By Kathryn Radigan, MD
Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago
Dr. Radigan reports no financial relationships relevant to this field of study.
Thrombocytopenia, defined as a platelet count of < 150 x 109/L, is a common acquired condition in critically ill patients.1 Approximately half of critically ill patients experience thrombocytopenia during the length of their ICU stay.2 In nearly 10% of these patients, platelet counts reach a nadir of < 50 x 109/L. In one study, the incidence of mild (100-149 x 109/L), moderate (50-99 x 109/L), and severe (< 50 x 109/L) thrombocytopenia in the critically ill was 15.3%, 5.1%, and 1.6%, respectively.3
CLINICAL SIGNIFICANCE
Thrombocytopenia is not only a pathologic entity, but the severity of thrombocytopenia and the recovery time of the platelets often predicts outcome, including overall mortality of ICU patients.1,4,5 Critically ill patients with moderate and severe thrombocytopenia demonstrate higher ICU and hospital mortality.3 If the recovery is delayed beyond day four, several studies have demonstrated higher morbidity and mortality. In one study, the morality rate of critically ill patients who experienced persistent thrombocytopenia for 14 days was 66% compared to a mortality rate of 16% for patients who exhibited normal or recovered platelets.6 Even when not associated with bleeding, thrombocytopenia often creates barriers to effective management of patients, including a hold or delay in necessary interventions, an increased number of prophylactic platelet transfusions, change or cessation of anticoagulation (especially in the setting of a concern for heparin-induced thrombocytopenia [HIT]), and a reduction in the intensity of anticoagulation for fear of complications.7
ETIOLOGY OF THROMBOCYTOPENIA IN THE ICU
Thrombocytopenia is most often multifactorial. The six major mechanisms that result in thrombocytopenia in the ICU include: hemodilution, increased platelet consumption, decreased platelet production, increased platelet sequestration, platelet destruction, and laboratory artifact of pseudothrombocytopenia.8 (See Table 1.) Often, more than one of these mechanisms is responsible for thrombocytopenia in the critically ill. Pseudothrombocytopenia may occur because of clots in the tube or platelet aggregates in ethylenediaminetetraacetic acid (EDTA)-anticoagulated blood.9 Automated cell counters cannot recognize these aggregates. This phenomenon may be triggered in patients taking glycoprotein IIb/IIIa antagonists such as abciximab, tirofiban, and integrillin.10 The timing of thrombocytopenia often is useful in determining etiology. Two different studies that included medical ICU patients revealed that platelet count usually decreases after admission, with a typical recovery after five days, which may reflect effective treatment of the primary disease process.11,12 Generally, a slow and steady fall in platelets over five to seven days is more consistent with a consumptive coagulopathy or bone marrow failure.7 If the platelets abruptly decrease within one to two days after an initial recovery, it is often immunologic or drug-related. When it occurs within a few hours of transfusion, there should be concern for bacterial contamination or passive alloimmunization.
DIAGNOSTIC APPROACH
To help determine whether the thrombocytopenia is acute or chronic, it is important to ask the patient or family about prior platelet counts, family history of bleeding disorders, the patient’s history of bleeding disorders, medication exposures, exposure to particular infections, dietary practices (including veganism and vegetarianism), and other comorbidities, including hematological disorders, rheumatological diseases, or poor diet (including a history of bariatric surgery.) On physical exam, look for petechiae, purpura, ecchymosis, lymphadenopathy, splenomegaly, and hepatomegaly.
Regardless of the presentation, it is always important to repeat the complete blood count with smear. This is especially important when pseudothrombocytopenia is suspected, but it should be performed using a non-EDTA anticoagulant such as heparin or citrate.7 EDTA can induce clumping or platelet rosettes around white blood cells, which then causes the platelets to be counted as leukocytes. Regardless, it is critical to consider an immunologic cause of thrombocytopenia whenever platelet counts decrease within 24-48 hours several days after ICU admission. Although drug-related platelet nadir may be < 10,000/uL, platelet nadir for HIT typically is 20,000 uL to 50,000 uL.5 If the onset of the thrombocytopenia started prior to ICU admission and fits the appropriate scenario, consider evaluation for autoimmune diseases, HIV, and liver disease, including hepatic enzymes, synthetic function, and hepatitis panel. If a consumptive coagulopathy is confirmed in the setting of thrombocytopenia, disseminated intravascular coagulation (DIC) is a major concern and further supported by decreasing serum fibrinogen levels and increasing thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrin degradation products.9 When microangiopathic changes are confirmed on smear, it is important to entertain the diagnosis of thrombotic thrombocytopenic purpura (TTP), Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS), or other syndromes of thrombotic microangiopathy. To narrow the differential and aid in diagnosis, it is important to note whether the thrombocytopenia occurs in isolation or with associated anemia or leukopenia. Pancytopenia also must be worked up further, especially with the concern for myelodysplastic syndrome. If TTP, ST-HUS, HIT, or an acute hematologic malignancy is suspected, it is a medical emergency and warrants an immediate hematology consult.
