This document provides an overview of approaches to evaluating and understanding the causes of thrombocytopenia in adult patients. It defines thrombocytopenia and normal platelet count ranges. The main causes of thrombocytopenia are decreased platelet production in the bone marrow and increased platelet destruction. Pseudothrombocytopenia, where the platelet count is falsely low, must first be ruled out. If actual thrombocytopenia exists, the clinician should determine whether it is caused by reduced production, increased destruction, dilution or distribution abnormalities.
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Approach to the adult patient with thrombocytopenia
This document provides an overview of approaches to evaluating and understanding the causes of thrombocytopenia in adult patients. It defines thrombocytopenia and normal platelet count ranges. The main causes of thrombocytopenia are decreased platelet production in the bone marrow and increased platelet destruction. Pseudothrombocytopenia, where the platelet count is falsely low, must first be ruled out. If actual thrombocytopenia exists, the clinician should determine whether it is caused by reduced production, increased destruction, dilution or distribution abnormalities.
This document provides an overview of approaches to evaluating and understanding the causes of thrombocytopenia in adult patients. It defines thrombocytopenia and normal platelet count ranges. The main causes of thrombocytopenia are decreased platelet production in the bone marrow and increased platelet destruction. Pseudothrombocytopenia, where the platelet count is falsely low, must first be ruled out. If actual thrombocytopenia exists, the clinician should determine whether it is caused by reduced production, increased destruction, dilution or distribution abnormalities.
Approach to the adult patient with thrombocytopenia
Approach to the adult patient with thrombocytopenia
Authors Stephen A Landaw, MD, PhD James N George, MD Section Editor Lawrence LK Leung, MD Deputy Editor Jennifer S Tirnauer, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2012. | This topic last updated: Oct 4, 2012. INTRODUCTION The clinician is frequently faced by a patient presenting with a low platelet count, the cause of which is not immediately apparent. This topic will provide a structure through which the cause(s) of such thrombocytopenia can be assessed. A related topic describes the most common outpatient and inpatient presentations of adults with newly recognized isolated thrombocytopenia (ie, patients in whom the remainder of the blood count is normal, and who may or may not have signs of systemic disease) and provides a general guideline for the evaluation and management of thrombocytopenic patients in the office and hospital settings. (See "Evaluation and management of thrombocytopenia by primary care physicians".) Other issues related to thrombocytopenia are presented separately: Thrombocytopenia in pregnancy. (See "Thrombocytopenia in pregnancy".) Evaluation of the patient with a bleeding diathesis. (See "Approach to the adult patient with a bleeding diathesis".) DEFINITIONS AND NORMAL VALUES The normal platelet count in adults ranges from 150,000 to 450,000/microL, with mean values of 237,000 and 266,000/microL in males and females, respectively [1]. Thrombocytopenia is defined as a platelet count less than 150,000/microL (150 x 109/L), keeping in mind that 2.5 percent of the normal population will have a platelet count lower than this. A recent fall in the platelet count by one-half, while still in the normal range, may herald severe clinical problems (see below), and requires active follow-up. However, thrombocytopenia is not usually detected clinically (see below) until the platelet count has fallen to levels below 100,000/microL. Variation of the platelet count in a given individual is limited; differences in the absolute platelet count greater than 70 to 90,000/microL will occur by chance less than 1 percent of the time [1]. As an example, even if the patient's platelet count is within the normal range, if the count has recently fallen 50 percent or more from a prior value, this should immediately raise the possibility of heparin-induced thrombocytopenia in any patient begun on heparin therapy within the preceding 5 to 10 days. If confirmed, this constitutes a medical emergency, requiring appropriate urgent action. (See "Heparin-induced thrombocytopenia".) Surgical bleeding due solely to a reduction in the number of platelets does not generally occur until the platelet count is less than 50,000/microL, and clinical or spontaneous bleeding does not occur until the platelet count is less than 10,000 to 20,000/microL. In a study of patients with idiopathic thrombocytopenic purpura, for example, minimal bleeding after trauma was uncommon unless the platelet count was less than 60,000/microL, whereas self-limited bleeding, spontaneous bleeding requiring special attention (eg, nasal packing for epistaxis), and severe life threatening bleeding did not occur until platelet counts were <40,000, <12,000, and <6000/microL, respectively [2]. OVERVIEW OF PLATELET KINETICS Platelets are produced in the bone marrow from megakaryocytes which are derived from more primitive precursors (picture 1). The megakaryocyte produces platelets by cytoplasmic shedding directly into bone marrow sinusoids (picture 2). It has been estimated