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| __NOTOC__ | | __NOTOC__ |
| '''Associate Editor-In-Chief:''' {{CZ}} | | {| class="infobox" style="float: right;" |
| | | style="vertical-align: middle; padding: 5px;" align=center | [[File:Siren.gif|30px|link=Heparin-induced thrombocytopenia resident survival guide]] |
| | | style="vertical-align: middle; padding: 5px;" align=center | [[Heparin-induced thrombocytopenia resident survival guide|'''Resident'''<br>'''Survival'''<br>'''Guide''']] |
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| '''Assistant Editor-In-Chief:''' Aric C. Hall, M.D. Beth Israel Deaconess Medical Center, Boston, MA [mailto:achall@bidmc.harvard.edu] | | {{Heparin-induced thrombocytopenia}} |
| | {{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}}, [[Priyamvada Singh|Priyamvada Singh, M.B.B.S.]] [mailto:psingh13579@gmail.com], Aric C. Hall, M.D., [mailto:achall@bidmc.harvard.edu] |
| | <br>{{SK}} ''Heparin-associated thrombocytopenia'', |
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| {{Editor Help}}
| | ==[[Heparin-induced thrombocytopenia patient information|Patient Information]]== |
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| | ==[[Heparin-induced thrombocytopenia overview|Overview]]== |
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| ==Overview== | | ==[[Heparin-induced thrombocytopenia historical perspective|Historical Perspective]]== |
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| '''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.<ref name="pmid20059332">{{cite journal |author=Arepally GM, Ortel TL |title=Heparin-induced thrombocytopenia |journal=Annu. Rev. Med. |volume=61 |issue= |pages=77–90 |year=2010 |pmid=20059332 |doi=10.1146/annurev.med.042808.171814 |url=}}</ref> 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 [[thrombosis|thrombotic]] disorder, with very high rates of [[thrombosis]], in the [[artery|arteries]] with or without [[vein|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.
| | ==[[Heparin-induced thrombocytopenia classification|Classification]]== |
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| HIT typically develops 4-14 days after the administration of [[heparin]]. The onset of thrombocytopenia in less than 4-5 days after the initiation of heparin treatment is extremely rare due to the time required for antibody production, 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 (<100 days) where the patient may have pre-existing antibodies against the heparin-PF4 complex.<ref name="pmid16928996">{{cite journal |author=Arepally GM, Ortel TL |title=Clinical practice. Heparin-induced thrombocytopenia |journal=N. Engl. J. Med. |volume=355 |issue=8 |pages=809–17 |year=2006 |month=August |pmid=16928996 |doi=10.1056/NEJMcp052967 |url=}}</ref>
| | ==[[Heparin-induced thrombocytopenia pathophysiology|Pathophysiology]]== |
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| [[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. | | ==[[Heparin-induced thrombocytopenia causes|Causes]]== |
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| There are two forms of HIT. Type II HIT is the main adverse effect of heparin use.
| | ==[[Heparin-induced thrombocytopenia differential diagnosis|Differentiating Heparin-induced thrombocytopenia from other Diseases]]== |
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| ===Type I=== | | ==[[Heparin-induced thrombocytopenia epidemiology and demographics|Epidemiology and Demographics]]== |
| 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.
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| ===Type II=== | | ==[[Heparin-induced thrombocytopenia risk factors|Risk Factors]]== |
| This form is due to an [[autoimmune disorder|autoimmune]] reaction with antibodies formed against platelet factor 4 (PF4), neutrophil-activating peptide 2 (NAP-2) and [[IL-8|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 [[antigen|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|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
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| 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.
| | ==[[Heparin-induced thrombocytopenia screening|Screening]]== |
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| 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.
