[12] Deep Vein Thrombosis Flashcards
1
Q
What is a DVT?
A
A venous thrombosus that develops in the deep veins of the body, most commonly the legs or pelvis
2
Q
How can a DVT lead to a pulmonary embolism?
A
The clot may dislodge and travel to the lungs, causing a pulmonary embolism
3
Q
What is very clinically important in DVT?
A
Early recognitin and appropriate treatment
4
Q
What is meant by thrombosis?
A
The formation of a solid mass of blood from the constituents of blood within the circulatory system during life.
5
Q
Is thrombosis the same thing as clotting?
A
No
6
Q
What are the three fundamental predisposing factors to thrombosis known as?
A
Virchow’s triad
7
Q
What is Virchow’s triad?
A
- Abnormalities to the flow of blood
- Abnormalities to the blood vessel wall
- Abnormalities of the constituents of blood
8
Q
Give two examples of when there are abnormalities to the flow of blood?
A
- Stagnation
- Turbulence
9
Q
Give 3 examples of where there are abnormalities to the blood vessel wall
A
- Atheroma
- Direct injury
- Inflammation
10
Q
Give three examples of where there may be abnormalities of the constituents of blood
A
- Smokers
- Post-partum
- Post-op
11
Q
How does the development of venous thrombosis differ from arterial thrombosis, regarding Virchow’s triad?
A
It seems that in venous thrombosis, blood vessel damage is less of a factor than in arterial thromosis
12
Q
How does a venous thrombosis form?
A
The beginning of a venous thrombosis is thought to be caused by tissue factor, which leads to the conversion of prothrombin to thrombin, and then thrombin causing the conversion of fibrinogen to fibrin
13
Q
How do venous thrombi appear?
A
As soft, gelatinous, and deep red
14
Q
How does the cell content of venous thrombi compare to that of arterial?
A
It is higher
15
Q
What are the risk factors for DVT?
A
- Previous history of VTE
- Family history of VTE
- Cancer
- Age >60
- Immobilisation
- Smoking
- BMI over 30
- Male gender
- Acquired or familial thrombophilia
- Heart failure
- Varicose veins
- Trauma to the vein, or chronic low grade injury e.g. vasculitis, stasis, chemotherapy
- COCP or HRT
- Pregnancy
- Dehydration
- Antiphospholipid syndrome
16
Q
Why is the clinical diagnosis of DVT very difficult?
A
It is often missed, and many DVTs progress to PE without the DVT being clinically apparent, and in those with classic clinical signs, only about 1/3 have DVT
17
Q
What are the classical clinical features of DVT?
A
- Limb pain and tenderness along the line of the deep veins
- Swelling of the calf or thigh
- Pitting oedema
- Distention of superficial veins
- Increase in skin temperature
- Skin discolouration
- Palpable cord
18
Q
Is swelling of the calf or thigh usually unilateral or bilateral in DVT?
A
Unilateral
19
Q
What colour might the skin be in DVT?
A
Erythematous, or occassionally purple/cyanosed
20
Q
What is a palpable cord?
A
A hard, thickened, palpable vein
21
Q
What condition can sometimes complicate a diagnosis of DVT?
A
Cellulitis
22
Q
Why can cellulitis sometimes complicate a diagnosis of DVT?
A
- Severe signs of DVT can resemble cellulitis
- Secondary cellulitis may develop with a primary DVT
- Primary cellulitis may be followed by a secondary DVT
- Superficial thrombophlebitis may hide an underlying DVT
23
Q
What are the differential diagnoses of DVT?
A
- Trauma
- Superficial thrombophlebitis
- Post-thrombotic syndrome
- Peripheral oedema
- Heart failure caused by heart failure, cirrhosis, or nephrotic syndrome
- Arteriovenous fistula and congenital vascular abnormalities
- Vasculitis
- Ruptured Baker’s cyst
- Cellulitis
- Septic arthritis
- Compartment syndrome
24
Q
What has been developed as a result of the unreliability of the clinical features of DVT?
A
Several diagnostic scoring systems
25
What do diagnostic scoring systems for DVT do?
Classify patients as having high, intermediate, or low possibility of developing DVT, based on history and clinical examination
26
What scores 1 point on the Well's score?
