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Incidence of Bleeding Following Invasive Procedures in Patients With Thrombocytopenia and Advanced Liver Disease

      Background & Aims

      Patients with advanced liver disease often undergo invasive procedures, so the combination of thrombocytopenia, coagulopathy, and bleeding should be carefully assessed. We evaluated the prevalence of thrombocytopenia in a series of patients with liver cirrhosis who were being evaluated for orthotopic liver transplantation (OLT) and determined the number of invasive procedures and procedure-related incidences of bleeding in patients with thrombocytopenia.

      Methods

      We studied 121 consecutive patients who were being evaluated for OLT. Thrombocytopenia was defined as a platelet count <150,000/μL and severe thrombocytopenia as a platelet count <75,000/μL. The presence of significant coagulopathy was defined as an international normalized ratio >1.5. Invasive procedures and incidences of procedure-related bleeding were recorded for each patient.

      Results

      The prevalence of thrombocytopenia and severe thrombocytopenia were 84% and 51%, respectively. Among the 102 thrombocytopenic patients, 50 (49%) underwent an invasive procedure (32 with severe thrombocytopenia; 64%). Bleeding occurred in 10 of the patients who underwent an invasive procedure (20%). Among the 50 patients who underwent invasive procedure, 32 had severe thrombocytopenia and 18 had moderate thrombocytopenia. Bleeding occurred in 10 of the 32 patients (31%) with severe thrombocytopenia and in none of those with moderate thrombocytopenia. There was no difference in prevalence of significant coagulopathy between patients with severe thrombocytopenia who underwent invasive procedure and bled (3/10; 30%) and those who did not bleed (10/22; 45%).

      Conclusions

      Thrombocytopenia has a high prevalence among patients with advanced liver disease. Bleeding related to invasive procedures occurs most frequently in patients with severe thrombocytopenia, whereas significant coagulopathy does not seem to be associated with bleeding.

      Keywords

      Abbreviations used in this paper:

      INR (international normalized ratio), MELD (model for end-stage liver disease), OLT (orthotopic liver transplantation)
      In patients with chronic liver disease, thrombocytopenia has a varying prevalence that mainly depends upon the criteria used to define this hematologic abnormality and the severity of the underlying liver disease in the studied population.
      • Giannini E.G.
      Review article: thrombocytopenia in chronic liver disease and pharmacologic treatment options.
      • Giannini E.G.
      • Savarino V.
      Thrombocytopenia in liver disease.
      In several studies, the occurrence of thrombocytopenia has been identified as an event with both diagnostic and prognostic significance for patients with chronic liver disease.
      • Liangpunsakul S.
      • Ulmer B.J.
      • Chalasani N.
      Predictors and implications of severe hypersplenism in patients with cirrhosis.
      • Ioannou G.N.
      • Splan M.F.
      • Weiss N.S.
      • et al.
      Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis.
      • Qumar M.M.
      • Grace N.D.
      • Groszmann R.J.
      • et al.
      Incidence, prevalence, and clinical significance of abnormal hematologic indices in compensated cirrhosis.
      Furthermore, from the practical point of view, the presence of thrombocytopenia has a negative impact on everyday clinical management of patients. Indeed, in patients affected by advanced liver disease, it may represent an obstacle to the performance of invasive procedures, and may be associated with an increased risk of bleeding.
      • De Gottardi A.
      • Thévenot T.
      • Spahr L.
      • et al.
      Risk of complications after abdominal paracentesis in cirrhotic patients: a prospective study.
      Despite these well-known shortcomings, the prevalence and degree of thrombocytopenia in patients with advanced liver disease, its clinical relevance in patients who undergo invasive procedures, and its relationship with coagulation abnormalities and procedure-related bleeding have seldom been assessed. Noteworthy, in this setting there is a general lack of consensus regarding the degree of thrombocytopenia that may be associated with an increased risk of bleeding, and also the relevance of coagulopathy to bleeding risk has recently been challenged.
      • Caldwell S.H.
      • Hoffman M.
      • Lisman T.
      • et al.
      Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management.
      • Tripodi A.
      • Primignani M.
      • Mannucci P.M.
      Abnormalities of hemostasis and bleeding in chronic liver disease: the paradigm is challenged.
      In this study our aim was to evaluate the prevalence of thrombocytopenia and severe thrombocytopenia in a series of patients with liver cirrhosis who were being evaluated for orthotopic liver transplantation (OLT), and to assess the number of invasive procedures and procedure-related bleedings in patients with thrombocytopenia. We further assessed whether the presence of significant coagulopathy was associated with an increased risk of bleeding in this patient population.

