(Table 69-3) The platelet count is the result of a balance between the rate at which platelets are produced and the rate at which they are removed from the circulation. Bone marrow normally has a six- to eightfold reserve production capacity for the formed elements released into the blood, which can help to compensate for shortening of the normal platelet life span of about 10 days. Although there is no simple, readily available test for the rate of platelet production corresponding to the reticulocyte count as an indicator of new red blood cell (RBC) production, the rate of platelet production can be estimated roughly from evaluation of Wright-stained peripheral blood smears for young (large, basophilic) platelets and from particle counter estimates of mean platelet volume.
Table 69–3. Thrombocytopenias in the Critically Ill ||Download (.pdf)
Table 69–3. Thrombocytopenias in the Critically Ill
|Mechanism||Selected Specific Causes|
|Underproduction of platelets|
| Bone marrow hypoplasia/aplasia||Drugs and chemicals (cytotoxic chemotherapy, ethanol, benzene, chloramphenicol, thiazides)|
|Infections (viral hepatitis, cytomegalovirus, tuberculosis)|
| Ineffective bone marrow||Myelophthisic (metastatic cancers, tuberculosis)|
|Megaloblastic (folic acid, B12 deficiencies)
|Primary marrow diseases (leukemia, myeloma)|
|Shortened platelet survival|
| Immune thrombocytopenia||Drugs (rifampicin, methicillin, sulfonamides, barbiturates, diphenylhydantoin, quinidine, α-methyldopa, thiazi desfurosemide, gold salts, heparin trimethoprim-sulfamethoxazole)|
|Collagen vascular diseases (systemic lupus erythematosus)|
|Viral infections, including HIV-1|
| Intravascular consumption||DIC|
|Sequestration||Hypersplenism (cirrhosis, lymphoma)|
Lack of platelet production, either as an isolated problem or as a factor contributing to thrombocytopenia, is suspected when decreased overall cellularity or a selective decrease in megakaryocyte number and size is found on bone marrow examination. A variety of suppressive factors may cause a generalized decrease in marrow mass or a selective decrease in megakaryocyte number. These include chemicals, both therapeutic drugs and environmental toxins; infectious agents, including bacteria, viruses, fungi, and mycobacteria; immune processes, in which the marrow may be inhibited by either a humoral or a cell-mediated mechanism; radiation injury; and idiopathic hypoplastic or aplastic marrow. Marrow hypoplasia will be evident on examination of a bone core biopsy. Care should be taken not to sample marrow that is in the port of prior radiotherapy. Hypoplasia is expected in such an area and may be misleading if interpreted as representing the status of the full marrow.
Ineffective marrow states are characterized by normal or increased cellularity but lack of release of precursors into the blood. Measurement of the reticulocyte response to anemia is a convenient way to monitor marrow “effectiveness” in this circumstance. A common cause of ineffective marrow function is folate deficiency causing megaloblastic hematopoiesis. The finding of hypersegmented polymorphonuclear leukocytes or ovalomacrocytes and the lack of a reticulocyte response in conjunction with thrombocytopenia should suggest this mechanism. Increased metabolic requirements, decreased folate intake in the diet, and therapy with certain chemotherapeutic agents predispose an individual to folate deficiency. Of course, vitamin B12
deficiency needs to be considered at the same time because of hematologic features identical to folate deficiency. Ineffective marrow function is also a feature of various myelophthisic conditions in which marrow may be replaced by tumor or granuloma or is impaired functionally by metabolic disturbances such as azotemia or hypothyroidism. A variety of inflammatory conditions may cause increased or decreased platelet counts via mechanisms not clearly defined.
Shortened Platelet Survival
The survival of platelets in the blood is usually shortened in patients who are ill. Fever, bleeding, and sepsis, in general, predispose to shortened platelet survival; some specific circumstances include immune-mediated platelet removal by the reticuloendothelial system, hypersplenism, and consumptive coagulopathy. An otherwise uncomplicated shortened platelet life span can be suspected from the findings of a low circulating platelet count, normal or (usually) increased numbers of megakaryocytes on bone marrow examination, and the presence of large, basophilic platelets on a blood smear (indicative of effective marrow release of platelets).