that about 1000 to 5000 platelets are produced by each megakaryocyte. In normal individuals, platelet production is approximately 35,000 to 50,000/microL of whole blood per day [3,4]; this value can be increased up to eight-fold during times of increased demand [4]. (See "Megakaryocyte biology and the production of platelets".) Platelets survive in the circulation for 8 to 10 days, after which they are removed from the circulation by cells of the monocyte-macrophage system, perhaps as a result of programmed apoptosis [5,6]. In normal individuals, approximately one-third of the total platelet mass is found in the spleen, in equilibrium with the circulating pool of platelets [7]. (See 'Distributional thrombocytopenia caused by splenomegaly' below.) Young versus old platelets The youngest platelets in the circulation are larger and appear to be more hemostatically active. Two observations are of interest in this regard: Thrombocytopenic patients with idiopathic thrombocytopenic purpura (ITP) do not usually have serious bleeding, suggesting that the small numbers of young platelets in these patients are more hemostatically active than mixed age platelets in normal subjects. Patients with ITP also appear to have less bleeding than patients with similar severities of thrombocytopenia caused by marrow failure, such as subjects with thrombocytopenia following chemotherapy, who also have a population of platelets of mixed age. Aged platelets in dogs are less responsive to thrombin [8] and collagen [9] than younger platelets. Reticulated platelets The youngest platelets in the circulation contain RNA and have been called reticulated platelets or the immature platelet fraction (IPF); they are analogous to the young, RNA-containing red cells (reticulocytes). This property allows them to be specifically analyzed by automated instrumentation. The clinical usefulness of analyzing for the IPF is currently being evaluated (figure 1) [10,11]. (See "Automated hematology instrumentation", section on 'Reticulated platelets' and "Platelet function testing", section on 'Reticulated platelets'.) As an example, the IPF was determined in three groups of patients, with the following results [12]: Normal subjects 1.3 percent (95% CI 1.1-1.5) Thrombocytopenia with "normal or decreased thrombopoietic activity" 7.5 percent (95% CI 5.3-9.7) Thrombocytopenia with "increased platelet turnover" 30 percent (95% CI 25-35) It has been suggested that analysis of the IPF can be used to determine the mechanism through which the platelet count is increased following the use of therapeutic agents in patients with immune thrombocytopenia (ITP). Thus, agents that decrease destruction of circulating platelets should result in little or no increase in the IPF, while those that stimulate platelet production should increase the IPF [11]. Additional studies will be required in order to substantiate these results and to determine the clinical utility of this measurement. MECHANISMS OF THROMBOCYTOPENIA Analogous to the red blood cell system, the major mechanisms for a reduced platelet count are decreased production and increased destruction. Two additional mechanisms include dilutional or distributional thrombocytopenia. However, before the evaluation of the mechanism of thrombocytopenia is considered, it is imperative to validate the platelet count to exclude the possibility of spurious or pseudothrombocytopenia and be certain that actual thrombocytopenia exists. Pseudothrombocytopenia The platelet count can be falsely low in a number of settings: If anticoagulation of the blood sample is inadequate, the resulting thrombin-induced platelet clumps can be counted as leukocytes by automated cell counters. In these circumstances, the WBC count is rarely increased by more than 10 percent and there is usually an associated spurious thrombocytopenia [13]. On occasion, pseudothrombocytopenia can be caused by platelet rosetting around neutrophils, monocytes, and rarely, around circulating lymphoma cells [14-18]. This in vitro phenomenon, induced at room temperature in EDTA-anticoagulated blood has been called platelet satellitism. In one case this resulted from the presence of an EDTA-dependent antibody with dual reactivity against both the platelet glycoprotein IIb/IIIa complex and the neutrophil Fc gamma receptor III [17]. Pseudothrombocytopenia can also occur after the administration of the murine monoclonal antibody abciximab, which is directed against the GP IIb/IIIa receptor [19]. (See "Drug- induced thrombocytopenia", section on 'Glycoprotein IIb/IIIa inhibitors'.) Platelet clumping in EDTA Approximately 0.1 percent of normal subjects have EDTA- dependent agglutinins which can lead to platelet clumping and spurious thrombocytopenia and spurious leukocytosis. This is thought to result from a "naturally occurring" platelet autoantibody directed against a normally concealed epitope on the platelet membrane glycoprotein (GP) IIb/IIIa, which becomes exposed by EDTA-induced dissociation of GP IIb/IIIa [20-26]. Pseudothrombocytopenia then occurs because EDTA is the anticoagulant employed in the tubes used for routine complete blood counts. EDTA-induced platelet clumping can be diagnosed by examination of the peripheral smear (picture 3). This is an established routine for laboratory technologists, but sometimes the physician only receives the report of the falsely low platelet count number, without the