Core Topics in General & Emergency Surgery: Companion to Specialist Surgical Practice (69 page)
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Authors: Simon Paterson-Brown MBBS MPhil MS FRCS
Table A31
Penis injury scale
*
Advance one grade for multiple injuries up to grade III.
Reproduced from Moore EE, Malangoni MA, Cogbill TH et al. Organ Injury Scaling VII: cervical vascular, peripheral vascular, adrenal, penis, testis and scrotum. J Trauma 1996; 41(3):523–4. With permission from Lippincott, Williams & Wilkins.
Table A32
Peripheral vascular organ injury scale
*
Increase one grade for multiple grade III or IV injuries involving > 50% vessel circumference. Decrease one grade for < 25% vessel circumference disruption for grades IV or V.
Reproduced from Moore EE, Malangoni MA, Cogbill TH et al. Organ Injury Scaling VII: cervical vascular, peripheral vascular, adrenal, penis, testis and scrotum. J Trauma 1996; 41(3):523–4. With permission from Lippincott, Williams & Wilkins.
prevention, diagnosis and treatment
Rhona M. Maclean
Venous thromboembolism (VTE) is the most common cause of preventable death in hospitalised patients, with an estimated 25 000 patients dying from preventable hospital acquired VTE in the UK each year.
1
The two most common manifestations of venous thrombosis are deep vein thrombosis (DVT) and pulmonary embolism (PE), both of which are associated with significant morbidity (post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension respectively). As surgery is associated with a high risk of postoperative VTE, evidence-based thromboprophylaxis strategies should be employed to reduce this risk, and those patients with symptoms and/or signs suggestive of VTE should be thoroughly investigated and managed accordingly.
The incidence of a first episode of VTE is estimated at 1–2 per 1000 person-years in white Caucasians, with a lower incidence in Hispanics and Asians.
2,
3
The risk of VTE increases progressively with age, with an incidence of > 5/1000 person-years in those over the age of 80.
3
The incidence of VTE is approximately equal in men and women; however, it is more frequent in women in the childbearing years, likely due to the use of the hormonal therapies (the combined oral contraceptive pill and hormone replacement therapy) and pregnancy, whereas after the age of 45 incidence rates are generally higher in men. Clinical studies, excluding autopsy data, have consistently shown that the incidence of DVT is approximately twice that of PE.
2,
3
It has been estimated that there are over 130 000 cases of VTE in the UK each year, at a cost (direct and indirect) of around £640 million annually.
4
DVT and PE are the result of the same disease process, VTE; of patients presenting with symptomatic PE, up to 80% will have asymptomatic DVT, and in those presenting with symptomatic DVT, 50–80% can be shown by imaging to have PE.
5
Approximately half of VTE episodes are idiopathic in nature (defined as having had no recent surgery, trauma, cancer, pregnancy or immobilisation), the remainder presenting after an obvious precipitating event.
2,
3
Of patients diagnosed with VTE, the majority (73.7%) present as outpatients and of these a significant proportion have either undergone surgery (23.1%) or been hospitalised (36.8%) in the preceding 3 months.
6
Presentation with VTE after surgery peaks at 21 days postoperatively, with the risk remaining significantly increased for 3 months after surgery.
7
VTE is associated with a surprisingly high mortality. In a retrospective epidemiological study, the 30-day fatality rate was 4.6% following DVT and 9.7% with PE.
3
Cancer was associated with a worse outcome, with a 30-day fatality rate of 19.1%. Mortality rates associated with PE are high, with approximately 25% of patients dying within a year, many due to malignancy, others from cardiopulmonary disease or recurrent VTE.
7
Overall, pulmonary emboli are thought to be responsible for 10% of hospital inpatient deaths,
8
with many diagnosed for the first time at post-mortem.
9
Thrombosis in the deep veins damages the deep venous valves, resulting in post-thrombotic scarring, stiffening of the vessel wall, venous insufficiency, reflux and venous hypertension, all of which can result in swelling, pain and heaviness in the affected leg – the post-thrombotic syndrome. In its severe form, this causes marked skin changes – lipodermatosclerosis (varicose eczema and atrophy of the subcutaneous tissues), hyperpigmentation and ulceration – and can be a major cause of morbidity. The incidence of the post-thrombotic syndrome has been reported at approximately 28% after 5 years, with 9% having a severe form.
7
Up to 5% of patients with PE will develop pulmonary hypertension.
7
Thrombus formation
DVTs usually start in the calf veins, and thrombi developing after surgery often originate in the valve cusps of the soleal veins. These thrombi are initially formed of red blood cells caught in a fibrin mesh, which then incorporate platelets and fibrin into the clot, propagating proximally to form a free-floating thrombus, or extending to occlude the vein.
