Sakr Critical Care 2011, 15:211 http://ccforum.com/content/15/2/211 REVIEW Heparin-induced thrombocytopenia in the ICU: an overview Yasser Sakr* This article is one of eleven reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2011 (Springer Verlag) and co-published as a series in Critical Care. Other articles in the series can be found online at http://ccforum.com/series/annual. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 Introduction inhibits adenylcyclase. Th is leads to a decrease in intra- Heparin, a negatively charged glycosaminoglycan (3,000– cellular cyclic adenosine monophosphate (cAMP) levels 30,000 Da), is an anticoagulant released by mast cells and with subsequent reduction in the platelet activation basophils during the normal clotting process [1]. Heparin threshold and mild platelet aggregation and thrombo- is widely used for the treatment and prophylaxis of cyto penia [4,5]. HIT type I may occur in patients with thrombo embolic diseases in medical and surgical sepsis, burn injuries, and vascular diseases, probably due patients [1]. Heparin-induced thrombocytopenia (HIT) to platelet hyperreactivity in these conditions [4,5]. is one of the most serious adverse events associated with Th rombocytopenia in HIT type I is usually mild and this drug. HIT is an immune-mediated, prothrombotic platelet counts rarely decrease below 100,000/μl [6]. complication that occurs with unfractionated heparin Heparin administration should be continued and no (UFH) and to a lesser extent with low-molecular-weight specifi c therapy is required. heparin (LMWH) [2]. Th e fundamental paradox of HIT Immune-mediated HIT type II is a disorder initiated by results from a platelet-activating immune response trig- an immunological response to heparin exposure and is gered by the interaction of heparin with a specifi c platelet characterized by an absolute or relative thrombocyto- protein, platelet factor 4 (PF4) [3]. penia with a paradoxically increased incidence of In this chapter, we review current knowledge about the thrombosis (Fig. 1) [1]. Th e major antigen responsible for pathophysiology, epidemiology, clinical manifestations, this syndrome is PF4, which is synthesized by mega- and treatment of HIT in the intensive care unit (ICU). karyo cytes and stored in platelet α-granules. Upon platelet activation, PF4 is released and binds anionic Pathophysiology of HIT glycosaminoglycans on cell surfaces. Th e main function Heparin causes mild platelet aggregation in vivo, of PF4 is to inhibit the formation of megakaryocytes and especially in patients with activated platelets, resulting in angiogenesis, as well as modulating the immune res- increased platelet sequestration in the spleen and throm- ponse. Considerable amounts of PF4 are released after bo cytopenia [1]. Th rombocytopenia can be triggered via trauma, infl ammation, surgical trauma, and in neoplasm non-immune and immune mechanisms. Clinically, two [7]. In HIT type II, heparin infusion displaces PF4 and types of HIT can be diff erentiated: HIT type I, a benign produces structural changes on it, leading to the for- non-immune condition; and HIT type II, an immune- mation of a PF4/heparin complex. Th is complex is recog- mediated syndrome caused by an antibody to the PF4/ nized as a `foreign’ antigen and triggers an immune heparin complex. response, which is characterized by the release of IgG Non-immune HIT, or HIT type I, is a self-limiting antibodies that bind to the PF4/heparin complexes with condition without any major complications that occurs in subsequent clustering of the platelet Fc-receptors 10–30% of patients within 4 days after exposure to (FcχRIIa, FcχRIIIa) resulting in platelet activation. Th is heparin. Heparin binds to PF4 with high affi nity and may lead to overt arterial thrombosis, historically, called “the white clot syndrome”. Activated platelets can also fragment into prothrombotic microparticles and stimu- *Correspondence: [email protected] Department of Anesthesiology and Intensive Care, Friedrich-Schiller-University, late venous thrombosis [5,8]. In addition, HIT antibodies Erlanger Allee 103, 07743 Jena, Germany may bind to Fc receptors on monocytes which produces © 2011 Springer-Verlag Berlin Heidelberg. This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Sakr Critical Care 2011, 15:211 Page 2 of 9 http://ccforum.com/content/15/2/211 HIT Antibodies (Anti-PF4/heparin complexIgG ) Activation of other cell lines Platelet activation Endothelial Monocytes PMPs Further PF4 cells release Tissue factor Thrombingeneration Venousand arterialthrombosis Figure 1. Schematic representation of the pathogenesis of HIT (see text for details). From [5] with permission. PF: platelet factor; PMPs: platelet microparticles. signifi