TREATMENT
Although there is usually no role for prophylactic platelet transfusions to decrease bleeding risk in critically ill patients, many consider it reasonable to prophylactically transfuse platelets in patients with severe sepsis at a threshold of ≤ 10 x 109/L or at < 20 x 109/L in particularly high-risk patients.13,14 If a patient is undergoing an invasive intervention, there are criteria for minimum platelet counts that have been defined and supported mainly by expert opinion rather than randomized, controlled trials.15 Of course, these are only suggested guidelines and may be adjusted by each individual patient scenario, including consideration for platelet function, history of bleeding, medications, liver and renal function, and/or in the setting of sepsis. Table 2 summarizes recommendations for prophylactic platelet transfusions before invasive procedures. Additional treatment guidelines are outlined below.
Thrombocytopenia with abnormal coagulation profiles. Thrombocytopenia with an abnormal coagulation profile is seen most commonly with septic DIC. DIC is a disease process characterized by systemic activation of the coagulation cascade that results in disseminated fibrin formation and is confirmed by abnormal elevation of the PT and aPTT, decreased fibrinogen and platelets, and schistocytes on smear.5 Since fibrinogen is an acute phase reactant, fibrinogen levels may be normal. DIC occurs most often in the setting of sepsis/systemic inflammatory response syndrome and often is associated with a very poor prognosis, especially when platelet counts fail to recover. Treatment includes addressing the underlying cause and supportive care, including transfusion of blood products as clinically indicated. Thrombocytopenia with abnormal coagulation profiles also may occur in the setting of severe liver impairment because of a lack of synthesis of coagulation factors and in association with coinciding splenomegaly and liver disease.5
Thrombocytopenia with microangiopathic hemolytic anemia (MAHA). MAHA is non-immune hemolysis that results from intravascular red blood cell fragmentation that produces schistocytes. Syndromes of microangiopathic thrombocytopenia, including TTP and ST-HUS, commonly present with MAHA, thrombocytopenia, and organ injury.
TTP is a prothrombotic thrombocytopenic disorder in which microangiopathic hemolytic anemia may be complicated by renal failure, neurologic disorders, fever, or other organ involvement.16 It is caused by a hereditary deficiency or acquired antibodies to the von Willebrand factor-cleaving protease ADAMTS13. Low levels of ADAMTS13 lead to large von Willebrand factor multimeres in which platelets bind. This dysregulation causes microvascular thrombosis and further destruction of red blood cells.17 TTP may complicate the course of stem cell transplant or autoimmune disease. It is rarely drug-mediated but may be prompted by non-dose-related idiosyncratic, immunologic reactions or a toxic dose-related reaction. Known culprits include quinine, quetiapine, gemcitabine, clopidogrel, ticlopidine, mitomycin C, calcineurin inhibitors, and chemotherapeutic agents.18 When drug-induced, the most important treatment is to stop the offending agent immediately. TTP also may occur postoperatively.19 Since anemia, thrombocytopenia, fever, renal failure, and mental status changes are common complications in a postoperative course, there is often significant delay in diagnosis of postoperative TTP. Non-immune-mediated postoperative TTP also may occur early after surgery because of increased ADAMSTS13 consumption, as opposed to the later presentation of immune-mediated postoperative TTP in which anti-ADAMTS13 antibodies lead to decreased ADAMTS13 levels. Early plasma exchange is critical for optimal treatment of TTP. Coinciding corticosteroids and rituximab may decrease the number of plasma exchange treatments needed for remission.8 Platelets should not be transfused in this setting.
