List causes of failure of platelet plug formation (failure of primary haemostasis)
Vascular disease
Low platelet count (thrombocytopenia)
Impaired platelet function
Von Willbrand Factor disease
What is the main vascular cause of failed primary haemostasis?
ACQUIRED: Vasculitis e.g. Henoch-Schonlein purpura
Others include heridatory causes e.g. Marfans
What is the commonest cause of primary haemostatic failure?
Thrombocytopaenia (usually acquired)
Thrombocytopenia can be due to what 2 factors?
Reduced platelet production (marrow disorder)
Increased platelet destruction
List the main causes of platelet destruction
Coagulopathy (DIC)
Autoimmunity (immune thrombocytopaenic purpura)
Hypersplenism (liver disease)
What is the main cause of a platelet functional deficit?
HERIDATORY: vWF deficiency
Other include acquired causes (NSAIDs, renal failure, aspirin)
Von Willebrand Factor deficiency is mainly hereditary and follows what inheritance pattern?
Autosomal dominant, typically producing a mild disease
In what two groups of patients should you be suspicious of vWF deficiency?
Women with menorrhagia
Patients who bleed excessively after surgery
List causes of failure of fibrin clot formation (failure of secondary haemostasis)
Multiple clotting factor deficiency
Single clotting factor deficiency
List causes of multiple clotting factor deficiency. What would a clotting screen look like?
DIC Liver failure Vitamin K deficiency Warfarin therapy Prolonged PT time and aPTT
What is the main cause of single clotting factor deficiency?
Haemophilia
Which clotting factors are carboxylated (activated) by vitamin K?
II
VII
IX
X
Why is vitamin K important for function of clotting factors?
Allows for clotting factor to aggregate at platelet plug: need a negative charge (carboxylation of glutamic acid) as Ca at plug is positive
List causes of vitamin K deficiency
Poor dietary intake
Malabsorption (absorbed at upper intestine)
Obstructive jaundice (requires bile salt for absorption)
Antagonists (warfarin)
Haemorrhagic disease of newborn
What is disseminated intravascular coagulation (DIC)?
Excessive and inappropriate activation of the haemostatic system, causing depletion of all clotting factors leading to microvascular thrombus formation
What are the main signs of DIC?
Abdominal bruising/purpura
Generalised bleeding
What is included in a coagulation screen for haemostasis?
Platelet count
Prothrombin time
APT time
D-dimer
List the main causes of DIC
Sepsis
Obstetric emergencies
Malignancy
Hypovolaemic shock
How is DIC treated?
Treat underlying cause
Replace clotting factors - platelet transfusions, plasma transfusions (FFP), fibrinogen replacement
What is haemophilia? What pattern of inheritance does it follow?
X-linked heridatory disorder with abnormal prolonged bleeding episodically at one or few sites
What are the two types of haemophilia? Which is more common?
Haemophilia A (VIII deficiency) Haemophilia B (IX deficiency) A is more common than B
Where does bleeding usually occur in haemophilia?
Ankles, knees (haemarthroses)
Soft tissue bleeds (bruising in toddlers)
Prolonged bleeding after dental extraction or surgery
Is haemophilia a disorder of primary or secondary haemostasis?
Secondary haemostasis
Prothrombin time is usually normal in a haemophiliac. True/False?
True
Isolated prolonged APT time
What is the main cause of arterial thrombosis?
Atherosclerosis
How is atherosclerosis treated?
Antiplatelet (aspirin)
Modify risk factors for atherosclerosis
Venous thrombosis is caused by Virchow’s triad. List the components of this triad
Hypercoagulability
Vessel wall damage (valves)
Stasis of blood flow
How is venous thrombosis treated?
Heparin/ warfarin
NOACs
List the main clinical signs of DVT. How is it diagnosed?
Hot limb Swelling, erythema Tenderness Pitting oedema Usually unilateral Duplex US Negative D-dimer
List the main clinical signs of PE. How is it diagnosed?
Pleuritic chest pain Dyspnoea Collapse Haemoptysis VQ scan if CXR normal, CTPA Negative D-dimer
What is the risk of a deep vein thrombosis in the leg?
Clot can form and end up in pulmonary circulation by passing up IVC, causing pulmonary embolism
Can result in post-thrombotic syndrome (chronic painful and swollen leg)
List risk factors for venous thromboembolism
Age Obesity Pregnancy Oestrogen therapy (OCP) Trauma/surgery Malignancy Infection Paralysis Thrombophilia Antiphospholipid syndrome Previous DVT/PE
What is a thrombophilia?
Familial/acquired disorder of haemostatic mechanism which are likely to predispose to thrombus
What are the main mechanisms of thrombophilia?
Increased coagulation activity
Decreased fibrinolytic activity
Decreased anticoagulant activity
What are the main naturally occuring anticoagulants?
Serine protease inhibitors (antithrombin)
Protein C and S
What is Factor V Leiden?
Variant of factor V that cannot be inhibited as effectively - increases risk of venous thrombosis due to less anticoagulation
List the main hereditary thrombophilias
Factor V Leiden
Antithrombin deficiency
Protein C and S deficiency
Prothrombin mutation
List clinical features that owuld make you suspicious of thrombophilia
VTE <45yo
Recurrent or unusual VTE
Family history of VTE
Family history of thrombophilia
How is thrombophilia managed?
Advice on avoiding risk
Short-term prophylaxis
Short-term anticoagulation to treat VTE
Long-term anticoagulation if recurrent events
What are the two factors that must be weighed up to decide whether a patient should be put on long-term anticoagulation?