      Methods

       Patients

      We studied 121 consecutive patients with cirrhosis who were being evaluated for OLT during a 6-month period (June to November, 2009). Only patients with thrombocytopenia, defined as a platelet count <150,000/μL, were considered for this study. During the 6-month observation period we recorded any invasive procedure performed in these patients, the number of platelets transfused prior to the procedures, and the presence of bleeding secondary to the invasive procedures.

       Methods

      We assessed demographic (age, gender), biochemical (alanine aminotransferase, serum bilirubin, serum albumin, serum creatinine, α-fetoprotein, international normalized ratio [INR]), hematological (hemoglobin, hematocrit, white blood cell count, platelet count), and clinical (presence of: hepatocellular carcinoma, esophageal varices, diabetes mellitus) parameters in all patients. The model for end-stage liver disease (MELD) scores were calculated in all patients.
      • Kamath P.S.
      • Kim W.R.
      Advanced Liver Disease Study Group
      The model for end-stage liver disease (MELD).
      Moderate thrombocytopenia was defined as a platelet count between 150,000/μL and 75,000/μL, while severe thrombocytopenia as a platelet count <75,000/μL. Presence of significant coagulopathy was defined as an INR >1.5. Bleeding was defined as any bleeding requiring: additional and nonexpected hemostatic measures; blood transfusions; hospitalization for patients in whom the procedure was carried out as outpatients; and bleeding-related extension of hospital stay in patients who received the procedure as inpatients.

       Statistical Analysis

      Discrete data are reported as absolute frequency and percentage, and continuous data are reported as mean and standard deviation. The Fisher exact test was used to compare discrete variables, and the Mann–Whitney U test was used to compare continuous variables. Wilcoxon test was used to compare platelet counts before and after transfusions. A 2-tailed P < .05 was considered statistically significant. Statistical analyses were carried out using MedCalc version 5.0 computer software (MedCalc Software, Mariakerke, Belgium).