| | ==[[Aplastic_anemia_natural_history,_complications_and_prognosis|Natural History, Complications, and Prognosis]]== |
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| Risk for HIT is higher in women than in men, and HIT occurs more commonly in surgical than in non-surgical settings.<ref>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.</ref>
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| ==Diagnosis== | | ==Diagnosis== |
| | | [[Heparin-induced thrombocytopenia diagnostic criteria|Diagnostic Criteria]] |
| 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. <ref>{{cite journal |author=Harenberg J, Huhle G, Giese C, Wang L, Feuring M, Song X, Hoffmann U |title=Determination of serotonin release from platelets by enzyme immunoassay in the diagnosis of heparin-induced thrombocytopenia |journal=Br J Haematol |volume=109 |issue=1 |pages=182-6 |year=2000 |pmid=10848798}}.</ref> <ref>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</ref> <ref>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</ref> <ref>Fabris F, Luzzatto G, Stefani PM, Girolami B, Cella G, Girolami A. Heparin-induced thrombocytopenia. Haematologica 2000 Jan; 85:72-81. PMID 10629596</ref>
| | | [[Heparin-induced thrombocytopenia history and symptoms|History and Symptoms]] |
| | | [[Heparin-induced thrombocytopenia physical examination|Physical Examination]] |
| | | [[Heparin-induced thrombocytopenia laboratory findings|Laboratory Findings]] |
| | | [[Heparin-induced thrombocytopenia electrocardiogram|Electrocardiogram]] |
| | | [[Heparin-induced thrombocytopenia chest x ray|Chest X Ray]] |
| | | [[Heparin-induced thrombocytopenia echocardiography and ultrasound|Echocardiography and Ultrasound]] |
| | | [[Heparin-induced thrombocytopenia CT|CT]] |
| | | [[Heparin-induced thrombocytopenia MRI|MRI]] |
| | | [[Heparin-induced thrombocytopenia other imaging findings|Other Imaging Findings]] |
| | | [[Heparin-induced thrombocytopenia other diagnostic studies|Other Diagnostic Studies]] |
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| ==Treatment== | | ==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 inhibitor]]s are used. [[Low molecular weight heparin]] is contraindicated in HIT.
| | [[Heparin-induced thrombocytopenia medical therapy|Medical Therapy]] |
| | | | [[Heparin-induced thrombocytopenia primary prevention|Primary Prevention]] |
| 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. <ref>{{cite journal |author=Hirsh J, Heddle N, Kelton J |title=Treatment of heparin-induced thrombocytopenia: a critical review |journal=Arch Intern Med |volume=164 |issue=4 |pages=361-9 |year=2004 |pmid=14980986}}
| | | [[Heparin-induced thrombocytopenia secondary prevention|Secondary Prevention]] |
| .</ref>
| | | [[Heparin-induced thrombocytopenia cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] |
| | | | [[Heparin-induced thrombocytopenia future or investigational therapies|Future or Investigational Therapies]] |
| == Pharmacotherapy ==
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| === Acute Pharmacotherapies === | | ==Case Studies== |
| * 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).
| | [[Heparin-induced thrombocytopenia case study one|Case #1]] |
| * 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 inhibitor]]s 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.
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| * 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.
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| == Patients Undergoing Surgery or PCI == | | ==See also== |
| Patients with HIT should be treated with [[Bivalirudin]], a direct thrombin inhibitor to support these procedures.
| | * [[Heparin]] |
| | | * [[Heparin-associated thrombocytopenia]] |
| == Secondary Prevention ==
| | * [[Heparin-binding EGF-like growth factor]] |
| Patients with HIT should be treated with [[Bivalirudin]], a direct thrombin inhibitor to support future procedures.
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| ==Reference==
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| {{Reflist|2}}
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| ==External links==
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| * [http://www.clevelandclinicmeded.com/medical_info/pharmacy/septoct2001/thrombocytopenia.htm Cleveland clinic] page on HIT | |
| * [http://www.clinicalschool.swan.ac.uk/wics/itugl/hit.htm HIT page]
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| ==Additional Reading==
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| * Kumar, Vinay, Abul Abbas, and Nelson Fausto. <u>Robbins and Cotran Pathologic Basis of Disease, 7th ed.</u> (2005). ISBN 0-7216-0187-1
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| {{SIB}}
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| [[Category:Hematology]] | | [[Category:Hematology]] |
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| [[de:Heparin-induzierte Thrombozytopenie]]
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| [[it:Trombocitopenia indotta da eparina]]
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