Heparin-induced thrombocytopenia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Assistant Editor-In-Chief: Aric C. Hall, M.D. Beth Israel Deaconess Medical Center, Boston, MA [3]
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Overview
Heparin-induced thrombocytopenia (HIT) with or without thrombosis (HITT) is thrombocytopenia (low platelet counts) due to the administration of heparin. While it is mainly associated with unfractionated heparin (UFH), it can also occur with exposure to low-molecular weight heparin (LMWH), but at significantly lower rates. The development of mild to moderate thrombocytopenia (platelet counts of 50-70,000) in the context of heparin exposure is suggestive of a possible diagnosis of HIT while severe thrombocytopenia and platelet counts less than 20,000 are quite unusual for the syndrome.[1] Alternatively, a decrease of platelet count by 30-50% with heparin exposure in the absence of absolute thrombocytopenia is also consistent with heparin induced thrombocytopenia. Given these relatively high nadirs in platelet count, clinically significant bleeding associated with the thrombocoytopenia is quite rare. Heparin induced thrombocytopenia is primarily a thrombotic disorder, with very high rates of thrombosis, in the arteries with or without venous complications. Of note, the rate of DVT (Deep Vein Thrombosis) is roughly 4 times that of arterial thrombosis, and while thrombocytopenia is the most common "event" in HIT, DVT is in fact the most common complication.
HIT typically develops 4-14 days after the administration of heparin. Given the time needed for development of the causal antibodies the syndrome should not be able to develop in less than four days and alternative explanations should be sought for the development of thrombocytopenia earlier in therapy. The primary exception to this is in the case of recent heparin exposures where the patient may have pre-existing antibodies against the heparin-PF4 complex.
Heparin (UFH) is used in cardiovascular surgery, as prevention or treatment for deep-vein thrombosis and pulmonary embolism and in various other clinical scenarios. LMWH is increasingly used in outpatient prophylaxis regimes.
There are two forms of HIT. Type II HIT is the main adverse effect of heparin use.
Type I
Patients have a transient decrease in platelet count without any further symptoms. This recovers even if heparin is continued to be administered. Platelet counts rarely fall below 100,000. It occurs in 10-20% of all patients on heparin. It is not due to an immune reaction and antibodies are not found upon investigation.
Type II
This form is due to an autoimmune reaction with antibodies formed against platelet factor 4 (PF4), neutrophil-activating peptide 2 (NAP-2) and interleukin 8 (IL8) which form complexes with heparin. The most common being to the heparin-PF4 complex. It appears that heparin binding to platelet factor 4 causes a conformational change in the protein, rendering it antigenic. The antibodies found are most commonly of the IgG class with or without IgM and IgA class antibodies. IgM and IgA are rarely found without IgG antibodies. Type II HIT develops in about 3% of all patients on UFH and in 0.1% of patients on LMWH, and causes thrombosis in 30% to 40% of these patients. The other patients are able to compensate for the activation of hemostasis that leads to thrombosis. Clot formation is mainly arterial and rich in platelets ("white clot syndrome"), in contrast with fibrin-rich clots (which are red due to trapped red blood cells). Most thrombotic events are in the lower limbs, skin lesions and necrosis may also occur at the site of the heparin infusion
The most important enzyme in type II HIT is thrombin, the generation of which is increased following platelet activation. Platelet activation follows the binding of heparin to PF4 and the cross linking of receptors on the platelet surface.
Genetic risk factors for thrombosis such as factor V Leiden, prothrombin gene mutation, methylenetetrahydrofolate reductase (MTHFR) polymorphism and platelet-receptor polymorphisms do not increase the risk of developing HIT associated thrombosis.
