Thrombocytopenia in the critically ill patient

REVIEWS

Thrombocytopenia David L. Bogdonoff,

in the Critically Michael

T

HROMBOCYTOPENIA occurs commonly in the intensive care unit (ICU). Patient care may be adversely affected by the development of a hemorrhagic diathesis. Additionally, management is complicated by the difficult decisions that revolve around the possibility of druginduced thrombocytopenia and the need to alter therapeutic regimens. Required platelet transfusions may result in both acute and chronic complications as well. This review will focus on causes of thrombocytopenia prevalent in the ICU (Table 1). SPURIOUS

THROMBOCYTOPENIA

Low platelet counts detected by automated equipment may be erroneous and ideally are confirmed by direct examination of the blood smear, which will also convey information regarding the other formed elements of the blood. If giant platelets are present (as in myeloproliferative disorders), the machine will exclude them by the upper sizing threshold. Review of the blood smear may reveal that it is difficult to size differentiate the giant platelets from immature white blood cells or lymphocytes. Platelet “satellitism” may rarely occur. This consists of the close grouping of platelets around polymorphonuclear leukocytes resulting in the automated machine “missing” the grouped platelets. The cause is unknown and in the cases reported by Kjeldsberg and Hershgold, there was no excessive bleeding during surgery.’ This phenomenon is easily detected by examination of the peripheral smear. Platelet cold agglutinins are an uncommon cause of spurious thrombocytopenia. These anti-

From the University of Virginia Health Sciences Center, Charlottesville, VA. Received November 18, 1989: accepted December 22, 1989. Address reprint requests to David L. BogdonoR, MD. Box 238, Department of Anesthesiology, University of Virginia Health Sciences Center, Charlottesville, VA 22908. o 1990 by W.B. Saunders Company. 0883-9441/90/0503-0005$05.00/0

186

E. Williams,

Ill Patient

and David J. Stone

bodies agglutinate platelets at temperatures less than 3VC and result in prominent platelet clumping on blood smears and in vitro samples. The agglutinating factor appears to be an IgM antibody and may or may not be independent of added anticoagulants2 Platelet function is not affected. It is important to distinguish platelet cold agglutinins from red blood cell (RBC) cold agglutinins, which should not cause spurious thrombocytopenia. Platelet clumping may also be induced by ethylenediamine tetraacetic acid (EDTA); this represents the most common cause of spuriously low platelet counts. It has been reported in 0.09% of all samples in a large laboratory series but is much more common in ill or hospitalized patients, with an incidence as high as 1.9% in another series.3 The mechanism probably involves platelet-specific antibodies that react with platelets in the presence of EDTA. All classes of antibodies have been involved, although IgG is usually implicated. The antibodies attach to platelet glycoproteins IIb or IIIa, but will not do so in the absence of EDTA. Techniques used to rule out EDTA-induced clumping include the microscopic examination of a smear made directly from a fingerstick. A comparison may also be made between samples collected in different anticoagulants. More modern automated counters may be capable of detecting the abnormal platelet clumps, drawing immediate attention to this unusual problem. Spurious thrombocytopenia can also be caused by improper collection. Traumatic venipuncture or inadequate anticoagulation may lead to thrombin release with platelet aggregation. At times, more than one blood smear should be reviewed because of uneven distribution of platelets on any single smear. DISORDERS

OF PLATELET

PRODUCTION

Low platelet counts can result from decreased megakaryocytopoiesis or ineffective platelet production. Marrow megakaryocytes may be suppressed by ionizing radiation and a large number

Journal

of Critical Care, Vol 5, No 3 (September).

1990:

pp 186-205

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Table

IN CRITICALLY

1.

Spurious Disorders

Causes

ILL

of Thrombocytopenie

thrombocytopenia of platelet production

Ethanol Selective megakaryocyte Nutritional deficiency Disorders of distribution Hypersplenism

hypoplasia and dilution

Hypothermia Massive transfusion Disorders of platelet destruction Extrinsic activation of coagulation Transfusion reaction Surface-mediated Pulmonary artery catheters Other foreign surfaces Cardiac valves and prostheses Burns RespiratorY

failure

Infections Fat embolism Drug-related Heparin Postransfusion Alloimmunization Cardiopulmonary

bypass

of drugs. Most of these are used therapeutically for malignancies or autoimmune disorders, and the resulting thrombocytopenia is not unexpected. Ethanol Ethanol suppresses megakaryocytes by an unknown mechanism. Low platelet counts are quite common in alcoholics and have been found even when other causes have been excluded.4 Withdrawal of alcohol results in rapid recovery of the platelet count and thrombocytosis will frequently follow. Lindebaum and Hargrove have proposed a direct toxic effect of alcohol on the megakaryocyte.5 Drugs Chlorothiazide is occasionally used intravenously in the ICU to supplement the action of loop diuretics. Nordquist et al reported six cases of thrombocytopenia apparently due to decreased production, although the specific results of bone marrow examinations were not given.6 Mild thrombocytopenia was found in almost one quarter of the patients with congestive heart failure treated with thiazides by Kutti and

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Weinfeld.’ The majority of these instances are felt to represent direct megakaryocytic suppression. Aplastic Anemia Aplastic anemia may present acutely with thrombocytopenia. This rare disorder has been reported following exposure to various chemical toxins and drugs, most notably chloramphenicol. Bone marrow aplasia has also been associated with bacterial and viral infections, particularly viral hepatitis.8 The mechanisms involved are unknown. Marrow replacement by malignant tissue is another mechanism for pancytopenia in patients with metastatic carcinoma, multiple myeloma, myelofibrosis, or other myeloproliferative disorders. Vitamins Ineffective production of platelets is characterized kinetically by decreased platelet turnover despite an increased megakaryocyte mass.’ This is in contrast to the previous disorders of direct suppression in which megakaryocyte mass is decreased. Ineffective production is the characteristic abnormality in vitamin B,, or folate deficiency. These are usually chronic problems, but may have an altered time course in critical illness. Mant et al reported 13 patients with what appeared to be the acute onset of folic acid deficiency during the first 1 to 2 weeks of hospitalization. lo The classic peripheral blood changes of megaloblastic anemia were absent and serum folate levels were indeterminate, but platelet counts responded to folate therapy. They postulated that the acute onset, use of blood transfusions, and impaired use of folate may have altered the usual clinical scenario. Bone marrow examination did reveal megaloblastosis. It is not clear whether discontinuation of heparin (in monitoring apparatus) coincided with the increases in platelet count. Contributing factors may include decreased intake, sepsis, renal failure, and dialysis. It is possible that sepsis and renal failure impair folate usage. Beard et al reported four patients with the acute onset of folate deficiency after surgery for ruptured aortic aneurysm. I1 This study u sed deoxyuridine suppression tests to demonstrate direct evidence of

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folate deficiency within marrow cells. Serum and RBC folate levels were normal but were drawn following transfusion. Easton reported two nonsurgical patients with hemorrhage due to thrombocytopenia who had folate levels drawn prior to transfusion therapy. I2 Serum and RBC folate levels were indeed low, although other evidence of megaloblastic anemia was absent from the peripheral smear. Platelet counts responded promptly to folate administration. Folate deficiency will develop over 2 to 5 months if folate is not supplemented in the diet. Acute folate deficiency may be due to increased folate requirement and impaired use occurring as intake ceases. It is probably prudent to administer folate to patients requiring more than 3 to 4 days of intensive care as it is inexpensive, benign, and may prevent thrombocytopenia. Purists may choose to measure vitamin B,, before folate is administered. Nitrous oxide can produce abnormalities in bone marrow as a result of interference with enzymes containing vitamin B,,, thus mimicking pernicious anemia. Vitamin B,, levels remain normal. Methionine synthetase, an important enzyme in DNA synthesis, can be shown to be inactivated by nitrous oxide.13 Transient bone marrow dysfunction in normal patients can be demonstrated after clinical exposures to nitrous oxide of greater than 12 hours but does not occur after 6 hours of exposure. Critically ill patients may be susceptible to exposures of less than 6 hours. Amos et al prospectively examined seriously ill patients admitted to the ICU.14 Thirtynine of 42 patients who had been exposed to nitrous oxide intraoperatively demonstrated an abnormal deoxyuridine suppression test on bone marrow aspirates. Only one control patient not exposed to nitrous oxide had this abnormal finding. The degree of abnormality was proportional to time of exposure and was present even in patients receiving nitrous oxide for as little as 1 hour. Although disturbances in DNA synthesis were documented, marrow changes and cytopenias did not always occur. Megaloblastic changes were found more commonly in patients exposed to nitrous oxide but were also more likely to occur in the sicker patients, suggesting that other factors relating to the severity of illness were also involved. The changes resolve over time and the

EOGDONOFF

long-term known.

