M. Levi, J.J. Hofstra, and S. Opal
Introduction
Thrombocytopenia is a common feature in intensive care patients. Similar to other settings in which thrombocytopenia may occur, the decrease in platelet count may be caused by impaired production, increased consumption, or enhanced degrada- tion of these cells. In this chapter, we will discuss the epidemiology and differential diagnosis of a decreased platelet count in critically ill patients, First, we will briefly introduce platelet function and platelet vessel wall interaction in the normal situa- tion and during severe infection and/or inflammation.
Platelet Function
Platelets are circulating blood cells that will normally not interact with the intact vessel wall but that may swiftly responding to vascular disruption by adhering to subendothelial structures, followed by interaction with each other, thereby forming a platelet aggregate [1]. The activated platelet (phospholipid) membrane may form a suitable surface on which further coagulation activation may occur. These pro- cesses are part of the first line of defense of the body against bleeding but may also contribute to pathological thrombus formation in vascular disease, such as throm- bus formation on top of a ruptured atherosclerotic plaque. In case of systemic inflammatory syndromes, such as the response to sepsis, disseminated intravascular platelet activation may occur, which will contribute to microvascular failure and, thereby, play a role in the development of organ dysfunction. In addition, in this sit- uation platelets may be directly involved in the inflammatory response by releasing inflammatory mediators and growth factors.
Under normal conditions, platelets continuously flow along the vascular surface in the human body without adhering or aggregating. However, upon disruption of the integrity of the vessel wall, a swift and complex interaction between circulating platelets, endothelial cells, and subendothelial structures occurs [2]. The result of this interaction is platelet adhesion to the vessel wall and formation of aggregates with each other, thereby creating a first line of defense against blood loss. The inter- action between platelets and the vessel wall is mediated by cellular receptors on the surface of platelets and endothelial cells, such as integrins and selectins, and by adhesive proteins, such as von Willebrand factor and fibrinogen.
Platelet-vessel Wall Interaction
Briefly, platelets attach to the subendothelium by molecular bridges between platelet glycoprotein receptors, GPIb/V/IX, and ligands, most prominently von Willebrand factor, that bind subendothelial matrix proteins, such as collagen [3]. Upon this binding, platelets become activated and change their shape, thereby releasing the contents of their storage organelles, including fibrinogen and adenosine diphos- phate, which will further promote platelet activation. The shape change will also result in the expression of active glycoprotein IIb/IIIa on the platelet surface, which will allow fibrinogen to form bridges between activated platelets, resulting in a platelet aggregate. During platelet activation and shape change, the platelet mem- brane turns into a phospholipid surface that is highly suitable for assembly of com- plexes of activated coagulation factors required for the formation of thrombin, thereby firmly linking the processes of platelet activation and thrombin generation.
In recent years, detailed information on the respective roles of the various cell recep- tors and adhesive proteins in the interaction between platelets and the vessel wall has been accumulated.
Cellular Adhesion Molecules in Health and Disease
Cellular adhesion receptors are integrated membrane proteins that recognize adhe- sive proteins in plasma or in the extracellular matrix or connect to other cellular adhesion receptors (counter-receptors) [2]. In the interaction between platelets and the vessel wall integrins, selectins and members of the Ig-gene superfamily, which can be found on both platelets and endothelial cells, are most important. The regula- tion of cellular adhesion by these receptors relies on the ability to rapidly change the affinity of the receptor for its ligand [4]. Cellular adhesive receptors are grouped in several families.
Integrins consist of a non-covalently associated [ q heterodimeric complex. In humans, there are 18 [ and 8 q subunits, which can form up to 24 combinations [5].
Most of the subunits contain 750 – 1000 amino acids and form transmembrane pro- teins, for the major part extracellular and with a short cytoplasma tail. Integrins can bind to ligands in plasma (such as von Willebrand factor, fibrinogen, or fibronectin), whereas in the extracellular matrix adhesive proteins such as vitronectin, collagen, laminin, elastin, fibronectin, and von Willebrand factor act as ligands. Besides bind- ing to adhesive proteins, integrins may also serve as signaling receptors, affecting the cytoskeletal apparatus (contributing to platelet aggregate stabilization) and trig- gering other processes, such as thromboxane A2 generation, increasing cytoplasma calcium, and phosphorylation of platelet proteins [6]. The most important integrin related to platelet aggregation is [ IIb/ q 3 (GPIIb/IIIa), which is the receptor that binds to fibrinogen to form molecular bridges between activated platelets. Another important integrin is the [ 2 q 1 (GPIa/IIa) receptor, capable of binding collagen. The role of [ 2 q 1 in platelet-collagen interaction is likely to be limited to low shear stress situations [7].
