haemostasis - bleeding

Question 1

what is haemostasis and what is it for?

Answer 1

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

Question 2

what are the main parts of haemostasis?

Answer 2

in response to injury to the endothelial lining

vessel constriction

primary haemostasis (unstable platelet plug)

secondary haemostasis (stabilisation with fibrin)

fibrinolysis

Question 3

what is the mechanism of vessel constriction ofter injury?

Answer 3

Vascular smooth muscle cells contract locally

purpose:
Limits blood flow to injured vessel

Question 4

what is the mechanism of primary haemostasis?

Answer 4

Formation of an unstable
platelet plug

process:
platelet adhesion

platelet aggregation

purpose:
Limits blood loss +
provides surface for coagulation

Question 5

what is the mechanism of secondary haemostasis?

Answer 5

Stabilisation of the plug with fibrin

process:
blood coagulation

purpose:
Stops blood loss

Question 6

what is the mechanism of fibrinolysis?

Answer 6

Vessel repair and dissolution of clot

process:
Cell migration/proliferation & fibrinolysis

purpose:
Restores vessel integrity

Question 7

Why do we need to understand haemostatic mechanisms?

Answer 7

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

Question 8

what is the balance involved in haemostasis?

Answer 8

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

Question 9

how can the haemostatic balance be tipped towards bleeding?

Answer 9

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

2. increase in Fibrinolytic factors
   Anticoagulant proteins

Question 10

quick overview of primary haemostasis?

Answer 10

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

Question 11

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

Answer 11

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),

Question 12

how can platelet number be effected?

Answer 12

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

Question 13

what is immune thrombocytopenia purpura (ITP)?

Answer 13

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

Question 14

how can platelet function be affected?

Answer 14

Impaired function:

Hereditary absence of glycoproteins or storage granules (rare)

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

Question 15

what hereditary platelet defects may effect their function?

Answer 15

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

Question 16

how can aspirin and clopidogrel impair platelet function?

Answer 16

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

Question 17

what is the role of VWF in haemostasis?

Answer 17

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

Question 18

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

Answer 18

Platelets:
Thrombocytopenia
Drugs

Von Willebrand Factor:
Von Willebrand disease

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

Question 19

what are the clinical features of disorders of primary haemostasis?

Answer 19

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

Question 20

how do we test for disorders of primary haemostasis?

Answer 20

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)

Question 21

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

Answer 21

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

i) Prophylactic
ii) Therapeutic

Stop drugs e.g. aspirin/NSAIDs

Question 22

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

Answer 22

Immunosuppression (e.g. prednisolone)

Splenectomy for ITP

Question 23

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

Answer 23

Treat cause

Replace as necessary

Question 24

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

Answer 24

• 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)

Question 25

what is the role of coagulation/secondary haemostasis?

Answer 25

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

Question 26

what are some causes of disorders of coagulation?

Answer 26

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)

Question 27

what are hereditary coagulation disorders?

Answer 27

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

Question 28

what is haemarthrosis?

Answer 28

used to be The hallmark of haemophilia. spontaneous bleeding in joints is now treated prophylactically with factor VIII/IX replacement

Question 29

what are some differences between different coagulation factor deficiencies?

Answer 29

(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

Question 30

what are some causes of acquired coagulation disorders?

Answer 30

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

Question 31

what is DIC?

Answer 31

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

Question 32

what are the clinical features of coagulation disorders?

Answer 32

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

Question 33

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

Answer 33

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

Question 34

how do we test for coagulation disorders?

Answer 34

``` 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

Question 35

what clotting factors does PT show problems with?

Answer 35

VII, X, V, II, and fibrinogen (only VII is unique to PT) not affected in haemophilia extrinsic pathway

Question 36

what clotting factors does APPT show problems with?

Answer 36

XII, XI, X, IX, VIII, V, II, and fibrinogen. (XII,XI,IX and VIII are unique to APPT) so affected in haemophilia intrinsic pathway

Question 37

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

Answer 37

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

Question 38

how are missing coagulation factors replaced?

Answer 38

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

Question 39

what is a timeline of haemophilia treatment?

Answer 39

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 ```

Question 40

what are some novel treatments of haemophilia?

Answer 40

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 ```

Question 41

what may cause an increase in fibrinolytic factors?

Answer 41

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