British Journal of Anaesthesia 90 (5): 676±85 (2003) DOI: 10.1093/bja/aeg063 REVIEW ARTICLE HIT/HITT and alternative anticoagulation: current concepts E. Pravinkumar* and N. R. Webster Academic Unit of Anaesthesia and Intensive Care, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK *Corresponding author. Email: [email protected] Downloaded from https://academic.oup.com/bja/article/90/5/676/269997 by guest on 28 September 2021 Br J Anaesth 2003; 90: 676±85 Keywords: blood, coagulation; blood, anticoagulants, heparin Accepted for publication: July 25, 2002 Heparin is a widely used anticoagulant for the treatment and factors, such as factors IX, X, XI and XII and kallikrein, and prevention of thromboembolic disorders in medical and on the conversion of prothrombin to thrombin.50 62 Once surgical patients. Its importance as an anticoagulant has active thrombosis has developed, larger amounts of heparin been well established by its effectiveness, rapid onset of can inhibit further coagulation by inactivating thrombin and action, ease of laboratory monitoring and cost.18 Heparin is preventing the conversion of ®brinogen to ®brin. Heparin a member of the heterogeneous family of glycosaminogly- also prevents the formation of a stable ®brin clot by cans, which range in size from 3000 to 30 000 Da. inhibiting the activation of the ®brin-stabilizing factor. The non-branching, negatively charged chain structure of heparin consists of repeating disaccharide units. Heparin is an anticoagulant released by mast cells and basophils in the Thrombocytopenia and heparin process of clot formation, as well as a drug that is Thrombocytopenia can result from conditions that lead to administered to the same effect. Standard unfractioned increased platelet destruction or decreased platelet produc- heparin is usually derived from porcine intestinal mucosa or tion (Table 2).84057Heparin can cause thrombocytopenia bovine lung.53 via immune and non-immune mediated mechanisms.41 Heparin plays many roles in human physiology, such as: There are two types of heparin-induced thrombocytopenia (i) binding to antithrombin III and increasing the ef®cacy of that can result from heparin administration: type I, non- antithrombin III as an inhibitor of the activation of thrombin immune-mediated; and type II, immune-mediated.23 67 68 In and certain clotting factors; (ii) inhibiting platelet forma- the interest of standardization, the term `non-immune tion; (iii) increasing the permeability of vessel walls; (iv) heparin-associated thrombocytopenia' is recommended for inhibiting the proliferation of vascular smooth muscle cells; type I, a benign condition in which no heparin-dependent and (v) playing a role in the regulation of angiogenesis. antibodies are present. The term `heparin-induced throm- In clinical use heparin has numerous activities, but the bocytopenia' (HIT) is recommended for thrombocytopenia most important is its anticoagulant property (Table 1). It is in which pathogenic heparin-dependent antibodies are also used as a thrombolytic, a fat-clearing anti-athero- detectable. This term is the most widely accepted designa- sclerotic and as a potentially effective anti-in¯ammatory tion for HIT type II.67 agent. Heparin inhibits reactions that lead to clotting of Non-immune-mediated thrombocytopenia, also known as blood and formation of ®brin clots both in vitro and in vivo. heparin-associated thrombocytopenia (HAT) and heparin- It acts at multiple sites in the normal coagulation system. It induced thrombocytopenia type I (HIT type I), denotes the binds to antithrombin III (heparin cofactor), causing a absence of heparin-dependent antibodies. It is probably conformational change in the structure of antithrombin III. caused by direct non-immune platelet activation by heparin. This conformational change converts antithrombin III from Type I HIT is usually associated with larger doses of heparin a slow- to a fast-acting inhibitor of thrombin activation. The in contrast to HIT type II, which can occur with variable complex has a further inhibitory effect on other clotting doses. HIT type I occurs earlier in the treatment course, Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2003 HIT/HITT and alternative anticoagulation within a period of 4 days, in 30% of patients receiving occur with warfarin treatment of HIT-associated DVT, and heparin. The platelet abnormality is usually mild and is characterized by a high international normalized ratio reversible even with the continuation of the heparin (INR), resulting from severe reduction in protein C caused (Table 3). The condition is self-limiting and there are no by warfarin. Adrenal vein thrombosis and cerebral sinus major complications associated with it. Heparin should