ET AL

significance of such changes is not

DISORDERS

OF DISTRIBUTION

AND DILUTION

Hypersplenism

The spleen normally sequesters up to one third of the (circulating) peripheral platelet mass. In cases of marked splenomegaly, the degree of splenic pooling may increase to 50% to 90% of available platelets.15 Despite increased platelet production, the redistribution of platelets from the peripheral circulation to the spleen is sufficient to decrease platelet counts. Platelet survival is nearly normal in such situations, as is platelet function. It is rare to have a platelet count of less than 50,000/mm3 on the basis of splenomegaly. Additionally, if the spleen tip is not palpable on physical examination, it is difficult to implicate hypersplenism as the principal cause of thrombocytopenia. Hypothermia

Hypothermia may lead to mild thrombocytopenia. This was described early in the cardiopulmonary bypass literature,16 and has been reported in hypothermic cases unrelated to extracorporeal perfusion as well.” Clinical bleeding is not a problem and platelet counts are reversible with rewarming. Platelet activation and aggregation are the likely mechanisms. Platelets are known to aggregate at low temperatures in vitro. In animal models, sequestration of platelets has been reported to be in the spleen and/or liver. Transfusion

Massive transfusion of banked blood will progressively dilute the platelet count. The drop in platelet count occurs early and correlates with the volume of transfused blood. Blood stored at 4°C contains defective platelets with impaired viability.‘* Apparently, the platelets are damaged and are consequently trapped and cleared by the reticuloendothelial system. Following 24 to 48 hours of storage, platelet activity is only 5% to 10% of normal. In acutely bleeding patients, a hemorrhagic diathesis is likely to occur with platelet counts less than 60,000/mm3 to 75,000/ mm3.19 Patients with chronic thrombocytopenia and without a traumatic lesion or surgical inci-

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sion can tolerate much lower platelet counts safely. Although the decreasing platelet count seen in massively transfused patients does correlate with the number of transfused units, the correlation does not fit the mathematic decay curve predicted by a purely dilutional phenomenon. Megakaryocyte mass and platelet production cannot increase acutely. However, other mechanisms exist that lead to the higher than expected platelet counts encountered. The implication is that platelets are released into the circulation from physiologic storage pools, most likely the spleen. Despite this endogenous release, platelet counts continue to drop and bleeding often occurs. The coagulopathy that is found with massive transfusion is complex and involves three major categories of coagulation defects: dilution of coagulation factors as well as platelets, the presence of disseminated intravascular coagulation (DlC) and fibrinolysis, and dysfunction of the platelet-endothelial cell interaction2’ Once coagulopathy is present, generalized bleeding results and leads to more rapid transfusion with further dilution. Initial therapy usually involves platelet transfusions, as this addresses two of the major categories of the coagulation problem. Because there is a significant reserve of coagulation factors, administration of fresh, frozen plasma is rarely required early in the course of massive transfusion. The prompt reversal of bleeding that is usually observed following administration of platelets has led to the general recommendation for prophylactic platelet transfusions whenever massive transfusion is undertaken. One unit of platelets for each 10 kg of body weight per 10 U of transfused banked blood is a reasonable guideline to follow for prophylactic platelet transfusion. A prospective clinical study, however, disputes this practice.” Massively transfused surgical patients were divided into groups. One received 6 U of platelets for every 12 U of transfused blood, while the other group received 2 U of fresh frozen plasma instead. The incidence of microvascular bleeding was one in six patients in each group; this was equivalent to the incidence of bleeding in their historic controls, who received no additional blood components along with transfused RBCS.~~ Study patients who

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developed microvascular bleeding had a source of ongoing platelet consumption that compounded the problem of early dilution of platelets. These investigators suggest withholding platelet transfusions until there is evidence of bleeding. since five of six patients may indeed not require such therapy. If platelet counts are able to be obtained quickly and the development of bleeding would not be lethal (as in intracranial hemorrhage, for example), it is reasonable to manage such patients expectantly. One must be aware, however, that this approach represents a minority opinion. The bulk of clinical impressions are in favor of prophylactic platelet administration whenever replacement of one blood volume has occurred. especially if further bleeding is anticipated.20 DISORDERS

OF PLATELET

DESTRUCTION

Excessive platelet destruction is the most common reason for thrombocytopenia in the critically ill. Two major mechanisms are responsible for platelet removal. The first involves nonimmune mechanisms that may be mediated by thrombin or surface interactions. These nonimmune mechanisms include both isolated and combined disorders; ie, the consumption of platelets may or may not coexist with consumption of clotting factors. Immune-mediated destruction represents the other major mechanism and results from interactions of platelets with antibody, immune complexes, or complement. The most common cause of acute destruction of platelets is the consumption that accompanies the activation and consumption of coagulation factors. Disseminated intravascular coagulation is the term most often used to describe such conditions. There is a diverse list of etiologies for DlC, including central nervous system or soft tissue trauma, acute respiratory failure, obstetric complications, venous thrombosis, and various infections.23 Characterization of these disorders on a kinetic basis would reveal reductions in both platelet and fibrinogen survival times. The consumption may occur as a local phenomenon or exist as a generalized disorder on a systemic level. Extrinsic Activation of Coagulation

Snake bites may lead to thrombocytopenia through rapid and profound consumption of

BOGDONOFF

platelets and coagulation factors. Different venoms initiate coagulation through direct activation of different clotting factors.24 Brain injury leads to the systemic release of thromboplastin or thromboplastin-like substances, and this leads to initiation of intravascular consumption with defibrination and thrombocytopenia.25 This etiologic mechanism may also contribute to the thrombocytopenia seen with crush injuries and other causes of tissue damage. Obstetric complications may lead to thrombocytopenia. Combined consumption is the likely mechanism involved in placental abruption and amniotic fluid embolism. Placental thromboplastin and the foreign debris found in amniotic fluid are potent initiators of coagulation. Necrotic fetal products leaching into the maternal circulation from a retained dead fetus may similarly lead to thrombocytopenia, although other mechanisms have been described. Bacterial, protozoal, viral, fungal, and rickettsial infections are associated with thrombocytopenia. Various causes exist and will be discussed. Platelet consumption following initiation of intravascular coagulation is just one of these causes. Transfusion Reaction

Disseminated intravascular coagulation accompanies other disorders associated with thrombocytopenia, which are discussed later as well. One final etiology of intravascular coagulation leading to profound thrombocytopenia is that which results from a hemolytic reaction complicating transfusion of incompatible blood. Treatment of this problem as well as all of the conditions involving platelet and coagulation factor consumption revolves around removal of the offending agents or underlying causes. Surface-Mediated

Destruction

There are various etiologies of surface-mediated nonimmune platelet destruction. Abnormal or injured vasculature or tissue provides the offending surface, or a foreign body may be involved. Most of these phenomena result in platelet consumption without simultaneous consumption of fibrinogen or other coagulation factors. Platelet consumption occurs locally in the majority of these disorders, but is by no means limited to local destruction.

