aprotinin. 507 PERIOPERATIVE BLEEDING AND MASSIVE BLOOD LOSS In life-threatening cases not responding to treatment consider rVIIa use after consultation with hematologist. Ensure Fgn >1g/dL, platelets > 50 \227 109/L, PT and APTT corrected as far as possible with FFP. Further reading Stainsby, D. et al. (2006). Guidelines on the management of massive blood l oss. Brit J Haematol, 135, 634 \200\22341. 508 CHAPTER 10 Haemostasis and thrombosis Massive blood loss \200 Total blood volume replaced within 24h, or \200 50% blood loss within 3h, or \200 Blood loss at a rate of 150mL/min. Treatment \200 Maintain tissue perfusion and oxygenation. \200 Correct surgical bleedin g. \200 Blood component therapy as for surgical bleeding \200\224maintain Hb >8g/dL, platelets >75 \227 109/L, PT and APTT ratios <1.5 \227 n, Fgn >1g/L. Contact key personnel \200\224e.g. anesthetist, blood bank. \200 Consider use of VIIa. 509 MASSIVE BLOOD LOSS 510 CHAPTER 10 Haemostasis and thrombosis Heparin Heparin remains the most widely used parenteral antithrombotic. \200 Naturally oc curring glycosaminoglycan. Pharmaceutical preparation is extracted from porcine (usually) or bovine mucosa. Heterogeneous mixture of straight chain anionic mucopolysaccharides spanning 20 \200\223100 monosaccharide units, alternating chains of uro nic acid and glucosamine, sulphated to varying degrees. LMWH manufactured from unfractionated heparin (UFH) by chemical or enzymatic methods \200\224no evidence that these diff erences in chemical struc ture aff ect biological function. The anticoagulant action of heparin is due to a combination of indirect antithrombin and anti-Xa activity. Elimination of heparin from the plasma appears to involve a combination of zero-order and 1st-order processes, the eff ect of which is that the plasma t1 \201\2042 alters disproportionately with dose, being 60min after 75U/kg and 150min after 400U/kg. LMWHs are less protein bound and have a predictable dose response profi le. They also have a longer t1 \201\2042 than standard heparin preparations. \200 Heparin is used when it is necessary to achieve immediate anticoagulation. Therapeutic dose UFH given either as a continuous IVI or by injection under the skin. Treatment is monitored by the APTT ratio, aiming to prolong the A PTT to 2.0 \227 n (range 1.5 \200\2232.5). n starting dose is 15 \200\22320U/kg/h. The APT T should be measured within 6 \200\22312h of starting treatment and the dose of heparin adj usted accordingly. Thereafter, the APTT should be measured (preferably on a daily basis) an d the dose of heparin adjusted each day. UFH is still used in some circumstances as the sho rt duration of action can be advantageous when it is necessary to vary the intensity of ant icoagulation over a short time period, e.g. in a high thrombosis risk patient undergoing su rgery. Nowadays the heparin of choice for prevention and treatment of DVT and PE and unstable coro nary disease is LMWH, given once daily SC injection without the need for monitoring or dose adjustment. Lower risk of HITT. Patients with acute VTE can be treated as outpatients. Osteoporosis may complicate long-term use. It is dose-related and is most frequently observ ed with use in pregnancy. The relative risk with LMWH is not yet established but appears le ss. Hypersensitivity reactions and skin necrosis (similar to that seen with warfarin) occur but are rare. Transient alopecia has been reported. Bleeding due to heparin \200 More common with impaired hepatic or renal function, with carcinoma, and in patients >60 years of age. An APPT ratio >3.0 is associated with an i risk of bleeding. 511 HEPARIN Treatment \200 Eff ect of UFH is short and so reversal with protamine sulfate is seldom required, except after extracorporeal perfusion for heart surgery. Protamine sulfate, 1mg by slow IV neutralizes 80 \200\223100U of UFH. \200 The dose given is usually estimated from the dose of heparin given and its expected t1 \201\2042. Protamine itself has some anticoagulant eff ect and overdosage must be avoided. The maximum dose must not exceed 50mg. \200 Its clinical eff ectiveness in patients treat ed with LMWH is unknown. Further reading Baglin, T. et al. (2006). Guidelines on the use and monitoring of heparin. Brit J Haematol, 133, 19 \200\22334. 