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Acquired coagulation disorders 

Acquired coagulation disorders

Chapter:
Acquired coagulation disorders
Author(s):

T.E. Warkentin

DOI:
10.1093/med/9780199204854.003.220605_update_001

Update:

Updated information on frozen plasma, the urgent reversal of coumarin anticoagulation, the withdrawal of Drotrecogin alfa, new oral anticoagulant overanticoagulation, and the treatment of heparin-induced thrombocytopenia (HIT).

Updated on 30 May 2013. The previous version of this content can be found here.
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date: 27 March 2017

Acquired disorders of coagulation may be the consequence of many underlying conditions, and although they may share abnormality of a coagulation test, e.g. a prolonged prothrombin time, their clinical effects are diverse and often opposing.

General clinical approach

Diagnosis—most acquired disorders of coagulation can be identified by screening haemostasis tests, including (1) prothrombin time (PT); (2) activated partial prothromboplastin time (aPTT); (3) thrombin clotting time (TCT); (4) fibrinogen degradation products (FDPs); (5) the cross-linked fibrin assay (D-dimer); (6) protamine sulphate paracoagulation assay; (7) bleeding time—now rarely required or performed; and (8) complete blood count with examination of a blood film. Few bleeding disorders give normal results in all these tests, but disorders predisposed to thrombosis as a result of deficiency of natural anticoagulants (e.g. antithrombin III, protein C, protein S) must be specifically sought.

Treatment—patients with coagulopathies who are bleeding or who require surgery are usually treated with blood products such as platelets and fresh frozen plasma. Other treatments used in particular circumstances include (1) vitamin K—required for the post-translational modification of factors II, VII, IX, and X as well as the anticoagulant factors, protein C and protein S; (2) cryoprecipitate—used principally for the treatment of hypofibrinogenaemia; (3) concentrates of specific factors—used in isolated deficiencies, e.g. of factors VIII, IX, or VIIa; (4) antifibrinolytic agents—e.g. ε‎-aminocaproic acid and tranexamic acid; (5) desmopressin (1-desamino-8-D-arginine vasopressin, or DDAVP)—increases factor VIII and von Willebrand factor.

Prohaemorrhagic coagulation disorders

Vitamin K deficiency—most haemostatic factors are produced exclusively by the liver, including the vitamin K dependent factors II, VII, IX, and X, deficiency of which can be caused by (1) malabsorption of fat-soluble vitamins; (2) coumarin overanticoagulation—minor bleeding episodes occur in about 6 to 10% of patients per year and major bleeding episodes in 1 to 3%; (3) liver disease. Diagnosed by finding a disproportionately prolonged PT in an appropriate clinical setting.

Disseminated intravascular coagulation (DIC)—clinical manifestations range from generalized haemorrhage to widespread microvascular thrombosis, predisposing to multisystem organ dysfunction and limb necrosis. Initiated by numerous triggers, e.g. the extrinsic coagulation pathway or interleukin-6 in the context of systemic inflammation. May be caused by a wide variety of conditions, including trauma and shock, infection, obstetric complications, acute haemolysis, immunological disorders, and vascular anomalies. The presence of DIC is often indicated by abnormal coagulation tests associated with thrombocytopenia and red cell abnormalities on examination of the blood film: FDPs and D-dimers are significantly increased, and the protamine sulphate paracoagulation assay usually indicates abnormalities of clinical significance.

Immunoglobulin-mediated factor deficiency—(1) Acquired factor VIII deficiency—this is suggested by the occurrence of bleeding, either spontaneously or after minor trauma, in association with a prolonged aPTT and a normal PT, with mixing experiments with normal pooled plasma indicating the presence of an inhibitory antibody. The condition is of unknown cause in 50% of cases, with the remainder associated with other autoimmune disorders (e.g. systemic lupus erythematosus), lymphoid and other malignancies, penicillin treatment, or the postpartum state. Aside from treatment with DDAVP (mild bleeding) or purified human factor VIII (or VIIa) concentrates (severe bleeding), patients with high antibody titres may require immunosuppressive therapy, e.g. high dose intravenous immunoglobulin, rituximab. (2) Other acquired coagulation-factor deficiencies caused by antibodies.

Other acquired coagulation-factor deficiencies—these include (1) haemodilution and massive transfusion; (2) heparin and acquired heparin-like anticoagulants; (3) coagulopathies secondary to plasma-cell dyscrasias; (4) hyperfibrinolysis—which may be a result of thrombolytic therapy, malignancy, cardiopulmonary bypass procedures, or liver disease, and (5) heterogeneous coagulopathies induced by venoms (snake bites).

Prothrombotic coagulation disorders

Heparin-induced thrombocytopenia—caused by IgG antibodies which recognize complexes of platelet factor 4 and heparin, typi cally leading to a fall in platelet count 5 to 10 days after starting the drug (but more abruptly in patients who have recently been exposed to it). Thrombosis is caused by several factors, including activation of platelets and stimulation of tissue factor expression on endothelium and monocytes. Clinical manifestations include (1) venous thrombosis—e.g. deep vein thrombosis, pulmonary embolism; (2) arterial thrombosis—e.g. major limb artery thrombosis, stroke, myocardial infarction. Treatment is discussed later in the section, Heparin-induced thrombocytopenia.

Adenocarcinoma-associated chronic disseminated intravascular coagulation—metastatic adenocarcinoma and other tumours may be associated with a prothrombotic state and large vessel thromboses. Tissue factor and prothrombotic cysteine proteases have been found in tumour extracts. Heparin is the preferred treatment.

Antiphospholipid antibody syndrome—caused by antibodies that are usually directed against protein cofactors such as β‎2-glycoprotein I and prothrombin. Clinical manifestations include intermittent thromboses and (rarely, but most dramatically) sudden life-threatening arterial occlusions. Lupus anticoagulant activity is shown by demonstrating inhibition of phospholipid-dependent coagulation assays (most commonly by prolongation of the APTT), with antiphospholipid antibodies also detected by enzyme-immunoassay using purified phospholipids as the target antigen, e.g. anticardiolipin antibody assay. Most patients require long-term anticoagulation.

Other conditions associated with microvascular thrombosis—these include (1) thrombotic microangiopathy—e.g. thrombotic thrombocytopenic purpura; (2) coumarin-induced skin necrosis; (3) coumarin-induced venous limb gangrene; (4) purpura fulminans.

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