Immune Thrombocytopenic Purpura (ITP)
Immune thrombocytopenic purpura (ITP) is confirmed by finding antiplatelet antibodies in the patient's serum or on the patient's platelets. When a drug is suspected to be the cause, these studies can be done in the presence and absence of the candidate drug in an effort to help confirm the diagnosis. Since the testing may take some time, often an empirical decision is made to stop administration of one or more suspect drugs, when possible. Immune-mediated thrombocytopenia also may be associated with such conditions as collagen-vascular disease, lymphomas, and viral infections, including HIV-1.
The first step in therapy consists of discontinuation of any potential offending agents (e.g., quinidine, trimethoprim-sulfamethoxazole, diphenylhydantoin, thiazides). In addition, drugs that impair platelet function are contraindicated. It is often difficult to sort out a responsible drug in patients with complex medical conditions who are taking multiple medications, but in our experience, a frequent offender in the ICU setting is intravenous furosemide given repetitively. Corticosteroids may improve platelet survival by loosening the attachment of antibodies to platelets and decreasing the reticuloendothelial clearance of the antibody-coated platelets. A longer-term effect of corticosteroids is suppression of antibody production. Administration of platelets is usually of temporary benefit because their survival is shortened, presumably by mechanisms similar to those affecting the patient's platelets. Another intervention that may help to improve platelet survival is infusion of intravenous γ-globulin, 0.4 to 1 g/kg per day for 3 to 5 days.7 This agent is thought to work by causing reticuloendothelial blockade and, possibly, because of the presence of anti-idiotypic antibodies in the preparation, by reducing the amount of antiplatelet antibody available to attach to platelets. In some patients receiving platelets, pretreatment with intravenous γ-globulin may help to prolong survival of the platelets. A benefit may not be seen for several days, and the resulting increase in platelet number, which may be life-saving and permit surgical procedures, is temporary. Subsequent repeat doses may be effective again, but cost becomes an important consideration when selecting this as an ongoing treatment.
Splenectomy may be an effective treatment for immune thrombocytopenia, but often the ICU patient is not a good candidate for the procedure, and therefore, the emphasis is more on the medical interventions just outlined. Intravenous human anti-Rho(D) IgG also may be effective in treating patients with immune thrombocytopenia who are Rh-positive and still have their spleen.8 The mechanism of benefit is not fully understood, but the rationale is to coat circulating Rh-positive red cells with the anti-D antibody, thereby inducing intrasplenic sequestration of the red cells, resulting in reduced available reticuloendothelial capacity to remove antibody-coated platelets. Careful monitoring of the expected (usually limited) hemolysis is necessary. Some patients may be already significantly anemic and unable to tolerate a significant fall in RBC count. Patients who have received anti-D should receive Rh-negative red cells if transfusion is needed. Other agents, such as azathioprine, vincristine, colchicine, danazol, rituximab, mycophenolate mofetil, and cyclophosphamide, or devices (e.g., staphylococcal protein A column treatment of plasma) may be helpful, but they are usually used in subacute and chronic management situations or for individuals with persistent thrombocytopenia after splenectomy.
Posttransfusion Purpura (PTP)
> Abrupt, often apparently unexplained, delayed appearance of severe thrombocytopenia may occur following blood transfusion in rare predisposed (usually P1A1-negative) individuals. The life span is shortened for both P1A1-positive donor platelets (to which isoantibodies have been produced) and the patient's own platelets (mechanism unclear). Infusions of intravenous γ-globulin (0.4 g/kg per day for 2 to 5 days) have been followed by good responses in patients with this potentially serious problem, regardless of the antibody implicated.9
Thrombotic Thrombocytopenic Purpura (TTP)
In TTP, intravascular clumping of platelets accounts for secondary vaso-occlusion and thrombocytopenia. Recent discoveries10 have supported a proposed pathogenetic mechanism to explain the TTP syndrome (see Chap. 70 for an in-depth discussion of this subject).
Triggers of the acquired syndrome include infections (e.g., HIV-1), various drugs (including the antiplatelet agents ticlopidine and clopidogrel), chemotherapeutic agents (especially mitomycin), and malignancies. The important diagnostic clues are schistocytes on blood smear, a low platelet count (usually with a disproportionately low incidence of hemorrhagic symptoms), a negative direct Coombs' test in the face of laboratory evidence of hemolysis, and (usually) normal findings on coagulation studies. Evidence of vaso-occlusion by platelet hyaline agglutinates may be seen in biopsy specimens from tissues such as skin, marrow, gingiva, and kidney. Treatment with corticosteroids and plasma exchange11 usually results in significant improvement. Also, favorable responses to intravenous vincristine, cyclophosphamide, rituximab,12 and in otherwise refractory cases, splenectomy have been reported. Because exacerbation of the vaso-occlusive process has been noted following platelet transfusions, these should be avoided unless there is serious bleeding or an invasive procedure is mandatory.
