Session 6

Question 0

How are blood vessels important in successful Haemostasis?

Answer 0

Blood vessels constrict to limit blood loss

Particularly arteries

Mechanism is not fully understood

If vessel was partially (rather than completely severed), mechanism is not as effective - bleeding continues.

Question 1

What does Haemostasis mean and what does successful Haemostasis depend on?

Answer 1

Haemostasis is the body’s mechanism to stop bleeding and loss of blood.

Successful Haemostasis depends on:

• Vessel wall
• Platelets
• Coagulation system
• Fibrinolytic System (clot breakdown - control mechanism)

Question 2

What do platelets do?

Answer 2

Adhere to damaged vessel wall and to each other to form platelet plug

Question 3

What is the Platelet Release Action?

Answer 3

ATP –> ADP

ADP and thromboxane A2 cause platelet aggregation

5HT and Platelet Factor 3 are also released

Platelet Factor 3 is important in stimulating coagulation cascade.

Platelets coalesce after aggregation.

Question 4

Describe Coagulation briefly

Answer 4

Amplification cascade

Series of inactive converted to active components.

Prothrombin is activated into Thrombin which activates Fibrinogen which becomes Fibrin which forms the clot.

1ml of blood can generate enough thrombin to convert all the fibrinogen in the body to fibrin therefore tight regulation is required.

Question 5

What balance of forces does Haemostasis represent?

Answer 5

An active ongoing balance of procoagulant and anticoagulant forces.

Maintenance of that balance is essential.

If the balance tips in favour of the anticoagulant forces, there will be excessive bleeding e.g. Haemophilia

If the balance tips towards the procoagulant forces, thrombosis will occur.

Question 6

Discuss the regulation of the coagulation system

Answer 6

Thrombin positively feeds back on Factors V, VIII and XI

Thrombin inhibitors: Anti-thrombin III, Alpha 1 anti-trypsin, Alpha 2 macroglobulin, Protein C and S

Alpha 1 anti-trypsin and Alpha 2 macroglobulin are wandering anti-proteases - non-specific

An inherited deficiency of anti-thrombin III or Protein C and S may lead to thrombophilia (blood is more inclined to clot) and thrombosis because their mechanism is specific

Question 7

What is Fibrinolysis?

Answer 7

Clog breakdown; breakdown of fibrin by Plasmin

Plasminogen activators are required to convert Plasminogen –> Plasmin.

Fibrinolytic therapy is widely used e.g. streptokinase which activated Plasminogen and tPA.

They are known as clot/thrombus busters.

This is a very drastic treatment used only in a serious situation e.g. Coronary artery occlusion or thrombus cutting off circulation to a limb.

Question 8

What does endothelium (flat lining of blood vessels) produce?

Answer 8

Anti-thrombotic factors:

Plasminogen activators

Prostacyclin

Nitric Oxide

Thrombomodulin

Question 9

What is Thrombosis?

Answer 9

The formation of a solid mass of blood within the circulatory system during life (post-mortem clotting is not thrombosis)

Question 10

Why does Thrombosis occur?

Answer 10

Virchow’s Triad

1. abnormalities of the vessel wall: atheroma (commonest cause), direct injury, inflammation (vasculitis - some autoimmune disorders)
2. abnormalities of blood flow: stagnation, turbulence
3. abnormalities of blood components: smokers’ blood is hyper-coagulative, post-partum (after birth), post operation and after major trauma

Question 11

Thrombin can form in any vessel. Describe the appearance of arterial thrombi (with fast flowing blood)

Answer 11

Pale Granular

Lines of Zahn (lamination - vertical lines)

Tend to have less RBCs (lower cell count)

Question 12

Describe the appearance of venous thrombi

Answer 12

Soft

Gelatinous

Deep red

Higher RBC cell count

Question 13

What are the 5 outcomes of thrombosis?

Answer 13

Lysis

Propagation

Organisation

Recanalisation

Embolism

Question 14

Describe the Lysis outcome of Thrombosis

Answer 14

Complete dissolution of the thrombus by active fibrinolytic system.

Blood flow re-established.

This is most likely when thrombi are small.