512 CHAPTER 10 Haemostasis and thrombosis Heparin induced thrombocytopenia/ with thrombosis (HIT/T) HIT (E see Heparin-induced thromb ocytopenia (HIT), p.542) with or without thrombosis (HIT/T) is due to an autoantibody again st heparin complexed with PF4, causing platelet activation. It occurs most com- monly with heparin derived from bovine lung. Thrombosis occurs in <1% of patients treated with LMWH bu t is associated with a mortality and limb amputation rate in excess of 30%. Diagnosis \200 Suspected in any patient in whom the platelet count falls by 50% or more after starting heparin. Usually occurs after \211 5d of heparin exposure (or sooner if the patient has previously been exposed to heparin). Treatment \200 When suspected all heparin (UFH and LMWH) stopped and an alterna- tive thrombin inhibitor, such as argatroban should be given. In patients with adequate renal function fondaparinux is often used as there is a very low risk of antibody cross-reactivity to this synthetic pentasaccharide. Warfarin should not be started until adequate anticoagulation has been achieved with one of these agents and the platelet count has returned to n. 513 HEPARIN INDUCED THROMBOCYTOPENIA/WITH THROMBOSIS 514 CHAPTER 10 Haemostasis and thrombosis Oral anticoagulant therapy (warfarin, VKAs) Warfarin is a coumarin derivative that inhibits vitamin K epoxide reductase. Leads to intrahepatic depletion of the reduced form of vitami n K which is a necessary cofactor for the post-translational modifi cation of vitamin K-dep endent proteins. Warfarin is the most widely used oral vitamin K antagonist. Rapidly accumu lates in the liver with t1 \201\2042 >40h with a prolonged dose-dependent terminal phase of elimination with detectable warfarin levels 120h after a single dose. Average dose require d to achieve an INR of 2.5 is between 3 \200\2235mg, although some patients require as litt le as 1mg and some as much as 30mg, or more. Warfarin is particularly eff ective for the pr evention and treatment of venous thromboembolism and prevention of embolization in associat ion with atrial fi brillation or prosthetic heart valves. \200 Oral vitamin K antagonists (VKAs) take several days to produce an anticoagulant eff ect, hence the need for an immediate acting anticoagulant, such as a hepa rin, in the fi rst few days of therapy if rapid anticoagulation is required. Response to warfarin, and other coumarins, varies within and between individuals and therefore the dose must be monitored regularly. Pharmacokinetics (absorption and metabolism) and pharmacodynamics (haemostatic eff ect) are infl uenced by vitamin K intake and absorption, by heritable functional polymorphisms aff ecting metabolism, by rates of synthesis, and cle arance of coagulation proteins and by drugs. Anticoagulant therapy with oral VKAs is monitored by the international normalized ratio (INR). The INR is derived from the PT ratio and is a standar dized method of reporting which permits comparability between laboratories. The ratio of th e patient \200\231s PT is divided by the geometric mean n PT (GMNPT) and the ratio is then raised to the power of the International Sensitivity Index (ISI) of the thromboplastin used to measure the PTs. Thus: INR = ( PT (patient) )ISI GMNPT For example using a thromboplastin with an ISI of 1.2 and a GMNPT of 13.5sec a patient taki ng a daily maintenance dose of warfarin pro- ducing a PT of 27sec would have an INR of (27 13.5)1.2 = 2.3. For rapid induction of anticoagulation (e.g. treatment of VTE) commence loading dose (e.g. 5 or 10mg with daily or alternate day INR measure- ment and appropriate dose adjustment) wh ilst treating with immediate acting anticoagulant, e.g. heparin. Daily maintenance dose is predicted by the INR on d4. For slow induction of anticoagulation (e.g. atrial fi brillatio n) a low dose can be started, e.g. 2mg of warfarin daily for 1 week and INR then meas- ured \200\224additional immediate acting anticoagulant not required. Daily dose of warfarin i b y 1mg each week, with weekly monitoring of the INR, and when the INR is >2.0 maintenance do se has been reached. \200 Maintain as stable a level of anticoagulation as possible. \200 Adopt the lowest eff ective target INR. \200 Educate patients regarding risk, parti cularly that associated with additional drug use. 515 ORAL ANTICOAGULANT THERAPY Bleeding due to oral VKA (warfarin) Risk of bleeding greatest with: \200 Age >65 years. \200 A history of stroke. \200 History of GI bleeding. \200 Other medical illness, inc luding renal failure and anemia. Warfarin embryopathy, central nervous system bleeding and fetal bleeding complicate adminis tration of warfarin and other oral VKAs to pregnant women. Therefore: \200 Warn women of childbearing age. \200 Indicate need for early pregnancy test (within 6 weeks) and cessat ion of therapy with switch to heparin if +ve. Acenocoumarol has a shorter t1 \201\2042 than warfarin. Indications, contraindi- cations, a nd side eff ects are similar to warfarin. The dose required to produce the same intensity o f anticoagulation as warfarin is about 50% of the warfarin dose. Phenindione is an oral VKA that is not a coumarin derivative. It is an indanedione. It is m ore toxic than the coumarin derivatives and is asso- ciated with an i risk of hypersensitiv ity reactions, including exfoliative dermatitis, renal and liver damage, and agranulocytosi s. For this reason it is rarely used. It also produces taste disturbance and pink/orange ur ine. It is also