Week 3 - C - Bleeding disorders - Primary&Secondary Haemostasis - Vascular/Platelet (reduction/destruction)/V.W.D - DIC/Liver/VitK/Hameophilia

Question 1

What are the components of the normal haemostatic system?

Answer 1

* Formation of platelet plug - primary haemostasis * Formation of fibrin clot - secondary haemostasis * Fibrinolysis * Anti-coagulant defenses This is the 4 main stages of haemostasis (not homeostasis) Once a clot is formed we start breaking it down almost immediately (fibrinolysis)

Question 2

When there are problems with haemostasis, it is mainly due to primary or secondary haemostasis failure What is primary haemostasis again? (How does it occur)

Answer 2

Endothelial damage occurs IN response collagen and vWF are exposed on the endothelial surface and these cause platelet adhesion to the site of injury When the platelets adhere, they release chemicals which cause other platelets to come to the site of injury and this is known as platelet aggregation

Question 3

Once formed platelet plug this is secondary haemostasis, clotting factors come to the positively charged platelet surface (due to the calcium on it) What is the internal pathway? What is the external pathway?

Answer 3

The internal pathway is where thrombin acts to amplify the clotting cascade by feeding back to increase Factors VIIIand IX (Factors VIII,IX,XI,XII) The external pathway is where there is tissue factor released from the site of damage which promotes factor VII activation (Factors VII,V,X,II)

Question 4

What are the different categories of the causes of primary haemostasis failure again?

Answer 4

Vascular causes - vessel wall - eg endothelial injury or collagen deficiency Platelets - there is a reduced number of reduced function Von willebrand disease

Question 5

What are the symptoms of primary haemostasis failure?

Answer 5

Symptoms - generalized bruising and purpura Epsitaxis, GI bleeds, conjunctival bleeds (cunjuctival injection), and menorrhagia Also can have intracranial bleeds if complete failure Vascular & platelet disorders lead to prolonged bleeding from cuts, bleeding into skin (bruising and purpura) and bleeding from mucous membranes (epistaxis, gums, menorrhagia) Coagulation disorders cause bleeding into joints and muscles

Question 6

How can collagen deficiency occur? What are the two ways for the collagen deficiency? One is rarely seen nowadays

Answer 6

Collagen deficiency can occur as senile purpura - collagen content decreases with age - less platelet adherance - commonly seen bruising on extensors in response to minor trauma VitC deficiency causes a condition known as scurvy - vit C is needed for synthesis of collagen - rarely seen nowadays

Question 7

As mentioned, collagen disorders are a cause of primary haemostasis dysfunction - senile pupura or scurvy These are acquired Can also have hereditary disorders Name two hereditary conditions associated with vacular abnormalities leading to bleeding? (tall people and stretchy people)

Answer 7

This could be Marfans syndrome and Ehlers Danlos syndrome

Question 8

What is the different mutation in Ehlers danlos and marfan syndrome? What are the different features?

Answer 8

Ehlers danlos syndrome - usually a mutation causing abnormal collagen and elastin formation - most autosomal dominant - the defect results in very stretchy skin and also increases vascular fragility so easy bruising and abnormal wound healing Marfan syndrome - due to a mutation in the firbillin gene - autosomal dominantn - tall people with long extremities, lens and retinal detachmenet, tension pneumotorax and cardiac abnoramlities, pectus abnormalities

Question 9

Most commonly vascular abnormalities are acquired vasculitis e.g. Henoch schonlein purpura What is henoch schonlein pupura? and what are the features of the disease?

Answer 9

It is a small vessel vasculitis mediated by IgA that is typically self limiting It produces classicial purpura on the buttocks and extensor surfaces and normally occurs in children Children may also present with abdo pain due to GI bleeds

Question 10

Platelet disorders were the next cause of failure of formation of the platelet plug They can be due to reduced number of reduced fucntion Reduced number covers both increased destruction and decreased production What is decreased production due to? What is low platelets known as?

Answer 10

This is due to marrow problems Eg aplastic anaemia, marrow infiltration (eg malignancies or Myelofibrosis), marrow suppression (cytotoxic drugs/radiotherapy) Low platelets - thrombocytopenia

Question 11

What are causes of an increased destruction of the platelets?

Answer 11

These would be Disseminated intravascular coagulation Autoimmune - eg immune thrombocytopenic purpura Hypersplenism HUS - haemolytic ureamic syndrome - endothelial damage triggers platelet consumption Thrombotic thrombocytic purpura - uses up platelet as well

Question 12

Both HUS and TTP come under microagniopathic haemolytic anaemia (MAHA) What is this MAHA? What are 4 conditions that cause it?

Answer 12

Microangiopathic haemolytic anaemia is when there is intravascular haemolysis + red cell fragmentation (shcistocytes) Caused by DIC, HUS, TTP, Prosthetic heart valves

Question 13

How does immune thrombocytopenic purpura occur? What is seen in the bone marow in patients with this condition?