Disseminated Intravascular Coagulation (DIC)
When thrombocytopenia is a manifestation of DIC,13 usually other features of the process are present that permit recognition of the syndrome. Accompanying microangiopathic hemolysis, hypofibrinogenemia, elevated levels of FDPs and D-dimers, and prolonged clotting times are cardinal features. In advanced DIC, the bleeding diathesis associated with low platelet counts is compounded by qualitative platelet dysfunction owing to thrombin-induced platelet storage pool depletion, which may make platelet transfusions less effective. Schistocytes are seen less frequently in DIC than in TTP and, paradoxically, may be less evident in more advanced stages when fibrinolysis may be brisk, leading to breakdown of fibrin strands responsible for red cell shearing.
Heparin-Induced Thrombocytopenia (HIT)
Bleeding is the most frequent complication of heparin therapy. An important cause of thrombocytopenia is the immune mechanism related to heparin.14 This is of special interest in the ICU because of the almost ubiquitous exposure of patients to heparin owing to its use in access and monitoring lines and the common insertion of “heparin bonded” or “heparin coated” catheters. In addition, certain patient populations, especially those who have undergone cardiac or orthopedic surgery, appear to be at increased risk of sensitization by heparin.
It is common for patients to have a small, reversible drop in platelet count (usually within the normal range) within 1 to 2 days of the initiation of heparin therapy. This effect is thought to reflect some platelet aggregation caused by the presence of high-molecular-weight heparin species in the commercially available unfractionated heparin. The immune-mediated thrombocytopenia (seen in less than 1% of heparin-treated patients) typically appears at about 5 to 7 days after first exposure, but an anamnestic response due to persistent antibody from previous sensitization to heparin may cause thrombocytopenia to develop earlier in some patients, usually if they are within about 100 days of their initial sensitization. The clinical picture may range from no symptoms to life-threatening thrombotic events, which may be venous or arterial. Hemorrhage is less frequent, despite quite severe thrombocytopenia in some individuals. It is often necessary to make the decision about discontinuing heparin on clinical grounds.
The clinical criteria for diagnosis of HIT include an otherwise unexplained fall in platelet count below 150,000/μL or a fall of 50% or more of platelet count within the normal range. A history of any adverse reaction to heparin in the past or of necrotic changes at subcutaneous heparin injection sites should alert one to risk of serious vascular consequences on re-exposure to the drug. It is often difficult in the ICU setting to sort out mechanisms of thrombocytopenia, but a high index of suspicion is important in avoiding adverse consequences of unrecognized HIT. The “gold standard” confirmatory test (normalization of the platelet count after stopping heparin) also may be difficult to achieve because of other coexisting causes of thrombocytopenia (e.g., other drugs, sepsis).
Current notions of the pathogenesis of HIT suggest that the normally formed platelet factor 4 (PF4)–heparin complex is immunogenic in some individuals. Antibodies developed against the PF4-heparin target antigen form antigen-antibody complexes that can activate platelets after interacting with their Fc receptors. The result is intravascular obstruction by platelet clumps.
Laboratory confirmation of the presence of heparin-dependent antibodies may be helpful but is not always available in a timely fashion for decision making. In addition, false-negative tests are not infrequent. When available, various functional assays, such as heparin-induced platelet aggregation, [14C]serotonin release, and flow cytometric methods, may increase the predictability of clinically significant vaso-occlusive events beyond the detection of sensitization using enzyme-linked immunosorbent assay (ELISA) techniques for antibodies to PF4.
It is important to emphasize that the severe antibody syndrome may occur with any type of heparin (although the incidence appears to be less with low-molecular-weight heparin15) given via either intravenous or subcutaneous route. If the syndrome is suspected clinically, all devices and practices that expose the patient to heparin should be discontinued (including use of heparin locks, flushes of indwelling lines, and indwelling catheters that are heparin-coated).