teratogenic. Management of overanticoagulation and/or bleeding due to oral VKA (warfarin) \200 No blee ding, INR <8.0: d warfarin dose or stop warfarin and restart appropriate new dose when INR <5.0 (response to warfarin dose change is delayed so INR will continue to fall after restar ting). No bleeding or minor bleeding, INR > 8.0: stop warfarin (restart when INR <5.0), consider oral vitamin K (0.5 \200\2232.5mg) especially if other risk factors for bleeding. Major bleeding: stop warfarin, give factor concentrate (II, VII, IX, and X) or FFP, give 5 \200\22310mg IV vitamin K. Perioperative management of oral anticoagulation \200 Unless high risk of thromboembolism stop warfarin. Complete reversal of anticoagulation will require stopping 5d before surgery, for partial reversal 3 d. Anticoagulation does not need to be stopped before dental surgery, including extraction. Safe to proceed as long as INR <4.0. Check INR preoperatively. \200 Short term risk of thromboembolism low in patients with me chanical prosthetic valves, mitral > aortic risk. When necessary to continue anticoagulatio n, e.g. metal mitral valve, bridge with heparin, e.g. therapeutic dose LMWH starting 3d aft er stopping warfarin, omitting in 24h before surgery, continuing postoperatively until INR >2.0 in response to reintroduction of warfarin. Further reading Keeling, D. et al. (2011). Guidelines on oral anticoagulation \200\224fourt h edition. Br J Haematol, 154, 311 \200\22324. 516 CHAPTER 10 Haemostasis and thrombosis New oral anticoagulant drugs Oral direct inhibitors of thrombin and factor Xa are now appro ved as anticoagulant drugs. Inhibitors of thrombin and factor Xa have now been shown to be selective, orally active, safe, and at least as eff ective as low- dose LMWH for thrombopro phylaxis and as eff ective as, if not superior to, warfarin for long-term prevention of thr omboembolism. Dabigatran, rivaroxaban and apixaban are the fi rst thrombin and X-a inhibito rs to be licensed for prevention of thromboembolism in patients with atrial fi brillation. For some patients these drugs off er substantial benefi ts over oral VKAs. For the majority of patients these drugs are prescribed at fi xed dose without the need for monitoring or d ose adjustment. There are no food interactions and very limited drug interactions.The rapid onset of anticoagulation and short t1 \201\2042 make initiation and interruption of antico agulant therapy considerably easier than with VKAs. As with all anticoagulants produced so far there is a correlation between intensity of anticoagulation and bleeding. Consequently, the need to consider the balance of benefi t and risk in each individual patient is no les s important than with VKA therapy. Dabigatran \200 Dabigatran is an oral anticoagulant with a short t1 \201\2042. \200 The risk of intracranial hemorrhage is signifi cantly less than with warfarin. License includes prevention of CVA and systemic embolism in patients with non-valvular atrial fi brillation. Given at a fi xed dose without monitoring and without dose adjustment. \200 INR not used. \200 Dose in patients with AF150mg bd under 75 years (in patients \211 75 years a dose of 110mg bd should be considered in the presence of risk fa ctors that increase the risk of bleeding, in patients \211 80 years a dose of 110mg bd is recommended regardless). Food has no signifi cant eff ect on dabigatran. \200 Use of dabigatran and the following drugs is contraindicated: ciclosporin, itraconazole, ketoconazole, tacrolimus. No dose adjustment is needed with digoxin. \200 No interaction with commonly used antibio tics or statins. \200 Caution required with amiodarone, verapamil, quinidine (e.g. reduce dose and take advice). Avoid aspirin and NSAIDS as with warfarin. \200 Dabigatran does not aff ect the action of proton pump inhibitors. (PPI). When using antacids in combination with dabigatran, it is a dvised to take dabigatran 2h before the antacid. \200 10% of patients suff er indigestion ; PPI can be given. \200 At eGFR<30mL/min do not prescribe. \200 At eGFR 30 \200\22350m L/min suggest take advice. \200 Suggest check eGFR once yearly (twice yearly if eGFR <60) . \200 Contraindicated if liver disease with coagulopathy, i.e. baseline PT >13sec. 517 NEW ORAL ANTICOAGULANT DRUGS For surgical, endoscopy and dental procedures including extraction omit doses of dabigatran on day of procedure (i.e. last dose 24h beforehand). Rivaroxaban \200 Rivaroxaban is an oral anticoagulant with a short t1 \201\2042. \200 T he risk of intracranial hemorrhage is signifi cantly less than with warfarin. License includes: (i) prevention of CVA and systemic embolism in patients with non-valvular atrial fi brillation and (ii) treatment and prevention of of DVT and PE. Given at a fi xed dose without monitoring and without dose adjustment. \200 INR not used. \200 Dose 20mg od all ages for treatment of DVT and prev ention