The superfamily of selectins consists of L-selectins and E-selectins, expressed on leukocytes and endothelial cells, respectively, and P-selectins, expressed on both platelets and endothelial cells. E-selectin and P-selectin mediate attachment of neu- trophils on cytokine-activated endothelial cells. P-selectin is stored in platelet gran- ules and in Weibel-Palade bodies in the endothelium [8]. On stimulation of platelets
and endothelial cells, it is released and integrated into the cell membrane. P-selectin may form a molecular bridge between activated endothelial cells, platelets, and neu- trophils. P-selectin also forms a bridge from platelet-vessel wall interaction to fibrin formation by enhancing the expression of tissue factor on monocytes [9]. Tissue fac- tor is the main initiator of thrombin generation and subsequent fibrinogen to fibrin conversion. P-selectin can be relatively easily shed from the surface of the platelet membrane and soluble P-selectin levels have been shown to be increased during acute coronary syndromes and systemic inflammation [9].
Cell adhesion receptors with leucine-rich motifs form a distinct group of recep- tors. The most important member of this group is glycoprotein Ib (GPIb), which is the receptor for von Willebrand factor, involved in platelet adhesion to the endothe- lium at high shear stress. GPIb, consisting of two subunits, GPIb[ and GPIb q , forms a transmembrane complex with GPV and GPIX, two other receptors in this family with leucine-rich motifs and this complex is firmly anchored in the platelet mem- brane. Relatively recent data indicate that GPIb/V/IX is involved in platelet tethering to and rolling on the endothelium mediated by endothelial expression of E-selectin [10]. GPIb/V/IX can also bind the neutrophil receptor Mac-1, thereby mediating platelet-neutrophil interaction [11].
The Ig-gene superfamily comprises a large family of molecules involved in the rec- ognition of adhering cells (such as cellular adhesion receptors) and of non-self anti- gens (such as T-cell receptors, antibodies and MHC molecules). The cellular adhesion receptors intercellular adhesion molecule (ICAM) 1 – 3, vascular cell adhesion mole- cule (VCAM), and platelet-endothelial cell adhesion molecule (PECAM) belong to this group and play an important role in leukocyte-endothelial cell interaction.
Regarding platelet-endothelial cell interaction, PECAM acts not so much as a direct adhesive receptor but rather as a negative regulator of platelet activation. Another adhesive receptor in the Ig-gene superfamily is GPVI, which is a platelet receptor for collagen [12]. Although GPVI may be directly involved in platelet adhesion to colla- gen, it is likely that it predominantly acts as an activator of the [ 2 q 1 receptor.
GPIV (CD36) is a glycoprotein expressed in platelets, endothelial cells, mononu- clear cells, and specific epithelial cells. On macrophages it acts as a scavenger for oxi- dized low-density lipoprotein (LDL). Platelet GPIV binds to thrombospondin and plays a role in the interaction between platelets and mononuclear cells [13].
Interaction between Cells and Adhesive Proteins
There are several pathways that play a role in platelet adhesion to the vessel wall but all are exemplified by cellular receptor-adhesive protein interactions. Most of these interactions have been precisely characterized using experiments with perfusion chambers containing for example de-endothelialized blood vessels. Although the mechanism by which platelets adhere to the vessel wall to achieve hemostasis is fairly well understood, the exact pathways that contribute to platelet adhesion and activation in many disease states, including infection and inflammation, are still unclear. Although essential aspects may be similar, factors like altered shear stress and local dysfunction of endothelial cells, potentially in association with inflamma- tory mechanisms are probably important in pathological thrombus formation [14].
Von Willebrand factor-mediated adhesion is the most prominent route of platelet adhesion. Von Willebrand factor is a large polymer of disulfide-linked subunits, each comprising 2050 amino acid residues and up to 22 carbohydrate chains [15]. The
molecular masses of the multimers range from about 500 kDa to more than 10.000 kDa. The multimers may form coiled molecules or thin filaments up to 1250 nm long (which means as large as a platelet). Data from clinical studies indicate that large von Willebrand factor multimers may be hemostatically more active than smaller molecules [16]. The biochemical basis for this observation probably relies on the fact that they contain a relatively large number of the domains that will sup- port multiple interactions between the vessel wall, subendothelial matrix, and cellu- lar receptors on platelets. Besides playing a role in platelet vessel wall interaction, von Willebrand factor may also be a ligand between platelet receptors IIb/IIIa, thereby competing with fibrinogen.
