What factors of the endothelium wall help prevent platelet adhesion?
- It's negative charge
- Thrombomodulin and heparin sulphate expression
- Synthesis of prostacyclin (PGI2) and NO
- Production of plasminogen activator
What vascular response occurs when the vessel is injured?
What molecules do platelets adhere to when the endothelium becomes damaged?
Bound von Willebrand factor
What molecule on the platelet binds to collagen and von Willebrand factor on the endothelium?
Glycoprotein (GP) 1b
What molecule is exposed after initial platelet binding to collagen and vWF and what does this molecule bind to?
Forms a second binding site for vWF
What granule type is fibrinogen stored within the platelet and what is the function of this fibrinogen?
It is stored in the α-granules
It forms bridges between adjacent platelets and helps hold them together via the activated GP IIb-IIIb receptor
What molecule causes the conformational change in the GP IIb-IIIa receptor?
ADP released from the dense body granules of the platelet
How does clopidogrel prevent the production of the platelet plug?
It blocks the ADP receptor on the surface of the platelet preventing its activation and subsequent change in GP IIb-IIIa receptor
What is the functions of thromboxane A2?
It is a powerful vasoconstrictor
Initiates the platelet aggregation
What molecule opposes the functions of TXA2?
What is the action of Tissue Factor (TF), once bound to factor VII?
Directly converts factor X to Xa and some IX to IXa
What inhibitor blocks the production of factors Xa and IXa, and what is required for its activation?
Tissue factor pathway inhibitor (TFPI)
Activated in the presence of factor Xa
Apart from TF, what other process can yeild factor IXa?
Factor XIa, which is activated by thrombin
What molecule activates factor VIII, and what is the function of factor VIIIa?
It dramatically enhances the activity of factor IXa, which together convert factor X into Xa
What molecule activates prothrombin into thrombin, and what molecule enhances its activity?
Its activity is enhanced by thrombin activated factor Va
What molecule does thrombin act upon, and what helps stabilise the products of its activity?
Fibrinogen to produce fibrin
Factor XIII in the presence of calcium ions
What factors of the coaguation cascade does antithrombin inhibit?
What factors of the coagulation cascade does activated protein C inhibit?
What molecule enhances its activity?
It inhibits factors V and VIII
Its activity is enhanced by thrombin being bound to thrombomodulin
What is the main enzyme of fibrinolysis and what enzyme activates it from its precursor form?
It is activated by tissue plasminogen activator (t-PA)
When is D-dimer produced?
When the cross-linked firbin is degraded.
What molecule inactivates t-PA?
Plasminogen-activator inhibitor-1 (PAI-1)
What coagulation factors are tested by the prothrombin time and what is the normal range?
Factors V, VII and X
Also tests fibrinogen and prothrombin
Normal range = 12-16s
(Also called the INR)
What coagulation factors are tested by the activated partial thromboplastin time (aPTT) and what is the normal range?
Factors V, VIII, IX, X, XI, XII
Prothrombin and fibrinogen
Normal range = 26-37s
Which coagulation factors are Vitamin K-dependent in origin
Factors VII, IX, and X
Protein C and S
What is the normal range of the thrombin time (TT) and what may produce a prolonged time?
Prolonged in fibrinogen deficiency, or if inhibitors such as heparin are taken
By what mode of inheritence is hereditary haemorrhagic telangectasia passed on?
Autosomal dominant inheritence
What genes have been associated with hereditary haemorrhagic telangectasia?
What are the symptoms of hereditary haemorrhagic telangectasia?
Dilated capillaries and arterioles producing small red branching spots, particularly around the nose and GIT
Chronic GI bleeding → chronic iron deficiency anaemia
Vascular malformations may also be present
What is the common age range of immune thrombocytopenic purpura (ITP) in children?
Between 2 and 6
What is the typical history of a child presenting with ITP?
Acute onset of mucocutaneous bleeding with a previous history of a recent viral infection, including varicella zoster or measles.
Why is there a low platelet count in ITP?
There are auto-antibodies against the platelets and are thus destroyed by macrophages etc.
What common symptoms are seen in ITP?
What coagulation factor is missing in haemophilia A?
What mode of inheritence is haemophilia A and how prevelant is the disease?
X-linked recessive inheritence pattern
Affects about 1 in 5000 men
What findings are seen in laboratory tests in haemophilia A?
Reduced level of factor VIII
Normal PT, bleeding time and vWF levels
What are the 3 grades of haemophilia A and what are the symptoms of each?
Severe haemophilia A ( Factor 8 < 1IU/dL):
- Spontaneous bleeding from birth, typically joints and muscle
Moderate haemophilia A (F VIII 1-5IU/dL):
- Severe bleeding following injury and occasional spontaneous bleeding
Mild haemophilia A (F VIII >5IU/dL):
- Bleeding only after injury or surgery, diagnosed late in life
What drug can be given to patients with haemophilia A
What coagulation factor is missing in haemophilia B and what is another name for this condition?
Which disease is more common, haemophilia A or B?
(Haemophilia B affects around 1 in 30,000, but mode of inheritence is the same)
What are the test results commonly seen in von Willebrand's disease?
Prolonged bleeding time
Normal/ or raised aPTT
Decreased levels of VIII and vWF
What is the cause of Factor V Leiden?
There is a mutation in V, which means it is less likely to be inactivated by protein C, therefore leading to thrombosis
By what mode of inheritence is antithrombin deficiency passed on?
What are some conditions that can cause an increased risk of thrombosis?
Factor V Leiden
Protein C and S deficiencies
What enzyme does aspirin inhibit within the platelet?
COX, resulting in a decrease in the production of TXA2
What molecule does streptokinase act upon and what is it used for?
It acts on plasminogen activating it to plasmin
Used for thrombolysis
What molecule does heparin bind to ?
Antithrombin, leadining to a conformational change increasing antithrombins inhibitory effects
What coagulation factor does Fondaparinux and LMWH inhibit?
What is the mechanism of action of warfarin?
It lowers the ability of the patient to form a blood clot by interfering with vitamin K metabolism and therefore reducing the vitamin K-dependent coagulation factors
What are the contraindications of giving warfarin?
- Severe uncontrolled hypertension
- Non-thromboembolic strokes
- Peptic ulceration
- Severe liver and renal disease
- Pre-existing haemostatic disease
Why should warfarin be avoided in pregnancy?
It is teratogenic in the first trimester
It can also cause foetal haemorrhage in later pregnancy
What class of drug are rivaroxaban and apixaban?