Thrombotic Disorder Flashcards
What is thrombophilia?
Inadequate fibrinolysis leading to excess clotting
Arterial thrombi:
— Composed of primarily platelets and fibrin with few red blood cells
— Often at the sites of atherosclerotic plaques
— Arterial thrombosis can lead to myocardial infarction or stroke
Venous thrombi:
— Composed of primarily red blood cells trapped in fibrin mesh
— Can occur anywhere but most common in lower limbs
— Venous thrombosis often presents as deep vein thrombosis (DVT)
or pulmonary embolism (PE)
What is a venous thromboembolism?
Thrombosis can affect any branch of the venous circulation
Venous thromboembolism (VTE):
- Deep-vein thrombosis (DVT)
- Pulmonary embolism (PE)
DVT affects 0.1% of persons per year
VTE presents as DVT in 2/3 cases
UK death rate from VTE ~60,000 pa
What inherited disorders can cause thrombis?
Deficiency of naturally occurring anticoagulants
- Protein C deficiency:
- PC, vitamin K dependant inhibitor
- Degrades FVa and FVIIIa
- Reduction of PC to ~50% of normal predisposes to venous thrombosis
- Typically present with deep vein thrombosis of legs,
- Or recurrent venous thrombosis - Protein S deficiency:
- PS vitamin K dependant protein that is cofactor for APC
(activate Protein C)
- Accounts for ~6% if familial thrombophilia
- Similar presentation to PC deficiency but also linked to arterial
thrombosis - Antithrombin deficiency
- DVT
What is Factor V Leiden mutation?
Factor V Leiden mutation is a point mutation in the gene for FV (arginine glutamine at 1691 or 1746)
It has autosomal dominant inheritance and is the most common cause of inherited thrombophilia
It leads to a hypercoagulable state as the point mutation is at the exact location where activated protein C will cleave FVa in its role as an
anticoagulant
- Makes factor 5 resistant to PC breakdown, so common pathway
continues
If the mutation is present the action of activated protein C is slowed down
What is Prothrombin Gene Variant: G20210A variant?
A G20210A transition of the prothrombin gene which has been identified as a common but mild hereditary risk factor for venous thromboembolism
Results in increased levels of prothrombin (factor II)
Can co-exist with the FV Leiden mutation – thrombosis risk is then amplified
Usually tested for at the same time as the Factor V leiden mutation in a
multiplex test
What are fibrin degradation products?
D-dimer is produced by the factor XIIIa-mediated crosslinking of fibrin
Can be detected by immunological based assays
Raised plasma D-dimer levels indicate thrombolysis
The D-Dimer level (raised) is used in emergency situations as an indication that someone has had a DVT
D-dimer measurement
- the exclusion of VTE
- the diagnosis and monitoring of coagulation activation in
disseminated intravascular coagulation (DIC)
How is thrombis treated?
Three types of treatment can be used to either break down an existing thrombus, or to prevent further thrombus formation:
- Anticoagulants
- Anti-platelet drugs
- Thrombolytic drugs
Many trials have been performed to assess the best strategy for patient
survival
The aim is rapid reperfusion of affected tissues
What is the action of heparin?
Heparin complexes with antithrombin and inactivates FXa
May cause heparin induced thrombocytopenia (HIT) → so monitor platelets
Also can not be used long term as can result in osteoporosis
Has immediate effects on clotting, given to prevent further MI or thrombosis
Heparin (unfractionated) dose monitoring:
APTT or heparin assay.
- APTT 1.5 – 2 x normal APTT
LMWH monitoring: Factor Xa measurement
What is the action of Warfarin?
A coumarin derivative
Produces an anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide)
- activates some coag factors. Why babies require vit K infections
to avoid intercranial bleeds. It is a cofactors for carboxylation of
glutamate residues on proteins so they can interact with calcium.
Vitamin K is a cofactor for the carboxylation of glutamate residues to γ-carboxyglutamates (Gla) on the N-terminal regions of vitamin K dependent proteins
- coagulation factors II, VII, IX, and X
- Post translational modification required by coag factors 2, 7 9
and 10 require this for activity.
They require γ-carboxylation by vitamin K for biological activity.
By inhibiting the vitamin K conversion cycle, warfarin induces hepatic production of partially decarboxylated proteins with reduced coagulant activity
What is the vitamin K cycle?
- Vitamin K must be reduced to its quinol or hydroquinone form.
- To activate enzyme the glutinates factors such as factor 2 7 9
and 10.
- To activate enzyme the glutinates factors such as factor 2 7 9
- This is achieved with Vitamin K oxide reductase
- The step inhibited by S-warfarin
- S-warfarin x3 more potent than R-warfarin
— WET 1972 = Warfarin acts on Extrinsic pathway, measured by
proThrombin time, affecting coagulation factors 10, 9, 7 and 2
How is Warfarin monitored?
Warfarin treatment is monitored using the International Normalised Ratio (INR)
INR= Patient Prothrombin Time
( ——————————— ) ^ ISI
Normal Prothrombin Time
ISI: international sensitivity index. Specific for thromboplastin used determined by the manufacturer
The ‘target’ INR level depends on the reason the patient is being treated with anticoagulants
Heart Valve replacement
- A target INR of 3-4 for life
Venous thromboembolism, Pulmonary embolism & antiphospholipid syndrome:
- A target INR of 2.5 for 3-6 months for first episode, life for
recurrent episodes