Aim of thrombolytic treatment is to achieve lysis

Question 15

Describe the Propagation outcome of Thrombosis

Answer 15

Progressive spread of thrombosis

Distally in arteries

Proximally in veins

Thrombosis gets bigger in diameter as it spreads further

Question 16

Describe the Organisation outcome of Thrombosis

Answer 16

Reparative process with ingrowth (development) of fibroblasts (new connective tissue) and capillaries (similar to granulation tissue)

Lumen remains obstructed and blocked

Question 17

Describe the Recanalisation outcome of Thrombosis

Answer 17

Blood flow re-established but usually incompletely.

One or more channels formed through organising thrombus (more than 1 lumen)

Not as effective as completely dissolving a thrombus

Question 18

Describe the Embolism outcome of Thrombosis

Answer 18

Part of thrombus breaks off and travels through bloodstream.

Lodges at distant site e.g. Coronary artery –> Myocardial Infarction.

Question 19

Describe the effects of arterial thrombosis

Answer 19

Ischaemia Infarction

Depends on site and collateral circulation - the effect of thrombosis will be less if the tissue has collateral circulation.

In an end artery e.g. In the retina, there is no collateral circulation so a thrombus could cause loss of vision.

Question 20

Describe the effect of venous thrombosis

Answer 20

Congestion

Oedema

Ischaemia Infarction

Normally thrombi in the veins do not cause infarction and Ischaemia but if tissue pressure rises (due to oedema) to become greater than arterial pressure, there is no blood flow which leads to ischaemia and infarction.

Question 21

What is an embolism?

Answer 21

Blockage of a blood vessel by solid, liquid or gas at a site distant from its origin

Question 22

What are the different types of emboli?

Answer 22

>90% of emboli are thrombo-emboli. Most common thrombo-emboli is Deep Vein Thrombosis.

Other types:

Air (e.g. From a cut throat, when a large vein has been severed so air is drawn into the circulation and blood is frothy)

Amniotic fluid

Bubbles of nitrogen (occurs in rapid decompression, divers get the ‘bends’)

Medical equipment e.g. From an artificial heart valve

Malignancy cells (tumour cells) - produces substances that make blood hyper-coagulative.

Question 23

What are the different types of Thromboembolisms?

Answer 23

From Systemic veins: pass to the lungs (pulmonary emboli) as they will not get stuck in the large veins near the heart. The next time the emboli meets a vessel smaller than itself where it can get stuck is the lung.

From the Heart: thrombus is more common in left side of the heart so from the heart passes via the aorta to renal, mesenteric and other arteries anywhere in the body

From atheromatous carotid arteries, pass to the brain via cerebral arteries –> stroke or transient ischaemic attack

From atheromatous abdominal aorta travelling to arteries of the legs.

Question 24

What are the predisposing factors for Deep Vein Thrombosis (common clinical example of thrombosis)?

Answer 24

Immobility/bed rest

Post-operative

Pregnancy and post partum (blood is hyper-coagulable)

Oral contraceptives

Severe burns

Cardiac failure

Disseminated cancer

Question 25

How can DVT be prevented?

Answer 25

High risk patients must be identified and offer prophylaxis (anticoagulant heparin - subcutaneously - often given to the abdominal wall; leg compression during surgery - e.g. Intermittently compressing the calves improves venous return to reduce risk of thrombosis)

Question 26

How do you treat DVT?

Answer 26

DVT can be treated with intravenous heparin (anti-coagulant, co-factor for anti-thrombin III) and oral warfarin (anti-coagulant, interferes with synthesis of Vitamin K dependent clotting factors - Vitamin K antagonist, slow effect).

Can put a filter/shield in the inferior vena cava to stop thrombi reaching the heart

Oral warfarin is also known as rat poison and is teratogenic so can only be given to pregnant women after the first trimester.

Question 27

What are the effects of Pulmonary Embolism?

Answer 27

Massive PE > 60% reduction in blood flow is rapidly fatal

Major PE - Medium sized vessels become blocked. Patients develop shortness of breath, +/- cough, blood stained sputum

Minor PE - small peripheral pulmonary arteries blocked. Asymptomatic or minor shortness of breath.

Recurrent minor PEs block off small parts of the circulation - leads to pulmonary hypertension.

A saddle embolus blocking the pulmonary trunk impairs the function of the heart which leads to death.

Question 28

What is the major physiological initiator of coagulation activation?