Collagen may be considered as another adhesive protein in platelet vessel wall interaction. Collagen types I and IV may directly bind to the integrin [ 2 q 1 (GP Ia/
IIa) [17]. The relevance of this pathway is underlined by studies with platelets from patients that are deficient in this glycoprotein, which show significantly decreased adhesion. Another platelet receptor for collagen is GPVI, although it is less likely that direct binding of this receptor to collagen is physiologically important [18]. The function of GPVI is rather related to activation of the [ 2 q 1 receptor upon binding to collagen and consequent intracellular signaling [19]. In addition, GPIB-V-IX may be considered as a collagen receptor acting via von Willebrand factor.
Other adhesive proteins involved in platelet vessel wall interaction are fibronectin thrombospondin, laminin, and vitronectin. Fibronectin is largely a dimer, composed of subunits with a molecular mass of 220 kDa. Fibronectin is produced by megakar- yocytes and stored in [ -granules of the platelet and is secreted upon thrombin- induced platelet activation. Fibronectin can serve as a ligand for platelet-platelet interaction through the GPIIb/IIIa receptor. Thrombospondin is released from [ - granules on platelet activation and binds to the platelet membrane, where it can interact with fibrinogen, fibrin, fibronectin, collagen, or other platelets. Binding of thrombospondin to the platelet is mediated by the GPIV receptor (CD36) and possi- bly by integrin [ 5 q 3, whereas recently a role for GPIb has been proposed [20]. Both thrombospondin and CD36 can bind erythrocytes infected with Plasmodium falci- parum (causing malaria tropica), which may account for the microvascular compli- cations of severe malaria [21], and a similar mechanism has been described for thrombospondin binding to sickling cells, which may contribute to microvascular thrombosis in patients with sickle cell disease [22]. Laminin is a large glycoprotein (920 kDa) and is located in the extracellular matrix and the basement membrane.
Laminin can bind to platelets but this interaction does not appear to result in plate- let activation [23]. Vitronectin is functionally similar to fibronectin and may bind to platelet GPIIb/IIIa or to a specific integrin ([ v q 3) [24]. Its affinity to artificial sur- faces, such as glass, may play a role in platelet deposition on such objects. The role of vitronectin in platelet-vessel wall interaction is unclear. Vitronectin can bind and stabilize the fibrinolytic inhibitor plasminogen activator inhibitor type 1 (PAI-1), which may render fibrin clots less susceptible for lysis, but simultaneously vitronec- tin provides PAI-1 with thrombin-inhibitory properties.
Platelets in Critically Ill Patients
Critically ill patients often present with thrombocytopenia [25]. The incidence of thrombocytopenia (platelet count ‹ 150 × 109/l) in critically ill medical patients is 35 – 44 % [26 – 28]. A platelet count of ‹ 100 × 109/l is seen in 20 – 25 % of patients,
whereas 12 – 15 % of patients have a platelet count ‹ 50 × 109/l. In surgical and trauma patients, the incidence of thrombocytopenia is higher with 35 – 41 % of patients having less than 100 × 109/l platelets [29, 30]. Typically, the platelet count decreases during the first four days on the intensive care unit (ICU) [31]. The primary clinical relevance of thrombocytopenia in critically ill patients is related to an increased risk of bleeding.
Indeed, severely thrombocytopenic patients with platelet counts of ‹ 50 × 109/l have a 4 to 5-fold higher risk for bleeding compared to patients with higher platelet counts [26, 28]. The risk of intracerebral bleeding in critically ill patients during intensive care admission is relatively low (0.3 – 0.5 %), but in 88 % of patients with this compli- cation the platelet count is less than 100 × 109/l [32]. Moreover, a decrease in platelet count may indicate ongoing coagulation activation, which contributes to microvascu- lar failure and organ dysfunction. Regardless of the cause, thrombocytopenia is an independent predictor of ICU mortality in multivariate analyses with a relative risk of 1.9 to 4.2 in various studies [26, 28, 29]. Several studies have shown that the number of platelets in critically ill patients is inversely related to survival. In particular, sus- tained thrombocytopenia over more than four days after ICU admission or a drop in platelet count of 8 50 % during the ICU stay is related to a 4 to 6-fold increase in mor- tality [31, 26]. The platelet count was shown to be a stronger independent predictor for ICU mortality than composite scoring systems, such as the Acute Physiology and Chronic Health Evaluation (APACHE) II score or the Multiple Organ Dysfunction Score (MODS). A platelet count of ‹ 100 × 109/l is also related to a longer ICU stay but not to the total duration of hospital admission [28].