ST-HUS is caused by an enteric infection with a Shiga toxin-secreting strain of Escherichia coli or Shigella dysenteriae.16 Excessive platelet activation leads to the formation of thrombi in the microcirculation, which leads to platelet consumption and subsequent thrombocytopenia. Clinicians can halt this process by using the monoclonal humanized anti-C5 antibody, eculizumab.20 Although this treatment is promising, its efficacy remains questionable.21 Additional systemic disorders that may present with MAHA and thrombocytopenia include DIC, systemic infection, systemic malignancy, pregnancy-related syndromes, solid organ transplant, and hematopoietic cell transplant.5 In addition, MAHA and thrombocytopenia may be present in the setting of coinciding systemic rheumatic disease and severe hypertension.5
Thrombocytopenia in combination with thrombosis. If thrombocytopenia develops in the setting of venous or arterial thromboses, the differential diagnosis narrows to HIT, antiphospholipid syndrome (APS), and other systemic disorders as discussed below. HIT is a life-threatening heparin-mediated, prothrombotic disorder caused by an autoantibody against platelet factor 4 (PF4) after complex formation with heparin. Typically, the platelet count falls more than half, usually nadiring between 50-80 x 109/L and may occur with catastrophic arterial and venous thrombosis.22 The probability of HIT in an ICU patient may be estimated using the 4Ts score (Thrombocytopenia, Timing, Thrombosis, and oThers).23 The reader is encouraged to look up the reference for more details in terms of calculating the score.24
A presumptive diagnosis of HIT is based solely on clinical findings and platelet counts until laboratory results are available.7 Commonly, the immunoassay is the initial test of choice. It is highly sensitive (> 99%) and often available within most institutions for a rapid turnaround time but also demonstrates poor specificity.23 Although this test is helpful in specific scenarios, more testing, such as a functional assay and/or the evaluation of serologic features (detection of IgG antibodies, quantification of the antibody level or optical density, or use of high heparin concentrations to dissociate or compete with binding of antibodies to PF4/H complexes), sometimes is necessary.24 One functional assay, the serotonin release assay, exhibits high specificity and positive predictive values, but is limited to major commercial laboratories or referral laboratories at academic medical centers. When HIT is suspected strongly, heparin must be stopped immediately, and a therapeutic dose of a non-heparin anticoagulant should be started. Platelets should not be transfused in HIT. APS typically presents with immune-mediated thrombocytopenia, arterial and/or venous thrombosis, and pregnancy loss. Blood tests typically are positive for antiphospholipid antibodies and/or lupus anticoagulant.25 It often presents with other autoimmune diseases, including lupus. In the ICU, it is critical to be aware of “catastrophic” APS, which presents with a more rapid and severe onset, often resulting in multi-organ failure. Treatment is early and appropriate anticoagulation, platelet inhibition (such as aspirin), corticosteroids, plasma exchange/immunoadsorption, and IV immunoglobulin.26 Long-term treatments often include cyclophosphamide or rituximab. Eculizumab often is used to block complement activation. Additional systemic disorders that may present with thrombosis and thrombocytopenia include cancer-associated DIC or massive clot thrombocytopenia.
Toxin- and medication-related thrombocytopenia. Chronic intoxication of substances such as alcohol also causes thrombocytopenia from impaired megakaryopoiesis and often occurs concurrently with splenomegaly and liver cirrhosis, which can further aggravate thrombocytopenia.27,28 Other acute intoxications include acetaminophen, which may cause thrombocytopenia, along with therapeutic doses of anticonvulsant drugs such as valproate, carbamazepine, phenobarbital, or phenytoin.8 Discussion of herbal medications with the patient or family members also is critical, especially in the setting of unknown etiology.