of stroke and embolism in AF. Food has no signifi cant eff ect on rivaroxaban. \200 Use of rivaroxaban and the followin g drugs is contraindicated: ketoconazole and other azole-antimycotics, HIV protease inhibitors. No dose adjustment is needed with digoxin. \200 No interaction with antibiotics or statin s. \200 At eGFR <15mL/min do not prescribe. \200 At eGFR 15 to 30 mL/min dose should be 15mg od. \200 Suggest check eGFR once yearly (twice yearly if eGFR <60). \200 Contrain dicated if liver disease with coagulopathy, i.e. baseline PT >13sec. For surgical, endoscopy and dental procedures including extraction omit dose of rivaroxaban on day of procedure (i.e. last dose 24h beforehand). Further reading Baglin, T. (2013). Clinical use of new oral anticoagulant drugs: dabigatran and rivaroxaban. Br J Haematol, 163, 160 \200\2237. 518 CHAPTER 10 Haemostasis and thrombosis Thrombosis Thrombosis is defi ned as coagulation within the circulation. Thrombosis may occ ur in any part of the circulation including the heart, arteries, veins, and the microcircul ation. The results of thrombosis are: \200 Local obstruction of the circulation. \200 E mbolization of clot. \200 Consumption of haemostatic factors (if thrombosis is extensive) . Venous thrombosis DVT and PE are diff erent clinical manifestations of a spectrum of diseas e termed collectively venous thromboembolism (VTE). Most patients pre- senting with PE have asymptomatic DVT and most patients presenting with symptoms of DVT alone have asymptomatic PE. \200 Annual incidence of 1/1000 increasing with age. \200 Case fatality rate range 1 \200\2235%. \200 Post-thrombotic syndrome \200\224characterized by chronic pain, swell ing and sometimes ulceration of the skin of the leg occurs in up to 1 \201\2043 of patients . Can occur early or up to 10 years. Cumulative frequency 30% at 5 years. Chronic thromboembolic pulmonary hypertension develops in 2% of patients presenting with symptomatic PE. May require pulmonary artery endarterectomy. DVT usually starts in the calf but by the time symptoms develop 80% of patients have proximal DVT (popliteal vein and above). Risk factors for VTE E See VTE risk assessment and thromboprophylaxis, p.524. DVT Diagnosis Investigation of suspected DVT is now frequently on combination of clinical a ssessment (pretest probability (PTP) score, Table 10.3) and result of D-dimer measurement ( see Box 10.1). D-dimer is a fi brin degradation product. Test can be performed on plasma. T hrombosis results in high D-dimer (+ve result) but not specifi c, i.e. most patients with + ve D-dimer do not have thrombosis (infection, infl ammation, malignancy, tissue trauma, pre gnancy). Therefore, D-dimer cannot be used to diagnose DVT it can only be used to exclude i t (depending on PPT probability score). 519 THROMBOSIS Table 10.3 Clinical probability (PTP) assessment (Well \200\231s score) score Active cancer (treatment ongoing or within previous 6 months or palliative) 1 Paralysis, plaster cast 1 Bed >3d or surgery within 4 weeks 1 Tenderness along veins 1 Entire leg swollen 1 Calf swollen >3 cm 1 Pitting oedema 1 Collateral veins 1 Alternative diagnosis likely \210\2222 Low: 0 or less; moderate: 1 or 2; high: 3 or more. 5%, 20% and 75% of patients with low, mo derate or high pretest probability, respectively, have DVT. D-dimer assay Measurement of D-dimer can then be used to determine which patients require i maging (now usually compression ultrasound or CT angiog- raphy) and which patients do not. \200 D-dimer should not be measured until after clinical score (pretest probability score). \210\222ve D-dimer has a role in excluding VTE. \200 D-dimer aff ected by heparin admini stration \200\224potentially giving false \210\222ve result. D-dimer may be false \210\222ve if the patient has had symptoms for >2 weeks. D-dimer assay with appropriately high sensitivity must be used.1 Box 10.1 Low PTP + \210\222ve D-dimer = DVT excluded. Moderate PTP + \210\222ve D-dimer = US \200 \224if \210\222ve DVT excluded. Moderate PTP + +ve D-dimer = US \200\224if \210\222ve rep eat US in 1 week. High PTP = US. 520 CHAPTER 10 Haemostasis and thrombosis Radiology Compression US is now preferred imaging technique. Inability to compress the vein lumen is the principal diagnostic criterion and other fi ndings do not increase sensitivit y. Sensitivity for proximal DVT of 97%. Advantage over conventional venography is the abili ty of US to identify alternative diagnoses of leg pain and swelling. The 1st test will dete ct any proximal thrombosis, a calf vein thrombus may remain undetected but a repeat scan 1 week later will pick up clinically important calf DVT that has extended. It is safe to with - hold anticoagulant treatment from patients with clinically suspected DVT who have \210 \222ve US and \210\222ve D-dimer or \210\222ve US and +ve D-dimer and \210\222ve repeat US 1 week later. If D-dimer