Differential Diagnosis of Thrombocytopenia in Critically Ill Patients
There are many causes for thrombocytopenia in critically ill patients. Table 1 sum- marizes the most frequently occurring diagnoses recognized in intensive care patients with thrombocytopenia.
Sepsis is a clear risk factor for thrombocytopenia in critically ill patients and the severity of sepsis correlates with the decrease in platelet count [33, 34]. The princi- pal factors that contribute to thrombocytopenia in patients with sepsis are impaired platelet production, increased consumption or destruction, or sequestration of platelets in the spleen or along the endothelial surface. Impaired production of platelets from within the bone marrow may seem contradictory to the high levels of platelet production-stimulating pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-[ and interleukin (IL)-6, and high concentrations of circulating throm- bopoietin in patients with sepsis. These cytokines and growth factors should theo- retically stimulate megakaryopoiesis in the bone marrow [35]. However, in a sub- stantial number of patients with sepsis marked hemophagocytosis may occur. This pathologic process consists of active phagocytosis of megakaryocytes and other
Table 1. Differential diagnosis of thrombocytopenia
in critically ill patients Sepsis
Disseminated intravascular coagulation Massive blood loss
Thrombotic microangiopathy Heparin-induced thrombocytopenia Immune thrombocytopenia Drug-induced thrombocytopenia
hematopoietic cells by monocytes and macrophages, hypothetically due to stimula- tion with high levels of macrophage colony stimulating factor (M-CSF) in sepsis [36]. Platelet consumption probably also plays an important role in patients with sepsis, due to ongoing generation of thrombin (which is the most potent activator of platelets in vivo), in its most fulminant form known as disseminated intravascular coagulation (DIC). Platelet activation, consumption, and destruction may also occur at the endothelial site as a result of the extensive endothelial cell-platelet interaction in sepsis, which may vary between different vascular beds in various organs [37].
In patients with DIC, the platelet count is invariably low or rapidly decreasing [38]. DIC is the most extreme form of systemic coagulation activation, which may complicate a variety of underlying disease processes, including sepsis, trauma, can- cer, or obstetrical calamities, such as placental abruption. It is important to empha- size that DIC is not a disease in itself but is always secondary to an underlying disor- der. DIC is a syndrome caused by systemic intravascular activation of coagulation, which may be secondary to various underlying conditions. Formation of microvas- cular thrombi, in concert with inflammatory activation, may cause failure of the microvasculature and, thereby, contribute to organ dysfunction. Ongoing and insuf- ficiently compensated consumption of platelets and coagulation factors may pose a risk factor for bleeding, especially in perioperative patients or patients that need to undergo invasive procedures. The trigger for the activation of the coagulation sys- tem is nearly always mediated by several of the pro-inflammatory cytokines, expressed and released by mononuclear cells and endothelial cells. Thrombin gener- ation proceeds via the (extrinsic) tissue factor/factor VIIa route. Tissue factor may be expressed on activated and inactivated mononuclear cells and endothelial cells and is capable of binding factor VIIa, which then activates downstream coagulation cascades. Concomitantly, impaired function of inhibitory mechanisms of thrombin generation, such as antithrombin and the protein C and S system, occurs. Anti- thrombin appears to be incapable of adequate regulation of thrombin activity in DIC for several reasons. Antithrombin levels are continuously consumed by the ongoing formation of thrombin and other activated proteases that are susceptible to anti- thrombin complex formation and antithrombin is degraded by elastase released from activated neutrophils. In addition, impaired synthesis of antithrombin, because of liver failure and extravascular leakage of this protease inhibitor as a consequence of capillary leakage, further contributes to low levels of antithrombin. There are sev- eral reasons for severe injury to the protein C system in DIC. Similar to antithrom- bin, enhanced consumption, impaired liver synthesis, and vascular leakage may result in low circulating levels of protein C. Second, activation of the cytokine net- work, in particular high levels of TNF-[ , results in a marked downregulation of thrombomodulin on endothelial cells, thereby prohibiting adequate protein C activa- tion. In addition, the anticoagulant capacity of activated protein C is reduced by low levels of the free fraction of protein S. In plasma, 60 % of cofactor protein S is com- plexed to a complement regulatory protein, C4b binding protein (C4bBP), and increased plasma levels of C4bBP, as a consequence of the acute phase reaction in sepsis, may result in a relative protein S deficiency. A third mechanism contributing to the enhanced fibrin deposition in DIC is impaired fibrin degradation, due to high circulating levels of PAI-1, the main physiological inhibitor of fibrinolysis. Recent studies have shown that a functional mutation in the PAI-1 gene, the 4G/5G poly- morphism, not only influenced the plasma levels of PAI-1 but was also linked to clinical outcome in sepsis and DIC. In other clinical studies in patients with DIC, a high plasma level of PAI-1 was one of the strongest predictors of mortality.