Drug-related thrombocytopenia in the critically ill may be non-immune, drug-induced thrombocytopenia (DTP) or drug-induced immune thrombocytopenia (DITP). Adverse drug reactions caused by drug-dependent, antibody-mediated platelet destruction are responsible for almost 20% of all hospitalized patients with thrombocytopenia.29 The most common culprits of drug-related thrombocytopenia in the ICU are new medications, as opposed to a patient’s daily list of medications. Common offending agents include trimethoprim/sulfamethoxazole, penicillin, vancomycin, ibuprofen, ceftriaxone, rifampin, abciximab, and mirtazapine.30 Commonly, non-immune culprits are histamine (H2) antagonists or nonsteroidal anti-inflammatory drugs. Notably, unfractionated heparin may cause a non-immunologic fall of platelets within the first days of initiating the medication. As for DITP, an abrupt platelet fall to < 5 x 109/L with mucocutaneous bleeding is typical.8 The drug often has been started five to 10 days prior to the platelet fall. If the patient has been sensitized by a previous exposure to the drug, the onset of thrombocytopenia may be more rapid. If DTP or DITP is suspected, the offending medication should be stopped immediately. Typically, the platelets will increase steadily after five half-lives of the drug, which usually occurs within three to five days. When DITP is associated with severe bleeding, IV immunoglobulin and platelet transfusion are common treatment strategies.31
Transfusion-related thrombocytopenia. Post-transfusion purpura is an extremely rare disorder of previously pregnant women that occurs approximately seven to 14 days after allogeneic blood transfusion in which the platelet count falls to < 10 x 109/L.7 During their previous pregnancy, the women are pre-immunized against a platelet blood group, most commonly human platelet antigen (HPA)-1a. Transfusion of HPA-1a-positive cellular blood products (red blood cell concentrates or platelets) triggers a response from memory B cells, which enhances the production of alloantibodies, subsequently destroying the autologous (antigen-negative) platelets. Preferred treatment is high-dose immunoglobulin G 1 g/kg per day for two consecutive days or 400-500 mg/kg per day for five days.32
Passive alloimmune thrombocytopenia, with platelet counts typically < 20 x 109/L, is caused by transfusion of plasma or red blood cells that contain high-titer platelet-specific antibodies.7 Although the platelet-specific antibodies may be detected in the donor’s plasma and on the recipient’s platelets, it is not detectable in the recipient’s plasma. This finding suggests that nearly 100% of the transfused alloantibodies bind immediately after transfusion. It is critical that these cases undergo further review to prevent other patients from developing the syndrome.
Additional causes of thrombocytopenia. In the setting of trauma, patients often experienced trauma-induced coagulopathy and hemodilution because of massive transfusion of other blood products. Although the optimal ratio for transfusion of blood products is highly controversial, studies support a survival benefit in patients who receive early plasma and platelet transfusions along with red blood cells.33 Thrombocytopenia usually is a manifestation of the pancytopenia caused by marrow suppression. Less commonly, the thrombocytopenia occurs in isolation as a previously unrecognized comorbidity such as myelodysplastic syndrome, acute leukemia, infiltration of bone marrow from other malignancies, or infection.
SUMMARY
Not only is thrombocytopenia common in critically ill patients, but it also is associated with a worse prognosis. It is critical to find the cause, and then pursue the appropriate treatment strategy.
REFERENCES
- Hui P, et al. The frequency and clinical significance of thrombocytopenia complicating critical illness: A systematic review. Chest 2011;139:271-278.
- Crowther MA, et al. Thrombocytopenia in medical-surgical critically ill patients: Prevalence, incidence, and risk factors. J Crit Care 2005;20:348-353.
- Williamson DR, et al. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: Frequency, risk factors, and outcomes. Chest 2013;144:1207-1215.
- Drews RE. Critical issues in hematology: Anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients. Clin Chest Med 2003;24:607-622.
- Thachil J, Warkentin TE. How do we approach thrombocytopenia in critically ill patients? Br J Haematol 2017;177:27-38.
- Akca S, et al. Time course of platelet counts in critically ill patients. Crit Care Med 2002;30:753-756.
- Greinacher A, Selleng K. Thrombocytopenia in the intensive care unit patient. Hematology Am Soc Hematol Educ Prog 2010;2010:135-143.
- Thiele T, et al. Thrombocytopenia in the intensive care unit—diagnostic approach and management. Semin Hematol 2013;50:239-250.
- Greinacher A, Selleng S. How I evaluate and treat thrombocytopenia in the intensive care unit patient. Blood 2016;128:3032-3042.
- Sane DC, et al. Occurrence and clinical significance of pseudothrombocytopenia during abciximab therapy. J Am Coll Cardiol 2000;36:75-83.
- Mirsaeidi M, et al. Thrombocytopenia and thrombocytosis at time of hospitalization predict mortality in patients with community-acquired pneumonia. Chest 2010;137:416-420.