not used it is safe to dispense with the follow-up US with a \210\222ve 1st US in patient with a low PTP. Treatment \200 Therapeutic dose LMWH for 3 \200\2235d (as outpatient for majority of patients but E see Contraindications to outpatient therapy, p.520). Loading dose of oral VKA when diagnosis confi rmed, using loading nomogram with prediction of daily maintenance dose for target INR 2.5. Particular risk of o veranticoagulation when elderly (>70 years), liver disease, alcohol abuse, body weight <50 kg, congestive heart failure. \200 Oral anticoagulation for 3 \200\2236 months for fi rst episode of VTE, longer if persistent risk factors (evidence of heritable thrombophilia not usually an indication of itself for prolonged anticoagulation). Treatment with rivaroxaban (15mg bd for 3 weeks then 20mg daily) is alternative to treatmen t with LMWH + VKA. Dabigatran and apixaban likely to be licensed for treatment of VTE in fu ture. \200 Compression stocking exerting pressure of at least 30mmHg at ankle (European Class 2, British Class 3 stocking). 50% reduction in post-thrombotic syndro me (PTS). Education of patient regarding risk avoidance and need for thromboprophylaxis at times of high risk. Testing for acquired thrombophilia as indicated. Antiphospholipid syndrome (APS, E see Acqu ired thrombolphilia, p.534), MPD including PNH. Review of family history with view to consideration of testing for heritable thrombophilia (E see Heritable thrombophilia, p.530) (may require completion of a nticoagulant therapy for full assessment). Contraindications to early/immediate outpatient treatment: coexistent serious medical patho logy, severe acute venous obstruction (phlegmasia cerulean dolens), severe pain, active ble eding, or signifi cant risk of bleeding, renal impairment (creatinine in excess of 200micro mol/L), liver disease (PT >2sec beyond normal range), uncontrolled hypertension (diastolic >110mmHg, systolic >200mmHg), recent eye or CNS surgery (within 1 month); recent haemorrhag ic stroke (within 1 month), known heparin allergy or previous HIT/T, active peptic ulcerati on, thrombocytopenia (<100 \227 109/L), suspected problems compliance. Advantages of LMWH over UFH: once daily SC dose calculated from patient weight, no monitoring of APTT required (platelet count at beginning and on d3 or 4), low risk of HIT/T (E see Heparin-induced thr ombocytopenia, p.542), interpatient and intrapatient variability in 521 THROMBOSIS UFH dosage requirement results in the APTT being in the therapeutic range in only 50% of ti me. PE \200 PE carries a higher mortality than DVT. Whilst many patients will require hospita l admission there is a subgroup of patients who present with peripheral PE (pleuritic chest pain and/or haemopytsis) who can safely be treated on an outpatient basis. Right heart strain and right ventricular muscle ischaemia causes release of troponin \200 \224sometimes used as prognostic indicator. Diagnosis All patients with possible PE should have clinical probability assessed. Clinical probability (PPT) Some assessment systems try and defi ne PE as likely or unlikely but require complex scoring systems (see Box 10.2). A simple pragmatic approach is: \200 Patient has clinical features compatible with PE \200\224dyspnoea and/or tachypnoea with o r without chest pain and/or haemoptysis (a). Absence of another diagnosis (b). \200 Presence of a major risk factor (c). Box 10.2 Probability score for PE High probability = (a) + (b) + (c) = CTPA. \200 Moderate probability = (a) + (b) or (c) = CTPA or high sensitivity D-dimer, and CTPA only if D-dimer +ve. Low probability = (a) = D-dimer and CTPA if +ve. D-dimer Same considerations of assay as for DVT. Radiology \200 CT pulmonary angiography is now recommended imaging method for non-massive PE. V/Q scan if CTPA not available and CXR is n and no signifi cant pre-existing cardiopul monary disease and non- diagnostic result is followed by further imaging. CTPA or echocardiography will reliably diagnose massive PE. \200 Good quality normal CTPA excludes PE. Treatment \200 Thrombolysis is 1st-line treatment for massive PE \200\224e.g. 10mg tPA ov er 2min followed by 90mg over 2h. May be started on clinical grounds if cardiac arrest immi nent, e.g. 50mg tPA IV bolus. Heparin should be started before imaging if moderate or high clinical probability. IV bolus of UFH recommended after thrombolysis for massive PE followed by LMWH. LMWH alone for non-massive PE. 522 CHAPTER 10 Haemostasis and thrombosis Oral VKA as for DVT when diagnosis confi rmed \200\224loading nomogram, target INR 2.5, 3 \200\2236 months \200\231 duration for 1st episode of VTE. Treatment with rivaroxaban (15mg bd for 3 weeks then 20mg daily) is alternative to treatmen t with LMWH + VKA. Dabigatran and apixaban likely to be licensed for treatment of VTE in fu ture. Vena cava (VC) \201 lters2 \200 VC fi lters are indicated to prevent