ET AL

Pulmonary Artery Catheters

Hoar et al found large clots along pulmonary artery catheters inserted only 1 to 2 hours earlier for cardiac surgery. *’ Platelet counts were not done. Richman et al noted that pulmonary artery (PA) catheters were thrombogenic and performed an investigation in dogs to determine whether thrombocytopenia occurred as a result. They found that platelet counts began to fall as early as 6 hours after catheterization, had a maximal fall of 64.2% s 15% (mean f SD) at 48 hours, and returned to normal levels over the next 4 days. A shortened platelet survival time was demonstrated to be the cause.28 This observation was then studied in humans undergoing cardiac surgery. Patients with central venous pressure (CVP) lines served as controls. Platelet counts in both groups did fall after bypass, but continued to fall only in the pulmonary artery catheter group to the level of about 150,000/mm3 at 24 hours. No differences in hematocrit or blood transfusion were noted in this small series. The investigators postulated that the larger surface area of the PA catheter (compared with the CVP catheter) may account for the observed reduction in platelet count.29 In an ICU study designed to examine catheter infection, Miller et al noted that only the patients with PA catheters (v single and triple lumen CVP catheters) developed statistically significant falls in platelet count. These levels then rose quickly (24 hours) following removal of the PA line to levels that were not different from those is the patients with CVP catheters.30 Another prospective study of ICU patients found significant decreases in platelet counts with PA lines at 6, 24,48, and 72 hours after insertion. No bleeding complications were observed and no count fell by more than 40% from the baseline count. No other cause for thrombocytopenia was found, and the rapid increase in counts following catheter removal was strong evidence for a catheter-induced etiology. 31The rapid onset of the thrombocytopenia makes heparin an unlikely cause. These data on thrombocytopenia with PA lines should initiate more thought in the use of such lines in the ICU, where patients may not have a normal baseline platelet count and a 40% fall could yield a dangerously low count. One theoretic possibility is that the local thrombogenesis may also result in biochemical byproducts that

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could contribute to the unexplained (negative blood cultures) vasodilated state often observed in patients with adult respiratory distress syndrome (ARDS), trauma, and multiple organ system failure. Other Foreign Surfaces

Thrombocytopenia has been reported as a rare complication of intraaortic balloon counterpulsation. Presumably, this is the result of platelet aggregation to the foreign surface of the balloon. Thrombocytopenia may result from platelet interactions with the foreign surfaces of dialysis membranes. Early studies showed retention of platelets on the dialysis membranes as well as the formation of platelet-fibrin thrombi despite anticoagulation. 33 Platelet counts decrease during the first few hours of dialysis but recover somewhat as dialysis continues. Chronic use of certain dialysis filters may lead to baseline low platelet counts. The mechanism responsible for platelet adhesiveness and retention in the dialysis membranes is activation of complement via the alternate pathway. 34 This also leads to platelet activation and aggregation outside of the dialysis circuit. Certain membranes initiate more complement activation and hence result in greater effects on circulating platelets. Cuprophane membranes have been shown to produce the most intense activation of complement while noncuprophane membranes, such as polymethylmethacrylate or polyacrylonitrile, produce minimal or clinically insignificant effects.34 Cardiac Valves and Prostheses

Patients with abnormal cardiac valves or surfaces and those with valvular or arterial prostheses have documented abnormalities in platelet lifespan. Jacobson et al reported a high incidence of increased immature platelet counts as well as thrombocytopenia in patients with isolated aortic valvular stenosis or hypertrophic cardiomyopathy. 35 However, they were unable to show a clear correlation between peripheral platelet destruction and the hemodynamic variables. Steele et al studied patients with rheumatic heart disease and found platelet survival to be shortened in the presence of mitral but not aortic valvular disease. 36 Thrombocytopenia did not occur in these patients. The exact cause of platelet destruction was not determined, but

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exposure to an abnormal valvular or atria1 wall was a suggested etiology. Direct proof of platelet consumption following interaction with prosthetic heart valves was demonstrated by Harker and Slichter, who found a direct correlation between the degree of consumption and the surface area of the prosthetic valve.37 This is less of a problem with the prosthetic valves in use today. Similarly, platelet survival is found to be diminished in the presence of arterial prostheses.38 Thrombocytopenia rarely develops in these cases. Burns

The occurrence of thrombocytopenia in thermally injured patients is commonly observed. Characteristically, there is an early drop in platelet count, which occurs within a few hours and persists for several days.3g,40Gehrke et al’s initial observations showed a drop in platelet count to 64% of baseline in surviving patients and to 50% of baseline in those patients who later succumbed to their thermal injury.41 The degree of drop in platelet count has been generally correlated with the severity of the burn. This decrease in circulating platelets is reproducible in animal models and has been shown to be the result of decreased platelet survival and burn wound sequestration.42 There is a return of platelet counts to normal and a subsequent thrombocytosis that is usually present 1 week following the injury. An additional mechanism of platelet destruction is the initiation of DIC by intravascular contamination with Hageman factor in the burned tissues.43 Thrombocytopenia persisting later into the course of the burn has been linked to pseudomonal sepsis.44Ineffective thrombopoiesis may represent another contributing factor to thrombocytopenia in burns. Persistent thrombocytopenia may be a prognosticator of poor outcome.45 Respiratory

Failure

Bone et al found that 19 of 30 study patients with ARDS developed thrombocytopenia.46 In seven patients, the low platelet count was attributed to disseminated intravascular coagulation. The remaining 12 patients had platelet counts reduced by at least 50% of initial values without evidence of DIC. Thrombocytopenia was seen

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frequently in a review of ARDS patients by Hill et a1.47 Platelet counts were less than lOO,OOO/ mm3 in 16 of 23 patients. Of these, four had counts less than 25,000/mm3 and four had counts between 25 and 50,000/mm3. The mortality rate was twice as high in those patients with thrombocytopenia as in those with normal platelet counts. Overt evidence of DIC was found in only three of these patients. A prolongation of prothrombin time or elevated fibrin degradation products made a contribution of DIC to the observed thrombocytopenia likely in half of the remaining patients. In another study, researchers from Colorado examined coagulation and fibrinolysis in 14 patients after the onset of ARDS.48 These patients were compared to 12 critically ill patients who were at risk for ARDS but did not develop the syndrome. There was no significant difference in platelet count between these two groups over a 60-hour period of observation. Both groups developed significant decreases in platelet count. The only difference in coagulation between groups was an increased fibrin/fibrin degradation product and D-antigen in the ARDS group. Deranged hemostasis is commonly observed in acute respiratory failure. Whether the observed coagulopathies are the result of the underlying abnormalities leading to ARDS or whether the resulting ARDS initiates coagulopathy is not known. There is evidence suggesting overt DIC or at least compensated intravascular coagulation in up to three quarters of ARDS patients. 49 The role of platelets in ARDS is the subject of a recent review article.50 Schneider et al studied platelet number and turnover in 15 patients with severe acute respiratory failure.51 Ten patients developed platelet counts less than 100,000/mm3. Platelet survival was reduced by approximately two thirds in all patients, and platelet sequestration was demonstrated in the lungs as well as the liver and spleen. Animal studies documented the pulmonary sequestration of platelets in experimental ARDS. The developing thrombocytopenia paralleled the onset of hypoxia. A human study also demonstrated pulmonary sequestration of platelets in patients with respiratory failure, but could not directly relate the observed thrombocytopenia with the measured loss of platelets into the lungs. 52Clearly, thrombocytopenia is common in ARDS. What remains unclear, however, are the