Patients with DIC have a low or rapidly decreasing platelet count, prolonged global coagulation tests, low plasma levels of coagulation factors and inhibitors, and increased markers of fibrin formation and/or degradation, such as D-dimer or fibrin degradation products (FDPs). Coagulation proteins with a marked acute phase behavior, such as factor VIII or fibrinogen, are usually not decreased or may even increase. One of the often advocated laboratory tests for the diagnosis of DIC, fibrin- ogen, is, therefore, not a very good marker for DIC, except in very severe cases, although sequential measurements can give some insight. There is no single labora- tory test with sufficient accuracy for the diagnosis of DIC. However, a diagnosis of DIC may be made using a simple scoring system based on a combination of rou- tinely available coagulation tests [39]. In a prospective validation study, the sensitiv- ity and specificity of this DIC score was found to be more than 95 % [40]. Further- more, this DIC score was found to be a strong and independent predictor of mortal- ity in a large series of patients with severe sepsis and identifies patients who will have most benefit of interventions on the coagulation system [41].
The group of thrombotic microangiopathies encompasses syndromes such as thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, severe malig- nant hypertension, chemotherapy-induced microangiopathic hemolytic anemia, and the HELLP syndrome [42]. A common pathogenetic feature of these clinical entities appears to be endothelial damage, causing platelet adhesion and aggregation, thrombin formation, and impaired fibrinolysis. The multiple clinical consequences of this extensive endothelial dysfunction include thrombocytopenia, mechanical fragmentation of red cells with hemolytic anemia, and obstruction of the microvas- culature of various organs, such as kidney and brain (leading to renal failure and neurologic dysfunction, respectively). Despite this common final pathway, the vari- ous thrombotic microangiopathies have different underlying etiologies. Thrombotic thrombocytopenic purpura is caused by deficiency of von Willebrand factor cleaving protease (ADAMTS-13), resulting in endothelial cell-attached ultra-large von Wille- brand multimers, that readily bind to platelet surface GPIb and cause platelet adhe- sion and aggregation [43]. In hemolytic uremic syndrome, a cytotoxin released upon infection with a specific serogroup of Gram-negative microorganisms (usually E. coli serotype O157:H7) is responsible for endothelial cell and platelet activation.
In case of malignant hypertension or chemotherapy-induced thrombotic microangi- opathy, presumably direct mechanical or chemical damage to the endothelium is responsible for the enhanced endothelial cell-platelet interaction, respectively. A
Fig. 1. Blood smear from a patient with thrombocytopenic thrombotic purpura, due to deficiency of ADAMTS-13. The arrows indicate schistocytes generated by mechani- cal damage to red cells. Also note the reduced number of platelets, indicating thrombocytopenia.
(Giemsa staining, x 40). Courtesy of Dr. J. van der Lelie, Academic Medi- cal Center, Amsterdam, the Nether- lands.
diagnosis of thrombotic microangiopathy relies upon the combination of thrombo- cytopenia, Coombs-negative hemolytic anemia, and the presence of schistocytes in the blood smear (Fig. 1). Additional information can be achieved by measurement of ADAMTS-13 and autoantibodies towards this metalloprotease and culture (usu- ally from the stool or urine) of microorganisms capable of cytotoxin production.