PE in patients wit h VTE who have a contraindication to anticoagulation. Anticoagulation should be considered in patients with a VC fi lter when a temporary contrai ndication to anticoagulant therapy is no longer present. VC fi lters are not indicated in unselected patients with VTE who will receive conventional anticoagulant therapy. VC fi lter insertion may be considered in selected patients with recurrent PE despite thera peutic anticoagulation. Alternative treatment options such as long-term high-intensity oral anticoagulant therapy (INR target 3.5) or LMWH should be considered prior to VC fi lter pl acement, particularly in patients with thrombophilic disorders (e.g. antiphospholipid syndr ome) or cancer. VC fi lter insertion may be considered in pregnant patients who have contraindications to anticoagulation or develop extensive VTE shortly before delivery (within 2 weeks). Retrievable fi lters should be considered. Free fl oating thrombus is not an indication for insertion of a VC fi lter. \200 Thrombol ysis is not an indication for fi lter insertion. \200 VC fi lters should be considered in any preoperative patient with recent VTE (within 1 month) in whom anticoagulation must be interrupted. Retrievable VC fi lters should be considered in this situation where a tempora ry contraindication to anticoagulation exists. IV drug users \200\224management of iliofemoral venous thrombosis in injecting drug users i s problematic because of poor venous access, non- compliance with prescribed treatment, ong oing IV drug use, and co- existent sepsis. Treatment with a LMWH results in a satisfactory clinical outcome. Use of a NOAC would likely achieve similar results. Cancer \200\224oral V KA therapy is inferior to therapeutic dose LMWH for treatment of VTE in patients with cance r. Therapeutic dose LMWH should be given for 4 weeks after which a 25% dose reduction can b e made. References 1. Keeling D. et al. (2006). on behalf of the Haemostasis and Thrombosis Task Fo rce of the British Committee for Standards in Hematology. The management of heparin-induced thrombocytopenia. Brit J Haematol, 133, 259 \200\22369. 2. Baglin, T.P. et al. (2006). Guidelines on use of vena cava fi lters. Br J Haematol, 134, 590 \200\2235. Further reading Keeling, D.M. et al. (2004). The diagnosis of deep vein thrombosis in sympt omatic outpatients and the potential for clinical assessment and D-dimer assays to reduce t he need for diagnostic imaging. Brit J Haematol, 124, 15 \200\22325. 523 THROMBOSIS 524 CHAPTER 10 Haemostasis and thrombosis Risk assessment and thromboprophylaxis Many studies have been performed to determine the in cidence of DVT and PE in various groups of patients and to identify risk factors. The risk of VTE in a hospitalized patient depends not only on the reason for admis- sion (procedural risk) but also on pre-existing patient-related factors (patient risk). Decision as to whet her patient requires thromboprophy- laxis depends on procedural and patient risks, and choi ce of prophylactic intervention depends also on procedural and patient bleeding risk. Thrombosis risk factors Procedural risk \200 Major orthopedic surgery to lower limb, e.g. hip or knee replacement. \200 Abdominal or pelvic surgery lasting >30min under general a nesthetic. \200 Major trauma is also a risk factor with hip fracture being associated with a very high risk of DVT. Patient risk \200 Age >40 years and particularly >60 years. \200 Obesity \200\224BMI >3 0kg/m2 and particularly >35kg/m2. \200 Previous VTE. \200 Known thrombophilia (a predis posing state which may be heritable). \200 Malignancy. \200 Heart failure. \200 Respi ratory disease. \200 Severe infection. \200 Estrogen therapy and high-dose progestogens . \200 Pregnancy and the postpartum. \200 Immobility. Bleeding risk factors Procedural risk \200 Neurosurgery. \200 Eye surgery. \200 Other procedures with a high bleeding risk. Patient risk \200 Hemophilia and other bleeding disorders. \200 Thrombocytopenia (plate lets <100 \227 109/L). \200 Recent cerebral hemorrhage (in previous month). \200 Sever e hypertension. \200 Severe liver disease (i PT or oesophageal varices). \200 Peptic ul cer. \200 Endocarditis. For each patient an assessment of risk should be undertaken on admis- sion and reviewed per iodically during hospitalization; depending on the degree of risk patients should receive a dvice and treatment to reduce risk. Patients should be mobilized early and low-dose heparin (LMWH or UFH) and graded pressure stockings, or alternative mechanical devices, should be considered for patients at moderate-to-high risk. 525 RISK ASSESSMENT AND THROMBOPROPHYLAXIS Methods for prevention of VTE Can be divided into mechanical and pharmacological methods: Mechanical methods include: \200 GCS. \200 IPC. The advantage of mechanical methods is the absence of an eff ect on coagulation so that the re is no i risk