10,
11
Many such thrombi start to develop intraoperatively; of these, half will resolve spontaneously within 72 hours and 18% will extend proximally, of which 50% will embolise. Some thromboses, however, begin postoperatively; 20–34% of patients diagnosed as having DVT by screening tests in hospital had been shown to have legs free of thrombosis postoperatively. It has been estimated that 10% of symptomatic PEs cause death within 1 hour of onset (
Box 14.1
). There is an ongoing debate as to the significance of calf vein thrombosis and whether, if detected, it should be treated. A recent study of isolated symptomatic muscular calf vein thromboses suggested that they are not as innocuous as originally thought; 7% of patients had symptomatic PEs at presentation, and after completing 1–3 months of anticoagulation, 18% had recurrent episodes of VTE within 3 years.
12
Box 14.1
Natural history of venous thromboembolism
The majority of deep vein thrombosis (DVT) originates within the calf veins
About half the episodes of DVT associated with surgery start intraoperatively, of which 50% resolve spontaneously within 72 hours
Those with persisting risk factors or those with a large initial thrombosis are at highest risk of progression of postoperative DVT
Symptomatic risk of venous thromboembolic disease is highest within 2 weeks of surgery but patients remain at high risk of VTE for 3 months postoperatively
Approximately 25% of episodes of untreated symptomatic calf DVT extend to the proximal veins within 1 week of presentation
Without treatment approximately 50% of patients with symptomatic proximal DVT or pulmonary embolism will have a recurrent thrombosis in 3 months
The mortality associated with PE is estimated to be 5–25%. The greatest risk of fatal postoperative pulmonary embolism occurs 3–7 days after surgery and 10% of symptomatic DVTs are fatal within 1 hour of first symptoms
Isolated calf DVT is associated with half the risk of recurrence of proximal DVT or pulmonary embolism
The risk of recurrence is similar following proximal DVT and pulmonary embolism
If a first thrombosis was a DVT, it is likely that a recurrence is a DVT. Similarly, if a first VTE was a PE, it is likely that a recurrence will be a PE
Pulmonary hypertension will develop in approximately 5% of patients with pulmonary embolism
In the 1860 s, Virchow described three factors implicated in the development of a venous thrombosis: slowing of venous blood flow (stasis), damage to the vessel wall (venous injury), and changes in the blood that increase the propensity to develop thrombosis (hypercoagulability). These are now widely known as Virchow's triad, and this model remains a valid concept today.
Stasis, the slowing of venous return, is associated with an increased risk of VTE (stroke patients have an increased risk of DVT in the paralysed limb
13
). It has been demonstrated that intraoperative paralysis causes ‘microtears’ in the venous endothelium, exposing circulating blood to procoagulant components in the subendothelium (e.g. collagen, von Willebrand factor, tissue factor).
14
Stasis, in and of itself, is likely to be insufficient to cause VTE, and most patients with significant immobility are likely to have a systemic illness, increasing the risk of VTE by other mechanisms.
Surgery or trauma cause venous injury, which increases the risk of venous thrombosis. Inflammatory cytokines also induce venous injury by down-regulating thrombomodulin, impairing fibrinolysis, stimulating tissue factor expression on monocytes or endothelial cells, and inducing apoptosis of endothelial cells, rendering them thrombogenic.
15
Hypercoagulability, both inherited and acquired, has been demonstrated to significantly influence the development of VTE. Studies undertaken in families in whom multiple members have presented with VTE have identified a number of inherited thrombophilias.
Inherited thrombophilias
Antithrombin (AT) is an anticoagulant protein, whose function is predominantly to inactivate thrombin and activated coagulation factor X, thereby limiting ongoing thrombus propagation.
AT deficiency
is found in 1% of consecutive patients presenting with VTE and increases the risk of VTE five- to 50-fold.
16,
17
Acquired AT deficiency can occur in a number of different clinical situations, including liver disease, sepsis, acute thrombosis, disseminated intravascular coagulation (DIC) and nephrotic syndrome.
Proteins C and S are both vitamin K-dependent proteins; their activity will be reduced by vitamin K antagonist anticoagulants(such as warfarin and sinthrome). The activated protein C/protein S complex inactivates coagulation factors V and VIII, also limiting ongoing thrombus propagation.
Inherited protein C deficiency
increases the risk of VTE six- to 15-fold and is found in 1–3% of patients presenting with VTE.
16
Protein S deficiency
is present in 1–3% of patients with VTE. Liver disease, sepsis, DIC and acute thrombosis reduce the levels of proteins C and S, resulting in acquired hypercoagulability.
Factor V Leiden
, a mutation of the factor V gene, is the most common inherited thrombophilia, present in 5% of the Caucasian population (and < 1% of Africans/South East Asians). It renders activated factor V relatively resistant to inactivation by the activated protein C/protein S complex, and confers an eightfold increased risk of VTE in the heterozygous form (80-fold increased risk in the homozygous form). In Caucasian populations, factor V Leiden is found in > 20% of unselected patients presenting with VTE.
