Haemostasis Flashcards
Define haemostasis
The cellular and biochemical process that enables cessation of bleeding in response to injury
What are the 3 roles of haemostasis?
To prevent loss of blood from intact vessels
To arrest bleeding from injured vessels
To enable tissue repair
What are the 4 mechanisms of haemostasis?
Vessel constriction
Primary haemostasis
Secondary haemostasis
Fibrinolysis
Describe the first mechanism of haemostasis
Vessel constriction occurs at the site of injury to limit blood flow, usually in vascular smooth muscle
Describe the second mechanism of haemostasis
Primary haemostasis is the formation of a temporary platelet plug, this occurs via:
Exposure of collagen on the endothelium wall at the site of injury
Platelets attach either directly via g1pIa receptor or indirectly via VWF and gp1b receptor
Platelets aggregate after release of contents, thromboxane is synthesised from arachidonic acid
This activates platelets by activating g1pIIb or IIa receptors
What are the 2 ways platelets attach at the endothelium wall? What receptors are involved?
Directly via g1pIa
Indirectly via VWF and gp1b receptor
What are the 3 components of primary haemostasis?
VWF
Platelets
Vessel wall
What content do platelets release?
ADP and thromboxane
What is thromboxane synthesised from?
Arachidonic acid
What is the 3rd mechanism of haemostasis?
Secondary haemostasis, this is the formation of a permanent platelet plug
What is the scientific term for secondary haemostasis?
Coagulation
What is the 4th mechanism of haemostasis?
Fibrinolysis, it involves breakdown of the fibrin clot and vessel repair so vessel integrity is restored
What is normal haemostasis the balance between?
Fibrinolytic factors and anticoagulant proteins vs coagulant proteins and platelets
What will a tip in the haemostatic balance cause either way?
Excess coagulant proteins/platelets= thrombosis
Excess fibrinolytic factors/anticoagulant proteins= bleeding
What are ways bleeding will occur?
Excess fibrinolytic factors/anticoagulant
Reduced nos of platelets and coagulant proteins, this could occur via
1) Reduced production (congenital or acquired)
2) Increased clearance or consumption (genetic or acquired)
What is the name of the condition where someone has low numbers of platelets?
Thrombocytopenia
What are the 3 main ways thrombocytopenia can arise?
Bone marrow failure causing reduced production
Increased clearance
Pooling and destruction in the spleen
How can bone marrow failure cause thrombocytopenia?
Leukaemia- white cells infiltrate the bone marrow and so platelets cannot be produced
B12 deficiency- causes megaloblastic anaemia so normal haemopoeisis ceases
How can accelerated platelets clearance manifest? Describe the pathophysiology of the conditions
ITP- platelets are destroyed in circulation by auto antibodies
DIC- small clots form all over the body in small vessels using up a lot of platelets
How does aspirin cause impaired platelet function?
It reversibly blocks the action if cyclo-oxygenase which reduces platelet aggregation
What drugs impair the function of platelets?
NSAIDs, clopidrogel, aspirin
How long does a dose of aspirin last?
7 days
How does clopidrogel impair platelet function?
Irreversibly blocks ADP receptor P2Y12 on platelet cell membranes
What is Glanzmann thrombothaenia?
Absence of GPIIb/IIIa receptors on platelets
What is Bernard Soullier syndrome?
Absence of GPIb receptors
What is storage pool disease?
A group of disorders where there is reduced granular contents in platelets
What are the 3 subcatagories of disorders of primary heamostasis?
Ones that affect
platelets (reduced numbers of impaired function)
or VWF
or the vessel wall
What is von willebrand disease?
When there is reduced quantity or function of VWF
How is von willebrand disease inheroted?
Autosomal
What are the different types of von willebrand disease?
Type 1 an type 3 are deficiency
Type 2 is abnormal function
What are the 2 functions of VWF in haemostasis?
Bind to collagen at injury site and capture platelets
Stabilise factor VIII
What may be low if VWF is low?
Factor VIII
What are inherited conditions that affect the vessel wall and cause disorders of primary heamostasis?
Hereditary haemorrhagic telangiectasia, Ehlers Danlos Syndrome and other connective tissue disorders
What are acquired conditions that affect the vessel wall and cause disorders of primary heamostasis?
Steroid therapy
Vasculitis
Scurvy
How does bleeding occur with disorders of primary haemostasis?
Immediate bleeding that is prolonged with cuts
Nose bleeds
Gum bleeds
Heavy menstrual bleeding
When do purpura appear?
If there are platelet or vascular problems
How does bruising change if there are disorders of primary haemostasis?