of bleeding. Disadvantages include cost (IPC), compliance (IPC and GCS), ex acerbation of arterial insuf- fi ciency in patients with peripheral arterial disease, and p ossibly lower effi cacy (GCS) than pharmacological methods. Pharmacological methods include: \200 LMWH. \200 NOACs \200 UFH. The advantage of pharmacological methods is established effi cacy and compliance, i.e. it i s known when a dose is given. The disadvantage is bleeding due to an eff ect on coagulation and idiosyncratic drug reactions including heparin allergy, skin necrosis, and HITT. UFH at a dose of 5000U, 2 or 3 \227 daily by SC injection reduces the risk of DVT and PE b y >50%. The risk of non-fatal hemorrhage is more than doubled but the absolute excess is sm all as most patients do not suff er any appreciable bleeding and there is no increase in li fe-threatening haemor- rhage. The use of LMWH has the advantage of once daily injection, an d a lower risk of bleeding relative to effi cacy. It is at least as eff ective as standard heparin and probably more eff ective. The combination of graded pressure stocking plus hepa rin appears to be more eff ective than either alone. LMWH reduces the risk of DVT and PE in high-risk medical patients by >50% when given at a high-risk patient dose, e.g. (enoxa- pa rin 40mg, dalteparin 5000 units). Suggested options for risk assessment and prophylaxis Thromboprophylaxis in high-risk medic al patients Risk assessment can be diffi cult and risk assessment methods are not fully val idated. \200 Age >60 years and likely hospitalization with immobility for >3d. \200 Or age >60 years and a diagnosis of heart failure, respiratory disease, sepsis, or infl ammatory disease. Or hospitalization with condition known to be associated with high risk of thrombosis, e.g. SLE with a lupus anticoagulant. Prophylaxis \200\224if low bleeding risk LMWH at high-risk dose (e.g. enoxaparin 40mg, dalteparin 5000 units), if high bleeding risk graded pressure stockings. Thromboprophylaxis in high-risk non-orthopedic surgery Risk assessment is easier. \200 Ab dominal or pelvic surgery lasting >30min under general anesthetic. Or low risk procedure but 1 or more patient-related related risk factors. 526 CHAPTER 10 Haemostasis and thrombosis Prophylaxis \200\224if low bleeding risk LMWH at standard risk dose (e.g. enoxaparin 20mg, dalteparin 2500 units), if high bleeding risk appropriate mechanical intervention. Thromboprophylaxis in high-risk orthopedic surgery \200 Major orthopedic surgery to lower limb, e.g. hip or knee replacement. Or hip fracture or major trauma. \200 Prophylaxis \200\224if low bleeding risk LMWH at hi gh risk dose (e.g. enoxaparin 40mg, dalteparin 5000 units), or a NOAC if high bleeding risk appropriate mechan ical intervention. Or low risk procedure but 1 or more patient-related related risk factors. \200 Prophylaxi s \200\224if low bleeding risk LMWH at standard or high-risk dose depending on perceived ri sks of thrombosis and bleeding. 527 RISK ASSESSMENT AND THROMBOPROPHYLAXIS 528 CHAPTER 10 Haemostasis and thrombosis Example of VTE risk assessment \200 Risk assessment is mandatory for all patients on admi ssion to hospital. This example of a risk assessment model is not for use in pregnant women or children less than 18 years old. All patients should be assessed on admission and periodically during inpatient stay as risk may change. Reassessment after 48 \200\22372h is recommended and out come and appropriate action must be recorded in the medical record. Step one \200 Review the patient-related factors shown on the assessment sheet (see Table 10.4) against thrombosis risk, ticking each box that applies (more than 1 box ca n be ticked). Use the highest category of risk if more than 1 box is ticked (e.g. if both m oderate and high risk are ticked, use guidance for high-risk patients). Any tick for thrombosis risk should prompt thromboprophylaxis. The choice of thromboprophyl axis will be determined by local policy but will likely utilize a combination of mechanical and pharmacological methods (E see Suggested options for risk assessment and prophylaxis, p.524). The risk factors identifi ed are not exhaustive. Clinicians may consider additional risks i n individual patients and off er thromboprophylaxis as appropriate. If the nurse or doctor completing this assessment is uncertain of risks, e.g. duration of s urgery, procedural bleeding risk, then medical staff should be consulted. Step two \200 Review the patient-related factors shown against bleeding risk and tick each box that applies (more than 1 box can be ticked). Any tick for bleeding risk should prompt medical staff review and to consider if bleeding risk is suffi cient to preclude pharmacological intervention. Step three \200 If no boxes are ticked, then the patient is at low risk of VTE and no intervention is indicated. Further reading This topic draws on the VTE risk assessment guidance from the Department of Health, Venous thromboembolism (VTE) risk assessemnt, September, 2008. 