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Y2 - BRS - CVR > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

What is 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 for?

A

Prevent blood loss from intact vessels
Arrest bleeding from injured vessels
Enable tissue repair

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3
Q

What are the stages of haemostasis?

A

Primary - vessel constriction and formation of unstable platelet plug

Secondary - stable platelet plug

Fibrinolysis - vessel repair and breakdown of blood clot

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4
Q

What is the mechanism of haemostasis?

[4 steps]

A

Vessel constriction = limits blood flow to site of injury

Formation of an unstable platelet plug = platelet adhesion, platelet aggregation, limits blood loss and provides surface for coagulation

Stabilisation of plug with fibrin = blood coagulation to stop blood loss

Vessel repair and dissolution of clot = cell migration / proliferation and fibrinolysis to restore vessel integrity

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5
Q

Why is it important 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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6
Q

What is the balance model of coagulation?

A

Normal haemostasis = delicate balance between bleeding and thrombosis

Equilibrium established between thrombosis factors (coagulant factors and platelets) and bleeding factors (fibrinolytic factors and anticoagulant proteins)

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7
Q

Why might the balance be tipped towards the bleeding side of the scale? (i.e. more bleeding occuring that thrombosis)

A

Lack of a specific factor e.g. failure of production OR increased consumption / clearance

Defective function of a specific factor - can be genetic or acquired (drugs, synthetic defect, inhibition)

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8
Q

What occurs in primary haemostasis?

A

3 main factors: platelets, VWF, and vessel wall

Damage to endothelium of vessel = exposure of collagen (in the vessel wall)

Platelets can attach directly to the collagen via the glycoprotein 1A (GlpIa) receptor
OR
Through a viable Von Willebrand Factor via Glp1b receptor

Platelets release their granular contents, which combine with thromboxane = activated platelets

Leads to activation of GlpIIb and GlpIIIa receptors on the platelets

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9
Q

Which 3 factors affected can cause disorders of primary haemostasis?

A

Primary haemostasis requires 3 main factors: platelets, VWF, and vessel wall

So if either of these 3 is in low production or not working, it can lead to primary haemostasis disorders

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10
Q

What is a low platelet count known as?

What causes low platelets?

A

Thrombocytopenia

  1. Production issue: bone marrow failure e.g. leukaemia, B12 deficiency
  2. Accelerated clearance issue: eg: immune thrombocytopenic papura (ITP), Disseminated Intravascular Coagulation (DIC)
  3. Pooling and destruction in an enlarged spleen (splenomegaly has many causes)
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11
Q

What is ITP?

A

Common cause of thrombocytopenia

Immune thrombocytopenic purpura = immune system forms antiplatelet autoantibodies

AutoAbs = bind to sensitised platelets

Platelets cleared by macrophages

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12
Q

What causes impaired function of platelets leading to primary haemostasis?

A
  1. Hereditary: absence of glycoproteins or storage granules (rare)
  2. Acquired due to drugs: aspirin, NSAIDs, clopidogrel (common)
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13
Q

What are conditions that impaired platelet function?

A

Glanzmann’s thrombasthenia = absence of GlpIIa and GlpIIIa receptors

Bernard Soulier syndrome = absence of GlpIb receptors

Storage Pool disease = group of disorders refering to reduction in granular content in the platelets

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14
Q

How can drugs impair the function of platelets?

A

Antiplatelet therapy, e.g. Aspirin, often used in treatmment of CVD

Aspirin blocks the cyclo-oxygenase enzyme to prevemt thromboxane production from arachidonic acid

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15
Q

What are the two functions of VWF?

A

Binding to collagen and capturing platelets

Stabilising co-agulation Factor VIII

Factor VIII may be low if VWF is very low

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16
Q

Why may VWF be reduced leading to primary haemostasis?

A

Low VWF is called Von Willebrand disease (VWD)

1: Hereditary: decrease of quantity +/ function (common)
2: Acquired due to antibody (rare)

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17
Q

What hereditary pattern is VWD?

A

Autosomal inheritance pattern

Hereditary VWD is cassified into types:
Types 1 and 3 lead to deficiency of VWF
Type 2 leads to VWF with abnormal function

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18
Q

How can the vessel wall be affected to cause primary haemostasis?

A

1: Inherited (rare) - abnormalities e.g. Hereditary haemorrhagic telangiectasia, Ehlers-Danlos syndrome and other connective tissue disorders
2: Acquired (common): steroid therapy, ageing (senile purpura), vasculitis, scurvy (Vit C deficiency)

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19
Q

Summary of Disorders of Primary Haemostasis:

A
  1. Platelets: thrombocytopenia; drugs
  2. VWF - VWD
  3. Vessel wall - hereditry vascular disorders; steroids, age, vaculitis, scurvy
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20
Q

What are the clinical features of 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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21
Q

What common feature is seen in patients with thrombocytopenia?