cant quantities of tissue factor, stimulating increases within 4 to 14 days [14]. HIT antibodies are thrombosis [5,9]. HIT antibodies may promote throm bo- transient, generally disappearing within 4 months. [15] sis through platelet adhesion to the vessel wall and for- HIT type II is the most important clinical entity and ma tion of platelet-leukocyte aggregates [5,10]. Davidson will be discussed in the following sections. For simplicity, et al. [11] reported elevated levels of von Willebrand we will refer to HIT type II simply as HIT. factor and soluble thrombomodulin in patients with HIT type II, suggesting that endothelial cell damage with the Epidemiology consecutive loss of its physiologic antithrombotic pro- Th e frequency of HIT in heparin-exposed patients is perties may contribute to the thrombotic risk. highly variable. Heparin preparation is one infl uential Heparin molecules bind PF4 in proportion to the length factor with bovine UFH being the most common trigger of the polysaccharide chain. Th is explains the higher followed by porcine UFH [12]. HIT occurs less commonly frequency of HIT among patients treated with UFH than in patients receiving LMWH. Th e incidence of HIT is among those treated with LMWH [12]. Th e amount of 1–5% when UFH is used but < 1% with LMWH [12]. anti-PF4/heparin antibodies produced is deter mined not Females are more likely to develop HIT than males and only by the dose and structure of heparin but also by the postoperative patients have a higher incidence of HIT amount of circulating PF4. In some clinical situations, such than have medical ICU patients [16]. Heparin dosage also as cardiac surgery, the relatively abundant circulating PF4 plays an important role. Prophylactic doses of heparin and heparin increase the risk of immunization [7]. PF4 increase the risk of antibody formation, whereas clinical bound in vivo to cell surface glycos aminoglycans can be manifes tations occur more in patients receiving thera- immunogenic and could explain why healthy individuals peutic doses [16]. Only a small proportion, at most 5% to may be positive for anti-PF4/heparin antibodies [13]. In 30%, of patients who form HIT-IgG will develop clinical fact, not all patients who have heparin antibodies develop HIT [12,17]. platelet activation and clinically relevant HIT. After Th e incidence of HIT varies from 0% in pregnant termination of heparin therapy, the platelet count women receiving LMWH to 5% in patients undergoing Sakr Critical Care 2011, 15:211 Page 3 of 9 http://ccforum.com/content/15/2/211 orthopedic surgery receiving UFH [18]. Despite the baseline platelet count [3]. Platelet count usually falls to relatively high prevalence of anti-PF4/heparin antibodies values between 40,000 to 80,000/μl. In only 5–10% of in patients undergoing cardiac surgery, the incidence of cases, does the platelet count reach a nadir below 20,000/μl HIT in this patient population is about 2.4% [18]. Th e [22], and in such cases other possible causes of thrombo- formation of anti-PF4/heparin antibodies varies from 2 to cytopenia should be considered. 5% in cardiology patients, from 15 to 30% in patients Th rombocytopenia is a common laboratory abnor- undergoing orthopedic surgery, and up to 30 to 70% in mality in critically ill patients. Prospective data from 329 patients undergoing cardiac surgery [19]. Several studies adult surgical ICU patients during one year showed that have assessed the frequency of HIT in ICU patients [3]; the 41.3% had a platelet count less than 150,000/μl at some incidence of HIT in ICU patients is generally less than 2%. point [23]. Th e most common etiology of thrombo cyto- penia in critical illness is sepsis (around 48%), although Clinical manifestations 25% of ICU patients have more than one cause [24]. HIT is a clinicopathological syndrome with one or more Drug-induced thrombocytopenia must be considered, clinical events (thrombocytopenia with or without since several medications can cause thrombocytopenia thrombosis) temporally related to heparin administration and critically ill patients usually receive numerous and caused by HIT antibodies [20]. Th e clinical manifes- medications [25]. Possible causes of thrombocytopenia tations of HIT are discussed below. are shown in Table 1. Onset Thrombotic complications In patients with HIT, thrombocytopenia typically occurs HIT is associated with thrombotic complications in 5–10 days after initiation of heparin therapy (typical 30–70% of cases. Th ese may develop without signifi cant onset HIT) as the immune system requires several days thrombocytopenia in 15% of patients [18]. In patients to produce suffi cient amounts of anti-PF4/heparin anti- with symptomatic deep vein thrombosis (DVT) after bodies [21].