Bruising is spontaneous and may be easy
What is the difference between petechiae, purpura and ecchymosis?
Petechiae are < 3mm
Purpura are 3-10mm
Ecchymosis (bruises) are >10mm
What might severe VWD cause? Why?
Haemophilia like bleeding due to low factor VIII
What will APTT and PT (coagulation screens) in those with disorders of primary haemostasis be?
Normal
How are disorders of primary haemostasis treated if theres failure of production or function
Replace whats missing
Stop drugs eg aspirin and NSAIDs
How are disorders of primary haemostasis treated if theres immune destruction?
Immunosupression eg with prednisolone
Splenectomy in ITP
How are disorders of primary haemostasis treated if theres increased consumption?
Treat the cause
Replace whats necessary
How does desmopressin help as a haemostatic treatment?
It is a vasopressin analogue and increases stores of VWF
What is the normal range of platelets?
100-400 (x 10^9/L)
What is the other name for secondary haemostasis?
Coagulation
What is the role of coagulation
To generate thrombin (IIa) which converts fibrinogen to fibrin
What are the 3 tyoes of coagulation disorder?
Deficiency of coagulation factor production
Dilution
Increased consumption
How may deficiency of coagulation factors cause coagulation disorder?
Hereditary (haemophilia A or B)
Acquired (liver disease, anitcoagulant drugs eg warafrin and DOACs)
How does dilution cause coagulation disorder?
Acquired via blood transfusion where lots of RBCs are given but not enough plasma (they are now transfused together)
How does increased consumption cause coagulation disorder?
Acquired- commonly DIC or immune via antibodies
What factor is deficient in haemophilia A?
Factor VIII
What factor is deficient in haemophilia B?
Factor IX
How does factor deficiency in haemophilia lead to bleeding?
There is failure to generate fibrin to stabilise the platelet plug so it breaks away and causes bleeding
What is spontaneous joint bleeding called?
Haemarthrosis
What must you avoid in those with haemophilia?
Intramuscular injections
The absence of which factor is lethal?
Prothrombin (factor II)
How does bleeding occur with factor XI deficiency?
Bleeding occurs after trauma but not spontaneously
How does bleeding occur with factor XII deficiency?
It doesn’t cause bleeding
How might liver failure affect haemostasis?
It results in reduced production of coagulation factors as most are synthesised in the liver
What is a marker of fibrinolysis? Why?
Raised D dimer, it is a product of the breakdown of fibrin
Describe bleeding patterns in disorders of coagulation
Superficial cuts don’t bleed
Bruising is common
Spontaneous bleeding is deep eg into muscles and joints
Bleeding frequently restarts after stopping
Severe bleeding after injury that is delayed
How does bleeding differ in coagulation disorders vs platelet/vascular disorders?
Platelet vascular: superficial bleeding into skin, bleeding is immediate after injury
Coagulation: Bleeding deep into joints and muscles, it is delayed after injury but severe
What pathway does prothrombin time measure? What factors does it involve
Extrinsic pathway, involves tissue factor and fcator VII
What pathway does activated partial thromboplastin time measure?
Intrinsic pathway
How is APTT measured?
Via contact activation using glass, silica or ellagic acid
When replacing missing coagulation factors, when is FFP given?
When you want to replace all coagulation factors
When replacing missing coagulation factors, when is cryopreciptate given?
To replace fibrinogen, factors VIII, XIII or VWF
When replacing missing coagulation factors, when are factor concentrates given? When can they not be given?
Given if you want to replace any singular factor but not available for factor V
What are some novel treatments for haemophilia?
Gene therapy
Bispecific antibodies- bind to FIXa and FX to mimic the procoagulant fucntion of FVIIII
RNA silencing
When is desmopressin effective?
It releases endogenous stores of VWF so only effective in mild conditions when these stores are present
What effect does tranexamic acid have?
Antifibrinolytic
What can cause high levels of fibrinolytic factors and anticoagulant proteins?
Drugs eg tPa and heparin
How does pulmonary embolism present?
Tachycardia, hypoxia, shortness of breath, chest pain, sudden death
How does DVT present?
Painful leg Swelling Red Warm Feeling like they've pulled a muscle
What triad is used in thrombosis?
Virchow’s traid
What is virchow’s traid?
Blood- dominant in venous thrombosis
Vessel wall- dominant in arterial thrombosis
Blood flow- dominant in both types of thrombosis
What is thrombophilia?
An increased risk of thromobosis
How does thrombophilia present?
Thrombosis at a young age
Multiple thrombosis (may be spontaneous)
Thrombosis even when anticoagulated
What might cause thrombophilia?