Answer 28

Tissue factor released at the site of tissue damage.

This is key in localising clot formation to the site of injury.

Question 29

Thrombin is a key enzyme because…

Answer 29

Acts in a feedback loop to activate several of the other coagulation factors (XI, VIII, V) and is therefore pivotal in the amplification system

It activates platelets through a specific receptor, ensures clot stabilisation by activating Factor XIII and helps to address the degree of clot formation by activating the natural anticoagulant, activated Protein C.

Question 30

What does the liver have to do with the coagulation cascade?

Answer 30

Almost all of the coagulation factors and inhibitors are synthesised in the liver. Liver disease is therefore a cause of abnormal bleeding.

Question 31

What do Factors II, VII, IX and X require?

Answer 31

Vitamin K for post-translational modification into their active forms,

Question 32

Coagulation inhibitors limit the extent of clotting and protect shading vessel occlusion especially in veins: Describe the roles of Proteins C and S

Answer 32

Proteins C and S require Vitamin K for their complete synthesis in the liver.

Protein C requires a cofactor, Protein S, for full activity.

When activated, Protein C inhibits activated factors V and VIII

Protein C requires thrombin bound to an endothelial protein, Thrombomodulin for its activation. Thrombin therefore not only acts to promote fibrin formation but also has a crucial role as part of a negative feedback loop to limit clot formation.

Question 33

Coagulation inhibitors limit the extent of clotting and protect shading vessel occlusion especially in veins: Describe the role of Antithrombin

Answer 33

Antithrombin acts at several sites to inhibit activated coagulation factors.

Antithrombin requires glycosaminoglycan ‘heparans’ present on the vascular endothelial cell surface for full inhibitory activity.

In clinical practice, the glycoasminoglycan heparin which enhances the inhibitory activity of Antithrombin several thousand fold is used as an anticoagulant.

Question 34

Coagulation inhibitors limit the extent of clotting and protect shading vessel occlusion especially in veins: Describe the roles of tissue factor pathway inhibitor

Answer 34

Acts early in the process of coagulation cascade, inhibiting both activated factors VII and X

Question 35

What are the two principal laboratory tests to assess coagulation?

Answer 35

Activated Partial Thromboplastin Time (APTT): the intrinsic pathway is activated in the test tube. Phospholipid is added to substitute for the role of platelets in coagulation.

The APTT therefore involves all clotting factors other than Factor VII and Factor XIII

Prothrombin Time (PT): tissue factor and phospholipid are added. The PT therefore assesses Factors VII, V, X, II and fibrinogen only.

Question 36

Describe Arterial Thrombosis (the process)

Answer 36

At its earliest phase, the atheromatous plaque may consist of a slightly raised fatty streak on the intimal surface of an artery.

With time, the plaque enlarges and protrudes into the lumen, causing a degree of turbulence in the blood flow.

This turbulence eventually causes loss of intimal cells and the denuded plaque surface is present to the blood cells including platelets -exposure of collagen.

The turbulence itself will predispose to fibrin deposition and to platelet clumping as platelets settle on the exposed collagen surface.

Thus the first layer of the thrombus is a platelet layer. This leads to precipitation of a fibrin meshwork, in which red cells are trapped, and a layer of this meshwork is developed on top of the platelet layer.

This complex structure now protrudes even further into the lumen, causing more turbulence and forming the basis for further platelet deposition.

Thrombi will grow in the direction of the turbulent blood flow (propagation)

Question 37

Describe Venous Thrombosis (the process):

Answer 37

Most thrombi seem to begin at valves which naturally produce a degree of turbulence because they protrude into the lumen and they may be damaged by trauma, stasis (slow-flowing blood) and occlusion.

Since normal flow is laminar, most of the blood cells are kept away form diseased walls or damaged vein valves.

However if the blood pressure fell during surgery or following an MI, then flow is slower through the vessels and thrombosis becomes a likely event.

Similarly the venous return from the legs is very reliant upon calf muscle contraction and relaxation which massages the veins and because of the valves, tends to return the blood upwards.

Question 38

What organelles do platelets contain?

Answer 38

Alpha granules contain several substances involved in the process of platelet adhesion to damaged vessel walls (fibrinogen, fibronectin, platelet growth factor and antiheparin).