Each of;
* Entire leg swollen
* Calf swelling by more than 3cm compared with asymptomatic leg (measured 10cm below tibial tuberosity)
* Pitting oedema confined to symptomatic leg
* Localised tenderness along the distribution of the deep venous system (such as the back of the calf)
* Recently bedridden for three days or more, or major surgery within the previous 12 weeks requiring general or regional anaesthesia
* Previously documental DVT
* Collateral superficial veins
* Active cancer
* Paralysis, paresis, or recent plaster immobilization of the legs
27
What do you do if an alternative cause is at least as likely as DVT in the Well's score?
Subtract 2 points
28
What Well's score indicates that DVT is likely?
2 or more
29
What should all patients in whom DVT is suspcted, and with a Well's score of 2 or more be offered?
A proximal leg vein ultrasound scan within 4 hours, and then a D-dimer test if the result is negative
*or*
A D-dimer with interim 24-hour dose of parenteral anticoagulation if an ultrasound scan cannot be carried out within 4 hours. This should be followed by an ultrasound scan within 24 hours
30
What should all patients in whom DVT is suspected with a Well's score of 0 or 1 be offered?
A D-dimer test
31
What should patients with suspected DVT, Well's score of 0 or 1, and a positive D-dimer test be offered?
A proximal leg ultrasound scan.
If the ultrasound scan is not available within 4 hours, an interim 24-hour dose of parenteral anticoagulant should be offered
32
What should DVTs be diagnosed and treated on the basis of?
A positive proximal leg vein ultrasound scan
33
What are D-dimers?
Specific cross-linked products of fibrin degradation
34
How are D-dimers used diagnostically in DVT?
They are raised in VTE, with a high sensitivity but poor specificity
35
Why does D-dimer testing have a poor specificity?
Because high concentrations occur in other disorders, such as malignancy, pregnancy, and other conditions where clots form, such as after surgery
36
What should all patients diagnosed with an unprovoked DVT or PE be offered?
Investigations for cancer,
37
What investigations for cancer should be offered in patients who have had an unprovoked DVT or PE?
* Physical examination
* CXR
* Blood tests - FBC, calcium, LFTs
* Urinalysis
Consider further investigations, e.g. abdomino-pelvic CT scan, mammogram, in all patients over 40
38
Give two examples of specific conditions that cause DVT that you might choose to test for while investigating a cause
* Antiphospholipid syndrome
* Hereditary thrombophilia
39
How quickly should people who are likely to have a DVT be assessed and managed?
Same day
40
What should be offered to patients with confirmed proximal DVT or PE?
LMWH or fondaparinux
41
What should be taken into account when offering patients with confirmed proximal DVT or PE LMWH?
Co-morbidities and contraindications
42
How quickly should LMWH be started in patients with confirmed proximal DVT or PE?
As soon as possible
43
How long should LMWH be continued for in patients with confirmed DVT or PE?
At least 5 days, or for those starting warfarin until INR is 2 or above for at least 24 hours - whichever is longer
44
How soon after confirmed DVT or PE should oral anticoagulants be offered?
Within 24 hours after diagnosis
45
How long after DVT or PE should oral anticoagulation be continued?
3 months
46
What are the options for oral anticoagulation in DVT/PE?
* Warfarin
* Rivaroxiban
* Dabigatran
* Apixiban
47
What should be done 3 months after starting oral anticoagulation for DVT/PE?
Should assess the risks and benefits of continuing anticoagulant treatment
48
When should you consider continuing oral anticoagulation beyond 3 months after DVT/PE?
In patients with unprovoked proximal DVT if their risk of VTE is high, and there is no additional risk of major bleeding
49
What is heparin?
Heparin is a injectable, rapidly acting anticoagulant that is often used acutely to interfere with the formation of thrombi
50
How does heparin occur naturally?
As a macromolecule complexed with histamine in mast cells
51
What is the physiologic role of heparin?
Unknown
52
What is heparin used for?
* Prevention of venous thromboembolism
* Treatment of a variety of thromboembolic diseases, such as pulmonary embolism and acute MI
53
What is unfractionated heparin?
A mixture of straight chain, anion glycosaminoglycans with a wide range of molecular weights
54
Why is unfractionated heparin strongly acidic?