note about clumping or a repeat count in a non-EDTA anticoagulant. If platelet clumping is observed, the platelet count is repeated using heparin or sodium citrate as an anticoagulant. If citrate is used, one should remember to correct the platelet count for dilution caused by the amount of citrate solution used; no such correction is needed for heparin. Alternatively, one can use freshly-shed non-anticoagulated blood pipetted directly into platelet counting diluent fluid. Decreased platelet production Platelet production by the bone marrow can be impaired when the marrow is suppressed or damaged. In almost all disorders caused by marrow suppression or damage, white cell and red cell production are also affected. Examples include: After viral infections (eg, rubella, mumps, varicella, parvovirus, hepatitis C, and Epstein- Barr virus). Decreased platelet counts also regularly occur in children receiving live attenuated measles vaccination, but the thrombocytopenia is rarely clinically important [27]. However, when viral infections occur in a patient who already has marrow suppression from another etiology, such as chemotherapy, the ensuing thrombocytopenia may be severe. Certain infectious agents are capable of damaging megakaryocytes directly, such as the human immunodeficiency virus. (See "Hematologic manifestations of HIV infection: Thrombocytopenia and coagulation abnormalities", section on 'Ineffective platelet production'.) Following chemotherapy or radiation therapy to sites of platelet production (eg, total nodal irradiation). In cases of congenital or acquired bone marrow aplasia or hypoplasia, such as Fanconi anemia, acquired pure megakaryocytic aplasia, and thrombocytopenia with absent radius (TAR) syndrome. Although congenital thrombocytopenias are more commonly diagnosed in children, many conditions are mild and not recognized until an adult has a routine blood count including a platelet count. (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis" and "Recombinant hematopoietic growth factors in inherited bone marrow failure syndromes", section on 'Amegakaryocytic thrombocytopenia'.) Direct alcohol toxicity. (See "Alcohol abuse and hematologic disorders".) Vitamin B12 and folic acid deficiency. (See "Etiology and clinical manifestations of vitamin B12 and folic acid deficiency".) Increased platelet destruction Increased platelet destruction is seen in a number of conditions, including: Idiopathic thrombocytopenic purpura (ITP) and systemic lupus erythematosus, in which the mechanism in many cases is presumed to be due to the presence of autoimmune anti-platelet antibodies. However, ineffective platelet production may also contribute to thrombocytopenia in patients with ITP [28,29]. This observation has led to the development of new treatments for ITP that stimulate platelet production. (See "Clinical manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in adults", section on 'Pathogenesis' and "Hematologic manifestations of systemic lupus erythematosus in adults", section on 'Thrombocytopenia' and "Chronic refractory immune (idiopathic) thrombocytopenic purpura in adults", section on 'Thrombopoiesis-stimulating agents'.) Certain drugs, most notably heparin, quinine, quinidine, and valproic acid (see below) (see "Heparin-induced thrombocytopenia" and "Drug-induced thrombocytopenia") Alloimmune destruction (post-transfusion, neonatal, post- transplantation) [30,31] Disseminated intravascular coagulation (DIC) (table 1) Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) (see "Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults") The antiphospholipid syndrome (see "Clinical manifestations of the antiphospholipid syndrome") The HELLP syndrome (hemolytic anemia, elevated liver function tests, and low platelet count) in pregnant women (see "HELLP syndrome") Following certain infections (eg, infectious mononucleosis, cytomegalovirus) Patients infected with HIV have a high incidence of thrombocytopenia, which bears a similarity to ITP (see "Hematologic manifestations of HIV infection: Thrombocytopenia and coagulation abnormalities", section on 'Primary HIV-associated thrombocytopenia') Physical destruction of platelets during cardiopulmonary bypass, within giant cavernous hemangiomata (Kasabach-Merritt syndrome), occasionally in large aortic aneurysms, and rarely in intravascular or intracardiac metastatic lesions [32]. Dilutional thrombocytopenia Patients who have had massive blood loss and transfusional support with packed RBC will have dilutional thrombocytopenia due to absence of viable platelets in packed RBC products. The usual platelet count in patients receiving 15 or 20 red blood cell units in 24 hours is 47,000 to 100,000/microL and 25,000 to 61,000/microL, respectively [33,34]. This problem can be obviated by giving platelet concentrates to patients receiving more than 20 units of packed RBC in a 24-hour period. Distributional thrombocytopenia caused by splenomegaly Normally, about one-third of circulating platelets are sequestered in the spleen, where they are in equilibrium with circulating platelets. Splenic sequestration of platelets can be increased to as high as 90 percent in patients with congestive splenomegaly due to portal hypertension (figure 2), although total platelet mass and overall platelet survival remain relatively normal [7]. Thus, patients with cirrhosis, portal hypertension, and splenomegaly may have