BOGDONOFF

ET AL

site and mechanism of destruction of the platelets and the pathophysiologic role of the platelet. Fat Embolism Fat embolism syndrome is a clinical syndrome that occurs 1 to 4 days following traumatic injury. Laboratory characteristics often include thrombocytopenia. This syndrome occurs almost exclusively in trauma. It is difficult to separate the concomitant variables of tissue injury and massive transfusion as possible contributors to the observed thrombocytopenia. Some investigators have found evidence of DIC in these patients and feel this is responsible for the thrombocytopenia as well as the pulmonary and cerebral effects.53’54 Virtually all series show the onset of thrombocytopenia to coincide with the onset of hypoxia. 55 Thrombocytopenia may result from consumption of platelets in the injured lung or may lead to lung injury by adhering to fat microglobules trapped in the lungs.56 The observed petechial rash is not solely due to thrombocytopenia but rather is likely the result of capillary endothelial damage secondary to embolic debris.” Platelet counts in fat embolism syndrome may drop below 100,000/mm3. Treatment is supportive including platelet transfusions with bleeding and/or platelet counts less than 50,000/mm3. The use of corticosteroids has been proposed but has not been universally accepted. Infections Thrombocytopenia often occurs in the face of systemic infections. It has been reported with viral, bacterial, fungal, rickettsial, and protozoa1 infections. The platelet is usually affected early in the course of septicemia.58 It has long been recognized that thrombocytopenia may be an early warning sign of sepsis.59 The incidence of thrombocytopenia has been reported to vary between 32% and 100% of patients with known septicemia. 6o The true incidence of thrombocytopenia associated with bacterial infections is difficult to quantitate. Many studies are not prospective and most studies do not separate patients on the basis of infectious agent or type of infection. Riedler et al studied septicemic patients prospectively. Thrombocytopenia was more common (80%) and occurred earlier in gramnegative septicemic patients than in those with gram-positive septicemia (65%).5s One prospec-

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tive study of surgical patients with peritonitis revealed an incidence of thrombocytopenia of 85% with the nadir in platelet count occurring 4.3 +- 2 days after surgery.6’ There are many explanations for the thrombocytopenia seen with infections. There is usually an element of increased platelet destruction, but there is some evidence for suppression of marrow thrombopoiesis as well. In an animal study of pseudomonal burn wound sepsis, Newsome and Eurenius documented selective suppression of the granulopoietic and thrombopoietic marrow components.44 Human documentation of this phenomenon is lacking for bacterial infections but has been suspected as contributing to thrombocytopenia in persistent sepsis. Viruses, on the other hand, are much more likely to directly affect the megakaryocyte. As previously mentioned, marrow suppression can occur secondary to viral hepatitis and this has also been seen with influenza and parvovirus infection. Certain viruses may directly damage the megakaryocyte, including those causing measles, varicella, cytomegalovirus syndrome, infectious mononucleosis, dengue, and Thai hemorrhagic fever. The most common mechanisms of increased destruction of platelets during bacterial infections involves consumption, usually during DIC. There are several mechanisms through which bacterial infection may initiate DIC. In fact, bacterial septicemia is the most frequent cause of DIC and was found in almost two thirds of the patients in the series reviewed by Wilson et a16’ Both gram-negative and gram-positive organisms may induce DIC. The most commonly implicated organisms are Neisseria meningitidis, Escherichia coli, Pseudomonas aerogenosa, and Klebsiella pneumoniae. Neame et al examined patients with septicemia from a variety of infectious causes and looked for evidence of DIC accompanying thrombocytopenia.62 Eighty-eight percent of gram-negative septicemic patients had thrombocytopenia compared with 5% in the grampositive septicemic group. Of those patients with platelet counts below 50,000/mm3, DIC was present in 11 of 12 cases. There was little evidence for intravascular coagulation, however, in eight of 11 patients with platelet counts between 50,000/mm3 and 150,000/mm3 or in seven of eight patients with normal platelet counts. Other groups have found high incidences

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of thrombocytopenia in bacterial infections without the concomitant presence of documented DIC.58,63,64 Other mechanisms for platelet destruction must be involved as well. Bacteria can directly interact with platelets, leading to aggregation and subsequent clearance from the circulation. Many bacterial strains are capable of initiating this aggregation, with Staphylococcus aureus being the most powerful.65 Bacterial and platelet clearance from the circulation is facilitated by these aggregates.66 Gramnegative bacterial endotoxin alone is capable of aggregating platelets by selective activation following stimulation via a specific platelet membrane receptor.67 An immune mechanism is likely involved in the platelet destruction seen during infection. Kelton et al examined 46 patients with septicemia, 21 of which became thrombocytopenic.‘j* Platelet-associated IgG was elevated in eight of 11 thrombocytopenic patients with gram-negative sepsis in contrast to one of 20 patients with gram-negative septicemia and normal platelet counts. Similarly, elevated platelet IgG was found in eight of 10 thrombocytopenic patients with gram-positive septicemia compared with none in their septicemic controls with normal platelet counts. The high association of IgG binding to the observed thrombocytopenia certainly suggests a causal role. Evidence for DIC was not present in most cases and, when found, was felt to only partially contribute to the decline in platelet counts. Possible mechanisms include nonspecific binding of IgG to bacterial fragments adherent to platelets (eg, endotoxin) or the binding of bacterial fragments to IgG, thus forming immune complexes that subsequently bind to platelets at the platelet F, receptor.60 Yet another contribution to platelet destruction is that caused by adhesion and aggregation of platelets to endothelium damaged by infectious agents or their products. In vitro studies clearly document endotoxin-induced damage to endothelial cells.69 Skin biopsies from patients with N meningitidis infections have shown endothelial necrosis.” How much this phenomenon contributes to thrombocytopenia and whether it does so by platelet trapping or by activation of DIC is unknown. Viral-induced thrombocytopenia is not unusual. Viral diseases are occasionally responsible

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for admission to critical care units and in these situations, thrombocytopenia is probably at least as common as it is in severe bacterial infections. Disseminated intravascular coagulation is frequently responsible, as is the mechanism of decreased platelet production previously discussed. Additional mechanisms include direct platelet-virus interactions which lead to platelet aggregation” and immune-mediated platelet destruction similar to that described for bacterial infections. Fat Emulsions

Early work with parenteral fat emulsions led to profound effects on platelet number and function with associated clinical bleeding. These early formulations were toxic and have been replaced with safe formulations that have been in use since the 1970s. Thrombocytopenia has been reported as a complication of Intralipid (Kabi Vitrum Inc, Clayton, NC) in a neonate, but is not a problem in the adult population.72v73 A series of 180 pediatric patients found that thrombocytopenia could not be attributed to Intralipid. Intralipid was even administered to 10 patients thrombocytopenic from other causes, and platelet counts rose in all cases.74 One review article noted that platelet counts are “minimally affected” by Intralipid.75 One case report that attributed a bleeding disorder to a “fat overload syndrome” in a 7-year-old child due to very large doses of Intralipid (>4 g/kg/d) noted that platelet numbers remained normal during the period of bleeding diathesis.76 A French group has attributed thrombocytopenia in children to long-term (>3 months) administration of Intralipid. The thrombocytopenia resolved when Intralipid was withheld and decreased platelet survival was demonstrated with labeling studies.” The group attributed this observation to hyperactivation of the reticuloendothelial system induced by the chronic administration of intravenous Intralipid. There is no data that adults receiving Intralipid in the usual doses (~60% caloric intake) can develop thrombocytopenia as a result. Drug-Related

Destruction

Drug-induced platelet destruction is a serious side effect of a wide variety of drugs. It is included in the differential diagnosis of thrombocytopenia in critically ill patients, many of whom

ET AL

are subjected to polypharmaceutical interventions. There are three basic groups of druginduced platelet destruction.‘* One involves direct toxic platelet destruction that has been shown to result from the drug ristocetin, initially used as an antibiotic. 79The other groups involve immune-mediated or the more rare autoimmunemediated destruction. The general subject has been well reviewed and this section will concentrate on aspects relevant to critical care medicine.78~80 The exact mechanisms of drug-induced immune thrombocytopenia are unknown. IgG has been implicated as the immunoglobulin that mediates almost all cases of drug-induced destruction.*’ Other causes of platelet-associated IgG do exist, so this finding alone cannot be used to prove the existence of a drug-related etiology. There is a body of evidence which suggests that a platelet membrane glycoprotein, possibly 1b, participates in the processE2 The exact nature of the binding of IgG to the platelet surface is uncertain. One theory suggests that antibody attaches to a drug-platelet membrane complex. Another implicates drug-dependent antibody that binds to drug alone or to a drug-protein carrier, forming an immune complex. This immune complex then binds to platelets through the Fc surface receptor. Most experimental evidence sides with the latter theory as that predominantly involved in most cases of drug-induced thrombocytopenia. Phagocytosis or complement-mediated lysis of the affected platelets then completes the final stage of the destructive process. More than 50 different medications have been shown to lead to immunologic destruction of platelets (Table 2). The majority of these drugs have been implicated in fewer than a dozen cases each. Five specific drugs or drug classes have caused 60% of all cases (quinidine, quinine, gold salts, sulfonamide or sulfonamide derivatives, and heparin). Quinidine and its stereoisomer quinine are the most common culprits and have been extensively studied. The usual clinical presentation of a patient with drug-induced thrombocytopenia is characterized by the sudden onset of petechiae, ecchymoses, and mucosal bleeding. In the ICU setting, presentation is more likely to be with falling platelet counts rather than clinical signs. Invariably, this follows reexposure to a drug, but the