Because of the presence of sulfate and carboxylic acid groups
55
What is LMWH also known as?
Enoxaparin
56
What is LMWH?
A heterogenous group of compounds that are 1/3 of the size of unfractionated heparin
57
How is LMWH produced?
By chemical or enzymatic depolymerisation of unfractionated heparin
58
What is the advantage of heparin over LMWH?
Speedy onset of action
59
Why are LMWH becoming the preferred agent over heparin?
* They can be conveniently injected subcutaneously on a patient weight-adjusted basis
* They have predictable therapeutic effects
* They have a more predictable pharmacokinetic profile
60
What is the result of LMWH being more predictable?
They do not need the same intense monitoring that heparin needs, subsequently saving laboratory costs as well as nursing time and costs
61
What is the mechansim of action of heparin?
Heparin acts at a number of molecular targets, but it's anticoagulant effect is a consequence of binding to antithrombin III, with the subsequent rapid inactivation of coagulation factors
It also acts as a catalyst for the interaction antithrombin III and activated coagulation factors
62
What happens when heparin binds to antithrombin III?
Heparin induces a conformational change in antithrombin III which accelerates it's rate of action by about 1000x
63
64
What is the result of the heparin acting as a catalyst for the interaction of antithrombin III and activated coagulation factors?
It allows antithrombin III to rapidly combine with, and inhibit, circulating thrombin and factor Xa
65
What is the mechanism of action of LMWH?
They complex with antithrombin III to inactive factor Xa, *but this complex does not bind as avidly to thrombin*
66
What is the result of LMWH not causing as much inhibition to thrombin as heparin?
LMWHs are less likely to activate resting platelets
67
What is antithrombin III?
An alpha-globulin
68
What does antithrombin III do\>?
Inhibits serine proteases, including several clotting factors, including thrombin (IIa) and factor Xa
69
How does antithrombin III act in the absence of heparin?
It interacts very slowly with thrombin and factor Xa
70
What are the therapeutic applications of heparin?
* Anti-thrombotic drug for the treatment of acute DVT and PE. Also decreases the incidence of recurrent thromboembolic episodes.
* Prophylaxis to prevent post-operative venous thrombosis in patients undergoing elective surgery, and those in acute phase of MI
* Preventing thrombosis in extra-corpreal devices, e.g. dialysis machine
* Anticoagulation in pregnant women with prosthetic heart valves or VTE
71
Why is heparin used in the anticoagulation of pregnant women?
Because it does not cross the placenta, due to it's large size and negative charge
72
What is the chief complication of heparin use?
Haemorrhage
73
What is required to minimise the problem of haemorrhage with heparin?
Careful monitoring of bleeding time
74
How is excessive bleeding caused by heparin administration managed?
Cessation of the drug, or with administration of protamine sulfate
75
How does protamine sulfate work?
When infused slowly, it combines ionically with heparin to form a stable 1:1 inactive complex.
76
How is protamine sulfate administered?
IV
77
How long does the onset of action of protamine sulfate normally take?
5 minutes
78
What does of protamine sulfate is administered?
1mg of protamine sulfate per 100 units of heparin
79
Why is it very important to titrate the dose of protamine sulfate?
Because protamine sulfate is a weak anticoagulant, so excess amounts may trigger bleeding episodes, or worsen bleeding potential
80
Other than bleeding potential, what are the adverse effects of protamine sulfate?
* Hypersensitiivty
* Thrombocytopenia
* Abnormal liver function tests
* Osteoporosis in long-term therapy
81
How long does the anticoagulation effect of heparin take?
It occurs within minutes of IV administration, or 1-2 hours after SC injection
82
When does the maximum anti-factor Xa activity of LMWH occur?
About 4 hours after SC injection
83
How is heparin administered?
It must be given parenterally, either by SC injection or IV
84
Why must heparin be administered parenterally?
Because it does not readily cross membranes
85
How is immediate anticoagulation achieved with heparin?
Administration in an IV bolus
86
What is given after immediate anticoagulation is achieved using an IV bolus?
Lower doses, or a continuous infusoin of heparin, for 7-10 days
87
How is the dose of heparin titrated after a DVT/PE?
It is titreated so the aPTT is 1.2-2.5% normal
88
How are LMWH administered?