Patients with HIT are hypercoagulable whether or not a clinically recognized vaso-occlusive event has occurred. As a result, they require immediate alternative anticoagulation. Once sensitized by unfractionated heparin (UFH), patients should not receive low-molecular-weight heparin (LMWH) as an alternative because of the high rate of cross-reactivity of antibodies to UFH with LMWH. The commonly used anticoagulants in this setting are direct thrombin inhibitors that do not cross-react with heparin-induced antibodies. Hirudin and argatroban usually are selected—the choice being made based on the patient's comorbidities (hirudin depends on renal clearance; argatroban depends on hepatic function status). Although each agent has a relatively short half-life, the lack of an antagonist for either increases the risk of bleeding complications. If patients require long-term anticoagulation with oral warfarin, it should not be started for at least 2 weeks because of reported adverse clotting problems when begun earlier in the course of HIT.
Mechanical Surface-Related Thrombocytopenia16
Variable lowering of platelet number is sometimes seen when platelets pass over or through foreign or distorted surfaces. Clinical situations of this type include cardiopulmonary bypass and the presence of intraaortic balloon pumps or pulmonary artery catheters. For cardiopulmonary bypass, at least, platelet-related bleeding during or after bypass is much more likely to be secondary to impaired platelet function (see below) than to severe depression of the platelet count.
Thrombocytopenia with or without anemia and neutropenia may be a feature of hypersplenism.17 This state of increased local sequestration, usually with shortened intrasplenic survival, frequently is accompanied by increased spleen size that is detectable on physical examination or imaging studies. Bedside ultrasound is a safe noninvasive method for assessing the spleen in ICU patients.
Hypersplenism may be a chronic, stable condition antedating and then complicating a new problem (e.g., cirrhosis with splenomegaly predating acute deterioration for another reason). In addition, acute onset of hypersplenism with progressive splenic enlargement and sequestration may be a feature of such processes as splenic venous occlusion and sickle cell splenic sequestration crisis in children. It is unusual to encounter a platelet count of less than about 30,000/μL in “compensated” hypersplenism associated with cirrhosis and portal hypertension accompanied by splenomegaly. Bone marrow evaluation is expected to reveal increased megakaryocyte number and overall hypercellularity. The peripheral smear should show decreased platelet numbers but some large basophilic platelets.
In situations of progressive splenomegaly with associated thrombocytopenia (and risk of splenic rupture), splenectomy may be the only available therapy. If the splenic enlargement is secondary to leukemic or lymphomatous involvement, radiation therapy may be of some benefit in shrinking the spleen, but the effect may be temporary, and there is the risk of paradoxical thrombocytopenia or neutropenia rather than count improvement.
Elevated platelet counts are seen commonly in critically ill patients because inflammation, bleeding, surgery, hemolysis, severe injury, and neoplasia are among the major causes of reactive thrombocytosis. Usually, the count is elevated to levels less than 1 × 106/μL, and no adverse effect is expected from such a secondary increase in qualitatively normal platelets.
In contrast, patients with elevated platelet counts secondary to myeloproliferative disorders18 are at an increased risk of bleeding or thrombotic sequelae, especially when the platelet count exceeds 1 × 106/μL. The diagnosis of an underlying myeloproliferative disorder may have been established prior to the patient's presentation with a complication, or it may be suspected from associated clinical features such as splenomegaly, abnormal platelet morphology on smear, and bone marrow examination revealing panmyelosis (increase in all cell lines) as well as qualitative abnormalities in megakaryocytes, which are also markedly increased in number.
If the patient is asymptomatic, a prolonged bleeding time may portend hemorrhagic problems. No definitive laboratory tests predict impending thrombotic complications in such patients, but it appears that the risk may be increased in older persons with fixed vascular disease. It is especially important to avoid splenectomy, either intentional or inadvertent, at the time of abdominal surgery for other reasons because marked platelet elevations may cause fatal vaso-occlusive events.
Platelet levels may be reduced quickly and effectively in symptomatic thrombocythemic individuals by plateletpheresis. Treatment with anagrelide or hydroxyurea can be used to maintain normal platelet counts (the usual goal is to keep the platelet count less than 500,000/μL).18 These drugs also can help to prevent secondary rises in platelet count following surgical procedures and other factors that may precipitate reactive thrombocytosis.
