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to perform the simple clotting tests frequently, both before and after clinical interventions, to judge their efficacy and the need for further blood product replacement therapy or interventions. The role of thromboelastography (TEG) in monitoring DIC has progressed in recent years, with the use of whole blood and near‐patient testing, particularly in operating theatres, able to direct the appropriate component to replace when bleeding is excessive.

Management

      The first principle of managing DIC should be toward resuscitation of the patient to achieve adequate oxygenation, blood pressure, circulation, and renal perfusion. Once resuscitation is complete, aggressive treatment of the DIC's underlying precipitating cause should be addressed. Most frequently, this is sepsis, and aggressive broad‐spectrum antibiotic therapy is necessary following the taking of appropriate microbiological samples. A few causes of disseminated malignancy, such as acute promyelocytic leukaemia and hormone‐responsive breast and prostatic carcinoma, may also be amenable to treatment, but the prognosis in DIC secondary to disseminated malignancy is usually poor; indeed, mortality overall remains high at 25–75% in various series.

      There is considerable controversy about the place of blood product support in DIC. Clearly, red cells and platelet support, together with plasma product support, are indicated in actively bleeding patients. In patients who are not actively bleeding or requiring surgical or other intervention, the use of transfused clotting factors and platelets only makes the microvascular thrombosis worse unless the underlying precipitating factors have been treated. However, once these issues have been addressed, if the patient is bleeding, it is appropriate to transfuse red cells to achieve a haemoglobin level of above 10 g l⁻¹ or haematocrit above 30%, to transfuse platelets to achieve a platelet count of >80 × 10⁹ l⁻¹, to transfuse FFP (10–15 ml kg⁻¹) to correct the PT and APTT to no more than 10% prolonged above the upper limit of normal, and to increase the fibrinogen to >1 g l⁻¹ through the appropriate use of cryoprecipitate (cryoprecipitate is particularly rich in fibrinogen) or fibrinogen concentrate. Following blood product intervention, the clotting screen should be repeated to assess the response to therapy and the need for additional future therapy.

      In DIC due to sepsis, there is now evidence that depletion of the natural anticoagulant pathway proteins such as antithrombin, protein C, and protein S contributes to microvascular thrombosis, the systemic inflammatory response, and a poorer prognosis. It is not clear if replacement of natural anticoagulants is of therapeutic benefit, but several trials have been published, especially with antithrombin concentrate, with inconclusive results.

      The use of heparin is even more controversial.^8,9 There are no adequate controlled trials to support its use, and although it would appear logical to use an anticoagulant in a condition where the major morbidity and mortality are due to thrombosis, the use of a systemic anticoagulant in patients either with active bleeding or at high risk of catastrophic bleeding is problematic. Furthermore, there are considerable problems in determining the dose and duration of treatment and monitoring heparin therapy in the presence of severely prolonged clotting times. As heparin works by potentiating the activity of antithrombin, which is usually severely depleted in DIC, its efficacy is uncertain. Fibrinolytic therapy with tranexamic acid is contraindicated in DIC unless the trigger mechanism is hyperfibrinolysis, and the use of aprotinin, prostacyclin, and antiplatelet drugs remains controversial and unproven. There is evidence that human recombinant activated FVIIa may be useful in uncontrolled life‐threatening haemorrhage, but it should be recognized that the product is not licensed for this indication; and its use in systemic bleeding disorders outside of haemophilia and platelet disorders is associated with a significant increase in arterial thrombotic events, particularly heart attacks and cerebrovascular accidents.

Chronic disseminated intravascular coagulation

Chronic DIC manifests very differently from acute DIC. The cause is usually, but not exclusively, disseminated malignancy or vascular malformation such as abdominal aneurysm, which may be manifest but may often remain occult for weeks or months after the initial presentation. Patients usually present with bruising from thrombocytopenia and on further investigation are found to have, in addition to thrombocytopenia, hypofibrinogenaemia and elevated D‐dimers. Bleeding is a rare manifestation of this condition, although bruising is common, while thrombosis in the form of superficial thrombophlebitis and deep venous thrombosis is common. Furthermore, sterile nonbacterial endocarditis is well recognized, which can result in presentation with arterial embolization.¹⁰

      Thus, the hallmarks of this condition are arterial and venous thrombosis rather than bleeding. The condition will usually resolve if the underlying cause can be successfully treated. If it cannot, the cautious application of anticoagulation rather than blood product support is the mainstay of treatment. Warfarin is notoriously difficult to use in this condition; low‐molecular‐weight heparin is the treatment of choice in terms of both efficacy and improving overall outcome, although some success has been achieved with the use of oral therapy in the form of direct‐acting oral anticoagulants (DOACs) such as rivaroxaban and apixaban. The treatment can be monitored with the platelet count and D‐dimers. Successful treatment results in increased platelet count, reduction in D‐dimer, and suppression of the chronic DIC.

      Key points

       DIC presents with haemorrhage, but it is the microvascular thrombosis that causes multiorgan damage.

       DIC is commonly due to sepsis or disseminated malignancy.

       Diagnosis requires a blood count, film, and clotting screen with D‐dimers.

       Treatment should address the underlying cause first, especially if sepsis; only then may blood product support be indicated.

       Chronic DIC presents with thrombosis rather than haemorrhage and is managed with anticoagulation.

References

      1 1. Hunt BJ. Bleeding and coagulopathies in critical care. N Engl J Med. 2014; 370(9):847–859

      2 2. Grando S, Levi M, Toh CH. Disseminated intravascular coagulation. Nat Rev Dis Primers. 2016; 2:16037

      3 3. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999; 341(8):586–592

      4 4. Toh CH and Hoots WK; Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the ISTH. The scoring system of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5‐year overview. J Thromb Haemost. 2007; 5:604–6.

      5 5. Favaloro EJ. Laboratory testing in disseminated intravascular coagulation. Semin Thromb Hemost. 2010; 36:458–67.

      6 6. Levi M, van der Poll T. Coagulation and sepsis. Throb Res. 2017; 149:38–44.

      7 7. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013; 369(9):840–851

      8 8. Falanga A, Marchetti M, Vignoli A. Coagulation and cancer: biological and clinical aspects. J Thromb Haemost. 2013; 11(2):223–233

      9 9. Cornet AD, Smit EG, Beishuizen A, Groeneveld AB. The role of heparin and allied compounds in the treatment of sepsis. Thromb Haemost 2007; 98:579–86.

      10 10. Kitchens CS. Thrombocytopenia and thrombosis in disseminated intravascular coagulation (DIC). Haematology Am Soc Hematol Educ Program. 2009:240–6.

CHAPTER 24 Disorders of haemostasis

       Kingsley K. Hampton

      Royal Hallamshire Hospital, Sheffield, UK

Introduction

      Bleeding causes or contributes to the death of about 5% of the

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