Heparin-induced thrombocytopenia (HIT) is caused by a heparin-induced anti- body that binds to the heparin-platelet factor IV complex on the platelet surface [37]. This may result in massive platelet activation and as a consequence a consump- tive thrombocytopenia and arterial and venous thrombosis occurs. The incidence of HIT may be as high as 5 % of patients receiving heparin and is dependent on the type and dose of heparin and the duration of its administration (especially when given for more than four days). A consecutive series of critically ill ICU patients who received heparin revealed an incidence of 1 % in this setting [44]. Unfractionated heparin carries a higher risk of HIT than low molecular weight (LMW) heparin [45].
Thrombosis may occur in 25 to 50 % of patients with HIT (with fatal thrombosis in 4 – 5 %) and may also become manifest after discontinuation of heparin [46]. The diagnosis of HIT is based on the detection of HIT antibodies in combination with the occurrence of thrombocytopenia in a patient receiving heparin, with or without concomitant arterial or venous thrombosis. It should be mentioned that the com- monly used ELISA for HIT antibodies has a high negative predictive value (100 %) but a very low positive predictive value (10 %) [44]. A more precise diagnosis may be made with a 14C-serotonin release assay, but this test is not routinely available in most settings [47]. Normalization in the number of platelets 1 – 3 days after discon- tinuation of heparin may further support the diagnosis of HIT.
Drug-induced thrombocytopenia is another frequent cause of thrombocytopenia in the ICU setting [29]. Thrombocytopenia may be caused by drug-induced myelo- suppression, such as is caused by cytostatic agents, or by immune-mediated mecha- nisms. Examples of drug-induced immune-mediated thrombocytopenia are HIT or quinine-induced thrombocytopenia. A large number of other agents may cause thrombocytopenia by similar mechanisms, including medications that are frequently used in critically ill patients such as antibiotics (including cephalosporins or tri- methoprim-sulfamethoxazole), benzodiazepines, or non-steroidal anti-inflammatory agents (NSAIDs). Novel inhibitors of platelet aggregation, such as GPIIb/IIIa antago- nists (e.g., abciximab) or thienopyridine derivatives (clopidogrel) are increasingly used in the management of patients with acute coronary syndromes and may also cause severe thrombocytopenia [48]. Drug-induced thrombocytopenia is a difficult diagnosis in the ICU setting as these patients are often exposed to multiple agents and have numerous other potential reasons for platelet depletion. Drug-induced thrombocytopenia is often diagnosed based upon the timing of initiation of a new agent in relationship to the development of thrombocytopenia, after exclusion of other causes of thrombocytopenia. The observation of rapid restoration of the plate- let count after discontinuation of the suspected agent is highly suggestive of drug- induced thrombocytopenia. In some cases, specific drug-dependent anti-platelet antibodies can be detected.
Management of Thrombocytopenia in Critically Ill Patients
As there are many causes for thrombocytopenia in critically ill patients and each of these underlying disorders may require specific therapeutic or supportive manage-
ment, it is of utmost importance to establish the underlying etiology of the throm- bocytopenia. It is evident that the primary focus of attention in the management of thrombocytopenia should be directed towards the management of the underlying condition. In addition to proper treatment for this underlying disorder, further sup- portive measures to correct the coagulation defects are often required.
Most guidelines advocate a platelet transfusion in patients with a platelet count of ‹ 30 – 50 × 109/l accompanied by bleeding or at high risk for bleeding, and in patients with a platelet count ‹ 10 × 109/l, regardless of the presence or absence of bleeding. After platelet transfusion, the platelet count should rise by at least 5 × 109/l per unit given. A lesser response may occur in patients with high fever, DIC, or splenomegaly, or may indicate allo-immunization of the patient after repeated transfusion. Platelet transfusion is particularly effective in patients with thrombo- cytopenia due to impaired platelet production or increased consumption, whereas disorders of enhanced platelet destruction (e.g., immune thrombocytopenia) call for alternative therapies, such as steroids, immunoglobulin, or splenectomy.
Thrombocytopenia due to HIT requires immediate cessation of heparin and institu- tion of alternative anticoagulant treatment regimens such as direct thrombin inhib- itors (argatroban or lepirudin) [49]. The importance of starting treatment with direct thrombin inhibitors is underlined by a recent overview showing that the inci- dence of new thrombosis in patients with HIT who were treated by discontinuing heparin alone or with warfarin was 19 % to 52 % [49]. Vitamin K antagonists should be avoided in the initial treatment of HIT, since these agents may cause skin necro- sis. In patients with a classic thrombotic microangiopathy due to low levels of ADAMTS-13, plasmapheresis and immunosuppressive treatment should be initiated [42].