A

Petechiae and purpura (bleeding under the skin)

Purpura = does not blanch under pressure

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22
Q

What does purpura only (no petechiae) indicate clinically?

A

Platelet (thrombocytopenic purpura) or vascular disorders

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23
Q

Why might VWD (von willebrand disease) cause haemophilliac-like bleeding?

A

Low FVIII

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24
Q

What are tests for disorders of primary haemostasis?

A

Platelet count, platelet morphology (electron microscpe used)

Bleeding time (now replaced with platelet function analysis in lab)

Measure levels and functions of of von Willebrand Factor (VWF)

Clinical observation

Note – coagulation screen (PT, APTT) is normal in disorders of primary haemostasis so cannot conclusively be used for a diagnosis (except more severe VWD cases where FVIII is low)

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25
Q

What are the typical ranges for platelet counts?

[x10^9]

A

150 - 400 = normal range

<100 = bleeding with trauma

<40 = spontaneous bleeding

<10 = severe spontaneous bleeding

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26
Q

What are the treatments if it is failure of production leading to primary haemostasis disorder?

A

Replace missing factor/platelets e.g. VWF containing concentrates can be used for prevention and treatment

Stop drugs e.g. aspirin/NSAIDs

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27
Q

What are treatments for immune destruction?

A

Immunosuppression via steroids (e.g. prednisolone)

Splenectomy for ITP

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28
Q

What are treatments for increased consumption?

A

Treat the underlying cause

In the meatime - continue with replacement therapy

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29
Q

What are some 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 (i.e. stops blood clots from breaking down)
  • Fibrin glue/spray used in surgery
  • Other approaches e.g hormonal (oral contraceptive pill for menorrhagia)
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30
Q

What is secondary haemostasis?

A

Coagulation of blood

By stabilising the platelet plug from primary haemostatic using fibrin

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31
Q

What are the causes of disorders of coagulation (secondary haemostasis)?

A

Coagulation generates thrombin (IIa), which then converts fibrinogen to fibrin

So deficiency in any of the coagulation factors result in failure of thrombin production and so fibrin formation

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32
Q

How can the balance between thrombosis and bleeding be tipped to cause bleeding?

A

An increase in fibrinolytic factors or anticoagulant proteins

A decrease in coagulation factors

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33
Q

What are the causes of coagulant factor deficiences?

A
  1. Hereditary deficiency of coagulation production e.g. Factor VIII/IX: haemophilia A/B
  2. Acquired deficiency of coagulation production e.g. liver disease, anticoagulant drugs, warfarin, direct Oral Anticoagulants (DOACs)
  3. Dilution e.g. blood transfusions
  4. Increased consumptions e.g. Disseminated intravascular coagulation (DIC) – common
    (Immune – autoantibodies – rare)
34
Q

What are some examples of inherited coagulation disorders?

How does it lead to bleeding?

A 
Haemophilia A (Factor VIII deficiency)
Haemophilia B (Factor IX deficiency)
sex linked
1 in 10^4 births
Others are very rare (autosomal recessive)

Although the platelet plug is formed, due to missing coagulation factors, fibrin cannot be formed so the unstable platelet plug breaks apart - leads to bleeding

35
Q

What is a characteristic clinical feature of haemophilia?

A

Haemarthrosis = spontaneous joint bleeding

Can lead to joint deformity and myscle wasting

36
Q

What should be avoided in patients with haemophilia?

A

Intramuscular injections - leads to extensive haematoma

37
Q

Why are different coagulation factor deficiencies not all the same in terms of symptoms and quality of life?

What are the differences between absence of:
Factor VIII and IX (haemophilia)
Prothrombin (Factor II)
Factor XI
Factor XII
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

38
Q

Why does liver failure cause coagulation disorders?

A

Most coagulation factors are synthesised in the liver

Except VWF (synthesised in the endothelial cells lining the vessels) and Factor V (synthesised in platelets)

39
Q

Why does dilution produce coagulation disorders?

A

Red cell transfusions no longer contain plasma

Major haemorrhage requires transfusion of plasma as well as red cells and platelets

40
Q

What are the features of increased consumption e.g. in DIC?

A

Generalised rather than localised activation of coagulation – tissue factor comes into contact with factorVIIa leads to widespread and unregulated activation of coagulation

Can be triggered by e.g. 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 and sheering of blood vessels

41
Q

How is DIC treated?

A

Increased consumption issue

So replacement therapy with fresh plasma transfers until underlying cause is found and treated

42
Q

What are the clinical features of coagulation disorders?

A

Superficial cuts do not bleed (platelets are working fine and platelet plug does not need stabilsing)

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

43
Q

So what is the difference in bleeding in primary haemostasis compared to secondary haemostasis (coagulation)?