SC
89
Is it necessary to monitor aPTT with LMWH?
Not usually
90
Why is it not usually necessary to monitor aPTT with LMWHs?
As the plasma levels and pharmacokinetics are predictable
91
What happens to heparin in the blood?
It binds to many proteins that neutralise it's activity
92
What results from heparin binding to proteins that neutralise it's activity in the blood?
* Resistance to the drug
* Unpredictable pharmacokinetics
93
In which patients is heparin binding to plasma proteins variable?
Patients with thromboembolic diseases
94
Where does heparin distribute in the body?
It is generally restricted to the circulation
95
How is heparin inactivated in the body?
It can be taken up by the monocyte/macrophage system, where it undergoes depolymerisation and desulfation to inactive products
96
What is the result of heparin being inactived by the monocyte/macrophage system?
Heparin has a longer half-life in patients with hepatic impairment
97
How is heparin, LMWH, and inactive metabolites excreted from the body?
Urine
98
What is the result of heparin and LMWH being excreted to urine?
Renal insufficient prolongs the half life
99
What is the half life of heparin?
1.5 hours
100
What is the half life of LMWH?
3-7 hours
101
Does heparin dose need to be adjusted in renal impairment?
Yes
102
What is warfarin?
A coumarin anticoagulant that antagonises the cofactor function of vitamin K
103
Why is the clinical use of warfarin decreasing?
Because of the increasing availability of LMWHs and platelet aggregate inhibitors, which are preferred due to the potential morbidity assocatied with the use of warfarin
104
What monitoring is required in warfarin?
Careful monitoring of INR
105
Does careful monitoring of INR in warfarin prevent bleeding complications?
No, not in many patients
106
How is vitamin K involved in coagulation?
Several of the protein coagulation factors require vitamin K cofactor dependent post-translational modification
107
Which protein coagulation factors require vitamin K as a cofactor?
* II
* VII
* IX
* X
108
What happens in vitamin K cofactor dependent post-translational modification?
A number of the protein coagulation factors' glutamic acid resiudes are carboxylated to form gamma-carboxyglutamic acid residues
109
What is the importantance of gamma-carboxyglutamic acid residues on coagulation factors?
They bind calcium ions, which are essential for the interaction between the coagulation factors and platelet membranes
110
What happens in the carboxylation reaction of protein coagulation factors?
Vitamin-K dependant carboxylase adds CO2 to form a COOH group on glutamic acid. The reduced vitamin K cofactor is converted to vitamin K epoxide in the reaction
111
How is vitamin K regenerated from vitamin K epoxide?
By the enzyme vitamin K epioxide reductase
112
What is the clinical importance of vitamin K epoxide reductase?
This is the enzyme that warfarin inhibits
113
What does warfarin treated result in, in terms of clotting factors?
The production of clotting factors with reduced activity (10-40% normal) due to the lack of sufficient gamma-carboxyglutamic acid side chains
114
How long does it take for warfarin to take effect?
The effects of warfarin are not seen for 8-12 hours after drug administration, and peak effects may be delayed by 72-96 hours
115
Why is the onset of action of warfarin delayed?
As this is the time it takes to deplete the pool of circulating clotting factors
116
How can the anticoagulation effects of warfarin be overcome?
Administration of vitamin K
117
How long does vitamin K reversal of warfarin action take?
24 hours
118
Why does vitamin K reversal of warfarin take 24 hours?
Because this is the time necessary for the degradation of already synthesised clotting factors
119
What are the indications for warfarin therapy?
* DVT and PE
* Atrial fibrillation
* Mechanical prosthetic valves
* Thrombosis associated with inherited thrombophilia conditions
* Cardiac thrombus
* CVA, especially with AF
* Cardiomyopathy
120
What is the principle adverse effect of warfarin?
Haemorrhage
121
What is important as a result of the risk of haemorrhage on warfarin?
To frequently monitor and adjust the anticoagulnt effect
122
How can minor bleeding on warfarin be manged?
Withdrawl of the drug and administration of oral vitamin K
123
How is severe bleeding on warfarin managed?
Greater doses of vitamin K given IV
Whole blood, frozen plasma, and plasma concentrates of blood factors may also be used for rapid reversal
124
Give 2 rare complications of warfarin
* Skin lesions
* Necrosis
125
What is purple toe syndroem?