References
1. Levi M (2005) Platelets. Crit Care Med 33:S523-S525
2. Hawiger JJ (1994) Adhesive interactions of blood cells and the vascular wall in hemostasis and thrombosis. In: Colman RW, Hirsh J, Marder VJ, Salzman EW (eds) Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 3rd edn. Lippincott Williams & Wilkins, Philadelphia, pp 639 – 653
3. Ware JA, Heistad DD (1993) Seminars in medicine of the Beth Israel Hospital, Boston. Plate- let-endothelium interactions. N Engl J Med 328:628 – 635
4. Woodside DG, Liu S, Ginsberg MH (2001) Integrin activation. Thromb Haemost 86:316 – 323 5. Ruoslahti E (1991) Integrins. J Clin Invest 87:1 – 5
6. Phillips DR, Prasad KS, Manganello J, Bao M, Nannizzi-Alaimo L (2001) Integrin tyrosine phosphorylation in platelet signaling. Curr Opin Cell Biol 13:546 – 554
7. Clemens R, Pramoolsinsap C, Lorenz R, Pukrittayakamee S, Bock HL, White NJ (1994) Acti- vation of the coagulation cascade in severe falciparum malaria through the intrinsic pathway.
Br J Haematol 87:100 – 105
8. Furie B, Furie BC, Flaumenhaft R (2001) A journey with platelet P-selectin: the molecular basis of granule secretion, signalling and cell adhesion. Thromb Haemost 86:214 – 221 9. Shebuski RJ, Kilgore KS (2002) Role of inflammatory mediators in thrombogenesis. J Phar-
macol Exp Ther 300:729 – 735
10. Romo GM, Dong JF, Schade AJ, et al (1999) The glycoprotein Ib-IX-V complex is a platelet counterreceptor for P-selectin. J Exp Med 190:803 – 814
11. Simon DI, Chen Z, Xu H, et al (2000) Platelet glycoprotein ibalpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 192:193 – 204
12. Clemetson JM, Polgar J, Magnenat E, Wells TN, Clemetson KJ (1999) The platelet collagen receptor glycoprotein VI is a member of the immunoglobulin superfamily closely related to FcalphaR and the natural killer receptors. J Biol Chem 274:29019 – 29024
13. Silverstein RL, Asch AS, Nachman RL (1989) Glycoprotein IV mediates thrombospondin- dependent platelet-monocyte and platelet-U937 cell adhesion. J Clin Invest 84:546 – 552 14. Ruggeri ZM (2002) Platelets in atherothrombosis. Nat Med 8:1227 – 1234
15. Ruggeri ZM (2003) Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost 1:1335 – 1342
16. Arya M, Anvari B, Romo GM, et al (2002) Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers. Blood 99:3971 – 3977
17. Jung SM, Moroi M (2000) Activation of the platelet collagen receptor integrin alpha(2) beta(1): its mechanism and participation in the physiological functions of platelets. Trends Cardiovasc Med 10:285 – 292
18. Massberg S, Konrad I, Bultmann A, et al (2003) Soluble glycoprotein VI dimer inhibits plate- let adhesion and aggregation to the injured vessel wall in vivo. FASEB J 18:397 – 399 19. Clemetson KJ, Clemetson JM (2001) Platelet collagen receptors. Thromb Haemost 86:189 –
197
20. Jurk K, Clemetson KJ, De Groot PG, et al (2003) Thrombospondin-1 mediates platelet adhe- sion at high shear via glycoprotein Ib (GPIb): an alternative/backup mechanism to von Wille- brand factor. FASEB J 17:1490 – 1492
21. Roberts DD, Sherwood JA, Spitalnik SL, et al (1985) Thrombospondin binds falciparum malaria parasitized erythrocytes and may mediate cytoadherence. Nature 318:64 – 66 22. Brittain JE, Mlinar KJ, Anderson CS, Orringer EP, Parise LV (2001) Activation of sickle red
blood cell adhesion via integrin-associated protein/CD47-induced signal transduction. J Clin Invest 107:1555 – 1562
23. Ill CR, Engvall E, Ruoslahti E (1984) Adhesion of platelets to laminin in the absence of activa- tion. J Cell Biol 99:2140 – 2145
24. Thiagarajan P, Kelly KL (1988) Exposure of binding sites for vitronectin on platelets follow- ing stimulation. J Biol Chem 263:3035 – 3038