Reduced fibrinolytic factors, anticoagulant proteins, antithrombin, protein C or protein S
Increased coagulant factors
Increased platelets
What does protein C inactivate?
Factor Va and VIIIa
What does antithrombin inactivate?
Factor IIa and Xa
What factor is thrombin?
IIa and Xa
What is the name for reduced blood flow
Stasis
How does reduced blood flow affect blood?
It increases the risk of thrombosis
How is venous thrombosis prevented?
Assess and tackle personal risk factors
Prophylactic anticoagulant therapy
What drugs can be given for reducing risk of thrombosis? Briefly explain how hey work
Warfarin and DOACs- they lower procoagulant factors
Heparin- increases anticoagulant therapy
What are the indications for anticoagulant therapy
Therapeutic: venous thrombosis, atrial fibrillation, mechanical prosthetic heart valve
Preventative: post-surgery, during hospital admission, during pregnancy
What class of molecule is heparin?
Glycosaminoglycan
How are long chains of heparin adminsitered?
Intravenously
How do long chains of heparin work?
They enhance antithrombin by changing its active site, this gives it a greater affinity for factor Xa and thrombin
What are long chain heparins targets (for increasing affinity between them and antithrombin)
Factor Xa
Thrombin
What does antithrombin inactivate?
Factors IXa, Xa and IIa (IIa is thrombin)
How is low molecular weight heparin administered?
Subcutaneously
How does low molecular weight heparin work?
It has anti Xa activity, does this by enhancing antithrombin
What is the main difference between the actions of low molecular weight heparin and long chain heparin?
Low molecular weight heparin is not long enough to wrap around both antithrombin and thrombin so it only has anti Xa activity and is therefore less powerful. Long chain heparin is more powerful and has both anti Xa and thrombin activity
What type of heparin doesnt need to be monitored? Why?
Low molecular weight heparin. It is less powerful and has a dose predictable effect
What is used to monitor the effects of heparin? Alongside the use of which type of heparin?
APTT (this will only be affected by long chain heparin though)
What is the method of action of warfarin?
It blocks vitamin K which is required to make clotting factors II, VII, IX, V, anticoagulant factors, protein C and protein S
What is the main downfall of warfarin?
It has a narrow therapeutic index that requires monitoring
What state does warfarin induce? How fast
An anticoagulant state, but slowly
Is warfarin reversible?
Yes
How is warfarin reversed slowly?
By vitamin K administration
How is warfarin reversed quickly?
Infusion of coagulation factors like prothrombin complex concentrate (contains factors II, VII, IX and X) or fresh frozen plasma
What are side effects of warfarin?
Bleeding (mostly minor)
Skin necrosis
Purple toe syndrome
Embryopathy
When must warfarin not be given?
During pregnancy, especially during the first trimester as then it will kill the baby
How is warfarin monitored?
Via the international sensitivity index (ISI)
What will happen to INR to indicate a higher risk of bleeding?
It will increase
What are some reasons patients may be resistant to warfarin?
Lack of compliance
Increased vitamin K in the diet
Increased metabolism
Reduced binding
What is the method of action of DOACs?
They directly inhibit factor Xa or thrombin
How does the onset/offset differ between warfarin and DOACS?
Warfarin is slow
DOACs is fast
How does the dosing differ between warfarin and DOACS?
Variable
Fixed
How does the effect on food between warfarin and DOACS?
Warfarin affects food
DOACs do not affect food
How do interactions differ between warfarin and DOACS?
Warfarin has many interactions
DOACs have few interactions
How does monitoring differ between warfarin and DOACS?
Warfarin requires monitoring
DOACs dont require monitoring
How does renal dependance differ between warfarin and DOACS?
Warfarin doesnt have renal dependance
Some DOACs have renal dependance
How does reversibility differ between warfarin and DOACS?
Warfarin is reversible via vitamin K and PCCs
There are specific antidotes to DOACs available
When are DOACs not given as first line treatment? Why?
To those with mechanical prosthetic heart valves because they aren’t effective, warfarin is given instead
They aren’t given in pregnancy as they aren’t safe
For medical thromboprophylaxis as they arent effective
When are DOACs given first line?
Venous thrombosis initial and long term treatment
Atrial fibrillation
Sometimes after surgery
When is LWMH given as first line treatment?
Following surgery
During hospital admission
During pregnancy
What is haemostasis a balance between?
Coagulant factors/platelets vs fibrinolytic factors/anticoagulant proteins
What are the 2 outcomes of a tip in the haemostatic balance?
Bleeding
Thrombosis
