Japanese Journal of Clinical Oncology Advance Access originally published online on June 22, 2006
Japanese Journal of Clinical Oncology 2006 36(8):527-531; doi:10.1093/jjco/hyl054
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© 2006 Foundation for Promotion of Cancer Research
Case Report |
Anticoagulant-Induced Pseudothrombocytopenia Occurring after Transcatheter Arterial Embolization for Hepatocellular Carcinoma
1 Department of Radiology, Kobe University Graduate School of Medicine, Kobe, 2 Department of Radiology, Miki City Hospital, Miki, Hyogo, 3 Department of Radiology, Himeji Medical Center, Himeji, Hyogo, 4 Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo, 5 Department of Radiology, Tenri Hospital, Tenri, Nara and 6 Blood Transfusion Division, Kobe University Hospital, Kobe, Japan
For reprints and all correspondence: Takeshi Yoshikawa, Department of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunokicho, Chuoku, Kobe, Hyogo 650-0017, Japan; E-mail: yoshikaw{at}med.kobe-u.ac.jp
Received January 13, 2006; accepted April 7, 2006
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Abstract |
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Pseudothrombocytopenia (PTCP) is the in vitro phenomenon of anticoagulant-activated platelet agglutination that results in spuriously low platelet counts. We report the case of a 65-year-old man with EDTA- and sodium citrate-dependent PTCP occurring after transcatheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) due to hepatitis C cirrhosis. Invasion of the portal and hepatic veins by HCC formed severe trans-tumoral arterio-venous shunts that were effectively treated by TAE. Two days after the therapy, PTCP was seen on blood count and continued for 4 months. The patient received unnecessary treatment for disseminated intravascular coagulation (DIC) until the diagnosis of PTCP was established. PTCP is a rare complication but should be considered after TAE for HCC; lack of recognition may lead the physician to misdiagnosis and patient mismanagement.
Key Words: pseudothrombocytopenia • transcatheter arterial embolization • hepatocellular carcinoma • portal invasion
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Introduction |
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TOPAbstractIntroductionCASE REPORTDISCUSSIONReferences |
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Transcatheter arterial embolization (TAE) has been regarded as the most effective conservative therapy for advanced hepatocellular carcinoma (HCC). Several researchers have reported that TAE is effective for portal and hepatic venous invasion of HCC, as well as for trans-tumoral arterio-portal and arterio-venous shunts (123–4). Upper abdominal pain, low grade fever, liver dysfunction and hepatic infarction have been reported as common complications after TAE (5). Disseminated intravascular coagulation (DIC) is a rare but potentially fatal complication (6). Pseudothrombocytopenia (PTCP) is an in vitro phenomenon of anticoagulant-activated platelet agglutination that results in spuriously low platelet counts (789–10). Failure to recognize PTCP leads to unnecessary diagnostic tests, treatment delay and unwarranted exposure to transfusion-related complications (11–12). We report the case of a 65-year-old man with multiple anticoagulant-dependent PTCP occurring immediately after TAE for HCCs invading the portal vein.
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CASE REPORT |
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A 65-year-old man with recent increase in abdominal girth, diarrhea and appetite loss was referred to our institution and was diagnosed to have hepatocellular carcinoma (HCC) invading the right and main portal veins by contrast-enhanced computed tomography (Fig. 1A and B). The patient had esophageal varices with red color sign on endoscopic examination but reported no history of bleeding tendency, hemoptysis, hematochezia or melena. Because of the advanced stage of disease, transcatheter arterial angiographic evaluation and TAE were planned. The patient's medical history was unremarkable except for tuberculous pleurisy 20 years ago and cholecystectomy 40 years ago. On physical examination, the vital signs were normal. The abdomen was severely distended due to massive ascites. Skin examination was unremarkable, and no petechiae were present. Laboratory evaluation on admission of venous blood collected into an EDTA-containing Vacutainer demonstrated a normal blood cell count (Table 1). The platelet count was 132 000/mm3. The patient was tested positive for hepatitis C virus and had moderate liver dysfunction. The concentrations of electrolytes, blood urea nitrogen and creatinine were normal. Hematological tests were all within normal ranges. Serum
-fetoprotein (AFP) and protein-induced by vitamin K absence or antagonist (PIVKA) II were markedly increased. At the time of admission, he was treated with oral spironolactone, lactomin and loperamide hydrochloride. Venous administration of glutathione, monoammonium glycyrrhizinate, glycine, aminoacetic acid and L-cysteine hydrochloride was started at the time of admission.