significant degrees of "apparent" thrombocytopenia (with or without leukopenia and anemia), but rarely have clinical bleeding, since their total available platelet mass is usually normal. CLINICAL PRESENTATION Patients with thrombocytopenia may be asymptomatic and thrombocytopenia may be first detected on a routine complete blood count. The symptomatic presentation of thrombocytopenia is bleeding, characteristically mucosal and cutaneous. Mucosal bleeding may be manifest as epistaxis and gingival bleeding, and large bullous hemorrhages may appear on the buccal mucosa due to the lack of vessel protection afforded by the submucosal tissue. Bleeding into the skin is manifested as petechiae or superficial ecchymoses. (See "Clinical manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in adults".) Menorrhagia (menstrual flow that does not taper after more than three days) and metrorrhagia (uterine bleeding between periods) are also common and there may be persistent, profuse bleeding from superficial cuts. Patients with thrombocytopenia tend to bleed immediately after vascular trauma; they do not experience the delayed bleeding that is characteristic of patients with coagulation disorders such as hemophilia. Posttraumatic or postoperative surgical bleeding usually responds to local measures, but may persist for hours or days after small injuries. Bleeding into the central nervous system rarely occurs; when it does there is often preceding trauma, but it is the most common cause of death due to thrombocytopenia. The pattern of bleeding in patients with thrombocytopenia (and in patients with disordered platelet function) differs from that seen in patients with coagulation disorders such as hemophilia, in that the latter group has delayed bleeding that begins several hours or a day after trauma, because normal platelet function can provide temporary hemostasis. Patients with coagulation disorders also have deep bleeding (into tissues, muscles, and joints), minimal bleeding after minor cuts, more delayed bleeding, more postsurgical bleeding, and tend not to have petechiae (table 2). Petechiae Petechiae are pinhead sized, red, flat, discrete lesions often occurring in crops in dependent areas (picture 4); they are most dense on the feet and ankles, where the hydrostatic pressure on the small superficial vessels is greatest, and fewer are present on the legs. Petechiae are not found on the sole of the foot where the vessels are protected by the strong subcutaneous tissue. Petechiae are due to the presence of red cells which have extravasated from capillaries; they are nontender and do not blanch under pressure. They are asymptomatic and not palpable, and should be distinguished from small telangiectasias, angiomas, and vasculitic purpura (picture 5). Purpura Purpura is a purplish discoloration of the skin due to the presence of confluent petechiae. Two types of purpura are generally recognized: Dry purpura is the term used when the only bleeding is in the skin, as in frame A of the picture (picture 4). Wet purpura is the term used when there is extensive mucous membrane bleeding, as in frame B of the picture (picture 4). It is generally felt that the presence of wet purpura is the more serious, and is a prognostic sign for potentially life-threatening hemorrhage. Ecchymoses Ecchymoses are nontender areas of bleeding into the skin, usually associated with multiple colors, due to the presence of extravasated blood (red, purple) plus the colors due to breakdown of heme pigment by skin macrophages (green, orange, yellow). Ecchymotic lesions characteristically are small, multiple, and superficial. They usually develop without noticeable trauma and do not spread into deeper tissues. INITIAL APPROACH There is no substitute for an accurate, comprehensive history and physical examination. However, a platelet count that does not make sense within the context of the clinical picture should be repeated before extensive evaluation is undertaken. For extremely low platelet counts in symptomatic patients, such re-testing should be performed immediately; for asymptomatic patients with modest reductions in platelet count (eg, 75,000 to 100,000/microL), testing may be repeated in one to two weeks, provided that the patient is advised to immediately report any changes in clinical status during this interval. If, after initial evaluation and retesting, the cause of the thrombocytopenia is not apparent, hematologic consultation is warranted. The general history Certain conditions associated with thrombocytopenia are obvious and can be immediately recognized by the clinician: Recent new drugs or drugs that are only taken intermittently Recent infection (viral, bacterial, rickettsial, etc.) Previously diagnosed hematologic disease (eg, acute and chronic leukemias, chronic myeloproliferative or myelodysplastic diseases) Nonhematologic diseases known to decrease platelet counts (eg, eclampsia, sepsis, DIC, anaphylactic shock, hypothermia, massive transfusions) A positive family history of bleeding and/or thrombocytopenia Recent live virus vaccination Poor nutritional status, especially in the elderly and alcoholics Pregnancy, especially late in the third trimester or at onset of labor (see below), but also with a prior history of ITP or TTP-HUS, or with preeclampsia or eclampsia (see "Thrombocytopenia in pregnancy"). Recent organ transplantation from a donor sensitized to platelet