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Table 2. Thrombocytopenia

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Selected Drugs Associated in the Intensive Care

Drugs that decrease

platelet

production

agents

(alkylators,

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With Unit Setting

Chlorothiazide Alcohol Chemotherapeutic Chloramphenicol

antimetabolites,

etc)

Drugs that increase platelet destruction Direct toxic effect-ristocetin Immune-mediated Antibiotics

destruction

Penicillins Cephalosporins Sulfonamides Rifampicin Analgesics Aspirin Acetaminophen Cardiac medications Digoxin Quinidine Digitoxin Neuropsychiatric drugs Diphenylhydantoin Desipramine Diazepam Phenothiazines Antihypertensives Alpha methyldopa Thiazides Furosemide Miscellaneous Quinine Heparin Gold salts

initial exposure may have been hours earlier or a gradual exposure over months or years. Onset is usually within 3 to 24 hours following reexposure, and this temporal relationship may help to implicate a particular drug as the etiologic agent. Definitive documentation of a drug etiology is difficult and requires the satisfaction of strict criteria. Hackett et al have suggested four criteria to define drug-induced immune thrombocytopenia.78 A consistent history is the first criterion and is one characterized by onset of thrombocytopenia during the use of the drug and resolution following its discontinuation. Other causes of thrombocytopenia must be absent or ruled out. This condition is extremely difficult to satisfy in the ICU setting. The ultimate diagnostic criterion is the recurrence of thrombocytopenia after a repeat administration of the drug. This, of course, does not help with the differential diagnosis

during the acute presentation. Additionally, readministration of the drug may lead to dangerously low platelet counts with clinical bleeding despite the use of a very small test dose. This often precludes the use of an in vivo test. In vitro tests are required if in vivo testing is deemed too dangerous to try. A variety of in vitro tests have been described and include the demonstration of platelet-associated IgG and studies of inhibitory effects on clot retraction, platelet migration, and platelet aggregation or agglutination. Complement fixation, platelet lysis, or serotonin release are other endpoints of in vitro tests. There are many causes of both false-positive and falsenegative tests, which may confuse the interpretation of laboratory studies.78 Quinidineand quinine-induced immune thrombocytopenia is well documented and clearly fits all of the required diagnostic criteria for a drug-related etiology.78*8’V82Platelet counts commonly drop to 10,000/mm3 and bleeding is not unusual. One may find increased numbers of megakaryocytes on marrow aspirates and the presence of large, young thrombocytes (megathrombocytes) on peripheral blood smears. Occasionally, the drug-related antibody may react with marrow megakaryocytes and temporarily curtail platelet production. Recovery of platelet count occurs over 4 to 14 days after withdrawal of the drug and parallels the disappearance of the platelet-associated IgG. The patient should be supported with platelet transfusions as clinically indicated during this time period. Corticosteroids have not been proven to be helpful, but may nevertheless be a prudent addition to management when a drug-induced etiology is unconfirmed. Sulfonamide antibiotics are commonly used drugs. They have proven myelosuppressive properties but have also been implicated in druginduced thrombocytopenia. Documentation of an immune-mediated mechanism has been shown with sulfisoxazole. 83*84The combination of trimethoprim and sulfamethoxazole may also be responsible. Interestingly, there is one report of a case with only sulfmethoxazole-dependent antibody” and another with only trimethoprimdependent antibody.86 Definitive documentation of drug-induced immune thrombocytopenia, including the use of in vitro and in vivo tests, exists for digitoxin8’ and

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digoxin.** Presumptive evidence without formal in vivo testing exists for several commonly used drugs including diphenylhydantoins3 diazepam,83 desipramine, and even aspirin.” An interesting report of immune thrombocytopenia in a patient taking analgesics demonstrated antibody dependent on a metabolite of acetaminophen rather than the parent drug itself.g0 H2 receptor antagonists have been associated with thrombocytopenia. Metiamide, the first widely used agent, was withdrawn due to the agranulocytosis that resulted from marrow suppression. Granulocytopenia, as well as thrombocytopenia, has been reported following the use of cimetidine. Direct marrow suppression is certainly a possibility, although cimetidine-dependent antibodies were also found.g1 Glotzbach reported a case of cimetidine-induced thrombocytopenia verified by accidental rechallenge with the drug. g2 Drug-depen d e nt antibodies were not identified in this case, but marrow examination showed normal megakaryocytes consistent with increased peripheral destruction of platelets. The estimated incidence of thrombocytopenia with cimetidine use is three per million. Spychal and Wickham presented a case of ranitidine-associated thrombocytopenia with elevated plateletassociated antibodies as well as maturation arrest of marrow megakaryocytes.g3 The platelet count and platelet-associated antibody level returned to normal levels with discontinuation of the drug. Reexposure was not attempted. Many antibiotics have also been reported to cause thrombocytopenia. These include methicillin,g4 penicillin,*l ampicillin,” cephalexin,” gentamicin,gs cephalothing6 and rifampicin.g7 Beta lactam drugs are also known to coat the surfaces of platelets and interfere with their function. In rare cases, antibody attacks platelets coated with these drugs, leading to their destruction. Such antibodies can be inhibited in vitro with excess drug.g6 Thrombocytopenia has resulted from methyldopa,” a drug known to cause autoimmune hemolytic anemia. Such a mechanism has also been proposed to explain thrombocytopenia associated with methyldopa that fails to recover rapidly following cessation of drug administration. Another drug-related thrombocytopenia that is slow to resolve after stopping the drug is that due to oral gold salts. ” Two percent of patients

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treated with gold salts develop immune thrombocytopenia with increased platelet-associated IgG.81*gg The mechanism involved in the prolonged recovery here is likely slow excretion, however, and treatment with dimercaprol may aid therapy by binding any remaining drug. Amrinone, a commonly used phosphodiesterase inhibitor, has been associated with thrombocytopenia on a frequent basis. Chronic oral use leads to diminished platelet counts in up to one half of patients, depending on the size of the administered dose. Usual doses lead to platelet counts below 100,000/mm3 in up to 16% of patients.lm Accelerated peripheral loss of platelets is responsible, but the cause of the destruction remains unclear. lo1 The rapid onset despite a lack of previous exposure to the agent and the absence of an amnestic response argue against an immune etiology. The dose-relatedness of the drop in platelet number may suggest direct nonimmunologic damage. Heparin

Heparin-associated thrombocytopenia (HAT) is a relatively common occurrence, especially when one considers that the vast majority of critically ill patients are exposed to this drug. Heparin is used in the prevention of deep venous thrombosis, for the routine flushing of indwelling hemodynamic monitoring lines and intravascular catheters, to prevent blood coagulation during intravascular diagnostic and cardiovascular surgical procedures, and, at times, as a therapeutic modality in syndromes of arterial or venous thrombosis. Heparin is not a pure compound, but rather is a mixture of complex mucopolysaccharides. It is available from various sources, including bovine lung and porcine intestinal mucosa. Thrombocytopenia has been reported following low-dose administration and high-dose therapy. Estimates of its incidence have ranged from 1% to 32% in prospective studies.102v’03It is likely that the incidence is significantly lower when low-dose subcutaneous therapy is used. There are three patterns of thrombocytopenia that have been described, and differences in definition represent a portion of the wide discrepancy in reported incidence. 78~102 An early, transient, and harmless fall in platelet count to 100,000/mm3 to 1 50,000/mm3 is one response. This occurs within 1 to 5 days and may actually resolve in the face of

