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Harry N Magnani
MB BSc MSc PhD
International Medical Consultant
Thrombosis and Haemostasis Business Unit
Heparin-induced thrombocytopenia (HIT) is an immune-mediated side-effect of the use of glycosaminoglycan (GAG) antithrombotics (eg, unfractionated [UFH] and low-molecular-weight heparin [LMWH]). It results in platelet and endothelial cell activation and thrombin generation. It has a 20-30% mortality rate and high thrombotic morbidity in survivors. Diagnostic pitfalls affect its recognition (see Table 1). Thus, HIT diagnosis requires a high state of awareness and suspicion.(1)
Platelet count reduction larger than 30% (PCR) or thromboenbolic events (TE) are common in sepsis, after major surgery and with many disorders and drugs, but together, without bleeding, especially between days 4 and 14 of heparin/LMWH therapy, they suggest HIT. Clinical scoring systems (eg, the 4 Ts, see Table 2) help early diagnosis and subsequent management but should be implemented daily until HIT is reasonably certain or refuted.(2)
Whenever possible, HIT should be confirmed by pathognomonic clinical signs (see Table 3) and/or serological testing. Thus, early access to the patient’s previous hospital records and a good clinical history are essential.
HIT can be confirmed by serological testing:
As serological tests may be unavailable and/or results are delayed, clinical status and platelet count progression provide the most important clues for HIT diagnosis and treatment decisions.
General management of HIT
Once reasonably suspected, the aims of treatment are (see Table 4):
Surgery, invasive vascular procedure or extracorporeal circuit use thrombolytic may also have to be considered. Hence, management of HIT must balance:
Unless the platelet count is extremely low and responsible for bleeding, platelet transfusions are prohibited.(3)
Drugs currently approved for HIT treatment
The alternative antithrombotic (see Table 5) must act immediately and have an efficacy/safety profile suited to the clinical status of the patient. It should preferably be approved for HIT, to avoid legal problems. Several drugs are available in Europe.
This nonheparin GAG inhibits thrombin generation and interferes with the HIT-antibody/platelet interaction. It has the highest recommendation for HIT treatment,(3) being safe and effective in children,(4) pregnancy,(5) renal failure requiring an extracorporeal circuit, and medical and surgical comorbidity.(6) Specific dosing regimens are available. Plasma anti-Xa activity monitoring is unnecessary except for patients with high or low body weight and severe renal dysfunction. Danaparoid use has been subcutaneously for up to three years and intravenously for intermittent haemodialysis for over four years. Excluding cardiopulmonary bypass surgery (CPBS), severe bleeding occurs in 4.8% of HIT patients.(7) In more than 1,709 reported HIT cases, serological cross-reactivity was found in 3.4%, but resultant prolonged/new PCR and/or thromboses occurred in less than 1.3%, with two fatalities. No spontaneous HIT has been reported with danaparoid; it does not cross the placenta or appear in breast milk.(5)
The LMWHs are not recommended(3) because of their high in-vivo cross-reactivity and spontaneous HIT.
Direct thrombin inhibitors (DTIs)(3)
Lepirudin (irreversible) and argatroban (reversible) are inhibitors of free and clot-bound thrombin. Intravenous administration restricts both to relatively short-term use. Argatroban is eliminated via the liver and lepirudin through the kidneys. Hence, in hepatic and renal dysfunction, respectively, dose adjustment is needed to reduce the bleeding risk.(8) Argatroban has relatively low efficacy compared with danaparoid and lepirudin.(9)
Antilepirudin antibodies (44%) interfere with activated partial thromboplastin time (aPTT) monitoring, increase its bleeding risk and limit reuse. Rare anaphylactic reactions, particularly following re-exposure, have a 44% fatality, and 14% of patients develop allergic reactions.
Venous limb gangrene may complicate the overlap of both DTIs with a vitamin K antagonist (VKA), and effects on the PT/INR (prothrombin time) when switching to a VKA increase the bleeding risk.(10)
Information on pregnancy and paediatric use is limited for both drugs.
Drugs currently used, but not approved,for HIT treatment
This direct, reversible, synthetic DTI analogue of hirudin is effective against free and clot-bound thrombin and approved for HIT in patients undergoing percutaneous coronary intervention. It is partly eliminated through the kidneys and safe (when administered with aspirin), but there is a lack of general dosing guidelines for HIT patients.
Vitamin K antagonists(3)
Coumarin derivatives inhibit synthesis of vitamin K-
dependent clotting factors and related proteins (such as protein C). Their slow onset of action and increased risk of microvascular thrombosis (skin necrosis and venous gangrene,(1) especially in combination with a DTI), mean that VKA treatment in HIT:
This stable prostacyclin inhibits platelet action. Its potential disadvantages are lack of thrombin inhibition, short half-life limiting it to intravenous use, vasodilation and cough.
This synthetic pentasaccharide, which binds antithrombin (AT), is an effective, safe antithrombotic. Although it may induce antibody formation, it is too small to induce clinical HIT. It does not cross-react with HIT antibodies. Potential disadvantages are bleeding, lack of (dosing) experience in HIT patients, placental transfer and secretion into (rat) milk.
Adjunctive measures to treat HIT
Some thrombi are amenable to thrombolytic therapy. Comedication with lepirudin or argatroban may seriously increase the bleeding risk, while combination with danaparoid, fondaparinux or bivalirudin appears to be safe.
Oral antiplatelet drugs
Aspirin or clopidogrel reduce platelet activation but have no antithrombin effects. They may be useful for arterial thromboembolism but may also increase the bleeding risk, and clopidogrel may cause thrombocytopenia.
Thrombectomy for thrombolytic-resistant thrombi (eg, too old), emergency bypass operations, PCI and amputation may be required. Insertion of a vena cava filter should be avoided because of its thrombogenicity.
Plasmapheresis reduces the HIT antibody load and also removes any anticoagulant responsible for HIT or bleeding.
Management of HIT
Table 6 shows some comorbid problems that may determine the drug of choice.
PCR -+ a TE, no serology result yet or confirmatory clinical signs: use prophylactic or therapeutic danaparoid doses, depending upon the patient’s thrombotic/bleeding risk balance. Fondaparinux has occasionally been used, but if HIT is only suspected, then it is better to start with the treatment that will be subsequently used to control it. If serology results are negative and the clinical score remains low, then restart the original antithrombotic.
PCR with positive serology. This requires full therapeutic dosing or less if a high bleeding risk is present. Danaparoid is recommended for all types of patients,(3) DTIs for nonsurgical patients without a high bleeding risk and for emergency CPBS that cannot wait until the HIT antibody clearance from the circulation allows UFH use. Fondaparinux and bivalirudin have also proved to be useful in selected patients.
A positive serological test or an intermediate or high clinical score. This is managed in the same way as isolated HIT.
For example, paediatric and pregnant patients. Most experience is with danaparoid use. For acute and chronic renal failure, both danaparoid and argatroban (with suitable dose modification) have been successfully used. Perioperative danaparoid is safe except for CPBS, where high doses and lack of an antidote restrict it to use postoperatively and when no other alternative is available.(3)