CME Haematology – II normal. The rare autosomal recessive Evidence-based management of deep vein Type 3 disease is a severe disorder. and pulmonary embolus Management of von Willebrand disease

At present, two main options are avail- Trevor Baglin FRCP FRCPath , Consultant VTE, whereas a patient with a high pre- able for the management of patients Haematologist, Addenbrooke’s University test clinical probability score has a one in with von Willebrand disease: DDA VP Hospitals Trust, Cambridge five risk of VTE even with a negative D- and blood products containing VWF. In Clin Med JRCPL 2001;1:438–41 dimer result 3. addition, tranexamic acid, an anti-fibri- nolytic agent, can be used alone in the Initial therapy: anticoagulation management of epistaxis and menor- Diagnosis of deep vein rhagia and it is used in combination with thrombosis1,2 Anticoagulation is standard therapy for DDAVP- or VWF-containing concen- patients with VTE who are clinically trates to cover dental extractions and (DVT) most stable (other treatment options are surgery. commonly arises in the leg. The diag- shown in T able 2), except patients in DDAVP causes VWF to be released nosis is designated distal when whom anticoagul ation is contraind i- from endothelial stores. The mechanism is confined to the calf, and proximal cated. Insertion of a vena caval filter may for the rise in factor VIII was thought to when the thrombus extends into the be more appropriate. Some patients are be due to its consequent stabilisation in popliteal, femoral or iliac veins. Recent haemodynamically unstable and may plasma. However, the use of DDAVP in studies indicate that DVT is present in benefit from initial thrombolytic therapy type 2N disease indicates that it must fewer than one in four ambulant out- before starting anticoagulation. also release factor VIII from a storage patients presenting with symptoms or signs suggestive of this diagnosis. pool. It is often effective in type 1 disease Unfractionated heparin where increasing levels 2-5 fold is suffi- Pulmonary embolus (PE) is present in at cient for haemostasis. It is of no use in least 50% of patients presenting with Unfractionated heparin (UFH) should type 3 disease. In types 2A and 2M, DVT, indicating that PE and DVT are be given either as a continuous intra- increasing the levels of the abnormal clinical manifestations of a single patho- venous infusion or by twice daily sub- VWF has a variable effect. DDA VP logical process, venous thrombo- cutaneous injection at a dose sufficient therapy is controversial in type 2B dis- (VTE). However, at presenta- to prolong the activated partial throm- ease as the release of the abnormal VWF tion only one in five patients with VTE boplastin time ratio to 1.5– 2.5 times may induce platelet agglutination and has symptoms due to PE. normal (level Ia). (The levels of evidence thrombocytopenia. If DDAVP cannot be The clinical assessment of symptoms are according to the US Agency for used or is ineffective, a plasma-derived and signs can do no more than raise a Health Care Policy and Research, concentrate must be used. suspicion of the diagnosis. Objective summarised in the British Committee diagnostic methods must be used to for Standards in Haematology (BCSH) confirm or exclude DVT and/or PE. 4 Further reading guidelines on oral anticoagul ation ). There is increasin g interest in the Weight-based dosing schedules have 1Mannucci PM, Tuddenham EGD. The negative predictive value of D-dimer been developed for both intravenous and hemophilias – from royal genes to gene tests, which can be used to limit the use subcutaneous therapy. T reatment with therapy. Review. N Engl J Med 2001;344: of radiology. D-dimer is a fibrin degra- 1773–9. heparin should continue for at least five 2Sadler JE. A revised classification of von dation product indicative of in vivo days (level Ib) and until the international Willebrand disease. Thromb Haemost 1994; thrombin activity. Rapid enzyme-linked normalised ratio (INR) is therapeutic. 71:520–5. immunosorbent assays (ELISA) and For patients with large thromboses 3Mannucci M. How I treat patients with von automated latex agglutination methods heparin may be administer ed for a Willebrand disease. Review. For the are both quick and sensitive. D-dimer Subcommittee on von Willebrand Factor of longer period (up to 10 days). the Scientific and Standardizat ion tests should be used in conjunction with UFH should be reserved for the small Committee of the International Society on pre-test clinical probability scoring number of patients who require emer- Thrombosis and Haemostasis. Blood 2001; because the negative predictive value gency invasive procedures when it is 97:1915–9. depends not only on the sensitivity and useful to be able to ‘turn on and off’ the specificity of the test but also on the anticoagulant effect at will. This is not Address for correspondence: prevalence of VTE. Thus, a patient with a possible with once daily administration Dr David Keeling, Oxford negative D-dimer result but a moderate of low molecular weight heparins Haemophilia Centre, The Churchill pre-test clinical probability score (see (LMWHs). Furthermo re, the anti- Hospital, Oxford OX3 7LJ Table 1) still has about a one in 50 risk of coagulant effect of UFH can be