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continued heparin administration. The second and more serious presentation is less common and occurs between 5 and 14 days after initial drug exposure. It is characterized by potentially severe drops in platelet count with the potential for clinical bleeding. The third presentation is a syndrome of arterial thrombosis that accompanies the latter, more severe, thrombocytopenia. It carries a 50% incidence of mortality or major morbidity, but fortunately is quite rare. The mechanisms responsible for these responses are not entirely clear. The early slight drop in platelet count likely results from nonimmunogenic mechanisms. Heparin is capable of a variety of direct interactions with platelets such as in vitro platelet aggregation,‘m in vitro inhibition of platelet prostacyclin activity,“’ and the acute production of thrombocytopenia following rapid intravenous administration.106 Perhaps certain heparin subfractions or impurities from its preparation are responsible for these effects. The clinical relevance of these phenomena is unknown and some investigators have even attributed them to laboratory artifacts. The more severe thrombocytopenia is most likely an immune-mediated drug thrombocytopenia similar to that caused by quinidine. The time course is usually consistent with that of an antibody-mediated process. High levels of platelet-associated IgG are found and these disappear with the resolution of the thrombocytopenia.“’ Complement-mediated platelet destruction initiated by IgG has been demonstrated in patients with HAT.“’ Antibody has been shown to specifically bind to platelets in the presence of heparin due either to the antigenic nature of heparinplatelet complexes or to conformational changes in the antigenic sites induced by heparin.“’ The sera of patients who have recovered from HAT do not always test positively in vitro as do sera from patients recovering from other druginduced immune thrombocytopenias; this casts some doubt on a clear-cut immune-mediated mechanism.‘07*110 Recent studies seem to suggest that the explanation is indeed a heparin-IgG interaction that results in an immune complex that subsequently binds to platelet Fc receptors and triggers platelet activation and release. The laboratory proof has been elusive due to weak in vitro interactions and disruption of the immune complexes by large concentrations of heparin.“’

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The incidence of this problem seems to be decreasing. This may be due to improvements in preparation with the elimination of impurities, proposed to contribute to thrombocytopenia directly or by activation of DIC, which has been found only in early reported series. Recent series show the incidence of serious HAT to be between 0% and 6%.112*1’3The controversy over the relationship between thrombocytopenia and the source of the heparin is also incompletely resolved. Two prospective series have reported statistically significant differences, with bovine sources being more commonly implicated than porcine-derived substances.‘14v1’sOther series fail to show such a difference.1’3T116 Beef heparin has been implicated most often in individual case reports of the most severe thrombocytopenias with associated complications. Prospective studies invariably show a low incidence when porcine intestinal mucosa heparin is used. Many different preparations have been used in all of the varied series, which perhaps invalidates the comparisons. The definition and mechanism of thrombocytopenia has also varied between the various series. Nevertheless, when the data from many series is combined, there is a higher incidence of thrombocytopenia (mild or severe) with bovine lung heparin.‘02~103~“2 Diagnosis of HAT can be very difficult. Without a definitive laboratory test, this disorder represents a diagnosis of exclusion. Many patients have concomitant conditions that themselves lead to thrombocytopenia. The search for an accurate diagnostic test for this condition continues. Measurement of platelet-associated IgG is not helpful as it may be elevated in other thrombocytopenic situations, as previously described (other drug-associated immune thrombocytopenia, septicemia). Most attention has been directed toward tests for heparin-dependent, platelet-aggregating factors. Such heparin-dependent aggregation is found in vitro in the absence of clinical thrombocytopenia and may be absent in some cases of known HAT.‘04*1’2,“7 The lack of a clearly positive endpoint for these in vitro tests leads to suboptimal sensitivity and specificity. Kelton’s group has recently developed an in vitro test with high specificity and sensitivity. Instead of measuring platelet aggregation, they measured 14C-labeled serotonin release from platelets in vitro when mixed with patient’s sera

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and heparin at various concentrations.“’ Further studies will be required to see if the diagnostic accuracy of these more refined methods will hold up over time, although a recently published review suggests that the techniques are valid.‘03 The syndrome of HAT with thrombosis is a much more serious clinical entity.“’ There are many case reports, but only three cases have occurred in prospective series, which suggests that its incidence is very low. Warkentin and Kelton report a frequency of three in 1,629 patients (0.18%) from the combined series they reviewed.lo3 All cases have shown that the thrombocytopenia was present at the time of the thrombotic complications. Thrombosis has not been reported with other syndromes of druginduced thrombocytopenia, but rather appears to be unique to heparin. Arterial thrombotic complications prevail, with the ileo-femoral and distal aortic bifurcation most commonly involved. There is a high incidence of amputations (21%) as well as cerebral infarction, myocardial infarction, skin necrosis, and even death (29%). The etiology is unknown, but is likely related to the mechanisms responsible for the drop in platelet count. Platelet-aggregating factors are found in serum but, as previously discussed, this is not uncommon and is also found in patients without this syndrome. Platelet serotonin release and thromboxane synthesis have been shown to be caused by a serum factor; this may lead to the severe platelet aggregation that causes the thrombotic complications. 12’ Recent experimental evidence suggests another possible explanation for the observed arterial thrombosis. Cines et al demonstrated immune injury to endothelial cells in patients with HAT.“’ Binding of immunoglobulin to endothelial cells was undetectable when heparin therapy was terminated and reappeared in one patient who was reexposed to the drug. Such immune injury to vascular endothelium would serve to amplify the effect of the concomitant platelet injury and aggregation. The management of patients with HAT can be very difficult. If thrombocytopenia is isolated and cessation of heparin therapy is deemed to represent a significant risk to the patient, heparin may be continued while oral anticoagulants are started. Frequent platelet counts are necessary and the patient remains at risk for a thrombotic or hemorrhagic event. Clearly, those patients with

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severe thrombocytopenia and bleeding require immediate cessation of heparin, as do those with HAT and thrombosis. The latter probably would also benefit from aspirin therapy in an attempt to diminish platelet aggregation and subsequent thrombotic complications. Arterial occlusions demand surgical intervention when appropriate and technically feasible. Fibrinolytic agents have been used on occasion when surgical intervention was not possible. Those patients with mild to moderate thrombocytopenia are even more difficult to manage. Some of these will resolve spontaneously despite maintenance of heparin administration. Other treatment modalities are often possible, such as oral anticoagulant therapy or caval interruption/ filter placement in the case of venous thrombosis and pulmonary emboli. Heparin can be easily eliminated from flushes of intravenous catheters by the use of a continuous infusion of fluids. Monitoring lines will usually not thrombose despite the removal of heparin from the continuous flushing devices. Prophylactic use of heparin would not be indicated in the face of thrombocytopenia. New anticoagulants are in use in other countries, but are not yet available in the United States. New preparations of low molecular weight heparin are under development. They appear to be free of in vitro platelet-aggregating effects and have been useful in some patients with HAT. Unfortunately, outcomes were not universally successful.lo3 Further clinical work is required before recommendations can be made for the use of these new preparations. Perhaps all ICU patients receiving heparin should have their platelet counts checked frequently.‘22 This may not be cost-effective’23 and may not prevent the serious complication of HAT with thrombosis, which presents concurrently with the drop in platelet count. One recent series has reported a reduction in both morbidity and mortality of HAT with and without thrombosis.124 These investigators claim that this was due to their practice of frequent platelet counts and early aggressive withdrawal of heparin. Perhaps this represents an improvement in care, but it may also represent a comparison of prospectively identified patients not destined for serious complications with retrospectively identified patients that did suffer complications. The decision to discontinue heparin must be made on

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the basis of the severity of thrombocytopenia, the degree of clinical bleeding tendency, and the likelihood of other factors contributing to the depressed platelet count.