alloantigens [30] Recent transfusion of a platelet-containing product in an allosensitized recipient (see "Immunologic blood transfusion reactions", section on 'Posttransfusion purpura') The bleeding history Patients with a suspected bleeding disorder should be questioned about past bleeding problems, a history of iron-responsive anemia, bleeding outcomes with surgical procedures and tooth extractions, history of transfusion, character of menses, and dietary habits or antibiotic use that might predispose to deficiencies of vitamin K, vitamin B12, and folic acid. A history of intermittent acute purpura suggests a drug (or herbal remedy, or food) induced thrombocytopenia. (See "Approach to the adult patient with a bleeding diathesis", section on 'Patient history' and "Preoperative assessment of hemostasis", section on 'Patient questionnaires'.) Medications, herbal remedies, diet supplements It is critical to review the list of ALL medications taken by the patient which might be associated with the development of thrombocytopenia (table 3). This list should also include any over-the-counter and herbal products, quinine containing beverages, aspirin and non-steroidal antiinflammatory agents. (See "Drug- induced thrombocytopenia", section on 'History of drug ingestion'.) Although medications may cause thrombocytopenia via induction of peripheral platelet destruction or production of bone marrow aplasia or hypoplasia, the most common cause is immune-mediated platelet destruction by drug-dependent, platelet-reactive antibodies. Some drugs can also exacerbate an underlying platelet disorder. Examples include the platelet dysfunction induced by aspirin and many other anti-inflammatory drugs; and the co-ingestion of drugs that potentiate the anticoagulant effects of warfarin. (See "Nonselective NSAIDs: Overview of adverse effects".) The timing of onset of clinical bleeding or first recognition of the thrombocytopenia with use of medications should be explored in depth, since it may focus attention on the most likely agent(s). Explicit questions about over-the-counter medicines, medicines taken irregularly or not prescribed by a physician (eg, medicines prescribed for a friend or a family member but taken by the patient), and herbal remedies are required, because patients are often reluctant to report their use of these medicines. It is good practice to review each of the patient's medications for the possibility of drug- induced thrombocytopenia, especially if a drug taken daily has been started within the past several weeks, if it is taken only occasionally for a longer period of time, and/or if its side effects are not generally known. The spectrum of drugs reported as causing drug-induced thrombocytopenia is continually increasing, reflecting both changes in drug consumption as well as increased recognition of drug- induced thrombocytopenia. A complete list and analysis of all published reports of drug-induced thrombocytopenia, as well as drugs identified as causes of thrombocytopenia by the documentation of drug-dependent, platelet-reactive antibodies is available [35]. These data are continuously updated and can be accessed at www.ouhsc.edu/platelets (see "Drug-induced thrombocytopenia"). As an example, the list of thrombocytopenia-inducing agents in Denmark contains 110 different drugs (excluding cytotoxic drugs); 20 percent of reported cases concerned drugs not previously listed, and 25 percent were caused by drugs which appeared on the list only sporadically [36]. Some of the most commonly cited agents causing thrombocytopenia include: Heparin (see "Heparin-induced thrombocytopenia") Valproic acid Gold salts (see "Major side effects of gold") Quinine and quinidine Trimethoprim-sulfamethoxazole and other sulfonamides Interferons Measles-mumps-rubella vaccine Glycoprotein IIb/IIIa inhibitors (eg, abciximab) Hospitalized patients often do not know what medications have been prescribed. In addition to reviewing the hospital chart for active medications and nursing notes and bedside flow sheets concerning the use of heparin flushes of vascular access lines, it may be important to review anesthesia records. In many medical centers, anesthesiologists give medications directly to the patient without the need for entering a medication order. Important medicines may also be contained in materials used in surgery, such as vancomycin mixed into joint replacement cement [37]. Recent travel Fever and thrombocytopenia in an adult or child with a history of recent travel may indicate infection; malaria or dengue virus infection are common causes [38,39]. Other infections that may be associated with recent travel and thrombocytopenia include leptospirosis, meningococcemia, rat-bite fever, rickettsial infections, hantavirus, and other viral hemorrhagic fevers (eg, Ebola, Lassa fever). (See "Clinical presentation and diagnosis of dengue virus infections", section on 'Laboratory findings' and "Evaluation of fever in the returning traveler", section on 'Differential diagnosis'.) Thrombocytopenia in the ICU patient The most common cause of thrombocytopenia developing for the first time in a patient in an intensive care unit (ICU) setting is sepsis, accounting for one-half of the cases [40]. However, many ICU patients have more than one cause of thrombocytopenia. The following conditions are likely contributors to this picture: Infection, sepsis, septic shock Use of heparin