438 Clinical Medicine Vol 1No 6 November/December 2001 CME Haematology – II

Table 1. Pre-test clinical probability safety of outpatient treatment of DVT 6,7 • patients with a first episode of scoring system (from Wells et al., Lancet (level Ib). The possibility of extending proximal DVT or PE: six months 1997;350:1795). home therapy to patients with sympto- idiopathic CVT: three months 8 • Criteria Score matic PE is supported by a recent study • postoperative calf vein clots: six and also the ability to identify low risk weeks. Active cancer 1 patients suitable for home treatment 9. Paralysis, plaster cast 1 Factors associated with death, recurrence Bed rest >3 days, surgery Calf vein thrombi: to treat or within 4 weeks 1 or haemorrhage are cancer, heart failure, Tenderness along veins 1 previous DVT , , hy potension not to treat? Entire leg swollen 1 and the presence of DVT on ultrasound 9. When confined to the calf, DVT is Calf swollen >3 cm 1 As outpatient therapy is now appropriate associated with a low risk of clinically Pitting oedema 1 for most patients with DVT, it is likely to Collateral veins 1 important PE. Untreated, or be extended to low risk patients with PE. inadequately treated, CVT may extend Alternative diagnosis likely –2 proximally in 5– 30% of patients 10. Warfarin Pre-test probability score : Symptomatic CVT that extend usually low 0 Warfarin can be commenced on day 1 in do so in the first five days after moderate 1 or 2 conjunction w ith heparin in most symptoms develop, with extension or high 3 11 patients with VTE. A standard protocol recurrence rare after the first week . for the commencement of oral anti- Treatment with heparin alone for five days does not eliminate the risk of exten- completely reversed with protamine coagulant treatment is recommended sion but simply delays this sulphate whereas this is not possible with and treatment should be monitored with until after anticoagulation is stopped. LMWH. the INR4. A target INR of 2.5 gives the lowest VTE recurrence and bleeding Treatment of CVT with anticoagulation rates (level Ib) 4. for six weeks to three months virtually Low molecular weight heparin eliminates the risk of proximal extension and PE. As an alternative to anti- Treatment w ith LMWH results in a Duration of anticoagulation lower risk of thrombotic and haemor- coagulant treatment, small CVT can be rhagic complications and a lower mor- Opinion varies as to the optimal dura- monitored with serial non-invasive tests tality than treatment with UFH 5 (level tion of therapy. After a first episode of (eg compression ultrasound examina- Ia). Most LMWH studies to date have VTE the recommendations range from tion) and treated as for a proximal selected patients with DVT . More three months when there is a reversible thrombus if extension occurs. recently, randomised studies of patients transient risk factor, to two years in with PE have extended the treatment young patients with idiopathic VTE. The Influence of thrombophilia indications to include patients with sub- BCSH considers the distinction between testing on management massive PE, thus making this class of proximal and calf vein thrombus (CVT) decisions heparin the treatment of choice for most as an important factor in decision patients with VTE. analysis. It makes the following recom- The ability to ‘ explain’ thrombosis has Two multicentre clinical trials have mendations for duration of treatment led to the increasing use of thrombo- confirmed the feasibility, efficacy and (level Ib)4: philia testing in the assessment of

Table 2. Treatment options for venous thromboembolism (VTE). Treatment Advantages Disadvantages

Thrombolysis DVT Venographic evidence of preservation of Four-fold higher risk of bleeding valve function Incidence of venous hypertension not shown to be reduced PEEarly improvement of haemodynamic No evidence of improved long-term benefit measurements May be life-saving in selected patients Caval filters VTE Reduced symptomatic PE Increased incidence of recurrent DVT Anticoagulation required to reduce risk of recurrence Thrombectomy DVT No evidence of benefit PEMay be life-saving in selected patients Postoperative risk of PE: 70% Anticoagulation or filter required postoperatively Prior thrombolysis is major risk factor for bleeding

DVT = deep vein thrombosis; PE = pulmonary embolus.