Answer 13

This conditions occur because anti-platelet antibodies bind to to the platelets causing them to be removed by the reticuloendothelial system (Mostly spleen but also in liver) - typically occurs a couple of weeks post-infection In the bone marrow it is normal to see increased megakaryocyte numbers as they are trying to produce platelets to combat the shortage IMportant to rule out secondary causes

Question 14

What is the treatment of ITP? Is there splenomegaly in ITP? Remember the spleen is removing the antibody bound platelets hence the thrombocytopenia Why are platelets not given when the platelet count reaches very low levles?

Answer 14

The treatment is none if mild If symtpomatic or platelets <20x10^9/L start the patient on prednisolone (IV steroids) Spleen is not enlarged in this condition Platelet transfusions are not given unless splenectomy has been carried out as they are quickly destroyed by the circulating anti-platelet antibodies Splenectomy considered in those unresponsive to steroids

Question 15

Disseminated intravascular coagulation was another cause of primary haemostatic failure (be aware this affects both primary and secondary) How does DIC work?

Answer 15

DIC occurs where all the blood clotting factors and platelets are used up due to widespread activation of coagulation due to the release of procagulants into the circulation Fibrin strands fill small vessels and haemolyse passing red blood cells resulting in red cell fragments on blood film DIC causes numerous clots usually in small vessels and since both platelets and clotting factors are used up, bleeding occurs

Question 16

Hypersplenism is the other cause of thrombocytopenia How is the platelet count reduced here?

Answer 16

Usually hypersplenism occurs due to splenomeglay as there is an increased blood cell flow into the spleen which then as it is bigger breaks more cells down resulting in penia

Question 17

What is the usual cause of reduced function of the platelets? These are drug effects

Answer 17

Usually due NSAIDs They affect the ability of platelets to function and form a proper plug NSAIDs prevent the release of TXA2 by inhibiting the enzyme COX (cycloxygenase) meaning platelet aggregation is impaired

Question 18

Vascular - Marfans, Ehlers Danlos, Scurvy, Senile purpura Reduced number - marrow failure, DIC, ITP, Hypersplenism Reduced function - aspirin Lets now talk about VWD What are the main functions of vWF? What is the inheritance of VWD?

Answer 18

The main mode of action of von willebrand factor are: To bring platelets into contact where there has been endothelial damage and to make the platelets bind together as well as binding to factor VIII in the blood preventing it form destruction in the circulation VWD is most commonly an autosomal dominant inheritance pattern

Question 19

What are the two main types of von willebrand disease?

Answer 19

Type 1 where there is a deficiency of VWF - accounts for 80% of cases - quantitative deficiency and Type 2 where wVF is produced but is abnormal - qualitative deficiency Von Willebrand disease (vWD) is the most common hereditary blood-clotting disorder in humans.

Question 20

In 80% of people it is just a problem producing vWFIn the second type they produce vWF that doesn’t work properly and they tend to have a greater bleeding tendency The main role of vWF is in primary haemostasis Therefore will see a primary bleeding As it will cause a primary bleeding, what are the symptoms?

Answer 20

Will have prolonged bleeding from cuts, bleeding into the skin (purpura and bruising) and bleeding from mucous membranes - bleeding after dental extraction, menorrhagia, epistaxis

Question 21

What tests are carried out for diagnosis of von willebrand disease?

Answer 21

Because vWF carries factor VIII around, this factor will fall with vWF and therefore with vWF disease, will end up with a prolonged APPT time Prolonged APTT and decreased Factor VIII concentration Prolonged bleeding time Platelets are a normal level

Question 22

What is the treatment of VWD in patients with mild bleeding? What is given to patients who have major bleeds or who are having surgery>

Answer 22

In patients with mild bleeding - desmopressin (an anti diuretic) can be given to treat the disease (desmopressin stimulates the release of vWF) In heavy bleeding or prep for surgery - vWF containing factor VIII concentrates can be given to the patient

Question 23

Thrombocytopenia is the commonest cause of primary haemostatic failure Can be caused by vascular defects and vWD also Secondary haemostasis failure is due to mutliple clotting factor deficiencies or single clotting factor deficiencies State two causes of each?

Answer 23

Multiple clotting factor deficiencies - Vit K deficiency, DIC or liver failure Single clotting factor deficiencies - Hameophila A or B

Question 24

Secondary haemostasis disorders tend to bleed into joints and muscles What are the two tests used to measure a basic coagulation screen? How are they carried out?

Answer 24

Prothrombin time Activated partial thromboplastin time Blood is taken from a patient into a citrate (anticoagulant) containing test tube to prevent the blood clotting * When ready to test: * PT - TF is added to test the extrinsic pathway factors (VII,V,X,II) * APTT -Kaolin is added to test the intrinsic pathway factors (VIII,IX,XI,XII)

Question 25

Where are all the coagulation factors synthesised? Which factors are carboxylated by vitamin K?

Answer 25

All the coagulation factors are synthesised in the liver Factors II,VII,IX and X are carboxylated by vitamin K - vitK gives them their negative charge which allows them to bind to positive calcium on the platelet plug

Question 26

What type of vitamin is vitamin K? What are the sources of vitamin K? Where is it absorbed? What does it require for its absorption?