A

Platelet/Vascular = superficial bleeding into skin, mucosal membranes; bleeding immediate after injur

Coagulation - bleeding into deep tissues, muscles, joints; delayed but severe bleeding after injury; prolonged bleeding

44
Q

What are the tests for coagulation disorders?

A

Screening tests (‘clotting screen’):
Prothrombin time (PT)
Activated partial thromboplastin time (APTT)
Full blood count (platelets)

Coagulation factor assays (for Factor VIII etc)

Tests for inhibitors

45
Q

What could cause prolonged APTT but normal PT?

What may cause prolonged PT but normal APTT?

What may cause prolonged PT and APTT?

A 
Prolonged APTT, normal PT:
Haemophilia A
Haemophilia B
Factor XI deficiency 
Factor XII deficiency

Prolonged PT, normal APTT:
Factor VII deficiency

Prolonged PT, prolonger APTT:
Liver disease
Anticogulant drugs 
DIC
Dilution following RBC transfusion
46
Q

What are the different types of factor replacement therapy?

A

Fresh Frozen Plasma - contains all coagulation factors

Cryoprecipitate - rich in fibrinogen, FVIII, VWF, FXIII

Factor Concentrates - available for all factors except V (so prothrombin complex concentrates, FII, FVII, FIX, FX)

Recombinate forms of FVIII and FIX - good for ‘on demand’ to treat bleeds, and to prevent bleeds

47
Q

How common is an increase in fibrinolytic factor and anticoagulant factors that lead to bleeding disorders?

A

V. rare

Bleeding disorders caused by increased fibrinolytic factors and anticoagulant proteins are usually due to drugs: tPA (used to bust clots in strokes) or heparin

48
Q

What is meant by thrombosis?

A 
Intravascular coagulation
Inappropriate coagulation
Venous or arterial
Obstructs flow
May embolise to lungs
49
Q

What are the 2 main venous disorders of thrombosis?

And how do they present clinically?

A 
Pulmonary embolism (PE) =
Tachycardia
Hypoxia
Shortness of breath
Chest pain
Haemopysis
Sudden death 
Deep Vein Thrombosis (DVT) = 
Painful leg
Swelling
Red
Warm
May embolise to lungs
Post thrombotic syndrome - longstanding pain and swelling
50
Q

What are 2 main arterial disorders of thrombosis?

A

MI

Cerebral vascular disease - stroke

51
Q

What is Virchow’s triad?

A

Considers 3 contibutory factors to thrombosis:

Changes in the blood = dominant in venous thrombosis

Changes in vessel wall = dominant in arterial thrombosis

Changes in blood flow (in particular slowing) = contributes to both thromboses

52
Q

What is thrombophilia?

How might it present clinically?

A

Increased risk of venous thrombosis due to imbalance in clotting factors - can be genetic or acquired

Thrombosis at young age
‘spontaneous thrombosis’ - unprovoked e.g. after sugery, pregnancy etc.
Multiple thromboses
Thrombosis whilst anti-coagulated

53
Q

What are examples of anticoagulant proteins?

A

Antithrombin
Protein C
Protein S

54
Q

What may cause the thrombosis bleeding balance to tip towards thrombosis?

A

Decrease in anticoagulant factors
OR
Increase in coagulant factors

55
Q

What is the role of the vessel wall in thrombosis?

A

Many proteins active in coagulation are expressed on the surface of endothelial cells and their expression is altered in inflammation (TM, EPCR, TF)

56
Q

What is the role of blood flow in thrombosis?

A

Reduced flow (stasis) increases risk e.g. surgery, long flight, pregnancy

57
Q

What are the risk factors for venous thrombosis?

A

Age
Genetics
Environment

Interactions between all 3 of these

58
Q

How can you prevent venous thrombosis?

A
  1. Prevention - thromboprophylaxis = especially during times of high risk
  2. Reduce risk of recurrence / extension - lower procoagulant factors e.g. warfarin, DOACs; increase anticoagulant activity e.g. heparin
59
Q

When is therapeutic anticoagulation used?

A

Venous thrombosis:
Initial treatment to minimise clot extension/embolisation (< 3 months)
Long term treatment to reduce risk of recurrence

Atrial fibrillation:
To reduce risk of embolic stroke

Mechanical prosthetic heart valve: reduce thrombosis risk

60
Q

When is thromboprophylaxis (preventative) used?

A

E.g. following surgery, during hospital admission, during pregnancy

61
Q

What is heparin?

Where is it found naturally?

What are the different types of heparin used in the UK and where are they administered?