Clinical Medicine Vol 1No 6 November/December 2001 439 CME Haematology – II patients with VTE 12. However, studies cardiolipin in a patient with thrombosis References confirming a beneficial outcome from indicates a high risk of future throm- 1Corris PA. A practical approach to the diag- bosis15. However, even in this situation a testing are lacking. Thrombophil ia nosis of venothromboembolism. Clin Med testing does not predict likelihood of conventional six-month period of anti- JRCPL 2001;1(4):274–81. heparin resistance, heparin failure or coagulation after a first event has recently 2British Thoracic Society, Standards of Care warfarin-induced skin necrosis 13. At been recommended by the BCSH as only Committee. Suspected acute pulmonary present, there is no evidence that recur- level IV evidence is available 16. embolism: a practical approach. Thorax 1997;52(Suppl 4):S1–S24. rence on treatment with warfarin with a 3Keeling DM, Wright M, Baker P, Sackett D. target INR of 2.5 is greater in patients Prevention of chronic venous D-dimer for the exclusion of venous throm- with thrombophil ia than in those hypertension boembolism: comparison of a new auto- without13. There is no conclusive mated latex particle immunoassay (MDA evidence that, in general, patients with The incidence of postthrombotic D-dimer) with an established enzyme- heritable thrombophilia are more likely syndrome (PTS) due to chronic venous linked fluorescent assay (VISA D-dimer). Clin Lab Haematol 1999;21:359–62. insufficiency has been decreasing in to suffer an earlier recurrence once treat- 4Guidelines on oral anticoagulation: third 14 ment is stopped . Possible exceptions recent years, suggesting that more edition. Br J Haematol 1998;101:374–87. are patients homozygous for the factor V efficient treatment of VTE and the 5van Den Belt AG, Prins MH, Lensing AW, Leiden mutation and patients with very prevention of recurrent DVT can have a Castro AA, et al. Fixed dose low molecular high factor VIII levels. Further manage- positive impact on this complication. A weight heparins versus adjusted dose unfractionated heparin for venous randomised study of calf length, made- ment studies are required to determine thromboembolism. Review. Cochrane whether the benefit:risk ratio of extended to-measure, elastic compression stock- Database Syst Rev 2000;2:CD001100. anticoagulant therapy is favourable in ings worn for two years compared with 6Koopman MM, Prandoni P , Piovella F , these small subgroups of patients. no stockings in patients with a first Ockelford PA, et al. Treatment of venous In contrast to heritable thrombophilia, episode of proximal DVT demonstrated thrombosis with intravenous unfraction- ated heparin administered in the hospital as a significant reduction in PTS 17. prospective data indicate that detection compared with subcutaneous low-molec- of acquired lupus anticoagulant or anti- ular-weight heparin administered at home. The Tasman Study Group. N Engl J Med 1996;334:682–7. Key Points 7Levine M, Gent M, Hirsh J, Leclerc J, et al. A comparison of low-molecular-weight heparin administered primarily at home Deep is present in less than one in four ambulant outpatients with unfractionated heparin administered presenting with symptoms or signs suggestive of this diagnosis in the hospital for proximal deep- vein thrombosis. N Engl J Med 1996;334: The majority of patients can be managed with non-invasive diagnostic tests 677–81. 8Wells PS, Kovacs MJ, Bormanis J, Forgie The negative predictive value of a test depends not only on the sensitivity and MA, et al. Expanding eligibility for out- specificity of the test but also on the prevalence of the disease: for example, a patient treatment of deep venous throm- patient with a high pre-test clinical probability score has a one in five risk of bosis and with low- venous thromboembolism (VTE) even with a negative D-dimer result molecular-weight heparin: a comparison of patient self-injection with homecare injec- Oral anticoagulation alone is insufficient for the initial treatment of VTE tion. Arch Intern Med 1998;158:1809–12. 9Wicki J, Perrier A, Perneger TV, Treatment with heparin should continue for at least five days Bounameaux H, Junod AF. Predicting Low molecular weight heparin is the treatment of choice for most patients with VTE adverse outcome in patients with acute pulmonary embolism: a risk score. Thromb Outpatient therapy is now appropriate for most patients with DVT Haemost 2000;84:548–52. 10 Lohr JM, Kerr TM, Lutter KS, Cranley RD, A standard protocol for the commencement of oral anticoagulant treatment is et al. Lower extremity calf thrombosis: recommended and a target international normalised ratio of 2.5 is totreat or not to treat? J Vasc Surg 1991; recommended for most patients with VTE 14:618–23. 11 Huisman MV, Buller HR, ten Cate JW, The relative risks and benefits of thrombolysis are uncertain and should be Vreeken J. Serial impedance plethysmo- reserved for life-threatening VTE graphy for suspected deep venous throm- bosis in outpatients. The Amsterdam The value of thrombophilia testing has not been evaluated in management studies. General Practitioner Study. N Engl J Med Where data are available there is little, if any, indication of a worse prognosis in 1986;314:823–8. patients with laboratory evidence of thrombophilia 12 Greaves M, Baglin T. Laboratory testing for heritable thrombophilia: impact on clinical Systematic audit and review of adverse outcomes is critical in order to determine management of thrombotic disease annota- whether new methods and practices have been implemented correctly and to tion. Br J Haematol 2000;109:699–703. ensure that acceptable standards of care have been achieved or maintained 13 Baglin T . Thrombophilia testing: what do we think the tests mean and what should we

