Intended for healthcare professionals

Endgames Case Report

Multiple emboli after gastrectomy

BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c1663 (Published 05 May 2010) Cite this as: BMJ 2010;340:c1663
  1. Matthew Rogers, core medical trainee year 2,
  2. Graham Smith, consultant haematologist
  1. 1Department of Haematology, Frimley Park Hospital, Surrey GU16 7UJ
  1. matthewjohnrogers{at}googlemail.com

    A 60 year old man underwent a total gastrectomy for T2a, N0, M0 gastric cancer. Seven days after the operation, while still recovering in hospital, he developed left lower leg pain of sudden onset. He described the pain as severe and said that his leg below the knee felt cold and numb.

    His medical history included one deep vein thrombosis and one pulmonary embolus several years apart. He had no other medical history of note. In particular, he had no history of peripheral vascular disease or intermittent claudication. Before the gastrectomy, the only drug that he was taking was long term warfarin; this had been changed to therapeutic dose low molecular weight heparin perioperatively, and he remained on heparin at the onset of leg pain. He was an ex-smoker.

    On examination he seemed to be in pain, with a regular pulse of 100 beats/min, blood pressure of 140/70 mm Hg, and temperature of 36.5°C. His left leg was cold and pale, with no pulses palpable below the thigh. The rest of the cardiovascular examination was normal. Computed tomography angiography showed abrupt occlusion of the left common femoral artery, with a further occlusion of the left popliteal artery.

    Blood tests were as follows: haemoglobin 99 g/l, white blood cell count 17.7×109/l, platelets 65×109/l, urea 4.7 mmol/l; creatinine 68 µmol/l, bilirubin 12 µmol/l, activated partial thromboplastin time 27.7 seconds (normal range 26-36), and prothrombin time 14.4 seconds (normal range 11-26). Three days before the onset of leg pain his blood results had been: haemoglobin 101 g/l, white blood cell count 17.6×109/l, and platelets 163×109/l.

    An embolectomy was performed. Two days later he developed left subchondral and pleuritic chest pain. Oxygen saturation fell to 92% on air. Respiratory examination was otherwise unremarkable; examination of the abdomen showed mild left upper quadrant tenderness. He had sinus tachycardia on electrocardiography. Computed tomography pulmonary angiography showed multiple pulmonary emboli; abdominal computed tomography showed low attenuation fluid around the tip of the spleen, consistent with a splenic infarct. Echocardiography was normal.

    Questions

    • 1 What is the most likely diagnosis, and what differentials should be considered?

    • 2 How would you confirm the diagnosis?

    • 3 How should he be treated?

    • 4 What treatments should be avoided?

    Answers

    1 What is the most likely diagnosis, and what differentials should be considered?

    Short answer

    Heparin induced thrombocytopenia is the most likely diagnosis. Important differentials are disseminated intravascular coagulation and thrombotic thrombocytopenic purpura.

    Long answer

    This presentation, with a fall in platelet count and arterial and venous thromboses, is highly suggestive of heparin induced thrombocytopenia.1 This condition is an immune phenomenon, brought about by the formation of antibodies—usually IgG—to complexes of heparin and platelet factor 4. These antibody-antigen complexes then activate platelets, leading to thrombosis and platelet consumption.2 Patients typically present at five to 14 days after exposure to heparin.3 The fall in platelet count is usually 50% or more4; it should be remembered that this may not lead to a platelet count below the normal range if the platelet count is high before exposure to heparin.5 The thrombocytopenia is usually moderate (median nadir 60×109/l).5 Very low platelet counts (<20×109/l) make other diagnoses, such as post-transfusion purpura, more likely.1 The risk of heparin induced thrombocytopenia is higher in surgical patients than in medical ones, and the incidence is 10 times higher with unfractionated heparin (5%) than with low molecular weight heparin (about 0.5%).4 The British Society of Haematology advises close monitoring of platelet counts for all patients treated with heparin, particularly between days four and 14.4

    The condition is also known as type II heparin induced thrombocytopenia. Type I heparin induced thrombocytopenia is now more commonly called heparin associated thrombocytopenia.6 Heparin associated thrombocytopenia is non-immune mediated, results from heparin induced platelet clumping, causes mild thrombocytopenia (usually >100×109/l), and does not lead to thrombotic complications.7

    Two important differentials in this case are disseminated intravascular coagulation and thrombotic thrombocytopenic purpura. Disseminated intravascular coagulation may be seen in the context of major surgery or postoperative sepsis; the diagnosis is suggested by deranged clotting indices, low fibrinogen concentrations, and raised concentrations of fibrin degradation products, features that are not seen in heparin induced thrombocytopenia.6 Thrombotic thrombocytopenic purpura is a thrombotic microangiopathy characterised by platelet aggregation and mechanical intravascular haemolysis, which leads to typical blood film appearances (schistocytes).8 Neurological features are also usually considered part of the syndrome of thrombotic thrombocytopenic purpura, but these may be mild or absent.9 It may be useful to measure the activity of the metalloprotease ADAMTS-13, because severe deficiency of this enzyme is associated with this disorder.9

    In patients who have recently received a blood transfusion, post-transfusion purpura should also be considered. In this disorder, antibodies to platelet antigens are produced after transfusion of red blood cells, and this leads to thrombocytopenia and bleeding. Platelet counts are usually very low (<20×109/l), and thrombosis is not a feature. This condition is more common in women, but should be considered in all patients with thrombocytopenia after blood transfusion.10

    2 How would you confirm the diagnosis?

    Short answer

    Clinical assessment based on platelet count, timing of exposure to heparin, and thrombotic complications, in combination with testing for antibodies to heparin-platelet factor 4 complexes.