Qualitative platelet abnormalities are encountered
frequently in the ICU setting.19 Often they contribute to other, more serious bleeding diatheses, but on occasion they present a significant problem in their own right. Exposure to external agents, such as ethanol, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs), prior to admission is common. Other drug-induced causes of thrombocytopathy in the hospital include exposure to the parenteral NSAID ketorolac (TORADOL) and glycoprotein (GP) IIb/IIIa inhibitors (e.g., abciximab, ticlopidine, clopidogrel). The resulting prolongation of bleeding time varies in duration and severity. Once the offending agent has been removed, the bleeding problem can be overridden promptly by administration of normal platelets or, in the case of aspirin or ticlopidine, by intravenous infusion of 1-diamino-8-D-arginine vasopressin (DDAVP), if necessary. Often, unless there is significant bleeding or invasive procedures are needed, it is sufficient to wait several days and let the patient's own production of new platelets unexposed to the offending agent correct the problem.
A more difficult problem is the thrombocytopathy associated with uremia. A variety of interventions may be helpful temporarily. Correction of the prolonged bleeding time may be needed prior to an intended surgical intervention (e.g., renal biopsy for diagnosis). The key step is appropriate dialysis; additional benefit sometimes is noted with administration of corticosteroids, infusions of cryoprecipitate20 (usually 10 cryopacks every 12 hours), intravenous DDAVP21 (0.3 μg/kg), platelet transfusions, and intravenous conjugated estrogens.22 Intravenous DDAVP, if effective in reducing the bleeding time, may be repeated at 6- to 12-hour intervals, but tachyphylaxis is expected after 1 to 2 days of this therapy. It is also important to seek and correct other coexisting coagulopathies, such as vitamin K deficiency.
Patients with myeloproliferative disorders may have platelet dysfunction, especially when platelet counts are elevated. Usually, normalization of the platelet count results in return of the bleeding time to normal, but individuals with long-standing polycythemia vera or myeloid metaplasia, for example, may still have abnormal bleeding, especially with surgical procedures, even when all counts have been normalized.
The classic drug inhibitor of platelet function is aspirin. It causes irreversible inhibition of cyclo-oxygenase, thereby leading to impaired prostaglandin metabolism. The net effect of aspirin is the result of inhibition of production of the platelet aggregant thromboxane A2 versus decreased synthesis of prostacyclin—the potent endothelium-derived inhibitor of platelet aggregation. In most individuals on Western diets that contain limited amounts of the omega fatty acid precursors of prostacyclin synthesis, the net result is a prolonged bleeding time. When aspirin is discontinued, the exposed platelets remain impaired, but newly synthesized platelets with normal function soon begin to contribute to normalization of the bleeding time. Usually, the effect of aspirin on bleeding time has dissipated significantly by 3 days after discontinuation.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
NSAIDs cause reversible inhibition of cyclo-oxygenase and, therefore, a shorter period of bleeding risk than aspirin after discontinuation.
Antibiotics of the penicillin family, epitomized by carbenicillin, may cause a complex coagulopathy. In addition to disturbance of the synthesis of vitamin K by the intestinal flora, a thrombocytopathy characterized by a prolonged bleeding time is recognized. These phenomena usually are not of major clinical significance, but they may add to other coagulation defects and affect the interpretation of coagulation laboratory evaluations. When bleeding from these mechanisms is serious, platelet transfusion after discontinuation of the drug should compensate for the impaired function of platelets exposed to the drug.
Abnormal immunoglobulin concentrations, as seen in myeloma and Waldenstrom's macroglobulinemia, interfere with platelet function (causing prolonged bleeding times) presumably by physically “coating” platelet surfaces and thus limiting the access of clotting factors to the phospholipid surfaces of platelets, which are needed to promote key reactions in the clotting cascade. In addition, prolongation of the TT is often noted.
Acquired thrombocytopathy is regularly produced by contact of platelets with membrane surfaces in bypass circuits. In some patients this effect may add to other causes of increased bleeding risk after bypass (such as hypofibrinogenemia and inadequate heparin neutralization). Transfusion of donor platelets (if clinically urgent) is expected to normalize the bleeding time once bypass is discontinued.
Thrombin-Induced Storage Pool Defect
Thrombocytopathy may contribute to the bleeding problems in DIC. During active DIC (e.g., in acute promyelocytic leukemia), an acquired platelet function defect with prolonged bleeding time may appear owing to release of granule contents by excess thrombin. This is likely to be especially troublesome when patients are thrombocytopenic as well. Control of the DIC is the key to successful correction of this problem. Infusion of donor platelets is of benefit for only limited periods because these platelets are also exposed to excess thrombin while the DIC is active.