- Stansbury LG, et al. The clinical significance of platelet counts in the first 24 hours after severe injury. Transfusion 2013;53:783-789.
- Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017;43:304-377.
- Lieberman L, et al. Platelet transfusions for critically ill patients with thrombocytopenia. Blood 2014;123:1146-1151.
- Executive Committee of the German Medical Association on the Recommendation of the Scientific Advisory Board. Cross-Sectional Guidelines for Therapy with Blood Components and Plasma Derivatives: Chapter 5 Human Albumin - Revised. Transfus Med Hemother 2016;43:223-232.
- George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med 2014;371:654-666.
- Furlan M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998;339:1578-1584.
- Zakarija A, et al. Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): Review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008). Kidney Int Suppl 2009:S20-4.
- Naqvi TA, et al. Post-operative thrombotic thrombocytopenic purpura: A review. Int J Clin Pract 2004;58:169-172.
- Gruppo RA, Rother RP. Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med 2009;360:544-546.
- Kielstein JT, et al. Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E. coli O104:H4 induced haemolytic-uraemic syndrome: An analysis of the German STEC-HUS registry. Nephrol Dial Transplant 2012;27:3807-3815.
- Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001;344:1286-1292.
- Lo GK, et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006;4:759-765.
- Lee GM, Arepally GM. Heparin-induced thrombocytopenia. Hematology Am Soc Hematol Educ Program 2013;2013:668-674.
- Nayer A, Ortega LM. Catastrophic antiphospholipid syndrome: A clinical review. J Nephropathol 2014;3:9-17.
- Asherson RA, et al. Catastrophic antiphospholipid syndrome: International consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530-534.
- Girard DE, et al. Hematologic effects of acute and chronic alcohol abuse. Hematol Oncol Clin North Am 1987;1:321-334.
- Afdhal N, et al. Thrombocytopenia associated with chronic liver disease. J Hepatol 2008;48:1000-1007.
- Aster RH, et al. Drug-induced immune thrombocytopenia: Pathogenesis, diagnosis, and management. J Thromb Haemost 2009;7:911-918.
- Arnold DM, et al. A systematic evaluation of laboratory testing for drug-induced immune thrombocytopenia. J Thromb Haemost 2013;11:169-176.
- Ray JB, et al. Intravenous immune globulin for the treatment of presumed quinidine-induced thrombocytopenia. DICP 1990;24:693-695.
- Mueller-Eckhardt C, Kiefel V. High-dose IgG for post-transfusion purpura-revisited. Blut 1988;57:163-167.
- Brown JB, et al. Debunking the survival bias myth: Characterization of mortality during the initial 24 hours for patients requiring massive transfusion. J Trauma Acute Care Surg 2012;73:358-364.
Table 1: Major Mechanisms of Thrombocytopenia in the Critically Ill |
|
|
Hemodilution |
|
|
Increased platelet consumption |
|
|
Decreased platelet production |
|
|
Increased platelet sequestration |
|
|
Increased platelet destruction |
|
|
Pseudothrombocytopenia |
|
|
Thiele T, et al. Thrombocytopenia in the intensive care unit—diagnostic approach and management. Semin Hematol 2013;50:239-250. |
|
Table 2: Minimum Platelet Counts for Common ICU Procedures |
|
|
Procedure |
Minimum Platelet Count (x 109/L) |
|
Central venous catheter insertion |
20 |
|
Elective lumbar puncture |
50 |
|
Emergency lumbar puncture |
20 |
|
Bronchoscopy |
20 |
|
Bronchoscopy with biopsy |
50 |
|
Gastrointestinal endoscopy with biopsy |
20 |
|
Transjugular liver puncture |
10 |
|
Thoracentesis |
50 |
|
Greinacher A, Selleng S. How I evaluate and treat thrombocytopenia in the intensive care unit patient. Blood 2016;128:3032-3042. |
|
Thrombocytopenia is not only a pathologic entity, but the severity of thrombocytopenia and the recovery time of the platelets often predicts outcome, including overall mortality of ICU patients. Critically ill patients with moderate and severe thrombocytopenia demonstrate higher ICU and hospital mortality. If the recovery is delayed beyond day four, several studies have demonstrated higher morbidity and mortality.
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