529 EXAMPLE OF VTE RISK ASSESSMENT Table 10.4 VTE risk assessment Mobility \200\224all patients (tick one box) Tick Tick Tick Medical patient NOT expected to have signifi cantly reduced mobility relative to normal sta te Surgical patient Medical patient expected to have ongoing reduced mobility relative to normal state Assess for thrombosis and bleeding risk below Risk assessment now complete Thrombosis risk Patient-related Tick Admission-related Tick Active cancer or cancer treatment Signifi cantly reduced mobility for 3 days or more Age >60 Hip or knee replacement Dehydration Hip fracture Known thrombophilias Total anesthetic + surgical time >90min Obesity (BMI >30kg/m2) Surgery involving pelvis or lower limb with a total anesthetic + surgical time >60min Acute surgical admission with infl ammatory or intra-abdominal condition One or more signifi cant medical comorbidities (e.g. heart disease; metabolic, endocrine or respiratory pathologies; acute infectious deiseases; infl ammatory conditions) Personal history or fi rst-degree relative with a history of VTE Critical care admission Use of hormone replacement therapy Surgery with signifi cant reduction in mobility Use of estrogen-containing contraceptive therapy Varicose veins with phlebitis Pregnancy or <6 weeks post partum (see NICE guidance for specifi c risk factors) Bleeding risk Patient-related Tick Admission-related Tick Active bleeding Neurosurgery, spinal surgery or eye surgery Acquired bleeding disorders (such as acute liver failure) Other procedure with high bleeding risk Lumbar puncture/epidural/ spinal anesthesia expected within the next 12h Concurrent use of anticoagulants known to increase the risk of bleeding (such as warfarin w ith INR >2) Acute stroke Lumbar puncture/epidural/ spinal anesthesia within the previous 4h Thrombocytopaenia (platelets< 75 \227 109/L) Uncontrolled systolic hypertension (230/120mmHg or higher) Untreated inherited bleeding disorders (such as hemophilia and von Willebrand \200\231s dis ease) Reproduced from Department of Health, Venous thromboembolism (VTE) risk assessment, Crow n copyright 2010. 530 CHAPTER 10 Haemostasis and thrombosis Heritable thrombophilia Blood tests can be done after an episode of DVT or a PE to test for evidence of a genetic predisposition for heritable thrombophilia. \200 Thrombophilia exp lains why some individuals suff er a blood clot. \200 The risk of a recurrent blood clot is not signifi cantly greater in most individuals with thrombophilia than it is in individuals without thrombophilia. Theref ore, duration of treatment is not generally diff erent in patients with and without laborat ory evidence of thrombophilia. Treatment decisions are based on the circumstances that led to the thrombosis, e.g. whether or not the clot followed an operation and if there is a strong fam ily history of DVT or PE. The most common type of heritable predisposition to DVT and PE is a change in the genetic c ode known as a mutation. Some mutations are present in about 1 in 15 people. 2 common mutat ions, each present in 3.5% of the Caucasian UK population are: \200 Factor V Leiden (FVL) . \200 F2G20210A, also known as the prothrombin gene mutation. Less common mutations aff ect natural anticoagulants including antithrombin, protein C (PC) , and protein S (PS) giving rise to low levels (type 1 defect) or impaired function (type 2 defects). 25% of unselected patients presenting with a 1st episode of VTE will have laboratory eviden ce of a heritable thrombophilic defect; 25 \200\22350% of patients with thrombosis and a +v e family history. The frequency of the commonly identifi ed heritable major factors is show n in Table 10.5. PC and PS de \201 ciency Many patients are asymptomatic and will never have a VTE. Clinica lly PC and PS defi ciency are similar in terms of risk of thrombophlebitis and VTE. In neon ates with severe PC defi ciency (homozygous) purpura fulminans is life threatening. This is due to microvascular thrombosis (DIC). Skin necrosis may complicate warfarin therapy in pa tients with PC or S defi ciency \200\224less likely if slow loading regimen or when heparin used in combination with rapid loading. Antithrombin (AT) de \201 ciency This was the fi rst major familial defect described (1965 ). VTE throm- bosis risk appears greater than PC/S defi ciency particularly during preg- na ncy. Homozygous severe AT defi ciency is probably incompatible with life. 531 HERITABLE THROMBOPHILIA Table 10.5 Heritable thrombophilic defects Defect Relative risk of VTE Patients with 1st VTE VTE with family history FVL 2 \200\2234 15 \200\22320% 15 \200\22325% F2G20210A 2 \200\2234 5% 5 \200\22310% AT defi ciency 10 \200\22320 1 \200\2232% 2 \200\2235% PC defi ciency 10 1 \200\2232% 2 \200\2235% PS defi ciency 5 \200\22310