders of primary haemostasis?

A

Platelets:
Thrombocytopenia
Drugs

Von Willebrand Factor:
Von Willebrand disease

The vessel wall:
Hereditary vascular disorders
Steroids, age, vasculitis, scurvy

19
Q

what are the clinical features of disorders of primary haemostasis?

A

Typical primary haemostasis bleeding:
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

Thrombocytopenia – Petechiae

Purpura – platelet (thrombocytopenic purpura) or vascular disorders

Severe VWD – haemophilia-like bleeding (due to low FVIII)

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

20
Q

how do we test for disorders of primary haemostasis?

A

Platelet count, platelet morphology (needs electron microscopy)

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)

21
Q

what are the principles of treatment of primary haemostasis: Failure of production/function?

A

Replace missing factor/platelets e.g. VWF containing concentrates

i) Prophylactic
ii) Therapeutic

Stop drugs e.g. aspirin/NSAIDs

22
Q

what are the principles of treatment of primary haemostasis: Immune destruction?

A

Immunosuppression (e.g. prednisolone)

Splenectomy for ITP

23
Q

what are the principles of treatment of primary haemostasis: Increased consumption ?

A

Treat cause

Replace as necessary

24
Q

what are some other treatments of abnormal primary haemostasis (apply to primary and scondary haemostasis problems)?

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)
25
Q

what is the role of coagulation/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

26
Q

what are some causes of disorders of coagulation?

A

Deficiency of coagulation factor production:
Hereditary - Factor VIII/IX: haemophilia A/B

Acquired - 
Liver disease
Anticoagulant drugs*
(Warfarin
Direct Oral Anticoagulants (DOACs))

Dilution:
Acquired - Blood transfusion

Increased consumption:
Acquired -
Disseminated intravascular coagulation (DIC) – common
(Immune – autoantibodies – rare)

27
Q

what are hereditary coagulation disorders?

A

Haemophilia: failure to generate fibrin to stabilise platelet plug

Haemophilia A (Factor VIII deficiency)

Haemophilia B (Factor IX deficiency)
sex linked
1 in 10^4 births

Others are very rare (autosomal recessive)

Intramuscular injections should be
avoided in patients with haemophilia

28
Q

what is haemarthrosis?

A

used to be The hallmark of haemophilia.

spontaneous bleeding in joints

is now treated prophylactically with factor VIII/IX replacement

29
Q

what are some differences between different coagulation factor deficiencies?

A

(complete absence)

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

30
Q

what are some causes of acquired coagulation disorders?

A

More common in hospital practice

Liver failure – decreased production:
Most coagulation factors are synthesised in the liver

Anticoagulant drugs*

Dilution:
Red cell transfusions no longer contain plasma
Major haemorrhage requires transfusion of plasma as well as red cells and platelets

also DIC

31
Q

what is DIC?

A

Disseminated intravascular coagulation

Increased consumption

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

combined clotting and bleeding pattern

32
Q

what are the clinical features of coagulation disorders?

A

superficial cuts do not bleed (platelets work fine)

bruising is common, nosebleeds are rare

spontaneous bleeding is deep, into muscles and joints

bleeding after trauma may be delayed and is prolonged

Bleeding frequently restarts after stopping

33
Q

what are the differences between bleeding due to platelet and coagulation defects?

A

Platelet/Vascular:

Superficial bleeding into skin, mucosal membranes

Bleeding immediate after injury

Coagulation:

Bleeding into deep tissues, muscles, joints

Delayed, but severe bleeding after injury.
Bleeding often prolonged

either can be life threatening

34
Q

how do we test for coagulation disorders?

A 
Screening tests (‘clotting screen’):
Prothrombin time (PT) (extrinsic)

Activated partial thromboplastin time (APTT) (intrinsic pathway)

Full blood count (platelets)

Coagulation factor assays (for Factor VIII etc)

Tests for inhibitors

35
Q

what clotting factors does PT show problems with?

A

VII, X, V, II, and fibrinogen
(only VII is unique to PT)

not affected in haemophilia

extrinsic pathway

36
Q

what clotting factors does APPT show problems with?

A

XII, XI, X, IX, VIII, V, II, and fibrinogen.
(XII,XI,IX and VIII are unique to APPT)

so affected in haemophilia

intrinsic pathway

37
Q

what are the principles of treatment of abnormal haemostasis due to coagulation?

A

Failure of production/function:
Replace missing factor/platelets
i) Prophylactic
ii) Therapeutic

Stop drugs e.g. aspirin/NSAIDs

Increased consumption :
Treat cause
Replace as necessary

38
Q

how are missing coagulation factors replaced?

A

factor replacement therapy

Plasma (fresh frozen plasma FFP):
Contains all coagulation factors

Cryoprecipitate:
Rich in Fibrinogen, FVIII, VWF, Factor XIII

Factor concentrates:
Concentrates available for all factors except factor V.
Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X

Recombinant forms of FVIII and FIX are available:
‘On Demand’ to treat bleeds
Prophylaxis to prevent bleeds

39
Q

what is a timeline of haemophilia treatment?

A

1969:
Plasma-Derived Clotting Factors
Widespread viral contamination

1990s:
Currently Approved Recombinant Clotting Factors
FVIII, FIX, FVIIa
Improved Safety
Eliminated potential for transmission of blood borne pathogens

2008-present:
investigational therapies
Prolonged half-life (FVIII/FIX): Fc fusion, PEG, albumin fusion
Gene therapy
Novel agents
Bispecific antibody (Emicizumab)
Anti TFPI antibody
Antithrombin RNAi
40
Q

what are some novel treatments of haemophilia?

A

Gene therapy (Haem A and B)

Bispecific antibodies (Haem A)
Emicizumab
Binds to FIXa and FX
Mimics procoagulant function of FVIII

RNA silencing (Haem A and B)
Targets natural anticoagulant - antithrombin
41
Q

what may cause an increase in fibrinolytic factors?

A

Both of these are exceedingly rare except when induced by drugs:
tPA (stroke)
Heparin

Yr2 Lily BRS CardioResp (10 decks)

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