Disseminated intravascular coagulation (DIC) Massive blood transfusion Post-transfusion purpura Cardiopulmonary resuscitation Cardiopulmonary bypass Adult respiratory distress syndrome Pulmonary embolism Use of intravascular catheters Solid organ allograft rejection Use of drugs associated with thrombocytopenia (eg, antibiotics, chemotherapy, antiplatelet agents such as abciximab) In one study, evolution of DIC, cardiopulmonary resuscitation as the admission category, and signs of organ failure at admission were independently associated with the development of thrombocytopenia, while septic shock, a higher APACHE II score, and a 30 percent decrease in platelet counts were significant risk factors for ICU death [41]. The physical examination There are a number of critical areas which must be examined. These include, but are not limited to: Examination of the ocular fundus for evidence of bleeding, since CNS bleeding is the most common cause of death in the thrombocytopenic patient Examination for lymphadenopathy, hepatosplenomegaly, and other masses which might suggest the presence of a disseminated disorder Examination of the stool for occult blood Examination of the skin Since bleeding into the skin is one of the most common findings in thrombocytopenia, this part of the examination should be the most detailed. Sites of bleeding should be noted, especially in the dependent parts of the body. This is normally the feet and ankles in ambulatory patients, as in panel A of the picture (picture 4), but may be the presacral area in bedridden patients. Sites of indwelling catheters and drains, areas of previous trauma, incision sites, and exit sites of venous access devices should be carefully examined. It is good practice to outline areas of bleeding with a marking pen, or to mark out involved and uninvolved skin areas and serially note changes in the number of petechiae or bleeding pattern within those sites, in order to obtain insight into the patient's progress. As noted above, the sites and timing of bleeding with thrombocytopenia differ from those in coagulation disorders (table 2). CBC AND PERIPHERAL SMEAR Laboratory examination should start with the complete blood count (CBC). The "gold standard" for evaluation of thrombocytopenia of any cause is examination of a peripheral smear prepared from a freshly-shed sample of non- anticoagulated blood. The importance of a careful examination of the peripheral smear for estimation of platelet numbers, morphology, presence or absence of platelet clumping, as well as evaluation of associated white and red blood cell changes cannot be overemphasized. It is especially important to use the CBC and blood smear to help rule in or out thrombotic thrombocytopenic purpura and acute leukemia as expeditiously as possible, since inordinate delay in making these diagnoses and initiating appropriate treatment may prove fatal. Pseudothrombocytopenia and artifacts It is critical to confirm that the reported thrombocytopenia is true and not a falsely low platelet count due to artifact, or represents blood taken from a different individual. A spuriously low platelet count owing to inadequate sample anticoagulation or to EDTA-induced platelet clumping can be confirmed by evaluation of the peripheral smear (preferably prepared from freshly-shed non-anticoagulated blood) for the presence of platelet clumps (picture 3). Repeat blood sampling and the use of an alternate anticoagulant, such as heparin or sodium citrate, helps to make this diagnosis. (See 'Pseudothrombocytopenia' above.) The following findings can give clues to the genesis of the thrombocytopenia [42]: Abnormal platelet morphology There are a number of congenital thrombocytopenic disorders. These can often be diagnosed following examination of the peripheral smear by virtue of alterations in platelet size, abnormal platelet granules, and/or neutrophilic inclusions [43]. Many of these patients have been initially (and erroneously) diagnosed as having immune thrombocytopenic purpura (ITP) May-Hegglin anomaly The May-Hegglin anomaly is an autosomal dominant trait characterized by giant platelets, mild to moderate thrombocytopenia, and leukocyte inclusions. Platelets are large (30 to 80 fL, normal: 7 to 10 fL) and some may be larger than red cells [44-47]. Because of their large size, the platelets may not be recognized by the laboratory particle counter; therefore the reported platelet count may be falsely low. Inclusions in neutrophils, eosinophils, and some monocytes resemble Dhle bodies seen in infection. The disorder has been linked to mutations of the non-muscle myosin heavy chain gene, MYH9, found on chromosome 22q [48,49]. Unlike the Fechtner, Sebastian, and Epstein syndromes, disorders also associated with mutations of the MYH9 gene, nephritis, deafness, and cataracts are not seen in patients with the May-Hegglin anomaly [50]. (See "Congenital and acquired disorders of platelet function", section on 'Giant platelet disorders'.) Most patients are asymptomatic, discovered incidentally (eg, at the time of a routine blood count), and require no specific treatment. The bleeding tendency, if present, is usually mild, but severe hemorrhages have been reported. Case reports suggest that infusions of DDAVP or platelets have been effective in controlling or preventing operative bleeding [51-55]. Similarly, use of antifibrinolytic agents or recombinant human factor VIIa