Posttransfusion Posttransfusion purpura (PTP) is a rare disorder characterized as an alloimmune thrombocytopenia. It occurs 7 to 10 days following transfusion of whole blood and is characterized by the rapid onset of purpura and moderate to severe bleeding. Thrombocytopenia is profound, with platelet counts usually below 10,000/mm3.125~126 Megakaryocytes are normal or increased in number. The process is initiated by the transfusion of platelets expressing a surface antigen that is absent on the recipient’s platelets. An amnestic alloantibody response results from exposure to this foreign antigen and leads to thrombocytopenia. Accordingly, the majority of reported cases have been in women (95%) with previous pregnancy or in those previously transfused. Most afflicted patients do not express the platelet antigen Al (PI*‘), found in 99% of the population, and form alloantibodies against it following exposure. Rare cases have been reported in Pl*‘-positive patients, suggesting that other platelet surface antigens may be involved.127 The pathophysiology remains unexplained. Perhaps the offending platelet antigen is eluted from donor platelets in stored blood and attaches to the native platelets following transfusion, leading to their destruction.‘28 In theory, one in 50 transfused patients (those who are Pl*‘-negative) should be at risk for immunization from transfusion with incompatible (PI*‘-positive) platelets. However, this disorder is rare. The course is one of gradual improvement over 1 to 2 months if left untreated. Treatment for PTP involves exchange transfusion or plasmapheresis to eliminate the titer of alloantibodies.‘29,‘30 Steroids have yielded occasional successes.t3’ Platelet transfusions from PI*‘negative donors do not necessarily increase platelet count. 13’ Very serious transfusion reactions may result. High-dose immunoglobulin may be effective if plasmapheresis has not been successful or is unavailable.‘33,134 Platelet counts usually rise rapidly over 1 to 4 days following aggressive plasmapheresis or immunoglobulin therapy. Another cause of posttransfusion thrombocy-

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topenia is the passive transfusion of a plateletspecific alloantibody. Blood from a donor who has formed antibodies against PI*’ or another platelet antigen may lead to platelet destruction in the recipient. Fortunately, this is rare, with a documented case report not having appeared until very recently.‘35

Alloimmunization The alloimmune-mediated platelet destruction responsible for PTP is rare. Alloimmunization, however, is not rare, and commonly occurs following transfusion of platelets. While not a primary cause of thrombocytopenia, this situation may lead to destruction of transfused platelets, which then results in a refractory thrombocytopenic condition. The likelihood of developing alloantibodies is between 35% and 100%. Some patients never develop antibodies despite extensive exposure to exogenous platelets. The antigens responsible for alloimmunization by platelet transfusion are either platelet-specific or are associated with other cells. Eight platelet-specific antigens have been identified and have been categorized into five systems. ‘36 The platelet antigen Al (implicated in PTP) is one example of these antigens specific to the platelet membrane. No documented cases of alloimmunization against these antigens have been presented to explain refractoriness to platelet transfusions,‘37 although it is likely that it contributes to the problem at times. ‘36 The major histocompatibility antigens are found on platelets as well as leukocytes. HLA-A and HLA-B antigens have been found, although the HLA-C and HLAD/DR products have not been identified on platelets. These major antigens are most commonly responsible for the alloimmunization that leads clinically to the refractory thrombocytopenic condition. ABO blood group antigens have been found on platelets, although probably via a mechanism of passive adsorption from serum rather than by primary expression.t3* Transfusion of ABO-incompatible platelets likely results in immediate destruction of those platelets coated with the foreign ABO antigen, while normal survival times characterize the fate of the unaffected platelets that did not adsorb ABO antigens.‘39 Diagnosis of a refractory state can be made by measuring the increment in platelet count 1 to 4

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hours following platelet transfusion. One must remember that other causes of thrombocytopenia may be present and lead to accelerated destruction of these transfused platelets (eg, sepsis or drug-associated antibodies). Since in most cases the alloantibodies are directed against HLA antigens, one may try HLA-matched platelets. 137~140 Family members have a higher likelihood of a good antigenic match.141 It is often difficult to find matches, and serologically related antigens may need to be substituted.13’ Despite HLA matching, about 20% of these transfusions will still fail to raise platelet counts. It is likely that platelet-specific alloantibodies are responsible for many of these cases, although unrecognized HLA antigenic incompatibilities could also be responsible. Sophisticated platelet crossmatching techniques represent the next step in management of these difficult cases.142*‘43 Cardiopulmonary

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Interestingly, this significant advantage of membrane oxygenators over bubble oxygenators is lost by the second postoperative day, by which time platelet counts are lower and nearly equal in both groups. 14*Platelet counts normally return to baseline over the next few days.144*147A final factor contributing to the decrease in platelet count post-bypass involves the use of protamine to neutralize the anticoagulant heparin. Protamine leads to a further drop of 20% to 30% in platelet count, which may be due to further platelet sequestration in the liver and lung. 146~148~150~151 The extent of the fall in platelet count does not justify prophylactic platelet replacement. ls2Clinically, thrombocytopenia has not been proven to be an important cause of bleeding following cardiopulmonary bypass. The deficit in hemostasis is in platelet function and it is for this reason that platelet transfusion is often justified.

Bypass

Cardiopulmonary bypass leads to a fall in platelet count up to 50% to 60%.144-‘48 Many mechanisms are responsible for the observed thrombocytopenia. Dilutional factors contribute to, but do not explain, the precipitous drop seen immediately after institution of bypass. Hypothermia is known to cause sequestration of platelets in the liver and spleen; however, this phenomenon is also observed in cases done under normothermic conditions. Contact of platelets with the artificial surfaces of the bypass circuits, particularly the oxygenators, has been shown to lead to platelet activation with release of cy-granule contents but not dense granule contents.149 This activation leads to sequestration during bypass. There is additional sequestration of platelets in the oxygenator itself equalling the number sequestered in the liver.146 Some of the circulating platelets are destroyed on the surface interfaces of the bypass circuit. Consumption of platelets in surgically traumatized tissue also contributes to the slow decline in platelet count during the bypass run, as do the use of cardiotomy suction, length of bypass time, and the type of oxygenator. Bypass times exceeding 60 minutes are associated with the lowest postoperative platelet counts, Membrane oxygenators cause significantly less platelet destruction and activation with resulting higher postoperative counts.148

MANAGEMENT

The management of the thrombocytopenic ICU patient is difficult because there are so many potential causes for the problem and because withdraw1 of the precipitating factors (eg, drugs) may be complicated and dangerous. After spurious thrombocytopenia is ruled out, correctable causes must be approached. If a PA catheter is in place, its usefulness (v a CVP line) should be reassessed. The possibility of infection should be investigated and treated if warranted. Adequate oxygenation at an acceptable Fro, should be reaffirmed in view of the association with ARDS. The patient’s medications are carefully reviewed with regard to the most likely contributing causes. Almost all patients receive heparin, as it is contained in the high-pressure flush devices used in arterial, central venous, and PA catheters. If possible, drugs should be stopped in an orderly fashion to identify the offending agent, but severe thrombocytopenia may at times justify discontinuation of all drugs not immediately essential for survival. Antacids or sucralfate can be substituted for H2-antagonists, phenobarbital for diphenylhydantoin, and ethacrynic acid or mannitol for furosemide. Non-beta lactam antibiotics probably suitable for substitution include vancomycin, aztreonam, and imipenem. An infectious disease consultation may be help-

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ful in the setting of a serious infection and possible antibiotic-related thrombocytopenia. If heparin must be discontinued, the need for arterial and central lines should be reassessed as they will need frequent flushing and may be more prone to thrombose in any case without constant heparinized flush solutions. Folate should be administered empirically (5 mg IV, then 1 mg IV every day). Severe thrombocytopenia ( t20,000/mm3) in the absence of trauma or surgery) or bleeding related to a reduction in platelet count will require platelet transfusions (1 U/10 kg). A 1-hour posttransfusion platelet count should be obtained. Disseminated intravascular coagulation-related thrombocytopenia should be approached with an initial attempt to treat the

triggering etiology. Disseminated intravascular coagulation secondary to oncologic sources such as acute promyelocytic leukemia or prostatic carcinoma may respond to heparin therapy (which reduces the intravascular coagulation that is consuming platelets). Disseminated intravascular coagulation that is causing primarily thrombotic manifestations may also justify a trial of heparin therapy. The lifespan of administered platelets may be quite short in disorders of peripheral platelet destruction. Severe and/or undiagnosed thrombocytopenia is an indication for hematologic consultation to assist with diagnosis and treatment. Further evaluation may consist of bone marrow examination and the immunologic studies discussed in this report.

