The management of heparin induced thrombocytopenia

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Harry N Magnani
MB BSc MSc PhD
International Medical Consultant
Thrombosis and Haemostasis Business Unit
NV Organon
Oss
The Netherlands
E:[email protected]

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)

[[HPE29_table1_84]]

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)

[[HPE29_table2_84]]

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.

[[HPE29_table3_84]]

HIT can be confirmed by serological testing:

• Functional test of platelet sensitivity:

1. The SRA and HIPAA are sensitive with a high positive predictive value for clinical HIT but are not generally available for routine use.
2. The PAT has lower sensitivity, which can be improved by using washed, reactive donor platelets. It has a high positive predictive value for clinical HIT. If negative, it should be repeated 24 hours later.

• ELISA methods to detect the HIT antibody are sensitive, faster and more practical but have low positive predictive value for clinical HIT because of reduced specificity. They are less sensitive for HIT due to drugs that bind PF4 poorly or not at all. They are useful for excluding HIT.

• Other tests have not been clinically validated.

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):

• Immediate reduction of thrombin production and platelet activation.
• Prevention of new thromboses and/or treatment of existing thromboses.
• Relief of ischaemic problems.
• Reduction of any comorbid disorder that may compromise recovery (eg, sepsis, organ failure, etc).

[[HPE29_table4_85]]

Surgery, invasive vascular procedure or extracorporeal circuit use thrombolytic may also have to be considered. Hence, management of HIT must balance:

• Unnecessarily stopping UFH/LMWH against continuation with the risk of complications.
• Switching to a safe and effective antithrombotic against one that may cause more harm than the natural progression of untreated HIT.

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.

[[HPE29_table5_85]]

Danaparoid
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)

Low-molecular-weight heparins
The LMWHs are not recommended(3) because of their high in-vivo cross-reactivity and spontaneous HIT.

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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

Bivalirudin
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:

• Should be delayed:

1. Until thrombin production is under control.
2. Until the platelet count is clearly increasing.
3. If an operation, invasive procedure or thrombolytic use is planned.

• Should avoid a loading dose.

Iloprost
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.

Fondaparinux
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

Thrombolytics
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.

Surgery
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
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.

[[HPE29_table6_86]]

Suspected HIT
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.

Isolated HIT
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.

Confirmed HIT
A positive serological test or an intermediate or high clinical score. This is managed in the same way as isolated HIT.

Special cases
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)

References

1. Warkentin TE. Clinical picture of heparin-induced thrombocytopenia.In: Heparin-induced thrombocytopenia.3rd ed. New York: Marcel Decker;2004: p. 53-106.
2. Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep 2003;2:148-57.
3. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment and prevention.  The 7th ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;126:311S-37S.
4. Bidlingmaier C, Magnani HN,Girisch M, Kurnik K. Safety and efficacy of danaparoid (Orgaran�) use in children. Acta Haematol 2006;115:237-47.
5. Lindhoff-Last E, Magnani HN, Kreutzenbeck H-J. Treatment of 51 pregnancies with danaparoid because of heparin intolerance.Thromb Haemost 2005;91/3:63-9.
6. Magnani HN, Gallus A. Heparin-induced thrombocytopenia (HIT): a report of 1478 clinical outcomes of patients treated with danaparoid (Orgaran�) from 1982 � mid-2004. Thromb Haemost 2006;95:967-81.
7. Magnani HN, Beijering RJR,ten Cate JW, Chong BH. Orgaran anticoagulation for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia In: New anticoagulants for the cardiovascular patient. Philadelphia: Hanley and Belfus Inc; 1997. p. 487-500.
8. Farner B, Eichler P, Kroll H,Greinacher A. A comparison of lepirudin and danaparoid in patients with heparin-induced thrombocytopenia (HIT). Thromb Haemost 2001;85:950-7.
9. Lubenow N, Warkentin TE, Greinacher A, Wessel A, Sloane D-A, Krahn EL, Magnani NH. Results of a systematic evaluation of treatment outcomes for heparin-induced thrombocytopenia in patients receiving danaparoid, ancrod and/or coumarin explains the rapid shift in clinical practice during the 1990s.Thromb Res 2006;117:507-15.
10. Greinacher A, Warkentin TE. Treatment of heparin-induced thrombocytopenia: an overview. In: Heparin-induced thrombocytopenia. 3rd ed. New York: Marcel Decker; 2004. p. 335-70.