may be transiently helpful [50]. Other MYH9 syndromes Related conditions, which vary according to the presence or absence of nephritis, neutrophilic inclusions, cataracts, and deafness have also been described (eg, Sebastian platelet syndrome, Fechtner syndrome, Epstein syndrome) [43,45] (picture 6). These conditions are all associated with mutations in the MYH9 gene. They should not be confused with Alport syndrome, which may also be associated with nephritis, deafness, and cataracts, but which is due to mutations in type IV collagen and does not have associated platelet abnormalities. (See "Genetics, pathogenesis, and pathology of hereditary nephritis (Alport syndrome)".) Bernard-Soulier syndrome The Bernard-Soulier syndrome is an autosomal recessive disorder presenting with mild thrombocytopenia, circulating "giant" platelets, marked platelet dysfunction, and bleeding. The bleeding is disproportionately more severe than suggested by the thrombocytopenia, and is explained by the absence of the platelet glycoprotein (GP) Ib-IX-V, a receptor for von Willebrand factor. Most patients with autosomal dominant macrothrombocytopenia share clinical and molecular features with heterozygous Bernard-Soulier syndrome [56]. (See "Congenital and acquired disorders of platelet function", section on 'Giant platelet disorders'.) Wiskott-Aldrich syndrome The Wiskott-Aldrich syndrome is a rare X-linked disorder which presents as a clinical triad of immunodeficiency, eczema, and moderate to severe thrombocytopenia with small (3 to 5 fL) platelets. Some male subjects with mutations of the Wiskott-Aldrich Syndrome Protein (WASP) gene may have only thrombocytopenia (which may be intermittent [57]) and small platelets, without immunodeficiency or eczema, a condition termed X-linked (congenital) thrombocytopenia [58]. (See "Severe combined immunodeficiency (SCID): An overview" and "Wiskott-Aldrich syndrome", section on 'X-linked thrombocytopenia' and "Wiskott-Aldrich syndrome", section on 'Thrombocytopenia and platelet abnormalities'.) Other inherited thrombocytopenic disorders These disorders, which are uncommon, some of which are associated with giant platelets, are discussed separately. (See "Congenital and acquired disorders of platelet function", section on 'Giant platelet disorders'.) Decreased platelet production Findings that suggest reduced production of platelets as the cause for the patient's thrombocytopenia include: Circulating blast cells, indicating the presence of acute leukemia (picture 7) A leukoerythroblastic blood picture (teardrop RBCs, nucleated RBCs, and early myeloid forms in the blood) suggests marrow invasion with tumor, fibrosis, or granulomatous infection, such as tuberculosis (picture 8A-B) Other cytopenias, with or without macrocytosis, monocytosis, or decreased neutrophil lobulation (Pelger-Huet anomaly) (picture 9), suggest the presence of a myelodysplastic state Oval macrocytic RBCs along with hypersegmentation of neutrophils suggest vitamin B12 or folic acid deficiency (picture 10A-B) Platelets that are normal sized or small, in contrast to large sized platelets, suggest a reduced bone marrow response to need [59]. Increased peripheral destruction Findings that suggest increased peripheral destruction of platelets as the cause of thrombocytopenia include: Microangiopathic blood picture, with fragmented RBCs, hemolytic anemia, and increased serum concentration of lactate dehydrogenase, as in disseminated intravascular coagulation (DIC) or thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) (picture 11) Large platelets (megathrombocytes) on the peripheral smear without significant bleeding suggest the presence of young, hemostatically active platelets in response to peripheral destruction [59]. Associated autoimmune disease, especially in a young women (see "Hematologic manifestations of systemic lupus erythematosus in adults") Underlying lymphoproliferative disease (eg, chronic lymphocytic leukemia or Hodgkin's disease) especially when a leukoerythroblastic blood picture is absent (see above) BONE MARROW EXAMINATION Bone marrow aspiration and biopsy may be helpful in some patients to determine the presence or absence of megakaryocytes, indicating thrombocytopenia caused by increased platelet destruction or decreased platelet production, respectively. Bone marrow aspiration and biopsy may be more helpful in older patients in whom isolated thrombocytopenia may be the initial abnormality of myelodysplasia. (See 'Diagnosis of ITP' below.) The following items need the most careful attention when examining the bone marrow in a thrombocytopenic patient: The presence of normal to increased numbers of megakaryocytes indicates that the patient's thrombocytopenia is due, at least in part, to increased peripheral destruction. Decreased numbers of megakaryocytes on the bone marrow biopsy, along with overall decreased or absent cellularity (picture 12 and picture 13), is consistent with thrombocytopenia due to decreased bone marrow production, as in aplastic anemia. (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis".) In a hypercellular marrow, the presence of megaloblastic changes in the red cell and granulocytic series suggests vitamin B12 or folic acid deficiency (picture 14), while the presence of dysplastic changes in the red cell, granulocytic, and megakaryocytic lineages suggests a myelodysplastic disorder (picture 15 and picture 