REFERENCES I. Kjeldsberg CR, Hershgold EJ: Spurious thrombocytopenia. JAMA 227628-630, 1974 2. Veenhoven WA, Van Der Schans GS, Huiges W, et al: Pseudothrombocytopenia due to agglutinins. Am J Clin Path01 72:1005-1008, 1979 3. Payne BA, Pierre RV: Pseudothrombocytopenia: A laboratory artifact with potentially serious consequences. Mayo Clin Proc 59:123-125, 1984 4. Post RM, Desforges JF: Thrombocytopenia and alcoholism. Ann Intern Med 68:1230-1236, 1968 5. Lindenbaum J, Hargrove RL: Thrombocytopenia in alcoholics. Ann Intern Med 68:526-532, 1968 6. Nordquist P, Cramer G, Bjorntorp P: Thrombocytopenia during chlorthiazide treatment. Lancet 1:271-272, 1959 7. Kutti J, Weinfeld A: The frequency of thrombocytopenia in patients with heart disease treated with oral diuretics. Acta Med Stand 183:245-250, 1968 8. Hagler L, Pastore RA, Bergin JJ: Aplastic anemia following viral hepatitis: Report of two fatal cases and literature review. Medicine 54:139-164, 1975 9. Harker LA, Finch CA: Thrombokinetics in man. J Clin Invest 481963-974, 1969 10. Mant MJ, Connolly T, Gordon PA, et al: Severe thrombocytopenia probably due to acute folic acid deficiency. Crit Care Med 7:297-300, 1979 11. Beard MEJ, Hatipov CS, Hamer JW: Acute onset of folate deficiency in patients under intensive care. Crit Care Med 8:500-503, 1980 12. Easton DJ: Severe thrombocytopenia associated with acute folic acid deficiency and severe hemorrhage in two patients. Can Med Assoc J 130:418-422, 1984 13. Brodsky JB: Toxicity of nitrous oxide, in Eger El (ed): Nitrous Oxide. New York, NY, Elsevier, 1985, pp 259-262 14. Amos RJ, Amess JAL, Hinds CJ, et al: Incidence and pathogenesis of acute megaloblastic bone-marrow change in patients receiving intensive care. Lancet 2:835-839, 1982 15. Aster RH: Pooling of platelets in the spleen: Role in

the pathogenesis of “hypersplenic” thrombocytopenia. J Clin Invest 45:645-657, 1966 16. Waddell WC, Fairley HB, Bigelow WC: Improved management of clinical hypothermia based upon related biochemical studies. Ann Surg 146:542-562, 1957 17. O’Brien H, Amess JAL, Millin DL: Recurrent thrombocytopenia, erythroid hypoplasia and sideroblastic anaemia associated with hypothermia. Br J Haematol 51:451-456, 1982 18. Murphy S, Gardner FH: Platelet preservation: Effects of storage temperature on maintenance of platelet viabilityDeleterious effect of refrigerated storage. N Engl J Med 280:1094-1098, 1969 19. Miller RD, Robbins TO, Tong MJ, et al: Coagulation defects associated with massive blood transfusions. Ann Surg 174:794-801, 1971 20. Dzik WH: Massive transfusion, in Churchill WH, Kurtz SR (eds): Transfusion Medicine. Cambridge, MA, Blackwell, 1988, pp 216-222 21. Reed RL, Heimbach DM, Counts RB, et al: Prophylactic platelet administration during massive transfusion: A prospective, randomized, double-blind clinical study. Ann Surg 203:40-48, 1986 22. Counts RB, Haisch C, Simon TL, et al: Hemostasis in massively transfused trauma patients. Ann Surg 190:9 l-99, 1979 23. Harker LA, Slichter SJ: Platelet and fibrinogen consumption in man. N Engl J Med 287:999-1005, 1972 24. Burstein SA, McMillan RM, Harker LA: Quantitative platelet disorders, in Bloom AL, Thomas DP (eds): Haemostasis and Thrombosis (ed 2). New York, NY, Churchill Livingstone, 1987, p 340 25. Goodnight SH, Kenoyer G, Rapaport SI, et al: Defibrination after brain-tissue destruction: A serious complication of head injury. N Engl J Med 290: 1043- 1047, 1974 26. Gilabert J, Estelles A, Aznar J, et al: Abruptio

202 placentae and disseminated intravascular coagulation. Acta Obstet Gynecol Stand 64:35, 1985 27. Hoar PF, Stone JG, Wicks AE, et al: Thrombogenesis associated with Swan-Ganz catheters. Anesthesiology 48:445447,1978 28. Richman KA, Kim YL, Marshall BE: Thrombocytopenia and altered platelet kinetics associated with prolonged pulmonary-artery catheterization in the dog. Anesthesiology 53:101-105, 1980 29. Kim YL, Richman KA, Marshall BE: Thrombocytopenia associated with Swan-Ganz catheterization in patients. Anesthesiology 55:261-262, 1980 30. Miller JJ, Venus B, Mathru M: Comparison of the sterility of long-term central venous catheterization using single lumen, triple lumen, and pulmonary artery catheters. Crit Care Med 12:634-637,1984 3 1. Rull JRV, Aguirre JL, de la Puerta E, et al: Thrombocytopenia induced by pulmonary artery flotation catheters: A prospective study. Intensive Care Med 10:29-31, 1984 32. Bolooki H: Complications of intra-aortic balloon pump and their treatment, in Bolooki H (ed): Clinical Application of Intra-Aortic Balloon Pump. Mount Kisco, NY, Futura, 1977.p 131 33. Lindsay RM, Prentice CRM, Davidson JF, et al: Haemostatic changes during dialysis associated with thrombus formation on dialysis membranes. Br Med J 4:454-458, 1972 34. Hakim RM, Schafer AI: Hemodialysis-associated platelet activation and thrombocytopenia. Am J Med 78:575580.1985 35. Jacobson RJ, Rath CE, Perloff JK: Intravascular haemolysis and thrombocytopenia in left ventricular outflow obstruction. Br Heart J 35849-854, 1973 36. Steele PP, Weily HS, Davies H, et al: Platelet survival in patients with rheumatic heart disease. N Engl J Med 290537-539, 1974 37. Harker LA, Slichter SJ: Studies of platelet and fibrinogen kinetics in patients with prosthetic heart valves. N Engl J Med 283:1302-1305,197O 38. Harker LA, Slichter SJ, Sauvage LR: Platelet consumption by arterial prostheses: The effects of endothelialization and pharmacologic inhibition of platelet function. Ann Surg 186:594-601, 1977 39. Hergt K: Blood levels of thrombocytes in burned patients: Observations on their behavior in relation to the clinical condition of the patient. J Trauma 12:599-606, 1972 40. Eurenius K, Rossi TD, McEuen DD, et al: Blood coagulation in burn injury. Proc Sot Exp Biol Med 147:878882,1974 41. Gehrke CF, Penner JA, Niederhuber J: Coagulation defects in burned patients. Surg Gynecol Obstet 133:613616,197l 42. Eurenius K, Mortensen RF, Meserol PM, et al: Platelet and megakaryocyte kinetics following thermal injury. J Lab Clin Med 79:247-257,1972 43. Caprini JA, Lipp V, Zuckerman L, et al: Hematologic changes following burns. J Surg Res 22:626-635,1977 44. Newsome TW, Eurenius K: Suppression of granulocyte and platelet production by pseudomonal burn wound infection. Surg Gynecol Obstet 136:375-379, 1973 45. Tian-Min C, Yuan L, De-Quan G, et al: Ultrastruc-

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