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Digitally subtracted celiac and proper hepatic arteriograms demonstrated massive arterio-portal and arterio-venous shunts (Fig. 2A). Visualization of the threads-and-streaks sign and early enhancement of the portal and hepatic veins indicated tumor invasion of these structures. Tumor stains were not observed because of the stealing of contrast medium through the shunts. TAE was performed without complications based on the method reported previously (1), with gelatin particles and epirubicin soaked in 2 ml of iodinated contrast medium. After TAE, arterio-portal and arterio-venous shunts were reduced (Fig. 2B). However, serial TAEs or other therapies were considered to be needed. The patient experienced no side effects except for low grade fever and slight worsening of appetite loss. He started to feel a decrease in abdominal girth 24 h after TAE. Oral administration of levofloxacin was started to prevent hepatic abscesses due to hepatic infarction after TAE. Because appetite did not improve, 500 ml/day of oral liquid alimentation was stated on day 2.
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Platelet counts from blood specimens collected into EDTA-containing Vacutainers decreased to 58 000/mm3 on day 2 and 17 000 on day 5, respectively (Fig. 3). Although there were no signs of either bleeding tendency or infection, DIC could not be ruled out. Because coagulation tests were not available at night in our institution, 10 units of concentrated platelets were subsequently transfused on the night of day 5, and intravenous heparin and human antithrombin III concentrates (AT III) were started. Next morning, the platelet count was 29 000/mm3. Changes in coagulation tests between the values before TAE and on day 6 were minimal (Table 1). He was suspected to have PTCP. Therefore, a microscopic evaluation of the blood sample was performed on day 7 and it indicated platelet agglutination resulting in spuriously low platelet counts measured by the automated analyzer (Fig. 3). In order to identify the real number of platelets, serial blood counts without using anticoagulant and using two anticoagulants (EDTA and sodium citrate) were performed from immediately to 120 min after venous sampling. The results are shown in Table 2. The patient's platelet counts decreased markedly with time when using either of the anticoagulants. He was diagnosed with multiple anticoagulant-dependent PTCP. After the diagnosis was established, intravenous heparin and human AT III were terminated.
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His PTCP prolonged for the next 4 months, and then his platelet count gradually increased (Fig. 3). The patient received serial TAEs and died due to progression of HCC 33 months after the first treatment. Relapse of PTCP was not observed. Cirrhosis and HCC were confirmed by autopsy.
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DISCUSSION |
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TOPAbstractIntroductionCASE REPORTDISCUSSIONReferences |
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TAE has been regarded as the most effective conservative therapy for advanced HCC. Recently, TAE has also been reported to be effective for the treatment of portal or hepatic venous invasion of HCC and trans-tumoral arterio-portal and arterio-hepatic venous shunts, either by itself (1–4) or in combination with radiotherapy (13,14). TAE can also be effective for symptoms associated with portal hypertension such as ascites and esophageal and gastrointestinal varices. In our case, TAE was effective for both intrahepatic tumors and venous invasion, as well as in the control of ascites.
Upper abdominal pain, low grade fever, liver dysfunction and hepatic infarction have been reported as common complications of TAE (5) but are usually self-limiting. However, hepatic necrosis or abscess, or necrotic cholecystitis, can also occur, as well as life-threatening conditions such as hepatic or renal failure or DIC. Of these, DIC is a rare but potentially fatal complication (6) that appears as rapid progression of thrombocytopenia and hemorrhagic diathesis or platelet dysfunction.