Risk of recurrent thrombosis
Risk of serious haemorrhage
What is the most important contributor to a risk of recurrent thrombosis?
A history of previous thrombosis
What is the main acquired thrombophilia?
Antiphospholipid syndrome
Which antibodies prolong phospholipid coagulation tests?
Lupus anticoagulants
List clinical features of antiphospholipid syndrome
Recurrent thrombosis (arterial, venous)
Recurrent fetal loss
Mild thrombocytopaenia
How is antiphospholipid syndrome managed?
Antiplatelet (aspirin)
Anticoagulant (warfarin, heparin if pregnant)
How does atherosclerosis form?
Foamy macrophages rich in cholesterol are attracted to damaged arterial endothelium, forming atherosclerotic cholesterol-rich plaques
What are the consequences of unstable atherosclerotic plaques?
Can rupture and cause arterial thrombosis/embolism (resulting in unstable angina/MI/stroke)
List risk factors for arterial thrombosis
Hypertension
Smoking
High cholesterol
Diabetes
Explain the process of formation of arterial thrombus
ENDOTHELIAL DAMAGE: exposes collagen and vWF
Platelet ADHESION to collagen and vWF at injury site
AGGREGATION of platelets at site of injury
ACTIVATION of platelets as they alter shape to expose more phospholipid on the surface, allowing greater coagulation activation and fibrin production to stabilise clot
SECRETION of granules to stimulate more platelet recruitment and activation forming platelet plug
Which chemicals released by platelets encourage platelet aggregation?
Thromboxane A2 (TXA2) ADP
Through which receptors do platelets bind together?
GP IIb/IIIa
How does aspirin work?
Antiplatelet that inhibits COX enzyme causing decreased TXA2 production and thus reduced platelet aggregation
List some side effects of aspirin
Bleeding
Blocks production of prostaglandins:
GI ulceration
Bronchospasm
How does clopidogrel work?
Antiplatelet that is an ADP receptor antagonist (blocks P2Y1) to reduce platelet aggregation
How does dypridamole work?
Antiplatelet acting as a phosphodiesterase inhibitor , reducing cAMP - messenger in platelet activation
How does abciximab work?
Antiplatelet acting as a GPIIb/IIIa inhibitor that prevents aggregation of platelets
How is bleeding managed in a patient taking antiplatelets?
If serious bleeding reverse with platelet transfusion
Stop antiplatelet agents 7 days prior to elective operations
How does atrial fibrillation increase the risk of stroke?
Stasis of blood flow (due to irregular heartbeat) causes congealing and clot formation in atrium, which may travel and lodge in the brain
Which factors do protein C and S inhibit in the clotting cascade?
V
VIII
IX
Xa
How does heparin work?
Anticoagulant that potentiates action of antithrombin (inhibitor of thrombin) to reduce clotting
Inhibiting thrombin reduces factor VIII/IX that speed up the system
How is heparin administered?
IV or subcutaneous
Which factors are inhibited by unfractionated heparin?
Thrombin
Xa
Which factors are inhibited by LMW heparin?
Xa only (indirectly inhibits thrombin since X is higher in the cascade)
Which coagulation test is used to monitor heparin?
APT time for unfractionated heparin
Anti-Xa assay for LMW heparin
List some side effects of heparin
Bleeding
Thrombocytopenia, causing thrombosis (monitor FBC)
Osteoporosis long-term
How can the effects of heparin be reversed?
Stop heparin Protamine sulphate (reverses AT so complete reversal for unfractionated heparin)
What is required for vitamin K absorption?
Bile salts
Which factors are vitamin K -dependent?
II (prothrombin) VII IX X Protein C and S
Where are vitamin K-dependant factors synthesised?
Liver
How does warfarin work?
Anticoagulant acting as an antagonist of vitamin K to cause reduced clotting factor activation (synthesis of non-functional clotting factors II, VII, IX, X)
How are patients on warfarin monitored? Why?
International Normalised Ratio (corrected PT ratio)
Warfarin has a narrow therapeutic window
What is the equation for calculating a patient’s INR?
(PT time / mean normal PT time)^ISI
How is acute thrombosis in hospital treated - heparin or warfarin?
Heparin (works immediately)
List adverse effects of warfarin therapy
Drug interactions, including alcohol
Bleeding (mild or severe)
How can the effects of warfarin be reversed?
Omit warfarin dose
Oral vitamin K (6 hours)
Administer clotting factors
What are the advantages of newer anticoagulants or NOACs?
Oral and no monitoring required Less drug interactions Less bleeding (no antidote for reversal)
Give an example of a direct thrombin inhibitor
Dabigatran
Give an example of an oral Xa inhibitor
Rivaroxaban
Why are Xa inhibitors preferred over a direct thrombin inhibitor in older patients?
Direct thrombin inhibitors are excreted renally
Check U+Es before prescribing
What does prothrombin time measure?
How long it takes your blood to clot by measuring the activity of the clotting factor prothrombin (II), focusing on the extrinsic pathway (tissue factor related)
What does activated partial thromboplastin time measure?
How long it takes clotting to occur by measuring the function of the intrinsic pathway (blood vessles)
What would an isolated thrombocytopaenia on blood test make you suspicious of?
Autoimmine thrombocytopaenic purpura
Outline the management of VTE
LMW Heparin or Warfarin TED stockings Physiotherapy Early mobilisation Intermittent pneumatic compression
Warfarin affects the PT time and heparin affects the APT time. True/False?
True
If the PT time is prolonged and the APT time is normal, which factors are causing the problem?
Tissue factor
VIIa
If the PT time is normal and the APT time is prolonged, which factors are causing the problem?
VIII
IXa