Haemostasis and thrombosis Flashcards
What is a typical presentation of a patient with DVT
Immobile for 3 weeks after major surgery
Right calf swollen & collateral superficial veins present
Palpation - localised tenderness & pitting oedema
Immobility (i.e after surgery) is a key risk factor for the development of a thrombus and therefore DVT.
What investigations should be carried out if you suspect that the patient has a DVT
Measure vital signs- although DVT will not alter these
Two-level Wells score- survery- 9 points assessed (e.g entire leg is swollen, pitting oedema confined to symptomatic leg, collateral superficial veins (non-varicsose). Scored out of 10 - closer to 10 -greater probability of DVT.
Take blood for D-dimer testing- measures fibrin degradation products
Arrange a proximal leg vein scan- ultrasound to look for thrombosis.
Summarise the diagnosis and treatment for DVT
Positive D-dimer test - diagnosis of deep-vein thrombosis (DVT) interim treatment with parenteral anticoagulant
Ultrasound scan confirms DVT maintenance treatment with oral anticoagulant
In which type of veins does DVT occur
And the most common disorder is deep vein thrombosis (DVT). DVT is the formation of a blood clot within one of the deep veins commonly occurring in the femoral or popliteal veins of the leg.
Summarise the cell based theory of coagulation
- Initiation – small scale production of thrombin.
a. Targeted by ANTI-COAGULANTS. - Amplification – large scale production of thrombin (on platelet surfaces).
a. Targeted by ANTI-PLATELETS. - Propagation – generation of fibrin strands by thrombin.
a. Targeted by THROMBOLYTICS.
Describe the initiation phase of the coagulation cascade
§ STEP 1 – Initiation – small scale thrombin production:
o Tissue factor:
§ TF-bearing cells activate F10 and F5 forming the prothrombinase complex.
o Prothrombinase complex:
§ This actives F2 (pro-thrombin), forming thrombin.
o Antithrombin (AT-III):
§ AT-III inactivates F10a and thrombin.
Essentially, what is thrombin
Thrombin is F2a
Describe the role of thrombin
Thrombin (factor IIa) cleaves fibrinogen, producing fragments that polymerise to form fibrin. It also activates factor XIII, a fibrinoligase, which strengthens fibrin-to-fibrin links, thereby stabilising the coagulum. In addition to coagulation, thrombin also causes platelet aggregation, stimulates cell proliferation and modulates smooth muscle contraction.
Describe the orally active direct thrombin inhibitors (or non-vitamin K dependent anti-coagulants)
Inhibit factor IIa
Dabigatran (oral) - factor IIa inhibitor
Inhibit factor Xa
Rivaroxaban (oral) - factor Xa inhibitor
Summarise the role of heparins as anti-coagulant drugs
Increase activity of AT-III
Heparin (IV, SC) - activates AT-III (fIIa & fXa)
Low-molecular weight heparins (LMWHs, e.g.Dalteparin) - activate AT-III (fXa)
Describe the mechanism of action of heparin
Heparin inhibits coagulation, both in vivo and in vitro, by activating antithrombin III. Antithrombin III inhibits thrombin and other serine proteases by binding to the active site. Heparin modifies this interaction by binding, via a unique pentasaccharide sequence, to antithrombin III, changing its conformation and increasing its affinity for serine proteases
Explain the difference in pharmacology between heparin and LMWHs
To inhibit thrombin, it is necessary for heparin to bind to the enzyme as well as to antithrombin III; to inhibit factor Xa, it is necessary only for heparin to bind to antithrombin III (Fig. 25.6). Antithrombin III deficiency is very rare but can cause thrombophilia and resistance to heparin therapy.
The LMWHs increase the action of antithrombin III on factor Xa but not its action on thrombin, because the molecules are too small to bind to both enzyme and inhibitor, essential for inhibition of thrombin but not for that of factor Xa
Explain the route of administration for heparins
Heparin is not absorbed from the gut because of its charge and high molecular-weight, and it is therefore given intravenously or subcutaneously (intramuscular injections would cause haematomas).