16
The prothrombin gene mutation (G20210A) is less prevalent, found in 1% of the general population, and confers a threefold increased risk of VTE. It is found in 5–6% of unselected patients with VTE.
16
Classical homocystinuria causes extremely high levels of plasma homocysteine and is associated with both venous and arterial thrombosis in addition to the other classical disease manifestations (mental retardation, seizures, musculoskeletal abnormalities, eye anomalies including lens dislocation). Neither the common mutation in the methylene tetrahydrofolate reductase gene (
MTHFR C677T
) nor mild elevations in homocysteine levels are associated with thrombosis.
18
Testing for inherited thrombophilia, whilst frequently undertaken, rarely helps in the management of patients with VTE. Such testing should usually only be performed in young individuals with a personal history of VTE who have a history of VTE in a first-degree relative. Testing should not usually be done while a patient is taking anticoagulant therapy.
19
Elevated factor VIII levels have been demonstrated to increase the risk of developing a first VTE, and also increase the risk of recurrent thrombosis.
16,
20
Association and linkage studies have identified a number of other proteins associated with VTE. This includes high levels of the coagulation factors fibrinogen, prothrombin, IX, XI and von Willebrand factor. There is also an association between VTE and platelet glycoprotein VI, blood group O and deficiencies of proteins associated with fibrinolysis (plasminogen and plasminogen-activated inhibitor-1 (PAI-1)). These proteins are associated with a weak increased risk of thrombosis (1.1- to 2.5-fold).
16,
21,
22
Antiphospholipid syndrome (APLS)
Diagnosis of the APLS requires the presence of both clinical (arterial or venous thrombosis or recurrent miscarriage) and laboratory (persistent detectable antiphospholipid antibodies such as lupus anticoagulant or anticardiolipin or anti-β2-glycoprotein 1 antibodies) criteria. The mechanism of these antibodies in the development of thrombosis has not been established; however, a number of hypotheses have been suggested, including the interference of antibodies with anticoagulant mechanisms, triggering procoagulant changes in leucocytes, platelets or endothelial cells, or activation of complement triggering an inflammatory reaction.
23
Patients with a diagnosis of APLS who have had a thrombosis should be therapeutically anticoagulated long term (usually with warfarin, target international normalised ratio (INR) 2.5).
23
HIT is a rare but life-threatening complication of heparin therapy; it confers a high risk of thrombosis (30–75%), and has a significant morbidity and mortality. It occurs more frequently in patients receiving unfractionated heparin (UFH) than low-molecular-weight heparin (LMWH), and the highest risk is in those who have had cardiothoracic surgery. General surgical patients receiving LMWH have a < 1% risk of developing HIT. The platelet count characteristically falls by ≥ 50% from baseline (rarely below 20 × 10
9
/L) between days 5 and 10 of heparin therapy. Less often, if a patient has received heparin within the last 100 days, HIT can present acutely after heparin administration with systemic symptoms (rigors, cardiorespiratory distress). Skin lesions at the site of heparin injections have also been shown to be associated with HIT.
24
Half of patients with HIT will develop thrombosis, and unless heparin is stopped and alternative anticoagulation commenced, there is a considerable risk of further thrombosis developing.
25
HIT is rarely associated with bleeding and so platelet transfusions should not be given due to the risk of thrombosis,
25
unless there is active bleeding.
Patients receiving heparin should have a platelet count checked on the day treatment is started, after 24 hours of therapy (if exposed to heparin within the previous 100 days) and thereafter every 2–4 days until day 14. If the platelet count falls by ≥ 50% of baseline or the patient develops new venous or arterial thrombosis or skin allergy, then a diagnosis of HIT should be considered and a clinical assessment undertaken; advice should be sought from haematology. If the diagnosis of HIT is thought to be likely, heparin should be stopped (including heparin flushes) and, due to the high risk of thrombosis, an alternative anticoagulant (e.g. danaparoid, argatroban or fondaparinux) should be commenced, pending the results of further investigations. Again, in such circumstances the advice of a haematologist is essential. Warfarin should not be started until the platelet count has fully recovered, and care should be taken to continue an additional anticoagulant until the INR is > 2.0 for 2 days.
Age
Age is an important risk factor for VTE, with many studies showing an increased risk in patients over 40 years of age and considerably greater in those > 70 years of age.
26
It is likely that this is a reflection of medical comorbidities, immobility and coagulation activation.
Those with a body mass index (BMI) of over 30 kg/m
2
have a two- to threefold increased risk of VTE. As with age, it is thought that this might be a reflection of immobility and coagulation activation.
26
A history of VTE in a first-degree family member (aged < 50 years) confers an increased risk of developing a VTE.