A

Naturally occurring glycosaminoglycan

Produced by mast cells of most species

Porcine products used in UK

Varying numbers of saccharides in chains of heparin – differing lengths:

  1. Long chains = Unfractionated (UFH) – intravenous administration, short half life
  2. Low molecular weight (LMWH) – subcutaneous administration
62
Q

How does unfractionated heparin work?

A

Enhances the effects of antithrombin

Changes active site of antithrombin = when the pentasaccharide sequence on the unfractionated heparin binds to the antithrombin, it gives it a far greater affinity for its target proteases (FXa and thrombin)

This allows the antithrombin to bind more securely and more quickly to thrombin and FXa leading to their inactivation

For the inactivation of thrombin, heparin binds and wraps itself around antithrombin and thrombin

But for the inactivation of FXa, heparin only binds itself to antithrombin

63
Q

How does low molecular weight heparin (LMWH) work?

A

Predominantly works against FXa

Shorter chains in the LMWH are not long enough to wrap around antithrombin AND thrombin

64
Q

What is the effect of unfractionated heparin on the APTT test?

A

Prolongation of APTT - exponential increase in APTT time (s)

So APTT can be used to monitor a patient on unfractionated heparin

65
Q

Why is the APTT test not used to monitor LMWH?

A

The APTT time is more predictable, it only increases slightly and steadily

Instead, measure anti-Xa to monitor LMWH

66
Q

How does Warfarin work?

A

Vitamin K antagonist - competes with Vitamin K

It blocks the recycling of vitamin K, and so enzymes dependent on vitamin K (e.g. vitamin K dependent carboxylase) no longer function for the activation of FII, FVII, FIX, FX, Protein C and Protein S

Therefore warfarin reduced the production of functional coagulation factprs and induces an anticoagulated state slowly

67
Q

What are the issues with administering Warfarin?

A

Has a very complicated metabolism = many dietary, physiological and drug interactions to keep in mind

This narrows the therapeutic index and requires monitoring

68
Q

How can the effects of Warfarin be reversed?

A

Reversed slowly by Vit K administration – takes several hours to work

Reversed rapidly by infusion of coagulation factors:

PCC (Prothrombin Complex Concentrate- contains Factors II, VII, IX and X)

FFP (Fresh Frozen Plasma)

69
Q

What is the order of half-lives, shortest to longest, of the factors: II, VII, IX, X?

[i.e. after the administration of wafarin, which factors fall from the fastest to the slowest?]

A

Shortest

FVII
FIX
FX
FII

Longest

70
Q

What are side effects of Warfarin?

A

Bleeding:
Minor 5%
Major 0.9 – 3.0%
Fatal 0.25%

Skin Necrosis - due to severe protein C deficiency (as Protein C has a shorter half life than the clotting factors, it falls before the warfarin has an effect on the clotting factors)

Purple toe syndrome - disrupted atheromatous plaques bleed = cholesterol emboli lodge in extremities

Embryopathy – Early fusion of epiphyses, warfarin is teratogenic (cause abnormal fetal growth) in 1st trimester Chondrodysplasia punctata

71
Q

How do you monitor warfarin?

A 
Calculate INR (from PT)
Un-anticoagulated normal INR = 1.0
Target with warfarin = 2-3

Can also use the ISI = International Sensitivity Index, this indicates the sensitivity of a particular thromboplastin for warfarin

72
Q

What can cause resistance to warfarin?

A

Lack of patient compliance

Dietary factors e.g. increased Vit K intake

Other drug interactions - may ead to increased metabolism of warfarin

Reduced binding

73
Q

What is DOAC?

A

Direct Oral Anticoagulant

Can directly interact with factors

e. g. Rivaroxaban, Apixaban, Edoxaban = inhibit FXa
e. g. Dabigatran = inhibit FIIa

74
Q

How do Warfarin and DOACs compare?

A 
Drug: Warfarin | DOACs
Onset: slow | rapid
Dosing: variable (monitor using INR) | fixed
Food effect: yes | no
Interactions: many | few
Monitoring required: yes | no
Renal dependence: no | some 
Reversibility: Vit K / PCCs | few specific antidotes available (expensive)
75
Q

What is the initial treatment for a venous thrombosis?

A

DOAC or LMWH for first few days
To minimise clot extension (< 3 months)
Then give warfarin or DOAC

76
Q

What is the long term treatment to reduce risk of recurrence?

A

DOAC or warfarin

77
Q

What is the treatment for AF?

A

DOAC or warfarin - reduces risk of stroke

78
Q

What is the long term treatment for mechanical prosthetic heart valves?

A

Warfarin (DOACs not effective and should be avoided)

79
Q

What treatment is given following surgery?

A

LMWH or DOAC

80
Q

What treatment is given during pregnancy?

A

LMWH (DOACs not safe in pregnancy)

Y2 - BRS - CVR (21 decks)

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