Summarise the use of warfarins as anti-coagulants
Reduce levels of other factors
Warfarin (oral) - vitamin K antagonist
Vitamin K - required for generation of factors II, VII, IX & X
Describe the mechanisms of action of warfarin
Vitamin K antagonists act only in vivo and have no effect on clotting if added to blood in vitro. They interfere with the post-translational γ-carboxylation of glutamic acid residues in clotting factors II, VII, IX and X. They do this by inhibiting vitamin K epoxide reductase component 1 (VKORC1), thus inhibiting the reduction of vitamin K epoxide to its active hydroquinone form (see Fig. 25.5). Inhibition is competitive (reflecting the structural similarity between warfarin and vitamin K; see Fig. 25.3).
What is vitamin K essential for
It is essential for the formation of clotting factors II, VII, IX and X, which are glycoproteins with γ-carboxyglutamic acid (Gla) residues
How long do the effects of warfarin take to develop
The effect of warfarin takes several days to develop because of the time taken for degradation of preformed carboxylated clotting factors. Onset of action thus depends on the elimination half-lives of the relevant factors. Factor VII, with a half-life of 6 h, is affected first, then IX, X and II, with half-lives of 24, 40 and 60 h, respectively.
Describe the importance of the different anti-coagulant drugs having different routes of administration.
Oral -improved patient adherence, less management required.
I..V/S.C- faster onset- useful in emergencies.
Outline the treatment pathway for patients with DVT.
interim treatment with parenteral anticoagulant. DALTEPARIN- fast-acting while the patient is in hospital
maintenance treatment with oral anticoagulant RIVAROXABAN / WARFARIN -dabigatran rarely used- associated with G.I bleeding.
What are the indications for these anti-coagulants
Venous thromboembolism (DVT + PE)
Prevent thrombosis during surgery
Atrial fibrillation – prophylaxis of stroke
What is a common consequence of DVT
Pulmonary embolsim
the thrombus embolises and is carried up through the venous system to the right side of the heart- where it then gets lodged in the lungs.
Describe the typical presentation of DVT
Chest pain Dyspnoea & Tachypnoea Low oxygen saturation <96% High RR >16 Low BP <120/80
How can we diagnose P.E
Two-level Wells score = 6
Multiple-detector computed tomographic pulmonary angiography (CTPA)
Outline the treatment for P.E
CTPA confirms pulmonary embolism (PE) DALTEPARIN / HEPARIN - as a general rule heparin is more potent- give I.V>S.C for rapid action
Ultrasound scan confirms DVT maintenance treatment - oral anticoagulant RIVAROXABAN / WARFARIN
Define thrombosis
Thrombosis is the pathological formation of a ‘haemostatic’ plug within the vasculature in the absence of bleeding (‘haemostasis in the wrong place’).
What determines how likely you are to develop a thrombosis
Virchow’s triad
Describe Virchow’s triad
Rate of blood flow
Blood flow slow/stagnating no replenishment of anticoagulant factors & balance adjusted in favour of coagulation (e.g when patient is immobile)
Consistency of blood
Imbalance between pro-coagulation & anticoagulation factors (e.g FV Leiden)
Blood vessel wall integrity
Damaged endothelia blood exposed to pro-coagulation factors (e.g in HTN- endothelia exposed to high shear stress).
Summarise Virchow’s triad
Over a century ago, Rudolph Virchow defined three predisposing factors – ‘Virchow triad’: injury to the vessel wall – for example, when an atheromatous plaque ruptures or becomes eroded; altered blood flow – for example, in the left atrial appendage of the heart during atrial fibrillation, or in the veins of the legs while sitting awkwardly on a long journey; and abnormal coagulability of the blood – as occurs, for example, in the later stages of pregnancy or during treatment with certain oral contraceptives (see Ch. 36).