A painful, blue-tinged discolouration of the toe caused by cholesterol emboli from plaques, which has been observed with warfarin therapy
126
What factors can alter warfarins therapeutic response?
* Drugs
* Changes in environment
* Diet
* Physical state
127
By what mechanisms can drugs increase the action of warfarin
* Inhibition of hepatic metabolism
* Inhibition of platelet function
* Reduction of vitamin K from gut bacteria
* Albumin displacement
* Decrease GI absorption of vitamin K
128
Give 5 drugs that inhibit hepatic metabolism to interact with warfarin
* Amiodarone
* Quinolone
* Metronidazole
* Cimetidine
* Alcohol (acute intoxication)
129
Give an example of a drug that inhibits platelet function to interact with warfarin
Aspirin
130
Give an example of a drug that reduces vitamin K from gut bacteria to interact with warfarin
Cephalosporin antibiotics
131
Give an example of a drug that causes albumin displacement to interact with warfarin
NSAIDs
132
How do drugs that cause albumin displacement or decrease the GI absorption of vitamin K vary in their interaction compared to other mechanisms?
They have less of an effect
133
Give 3 examples of drugs that inhibit the action of warfarin?
* Anti-epileptics, except sodium valproate
* Rifampicin
* St Johns Wort
134
How do drugs that inhibit the action of warfarin do so?
Most of these drugs work by inducing hepatic enzymes, thereby increasing the metabolism of warfarin
135
What disease states can affect the therapeutic action of warfarin?
* Vitamin K deficiency
* Hepatic diseases that impair synthesis of clotting factors or affects warfarin metabolism
* Hypermetabolic setates
* Neoplastic disease
* Hyperlipidaemia
* Hypothyroidism
136
What are the contraindications to warfarin use?
Pregnancy
137
Why should warfarin never be used in pregnancy?
Because it is teratogenic, and can cause abortion of birth defects
138
What should be used instead of warfarin if anticoagulant therapy is needed during pregnancy?
Heparin or LMWH
139
Is warfarin rapidly absorbed after oral administration?
Yes
140
What is the oral bioavailability of warfarin?
100%
141
What effect does food have on the absorption of warfarin?
It may delay absorption, but it does not affect the extent of absorption
142
What % of warfarin is bound to plasma albumin?
99%
143
What is the result of the high protein binding of warfarin on its distribution?
It prevents diffusion into CSF, urine, and breast milk
144
Can warfarin be displaced from it's albumin binding site?
Yes, drugs that have a higher affinity for the binding site can displace it
145
What happens when warfarin is displaced from it's albumin binding sites by drugs with a higher affinity?
It leads to a trasient elevated activity
146
What problems can drugs that affect warfarin binding to plasma proteins cause?
Drug interactions and viability in the therapeutic response to warfarin
147
What is the half-life of warfarin?
The average half life is about 40 hours, but this is highly variable among individuals
148
How is warfarin metabolised?
By the CYP450 system
149
What is warfarin metabolised to?
Inactive metabolites
150
What happens to the inactive metabolites of warfarin?
After conjugation to glucuronic acid, they are excreted in uine and faeces
151
What is INR?
A measure adopted to measure warfarin concentration
152
What is the purpose of measuring warfarin using INR?
It corrects for variations that would occur with various thromboplastin reagents, among difficult hospitals or the same hospital when they recieve new batches of reagent
153
Why is it important INR is maintained within the optimal range?
Because warfarin has a narrow therapeutic index
154
Other than INR, what can be used to measure warfarin therapy?
The prothrombin time
155
What is prothrombin time a measure of?
The extrinsic pathway
156
What INR range should be aimed for in DVT?
2.0-3.0
157
What INR range should be aimed for in atrial fibrillation?
2.0-3.0
158
What INR range should be aimed for in atrial fibrillation?
2.0-3.0
159
What INR range should be aimed for in mechanical prosthetic valves?
2.5-4.5
160
What INR range should be aimed for in patients with recurrent thrombosis on warfarin?
2.5-4.5
161
What INR range should be aimed for in thrombosis associated with inherited thrombophilia conditions?
2.5-4.5
162
How should should warfarin therapy be continued for after DVT?