27
Hospitalisation itself is associated with an eightfold increased risk of VTE, with specific patient groups being at particularly high risk. Congestive cardiac failure, acute infection, central venous access, paralytic stroke, nephrotic syndrome, cancer and chemotherapy are all moderate risk factors for VTE (odds ratio 2–9).
28
It has therefore been proposed that hospitalised medical patients are risk assessed for their level of risk of developing VTE (NICE guideline,
29
SIGN guideline,
30
ACCP guideline
8
).
Cancer is strongly associated with VTE; 15% of patients with VTE have malignancy and 2–3% of patients with VTE are newly diagnosed with malignancy at presentation. Patients with certain cancers (stomach, lung, breast, pancreas, gynaecological, lymphoma) are at particularly high risk of thrombosis, thought to be caused by tissue factor-like substances and microparticles activating the coagulation cascade. Surgery and immobilisation further increase this patient group's risk of thrombosis.
The risk of VTE is increased two- to fourfold in users of the cOCP.
31
The risk is highest in the first year of use, diminishes thereafter, and is reduced by the use of the lower dose oestrogen preparations. Obese women (BMI > 30) have a twofold increased risk of VTE, but a 10-fold increased risk if taking the cOCP. The risk of VTE after surgery in women taking the cOCP is increased 2.5-fold. There is no evidence that the progesterone-only contraceptive increases the risk of VTE. Women with thrombophilia (antithrombin, protein C or S deficiencies, factor V Leiden of the prothrombin gene variant) who take the cOCP are at particularly high risk of VTE.
32
More recently, transdermal contraceptive patches have been introduced containing both oestrogen and progestogen, but the risk of VTE with these preparations appears to be similar to the oral preparations.
33
HRT is associated with a two-to fourfold increased risk of VTE in women using HRT compared with non-users.
32
–
34
As with the cOCP, the risk is highest in the first year of HRT,
35
and there is a synergistic effect with the inherited thrombophilias.
36
Unlike the cOCP, there appears to be a lower risk of VTE when the transdermal route is used compared with oral preparations.
37
VTE is a leading direct cause of maternal death in the UK, primarily due to pulmonary embolism. There is a 10-fold increased risk of VTE in pregnancy and a 25-fold increased risk during the puerperium. Many of these thrombotic events are preventable by the use of appropriate thromboprophylaxis
38
and it therefore follows that all pregnant women, including those in the postpartum period, should be considered ‘at risk’ of VTE if admitted with an acute illness, and given thromboprophylaxis unless contraindicated. Low-molecular-weight heparins are safe to use in pregnancy as they do not cross the placenta into the foetal circulation.
Travel of long duration is a relatively weak risk factor for VTE, with risks higher in those with pre-existing risk factors. Studies that have investigated the role of risk factors in travel-related thrombosis have mentioned the role of recent trauma or surgery, in addition to obesity, cancer and hormone therapy. It is important to remember that the risk of developing symptomatic VTE after long-duration travel remains increased in the 8 weeks after the flight.
39
–
41
Superficial thrombophlebitis (STP) of the lower leg is a significant risk factor for VTE and a large prospective epidemiological study found that 3.3% of patients with STP develop symptomatic VTE if untreated. Those with STP > 5 cm in length were more likely to have associated DVT if the STP was in the proximal long saphenous vein. STP within a varicose vein was less likely to be associated with DVT.
42
One-third of patients with VTE will have had surgery in the preceding 3 months, with the risk greatest following major abdominal and pelvic surgery (especially if associated with malignancy), and major orthopaedic procedures. Without appropriate thrombosis prevention strategies, 60–80% of such patients will develop venous thrombosis.
8
Major trauma is also associated with a very high risk of VTE. It has been recognised that, in addition to the surgical procedure itself, a number of other factors increase the risk of thrombosis in the surgical patient (
Box 14.2
). It is also now understood that the risk of VTE does not end at the point of discharge as 56% of all VTE episodes within 91 days of surgery occur after discharge.
43,
44
Box 14.2
Risk factors for venous thromboembolism
Inherited
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden
Prothrombin G20210A
Elevated factor VIII levels
Dysfibrinogenaemia
Acquired
Surgery
Trauma
Acute medical illness
Malignancy
Cancer therapies (hormonal, chemotherapy or radiotherapy)
Previous VTE
Antiphospholipid syndrome
Increasing age
Pregnancy and puerperium
Oestrogen-containing oral contraceptives or hormone replacement therapy
Selective oestrogen receptor modulators
Infection/sepsis
Immobility/paresis
Heart or respiratory failure
Inflammatory bowel disease
Nephrotic syndrome
Haemoglobinopathies
Myeloproliferative disease
Paroxysmal nocturnal haemoglobinuria
Paraproteinaemia
Obesity
Smoking
Varicose veins and superficial vein thrombophlebitis
Central venous lines