16). (See "Clinical manifestations and diagnosis of the myelodysplastic syndromes".) The presence of granulomata, increased reticulin or collagen fibrosis (picture 17 and picture 18), or infiltration with malignant cells (picture 19) establishes the diagnosis of marrow invasion, especially when a leukoerythroblastic blood picture is also present (see above). In rare cases, severe reduction or absence of megakaryocytes with no other abnormalities (ie, acquired amegakaryocytic thrombocytopenia, acquired pure megakaryocytic aplasia), may be due to the presence of an autoantibody directed against the thrombopoietin receptor, most often reported in patients with systemic lupus erythematosus. (See "Recombinant hematopoietic growth factors in inherited bone marrow failure syndromes", section on 'Amegakaryocytic thrombocytopenia'.) DIAGNOSIS OF GESTATIONAL THROMBOCYTOPENIA Incidental thrombocytopenia of pregnancy, also termed gestational thrombocytopenia, is defined by the following five criteria: Mild and asymptomatic thrombocytopenia No past history of thrombocytopenia (except possibly during a previous pregnancy) Occurrence during late gestation No association with fetal thrombocytopenia Spontaneous resolution after delivery Platelet counts are typically greater than 70,000/microL, with about two-thirds being 130,000 to 150,000/microL. The frequency of gestational thrombocytopenia in the largest series of consecutive women admitted for labor and delivery is 5 percent. Neonatal thrombocytopenia did not occur in infants born to mothers with gestational thrombocytopenia (except in one infant with congenital myelodysplasia). Gestational thrombocytopenia is considered to be benign and any change from routine obstetrical care is discouraged. (See "Thrombocytopenia in pregnancy".) DIAGNOSIS OF ITP There is no "gold standard" test that can establish the diagnosis of ITP, and testing for antiplatelet antibodies is not recommended. (See "Clinical manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in adults".) The diagnosis is based on exclusion of other causes of thrombocytopenia (table 4). Few diagnostic studies other than the history, physical examination, complete blood count, and examination of the blood smear are necessary. A presumptive diagnosis of ITP is made when the history (eg, lack of ingestion of a drug that can cause thrombocytopenia), physical examination, complete blood count, and examination of the peripheral blood smear do not suggest other etiologies for the isolated thrombocytopenia. The only recommended further tests in such patients are: HIV testing in patients with risk factors for HIV infection Bone marrow aspiration to rule out myelodysplastic syndrome, especially in patients >60 years of age SUMMARY AND RECOMMENDATIONS While thrombocytopenia can be caused by a myriad of conditions including systemic disease, infection, drugs, beverages, foods, and primary hematologic disorders, a number of salient points will help the physician in determining its cause: Thrombocytopenia is defined as a platelet count less than 150,000/microL (150 x 109/L), keeping in mind that 2.5 percent of the normal population will have a platelet count lower than this. A fall in platelet count to levels less than 150,000/microL may herald severe clinical problems, and requires active follow-up, although thrombocytopenia is not usually detected clinically until the platelet count has fallen to levels significantly below 100,000/microL. The importance of a careful examination of the peripheral smear for estimation of platelet numbers, morphology, presence or absence of platelet clumping, as well as evaluation for red and white blood cell abnormalities cannot be overemphasized Findings that suggest reduced production of platelets as the cause for the patient's thrombocytopenia include the presence of small platelets, malignant cells, a leukoerythroblastic blood picture, leukopenia, anemia, and/or large (macrocytic) red cells Large platelets (megathrombocytes) on the peripheral smear without significant bleeding suggest the presence of young, hemostatically active platelets in response to peripheral destruction. However, very large platelets, approaching the size of red cells, suggest a congenital thrombocytopenia. Other findings that suggest increased peripheral destruction of platelets as the cause of thrombocytopenia include the presence of fragmented red cells, hemolytic anemia, and an increased serum concentration of lactate dehydrogenase A presumptive diagnosis of idiopathic thrombocytopenic purpura (ITP) is made when the history (eg, lack of ingestion of a drug, beverage, or food that can cause thrombocytopenia), physical examination, complete blood count, and examination of the peripheral blood smear do not suggest other etiologies for the isolated thrombocytopenia Bone marrow aspiration and biopsy is indicated in virtually all patients with unexplained thrombocytopenia severe enough to constitute a risk for major bleeding. The only valid exclusion to this requirement is the patient less than 60 years of age with a presumptive diagnosis of ITP (see above). Management issues Management issues for patients with thrombocytopenia, including activity restrictions, indications for treatment, and management of invasive procedures, are discussed separately. (See "Evaluation and management of thrombocytopenia by primary care physicians", section on 'Patient management'.)