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do with the results? J Clin Pathol 2000;53: Sickle cell disease (HbSS), usually the most severe 167–70. form of SCD, and 14 Baglin C, Brown K, Luddington R, Baglin T. Risk of recurrent venous thrombo- • compound heterozygosity with embolism in patients with the factor V Anne Yardumian MD FRCP FRCPath , other abnormal b genes, resulting in Leiden (FVR506Q) mutation: effect of Consultant Haematologist, North Middlesex HbSC, Sb thalassaemia, SD Punjab, SE warfarin and prediction by precipitating Hospital, London and SOArab, and some rarer factors. East Anglian Thrombophilia Study Charles Crawley MD MRCP MRCPath , phenotypes such as SLepore. Group. Br J Haematol 1998;100:764–8. 15 Greaves M. Antiphospholipid antibodies Specialist Registrar, Hammersmith Hospital, Abnormal b globin chains cause and thrombosis. Review. Lancet 1999;353: London deranged conformation of haemoglobin 1348–53. molecules producing distorted erythro- 16 Greaves M, Cohen H, MacHin SJ, Mackie I. Clin Med JRCPL 2001;1:441–6 cytes, some sickle-shaped. Erythrocyte Guidelines on the investigation and management of the antiphospholipid survival is shortened, rheology deranged syndrome. Br J Haematol 2000;109:704–15. with disturbed interacti on between Sickle cell disease (SCD) affects 12,000 17 Brandjes DP , Buller HR, Heijboer H, erythrocytes and vascular endothelium, individuals in the UK 1 and imposes a Huisman MV, et al. Randomised trial of and dysregulation of vascular reactivity. effect of compression stockings in patients severe health burden on many. Frequent Small and large vessel occlusions result. with symptomatic proximal-vein throm- crises mean interrupted education and Lack of significant morbidity for HbAS bosis. Lancet 1997;349:759–62. cause employment difficulties. In the heterozygotes (sickle cell trait) and their third and fourth decades, chronic end- relative protection against death from organ damage may predominate . malaria in childhood are well Address for correspondence: Median life expectancy is reduced to the documented. Current theories of patho- Dr Trevor Baglin, Consultant mid-40s even with optimal care 2. genesis are reviewed by Steinberg 3 Haematologist, Addenbrooke’s Although some complications require (alsoat www.asheducationbook.org/ University Hospitals Trust, hospital admission, a wider care model is current.shtml). Cambridge CB2 2QQ. appropriate involving health and social E-mail: [email protected] care agencies across acute and com- munity boundaries. Full involvement of Screening patients and carers in developing services Up to 40% of African, Afro-Caribbean, is critical. Asian, South-East Asian and The term ‘SCD’ includes: Mediterranean populations are carriers. • homozygosity for the bS gene, Only in people of strictly Northern resulting in sickle cell anaemia European origin are carriers rare.

Key Points

Sickle cell disease affects people from a wide range of ethnic origins. There are about 12,000 affected individuals in the UK, many of whom have major chronic health problems

Antenatal screening and counselling give carrier parents informed choice regarding their options in pregnancy. Neonatal screening identifies affected babies and reduces their risks

Pneumococcal infection has a high mortality, especially in infants. This can be reduced by regular penicillin prophylaxis and immunisation

Vaso-occlusive painful crises, often severe, dominate the clinical course but there are many additional acute and long-term complications, some life-threatening

Most pain episodes are managed at home. Although hospital analgesia has usually been with parenteral opiates, there is evidence in children that oral morphine is as effective

Management requires a comprehensive long-term multidisciplinary approach with full involvement of the patient and carers

Treatment with oral hydroxyurea and allogeneic bone marrow transplantation can change the course of the disease. These options should be discussed fully with potentially suitable, severely affected patients and families

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