be thrombosis are other unusual venous thromboses that continued despite the low platelet count.23 67 The clinical complicate HIT. Arterial thromboses associated with importance of the asymptomatic, self-limiting disease HIT HITT may result in ischaemic limb damage that often type I lies in the necessity of differentiating it from the more requires amputation. Myocardial infarction, ischaemic serious HIT type II. stroke and end-organ thromboses, such as mesenteric, Immune-mediated HIT type II exists in three separate renal, brachial, splenic and hepatic arterial thromboses, diagnosable forms: can also occur (Table 4).10 23 47 74 HIT develops in 3% of (i) latent: antibodies without thrombocytopenia; patients treated with unfractioned heparin for more than (ii) HIT: antibodies with thrombocytopenia; and 4 days.72 Without treatment, mortality in HIT patients (iii) HITT: antibodies with thrombocytopenia and throm- with new thromboembolic complications is about 20±30%, Downloaded from https://academic.oup.com/bja/article/90/5/676/269997 by guest on 28 September 2021 bosis. with equal morbidity caused by arterial and venous HIT/HITT (heparin-induced thrombocytopenia and he- thrombosis.11 20 75 The risk of venous thromboembolism parin-induced thrombocytopenia with thrombosis syn- from HIT is greater in high-risk surgical patients than in drome) is an immune-mediated adverse reaction to medical patients. Also, 40±50% of HIT patients will have a heparin that is often underdiagnosed and can result in thrombotic event when heparin is discontinued.25 65 74 76 venous and arterial thrombosis.6 56 67 69±73 79 The alternative name of HITT, white clot syndrome, refers to the gross pathology of the clots. The platelet±platelet adhesion Mechanism of heparin±PF4±IgG complex without erythrocyte involvement gives a classic appearance Most patients with HIT produce immunoglobulin G (IgG) of a white clot. Patients with HITT may suffer from venous antibodies, commonly IgG141755against macromolecular thrombosis, most often deep venous thrombosis (DVT), complexes of platelet factor 4 (PF4) and heparin which can be extensive and complicated by pulmonary (H±PF4).2112637416364The high binding af®nity between embolism. Venous limb gangrene has been reported to heparin and PF4 is probably attributable to a high concen- tration of C-terminus lysine residues that interact strongly Table 1 Clinical uses of heparin Vascular Acute-phase myocardial infarction Table 2 Causes of thrombocytopenia Venous and arterial thromboembolism Pulmonary embolism Increased platelet destruction Peripheral arterial disease Non-immune Septicaemia/in¯ammation Atherosclerosis Disseminated intravascular coagulation (DIC) Atrial ®brillation with embolization Thrombotic thrombocytopenic purpura (TTP) Acute ischaemic stroke Immune Autoimmune: idiopathic or secondary immune Deep vein phlebitis thrombocytopenia Topical Flap survival/pruritus Alloimmune: post-transfusion purpura Leg ulcers Drug-induced: prothrombic (heparin), Surgery Open-heart surgery prohaemorrhagic (quinine, quinidine, gold, Vitreoretinal surgery sulpha antibiotics, rifampicin, vancomycin, Prophylaxis Pulmonary embolism NSAIDs) Deep vein thrombosis Decreased platelet production Alcohol, cytotoxic drugs Support systems Extracorporeal circulation Leukaemia, aplastic anaemia Renal replacement therapy Myelodysplasia Critical care Heparin-coated central venous and pulmonary Metastatic bone marrow involvement arterial catheters Infections Heparin ¯ushes in arterial and central venous Other causes Hypersplenism lines Haemodilution (infusion of blood products, Other (as anticoagulant) Laboratory samples colloids, crystalloids) Blood transfusion NSAIDs=non-steroidal anti-in¯ammatory drugs. Table 3 Heparin-induced thrombocytopenia68 Non-immune-mediated HAT (type I HIT) Immune-mediated HIT (type II HIT) Onset Within 4 days 5±14 days or sooner Platelet count Typically 100 000±150 000 ml±1 Typically 20 000±150 000 ml±1 Incidence 5±30% 1±3% Complications None Thromboembolic lesion Recovery 1±3 days 5±7 days Cause Benign: tiny platelet aggregates IgG-mediated platelet activation 677 Pravinkumar and Webster with the highly negatively charged heparin molecule. between days 5 and 15 after the introduction of heparin,72 Neither heparin nor PF4 is normally antigenic, but the but can develop earlier in patients exposed to heparin during formation of an H±PF4 complex induces a conformational the previous 3 months.41 Case reports have shown change in both molecules. Upon binding to the heparin thrombocytopenia developing within 10.5 h in patients molecule, PF4 exposes several antigenic epitopes, which exposed to heparin in the last 100 days. Thus, a patient with trigger the immune reaction and the production