    Long answer

    Antibody tests looking for IgG to heparin-platelet factor 4 complexes are widely available, highly sensitive (80-100%), and recommended by the British Society of Haematology as the first line investigation for heparin induced thrombocytopenia.4 However, their specificity is low—20% of patients given unfractionated heparin develop these antibodies, but only 1-3% will develop heparin induced thrombocytopenia.7

    These tests should therefore be used in conjunction with clinical assessment when determining the likelihood of heparin induced thrombocytopenia.4 One widely used assessment tool is the “4 Ts” score.1 This looks at the degree of thrombocytopenia (with a nadir of 20-100×109/l but no lower, or a fall of more than 50%, being most characteristic of heparin induced thrombocytopenia); at timing (day five to 10 after introduction of heparin is most characteristic); at the presence of thrombosis or skin necrosis; and the absence of any other explanation for thrombocytopenia.

    Testing for heparin-platelet factor 4 antibodies is only of diagnostic use if results are available quickly. A commercially available Particle Gel Immunoassay (Diamed, Midlothian, UK) is simple to use and can give results from a single clotted blood sample. In our hospital results are available within hours, even out of normal working hours. Centres that use more time consuming enzyme linked immunosorbent assays (ELISAs) or refer tests to external laboratories may encounter longer delays. If such a delay occurs, and heparin induced thrombocytopenia is strongly suspected clinically, treatment should be started pending confirmation.4

    When diagnostic doubt remains, platelet activation tests—which have better specificity for heparin induced thrombocytopenia than antibody tests—can be used. Platelet aggregometry is the more commonly available of these: washed platelets are mixed with the patient’s plasma in the presence of heparin and their aggregation measured using an aggregometer. At best the specificity of this technique is 85%.4 The serotonin release assay is more sensitive (95%) and specific (95%).7 Donor platelets are loaded with radiolabelled serotonin and exposed to the patient’s serum in the presence of heparin. If specific antibodies are present they lead to platelet activation and serotonin release, which can be measured.

    Some authors have advocated combining antibody tests with platelet activation tests to improve diagnostic accuracy.6 However, activation tests are not widely available, and require considerable expertise. The British Society of Haematology therefore does not recommend them for routine use.4

    3 How should the patient be treated?

    Short answer

    All heparin should be stopped, and anticoagulation started with lepirudin or danaparoid.

    Long answer

    Use of all heparin products, including heparin flushes, should be stopped.6 An alternative anticoagulant should be started immediately, because the risk of further thrombosis remains high even after heparin is stopped.7 Two agents are approved for anticoagulation in patients with heparin induced thrombocytopenia in the United Kingdom.4 Lepirudin is a direct thrombin inhibitor, given by intravenous infusion and the dose adjusted according to the activated partial thromboplastin time. Although we have no randomised controlled evidence for the effectiveness of lepirudin, a recent meta-analysis of two small historically controlled studies showed a 27% relative risk reduction in the combined end point of death, amputation, or new thrombosis with lepirudin.11 Lepirudin is renally excreted, so patients should be tested for renal impairment. It can also cause anaphylactic reactions, particularly on re-exposure.12

    Danaparoid is a mixture of three glycosaminoglycans that inhibits factor Xa in the presence of thrombin. It is also given as an intravenous infusion; monitoring is by measurement of factor Xa concentrations. One small randomised controlled trial showed that danaparoid was much more likely than dextran 70 to bring about recovery from heparin induced thrombocytopenia (odds ratio 4.55).13 In another study, danaparoid had similar efficacy to lepirudin, but bleeding events were less common with danaparoid.14 The full therapeutic dose of danaparoid should be used for treating heparin induced thrombocytopenia, rather than the prophylactic dose.4 Danaparoid has a long half life, so over-anticoagulation is hard to reverse. It also crossreacts with heparin-platelet factor 4 antibodies in 10-50% of cases. This rarely leads to clinical heparin induced thrombocytopenia, but isolated cases have been reported.15

    Other possible treatments not currently approved for use in the UK include argatroban, a small molecule, hepatically metabolised direct thrombin inhibitor popular in North America,16 and bivalirudin, a synthetic direct thrombin inhibitor, which has been used successfully for percutaneous coronary intervention in patients with heparin induced thrombocytopenia,17 but which has not yet been approved for use outside this context.6 Activated protein C has been used successfully in one patient with heparin induced thrombocytopenia.18

    4 What treatments should be avoided?

    Short answer

    Platelet transfusion. Warfarin should not be started until the platelet count has recovered.

    Long answer

    As platelet activation is central to the pathogenesis of heparin induced thrombocytopenia, platelet transfusion should be avoided if possible.4

    Although warfarin is used for longer term anticoagulation in patients with heparin induced thrombocytopenia, its use acutely can increase the likelihood of microvascular complications—skin necrosis and limb gangrene—probably because of early inhibition of protein C. Warfarin should therefore not be introduced until the platelet count is normal (>150×109/l).4

    Patient outcome

    Our patient underwent surgical removal of emboli in the left femoral and popliteal arteries, followed by anticoagulation with lepirudin. He had no further thrombotic complications, and his platelet count gradually normalised, at which time warfarin was reintroduced uneventfully.

    Notes

    Cite this as: BMJ 2010;340:c1663

    Footnotes

    • Competing interests: None declared.

    • Provenance and peer review: Not commissioned; externally peer reviewed.

    • Patient consent obtained.

    References

    View Abstract

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