Dense granules contain substances such as ADP that causes the platelets to aggregate

Question 39

What happens when platelets are activated and how are they activated?

Answer 39

Platelets are activated and the contents of their granules are released when the platelets come into contact with collagen or with polymerising fibrin.

The platelets form a mass that covers the vessel wall defect until the endothelial cells have regenerated and repaired the vessel permanently. H

owever if this process is activated within an intact vessel, it results in a thrombus.

Question 40

Describe Fat embolism

Answer 40

Usually arises following severe trauma with fracture to long bones, extensive soft tissue injury or severe burns.

With extensive bone fractures it is possible that fat from the bone marrow is released into the circulation and comes to lodge in various organs.

However it is also possible that systemic effects of trauma, particularly in burns, can cause changes in the stability of fat held in micelles suspension resulting in free fat appearing in the circulation.

Rash, shortness of breath, confusion

Question 41

Describe Tumour Embolism

Answer 41

Usually small and break off as tumours that penetrate vessels.

They do not usually cause immediate physical problems in a way that other emboli do but this mechanism is a major route of dissemination of malignancies through the body (metastasis)

Question 42

Describe embolism of foreign matter

Answer 42

Particles of foreign matter may contaminate fluids injected intravenously.

They elicit a Granulomatous reaction in the organs in which they lodge; they are often prominent in liver biopsies taken to assess the activity of hepatitic viral damage in drug abusers.

Question 43

Describe Amniotic embolism

Answer 43

With the vastly increased pressures in the uterus during labour, amniotic fluid may be forced into the maternal uterine veins.

These amniotic fluid emboli travel in the circulation and lodge in the lungs, causing respiratory distress like other pulmonary emboli.

They can recognised histologically because they contain the shed skin cells of the infant.

Question 44

Describe Cerebral embolism

Answer 44

Atrial fibrillation –> stasis –> thrombus

If in left heart, can go to the brain and cause a stroke or transient ischaemic attack

Question 45

Describe Iatrogenic embolism

Answer 45

Embolism due to medical treatment e.g. Embolism from an injection

Question 46

Describe Nitrogen embolism

Answer 46

Nitrogen bubbles form in the blood with rapid decompression

The ‘bends’ (decompression sickness)

Question 47

What is Disseminated Intravascular a Coagulation (DIC)?

Answer 47

Pathological activation of coagulation mechanisms that happen in response to a variety of diseases

Small clots form throughout the body, disrupting normal coagulation as they use up all the clotting factors

Abnormal bleeding occurs from the skin

Triggers: infection, trauma, liver disease, obstetric complications

Question 48

What is Haemophilia?

Answer 48

X linked recessive so more common in boys

Deficiencies in different clotting factors (A= Factor VIII, B = Factor IX)

Can be mild, moderate or severe due to various mutations

Due to a nonsense point mutagion

Haemorrhage into major joints, synovial hypertrophy, pain

Muscle bleeding causes pressure and necrosis of nerves (painful)

Can haemorrhage into retroperitoneum/urinary tract

Treat with self-administered factor replacement therapy

Question 49

What is Thrombocytopenia?

Answer 49

Platelet count is way below the reference range

Due to either: failure of platelet production, increase in platelet destruction, sequestering of platelets

Usually accompanied by a bone marrow dysfunction, e,g, leukaemia, anaemia

If it is due to sequestering, cause may be DIC

Question 50

A patient of 16 has extensive bruising at multiple sites. He was well apart from a viral illness a week previously. His blood count shows an extremely low platelet count. What could be the cause?

Answer 50

• Idiopathic thrombocytopenic purpora (ITP) is an autoimmune disease affectign platelets. Antibodies are made against platelets and once attached to platelets, the platelets do not work as well and are almost removed from the spleen very quickly because they are abnormal.
• Cause is not clear - something to do with the immune system
• Many people have no symptoms but symptoms can include bruising, purple rash and occasionally bleeding. The condition often occurs about 2-3 weeks after an infection (often a common viral infection).
• Symptoms disappear over 6-8 weeks in most cases - it is a temporary immune reaction that lasts several weeks only and then symptoms go.
• Very occasionally it causes severe bleeding which results in emergency treatment.
• But in a few cases the immune system continues to be faulty and the condition becomes long-standing.