3-6 months
163
How should should warfarin therapy be continued for after PE?
6 months
164
How should should warfarin therapy be continued for in atrial fibrillation?
Until risk \> benefit
165
What is rivaroxiban?
An oral anticoagulant medication
166
What is the mechanism of action of rivaroxiban?
It is a highly selective inhibitior of both free factor Xa and factor Xa bound to the prothrombinase complex. Through this, it interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting thrombin formation and the development of thrombi
167
What is the advantage of rivaroxiban over warfarin?
It provides predictable anticoagulation, so dose adjustment, routine coagulation monitoring, and dietary restrictions are not needed
168
What is the most serious adverse effect of rivaroxiban?
Bleeding, including severe internal bleeding
169
How does the bleeding risk of rivaroxiban compare to warfarin?
It is associated with higher risks of bleeding in the GI tract
170
Is there an antidote for rivaroxiban?
No
171
What is the problem with there not being an antidote for rivaroxiban?
Serious bleeding may be more difficult to manage
172
In what patients does rivaroxiban have predictable pharmacokinetics?
A wide spectrum of patients, irrespective of age, gender, weight, and race
173
Over what dose range does rivaroxiban have a flat rose response?
5-40mg
174
How long does the effects of rivaroxiban last for?
Approx 8-12 hours, but factor Xa activity does not return to normal within 24 hours
175
What is the result of factor Xa not returning to normal under 24 hours after rivaroxiban?
Dose daily dosing is possible
176
How are DVTs prevented?
* Avoid dehydration
* Encourage early mobilisation
* Stop oral contraceptives or HRT containing oestrogen 4 weeks before surgery
* Mechanical prophylaxis
* Pharmacological prophylaxis
177
Wbat is the purpose of vena cava filters?
They stop a DVT developing into a PE
178
When should a temporary inferior vena cava filter be considered?
In patients with very high risk of VTE, if there are contraindications to pharmacological and mechanical prophyalxis
179
What can be used in the mechanical prophylaxis of DVT?
* Graduated compression stockings
* Intermittent pneumatic compression
* Foot impulse devices
180
How can graduated copmresion stockings be used to decrease the risk of DVT?
Either alone or in combination with pharmacological prophylaxis in high risk patietns
181
Should graduated compression stockings be used routinely for surgical inpatients?
Yes
182
What should staff members trained in the use of compression do when a patient is given compression stockings?
* Show the patient how to wear them correctly
* Monitor their use
* Provide assistance when needed
183
How long should patients be advised to wear graduated compression stockings for?
From admission until they return to their normal level of mobility
184
Give two conditions where the use of graduated compression stockings is contraindicated?
* Established PVD
* Diabetic neuropathy
185
When can intermittent pneumatic compression or foot impulse devices be used?
Instead of, or as well as, graduated compression stockings while patients are in hospital
186
How long should intermittent pneumatic compression or foot impulse devices be used for?
As long as possible before surgery
187
What are the options for pharmacological prophylaxis of DVT?
* Fondaparinux sodium
* Low molecular weight heparin, or synthetic alternatives
* Unfractionated heparin
188
What should the choice of pharmacological prophylaxis for DVT depend on?
* Co-morbidities, e.g. CKD
* Patient's wishes
* Local policies
189
What should always be considered when giving thromboprophylaxis?
The risk of bleeding
190
What is the recurrence rate of first episode DVT or PE without anticoagulation?
50%
191
What is the most serious complication of DVT?
PE
192
In what kind of DVT is the risk of PE higher?
Proximal PE
193
What is post-thrombotic system?
Chronic venous hypertension
194
What can post-thrombotic system result in?
* Pain
* Swelling
* Hyperpigmentation
* Dermatitis
* Ulcers
* Gangrene
* Lipodermatosclerosis
195
Why might post-thrombotic syndrome develop after DVT?
Due to damage to the deep veins and their valves
196
What % of DVT patients are affected by post-thrombotic syndrome?
20-40%
197
What are the risk factors for post-thrombotic syndrome?
* Older age
* Obesity
* History of previous ipsilateral DVT
* Iliofemoral location of DVT
* Failure to recover promptly from acute symptoms
* Insufficient quality of oral anticoagulant therapy