Risk for HIT is higher in women than in men, and HIT occurs more commonly in surgical than in non-surgical settings.[2]
Diagnosis
The most specific tests are: the serotonin release assay (SRA), the heparin induce platelet aggregation (HIPA) assays and the solid-phase immunoassay (SPI). The sensitivity of these tests is 94% at best. The gold standard is the SRA where antibodies from the patient’s serum result in release of radiolabeled serotonin attached to platelets from a normal patient. The HIPA looks for platelet aggregation that is present with heparin, platelets and patient serum but does not occur in the absence of heparin. It has a >90% specificity but is limited by low sensitivity. The SPI is an enzyme-linked immunosorbent assay (ELISA) that tests for the presence or absence of heparin-PF4 complexes. Because it does not determine whether the antibodies are functionally significant, it is best used in conjunction with one of the two prior tests. [3] [4] [5] [6]
Treatment
Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. To block the thrombotic state, lepirudin, fondaparinux, bivalirudin, argatroban, danaparoid or other direct thrombin inhibitors are used. Low molecular weight heparin is contraindicated in HIT.
According to systematic review, patients treated with lepirudin for heparin-induced thrombocytopenia showed a relative risk reduction of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls. In addition, patients treated with argatroban for HIT showed a relative risk reduction of the above clinical outcomes to be 0.20 and 0.18. [7]
Pharmacotherapy
Acute Pharmacotherapies
- Check platelet counts twice weekly while on heparin. Withdrawal heparin immediately of HIT is suspected. Platelet transfusion worsens thrombosis, and warfarin therapy is should be avoided for 3-5 days after heparin cessation and/or until thrombocytopenia resolves (>100,000).
- Use of heparinoids and direct thrombin inhibitors is the safest and most effective therapeutic approach to HIT for both those who need ongoing anticoagulation and for thrombosis prevention. Hirudin or Leprudin are direct thrombin inhibitors that have been shown to be effective. Danaproid (Orgaran) is a heaparinoid composed of 85% heparan sulphate, 10% dermatan sulphate and 5% chondroitin sulphate that has approximately 10% cross reactivity with heparin. It has been shown to reduce mortality from thrombotic complications to 5% from 28%. Other agents that have been used include aspirin (ASA), acrid (viper venom), prostaglandin’s and GpIIb/IIIa have not been had reproducible efficacy or have not been used in enough patients to warrant routine use.
- The in vitro cross reactivity of LMWH with heparin dependant antibodies is approximately 60-100%. Nonetheless, a theoretical argument for the use of LMWH in therapy for HIT has been made. The theory is that the LMWH overall interaction of heparin with PF4 will diminish. Though there are reports of LMWH being effective in controlling HIT in the presence of cross-reacting antibodies, the consensus is not to administer LMWH unless the absence of cross reactivity has been determined.
Patients Undergoing Surgery or PCI
Patients with HIT should be treated with Bivalirudin, a direct thrombin inhibitor to support these procedures.
Secondary Prevention
Patients with HIT should be treated with Bivalirudin, a direct thrombin inhibitor to support future procedures.
Reference
- ↑ Arepally GM, Ortel TL (2010). "Heparin-induced thrombocytopenia". Annu. Rev. Med. 61: 77–90. doi:10.1146/annurev.med.042808.171814. PMID 20059332.
- ↑ Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood 2006;108:2937-41. PMID 16857993.
- ↑ Harenberg J, Huhle G, Giese C, Wang L, Feuring M, Song X, Hoffmann U (2000). "Determination of serotonin release from platelets by enzyme immunoassay in the diagnosis of heparin-induced thrombocytopenia". Br J Haematol. 109 (1): 182–6. PMID 10848798..
- ↑ Hirsh J, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1992; 102:337S-351S. PMID 1327666
- ↑ Walenga JM, Bick RL. Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of heparin therapy. Med Clin North Am 1998; 82:635-58. PMID 9646784
- ↑ Fabris F, Luzzatto G, Stefani PM, Girolami B, Cella G, Girolami A. Heparin-induced thrombocytopenia. Haematologica 2000 Jan; 85:72-81. PMID 10629596
- ↑ Hirsh J, Heddle N, Kelton J (2004). "Treatment of heparin-induced thrombocytopenia: a critical review". Arch Intern Med. 164 (4): 361–9. PMID 14980986. .
External links
- Cleveland clinic page on HIT
- HIT page
Additional Reading
- Kumar, Vinay, Abul Abbas, and Nelson Fausto. Robbins and Cotran Pathologic Basis of Disease, 7th ed. (2005). ISBN 0-7216-0187-1
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