A similar pattern of changes in platelet counts can be seen in PTCP, which reflects an in vitro phenomenon of anticoagulant-activated platelet agglutination that results in spuriously low platelet counts by electronic counting machines (7–10). PTCP, however, has never been associated with hemorrhagic diathesis or platelet dysfunction. In most cases, the phenomenon is EDTA dependent. With other anticoagulants such as heparin and sodium citrate this phenomenon is still possible, but rare. PTCP is induced by agglutinating antibodies that cause in vitro platelet clumping by binding glycoprotein IIb/IIIa receptors on platelets (9,10). This phenomenon is most frequently observed in severely ill patients in association with autoimmune, neoplastic, cardiovascular or chronic liver diseases, as well as viral infection or sepsis (7,8,15,16). EDTA-dependent PTCP is reported to occur in 
0.2% of asymptomatic individuals, but the incidence may be as high as 1.9% in hospitalized patients (17). No correlation between patient age or sex has been found. No consistent association has been confirmed between particular pathophysiological conditions or medications.
Most of the agglutinins react most strongly at room temperature and are IgG in 30% of cases, IgA in 40% and IgM in only 10% (10). The normal bleeding time, absence of physical findings or positive medical histories, absence of autoimmune markers, and normal mean platelet volume, lead to the supposition that the low platelet count was spurious. Examination of the peripheral blood smear provides definitive evidence of PTCP in the form of overt platelet clumping. A simple, inexpensive and quick diagnostic method consists of evaluating the platelet number in a blood sample immediately after blood withdrawal without using an anticoagulant. Failure to recognize PTCP leads to unnecessary diagnostic tests, unnecessary therapies such as steroid administration and splenectomy, delay in treatment and unwarranted exposure to transfusion-related complications (11,12). In addition, the presence of PTCP can mask true thrombocytopenia.
In our case, the cause of PTCP was not clarified. Cases of PTCP associated with chronic liver disease or cirrhosis have been reported (7,8,15). Although histopathological investigation was available only postmortem, our patient was considered to have cirrhosis secondary to hepatitis C virus infection, which may have been a cause of PTCP. In addition, because there have been several cases of PTCP associated with malignancies, HCC itself was also a possible cause. However, the abrupt occurrence of PTCP calls for the discussion of potential triggers. In our case, PTCP emerged a few days after TAE. Arterio-hepatic venous shunts caused portal hypertension and massive ascites. The marked reduction of the latter after TAE suggests a decrease in portal pressure and possibly rapid changes in systemic hemodynamics, which could have been a trigger for PTCP. In addition, Katsushima et al. (6) reported the release of various kinds of cytokines and marked changes in the concentrations of coagulants and anticoagulants after TAE, which may also have caused or triggerred PTCP in our case. On the other hand, there have been several case reports of drug-induced PTCP, although the mechanism is unknown. Valproic acid, olanzapine, 1-desamino-8-D-arginine (DDAVP) and mexiletine have been reported to cause PTCP. Several reports have also described PTCP occurring after antibiotic administration (18–20). The use of antibiotics should be considered as a possible cause of PTCP in our case. In previous reports, PTCP occurred a few days after antibiotic administration and continued for several weeks or months. The patterns of changes in platelet counts were similar to that of our case. However, these patients had different general conditions and medical backgrounds from ours.
In the treatment of HCC, differentiation between PTCP and real thrombocytopenia is important to prevent unnecessary tests, therapies and delay in treatment when abnormally low platelet counts are observed. If a patient presents a rapid progression of thrombocytopenia, we should evaluate hemorrhagic diathesis, platelet dysfunction and the platelet number in a blood sample immediately after blood withdrawal without using anticoagulant, in order to make differential diagnosis between DIC and PTCP.
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References |
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