25. Levi M, Opal SM (2006) Coagulation abnormalities in critically ill patients. Crit Care 10:
222 – 228
26. Vanderschueren S, De Weerdt A, Malbrain M, et al (2000) Thrombocytopenia and prognosis in intensive care. Crit Care Med 28:1871 – 1876
27. Baughman RP, Lower EE, Flessa HC, Tollerud DJ (1993) Thrombocytopenia in the intensive care unit. Chest 104:1243 – 1247
28. Strauss R, Wehler M, Mehler K, Kreutzer D, Koebnick C, Hahn EG (2002) Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, and outcome. Crit Care Med 30:1765 – 1771
29. Stephan F, Hollande J, Richard O, Cheffi A, Maier-Redelsperger M, Flahault A (1999) Throm- bocytopenia in a surgical ICU. Chest 115:1363 – 1370
30. Hanes SD, Quarles DA, Boucher BA (1997) Incidence and risk factors of thrombocytopenia in critically ill trauma patients. Ann Pharmacother 31:285 – 289
31. Akca S, Haji Michael P, de Medonca A, Suter PM, Levi M, Vincent JL (2002) The time course of platelet counts in critically ill patients. Crit Care Med 30:753 – 756
32. Oppenheim-Eden A, Glantz L, Eidelman LA, Sprung CL (1999) Spontaneous intracerebral hemorrhage in critically ill patients: incidence over six years and associated factors. Intensive Care Med 25:63 – 67
33. Mavrommatis AC, Theodoridis T, Orfanidou A, Roussos C, Christopoulou-Kokkinou V, Zakynthinos S (2000) Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med 28:451 – 457
34. Levi M (2005) Platelets in sepsis. Hematology 10 (Suppl 1):129 – 131
35. Folman CC, Linthorst GE, van Mourik J, et al (2000) Platelets release thrombopoietin (Tpo) upon activation: another regulatory loop in thrombocytopoiesis? Thromb Haemost 83:923 – 930
36. Francois B, Trimoreau F, Vignon P, Fixe P, Praloran V, Gastinne H (1997) Thrombocytopenia in the sepsis syndrome: role of hemophagocytosis and macrophage colony-stimulating factor.
Am J Med 103:114 – 120
37. Warkentin TE, Aird WC, Rand JH (2003) Platelet-endothelial interactions: sepsis, HIT, and antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program 497 – 519
38. Levi M, ten Cate H (1999) Disseminated intravascular coagulation. N Engl J Med 341:
586 – 592
39. Taylor FBJ, Toh CH, Hoots WK, Wada H, Levi M (2001) Towards definition, clinical and labo- ratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 86:1327 – 1330
40. Bakhtiari K, Meijers JC, de Jonge E, Levi M (2004) Prospective validation of the international society of thrombosis and maemostasis scoring system for disseminated intravascular coagu- lation. Crit Care Med 32:2416 – 2421
41. Dhainaut JF, Yan SB, Joyce DE, et al (2004) Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation.
J Thromb Haemost 2:1924 – 1933
42. Moake JL (2002) Thrombotic microangiopathies. N Engl J Med 347:589 – 600
43. Tsai HM (2003) Platelet activation and the formation of the platelet plug: deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura. Arterioscler Thromb Vasc Biol 23:388 – 396
44. Verma AK, Levine M, Shalansky SJ, Carter CJ, Kelton JG (2003) Frequency of heparin- induced thrombocytopenia in critical care patients. Pharmacotherapy 23:745 – 753
45. Warkentin TE, Levine MN, Hirsh J, et al (1995) Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 332:1330 – 1335
46. Warkentin TE (2003) Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol 121:535 – 555
47. Sheridan D, Carter C, Kelton JG (1986) A diagnostic test for heparin-induced thrombocyto- penia. Blood 67:27 – 30
48. Makoni SN (2001) Acute profound thrombocytopenia following angioplasty: the dilemma in the management and a review of the literature. Heart 86:18e-
49. Hirsh J, Heddle N, Kelton JG (2004) Treatment of heparin-induced thrombocytopenia: A crit- ical review. Arch Intern Med 164:361 – 369