Answer 26

Vitamin K is a fat soluble vitamin and requires bile salt for its absorption VitK is obtained from the diet and from intestinal synthesis All forms of vitamin K are absorbed in the small intestine via a mechanism requiring bile salts

Question 27

What are the causes of vitamin K deficiency?

Answer 27

Poor dietary intake Malabsorption Obstructive jaundice - eg gallstones preventing bile salts release Vitamin K antagnosits eg warfarin Haemorrhagic disease of the newborn - vitK supply in neonates is very low as poor supply in breast milk and gut is immature so cannot produce the vitamin properly

Question 28

What is recommend to be given to all children within the first 24 hours of birth to prevent haemorrhagic disease of the newborn?

Answer 28

Babies are defieicnt of vit K at birth, not much from diet and breast fed is poor for vitK, also no bacteria in bowels making vitK either On top of this liver is immature also and therefore not many clotting factors are given either Therefore all babies are given a 1mg intramuscular shot of vitamin K at birth

Question 29

Excessive and inappropriate activation of the haemostatic system * Primary, secondary and fibrinolysis What is this condition? What are the features caused by the excessive and inappropriate activation of the haematopoeitc system?

Answer 29

This is disseminated intravascular coagulation Features in include end organ damage due to microvascular thrombus formation ie kidney failure Also bruising, purpura and generalised bleeding

Question 30

What are causes of DIC?

Answer 30

Sepsis Hypovalaemia Obstetric emergencies Malignancy

Anything that causes endothelial damage therefore resulting in the release of tissue factor can set off DIC

Question 31

There is essentially lots of tissue damage in DIC (septic, hypoxic etc), when there is lots of tissue damage, collagen is exposed and tissue factor is released and therefore lots of blood clots start to form in the blood vessels – this prevents blood flow for oxygen and critical organs start to fail – not enough blood to kidneys (renal failure), brain (confusion), lungs (tachypnoeic) All these organs failing leads to more tissue damage and more activation. What is given as treatment in DIC?

Answer 31

TREAT THE CAUSE OF THE DIC Treatment of low cell components - red cell transfusions, platelet transfusions, fibrinogen transfusions (cryoprecipitate), FFP to replace the clotting factors

Question 32

When screening for the problems due to secondary haemostasis, the APTT, PT time are measured (bleeding time is rarely measured and platelets are measured if expecting a primary haemostatic problem as well) What times will be raised in: Liver disease? DIC? What is a way of distinguishing between liver and DIC?

Answer 32

Liver disease - raised APTT and PT (platelets may be normal) DIC - Raised APTT, PT and low platelets Measure D-dimers to distinguish between DIC and liver disease In DIC the D-Dimer spike will be very large a there is a big attempt to breakdown the clots formed by the coagulation process

Question 33

Describe haemophilia Which type is more common Which coagulation test would be raised?

Answer 33

Hameophilia is an X-linked recessive condition - the genetic disorder impairs the bodies ability to make clots therefore Haemophilia A results from the deficiency of clotting factor VIII and is 5 times more common than Haemophilia B which results from the deficiency of clotting factor IX.

Question 34

What is the difference in the symptoms of haemophilia compared to a primary haemoastasis bleed?

Answer 34

Haemophilia - dont tend to have the bleeding from small cuts Usually get bleeding into joints or muscles (bleeding into muscles can cause compartment syndrome) Prolonged bleeding after surgery and invasive procedures

Question 35

In haemophilia, once there is a bleed into the joint, this damages the synovium and forms new blood vessels known as neovascularisation which are prone to bleeding Therefore once there is one bad bleed, the joint can bleed often – known as target joints What are the most common joints affected in haemophilia?

Answer 35

The joints which carry the most pressure Ankle then knee then elbow are the most common spots for bleeds in haemophilia

Question 36

In child who comes in with a hugely swollen knee (haemarthrosis), check blood counts What will be seen on the coagulation tests and the platelet count in haemophilia?

Answer 36

Check - prothrombin time – will be normal as nothing wrong with facor VII, X, V or prothrombinCheck APTT – prolonged as problem either in VIII,IX, XI,XII – in hemophilia it is VIII or IX

Question 37

After finding a prolonged APTT, a mixing study is carried out to confirm a most likely diagnosis of a coagulation deficiency. What happens when carrying out a mixing study?

Answer 37

The patients plasma is mixed with normal plasma and this should correct the APTT Correction of aPTT with mixing study suggests coagulation factor deficiency.

Question 38

After having a prolonged APTT and a corrected APTT on mixing study, what is measured to diagnosed the type of haemophilia?

Answer 38

Plasma factor VIII and IX assay The decreased level of either will show which type of haemophilia is present

Question 39

What is the treatment of haemophilia?

Answer 39

In mild haemophilia A - desmopressin may suffice (it increases vWF which increases factor VIII in the blood) Usually treat haemophilia A and B with Factor VIII and Factor IX concentrates respectively