      Results

      Among the 121 patients being evaluated for OLT during the study period, 102 patients (84%) had thrombocytopenia and therefore represented this study population. Table 1 shows the main characteristics of the 102 study patients. Patients were prevalently male (67 patients, 66%). Esophageal varices were present in 81 patients (79%), and in 27 (33%) they were medium-sized or large. Twenty-nine patients had hepatocellular carcinoma (28%), and 31 patients suffered from diabetes (30%). The majority of patients (85 patients, 83%) had creatinine serum levels within the upper limit of normal range (ie, ≤1.2 mg/dL). Severe thrombocytopenia was observed in 52 patients (51%).
      Table 1Main Characteristics of the Study Population
      MeanStandard deviation
      Age, y569
      ALT, IU/L4940
      Albumin, g/dL3.40.6
      Bilirubin, mg/dL2.52.4
      Creatinine, mg/dL0.990.48
      Hemoglobin, g/dL11.92.2
      Hematocrit, %34.07.6
      White blood cells, n/μL48072329
      Platelet count, n/μL79,00230,954
      INR1.400.24
      αFetoprotein, ng/mL4959
      MELD score225
      Spleen diameter, mm15627
      ALT, alanine aminotransferase.
      Invasive procedures were performed in 50 patients (49%), and were more frequently carried out in patients with severe (32/52, 62%) rather than moderate (18/50, 36%) thrombocytopenia (P = .011). Table 2 shows the type and frequency of invasive procedures that were carried out in these patients. Procedure-related bleedings occurred in 10 patients (20%), and were more likely to occur in patients with severe thrombocytopenia (10/32, 31%) rather than moderate (0/18, 0%) thrombocytopenia (P = .008, Figure 1). Bleeding occurred during or after the following invasive procedures: endoscopic polypectomy (2 patients), dental extraction (4 patients), transcatheter arterial chemoembolization (1 patient), radiofrequency thermal ablation of hepatocellular carcinoma (1 patient), endoscopic gastric biopsies (1 patient), and large volume paracentesis (1 patient). Six patients required red blood cell transfusions because of postprocedural bleeding, and all bleeding episodes were treated conservatively and required no surgical intervention. We recorded no bleeding-related deaths. The presence of significant coagulopathy (ie, INR >1.5) was not differently distributed between patients who underwent invasive procedures and bled (3/10 patients, 30%) and those who did not bleed (14/40 patients, 35%). None of the patients received fresh frozen plasma transfusion to correct coagulopathy.
      Table 2Type of Invasive Procedures Subdivided According to the Degree of Thrombocytopenia
      Platelet count
      <75,000/μL (n = 32)>75,000/μL (n = 18)
      Endoscopic variceal ligation99
      TACE83
      TIPS32
      Dental extraction40
      Large volume paracentesis31
      Endoscopic polypectomy21
      RFTA11
      Thyroid biopsy10
      Endoscopic gastric biopsies10
      Liver biopsy01
      RFTA, radiofrequency thermal ablation; TACE, transcatheter arterial chemoembolization; TIPS, transjugular intrahepatic portosystemic shunt.
      Figure thumbnail gr1
      Figure 1Number and proportion of thrombocytopenic patients who had procedure-related bleeding subdivided according to the degree of thrombocytopenia.
      Among the 50 patients who underwent invasive procedures, 7 patients (14%) received a total of 11 prophylactic platelet transfusions, and all these patients had severe thrombocytopenia. There was no significant difference in mean platelet count between patients who received (45,285/μL ± 13,756/μL) and those who did not receive a prophylactic platelet transfusion (51,920/μL ± 13,916/μL) prior to the invasive procedure. Mean platelet counts after platelet transfusion were 60,323/μL ± 18,154/μL. Furthermore, also INR was not different in these 2 groups (1.49 ± 0.26 vs 1.33 ± 0.26).
      As procedure-related bleedings occurred in patients with severe thrombocytopenia alone, in a posthoc analysis we further investigated the presence of additional parameters that were possibly associated with an increased risk of bleeding in this subgroup of 32 patients. Table 3 shows that among demographic, biochemical, hematological, and clinical characteristics there was no additional parameter associated with increased risk of bleeding during invasive procedures in these patients. Both the proportion of patients who received a prophylactic platelet transfusion (40% vs 14%) and the units of platelets transfused per patient receiving a transfusion (2 units/patient vs 1 unit/patient) were greater in patients who bled as compared with those who did not bleed after the procedure. Lastly, the prevalence of significant coagulopathy (ie, INR >1.5) was similarly distributed among bleeders (3/10, 30%) and nonbleeders (10/22, 45%).
      Table 3Characteristics of the 32 Patients With Severe Thrombocytopenia Who Underwent Invasive Procedures, Subdivided According to the Occurrence of Procedure-Related Bleeding
      UnitBleeders (n = 10)Nonbleeders (n = 22)P
      AgeYears56 ± 958 ± 8NS
      GenderMale8 (80%)14 (64%)NS
      ALTIU/L44 ± 2458 ± 62NS
      Albuming/dL3.3 ± 0.43.4 ± 0.7NS
      Bilirubinmg/dL1.8 ± 0.82.5 ± 1.9NS
      Creatininemg/dL0.8 ± 0.20.9 ± 0.3NS
      Hemoglobing/dL12.3 ± 1.211.7 ± 1.9NS
      Hematocrit%35.5 ± 3.633.7 ± 5.6NS
      White blood cellsn/μL4242 ± 26283674 ± 1842NS
      Platelet countn/μL50,200 ± 12,30850,591 ± 14,895NS
      INR1.36 ± 0.211.49 ± 0.27NS
      αFetoproteinng/mL16 ± 1628 ± 50NS
      MELD score20 ± 423 ± 6NS
      DiabetesYes1 (10%)5 (23%)NS
      Hepatocellular carcinomaYes5 (50%)8 (36%)NS
      Esophageal varicesYes6 (60%)19 (86%)NS
      Platelet transfusionYes4 (40%)3 (14%)NS
      NOTE. Continuous data are shown as mean and standard deviation and categorical data as absolute count and percentage.
      ALT, alanine aminotransferase; NS, not significant.

      Discussion

      In this study, carried out in clinical practice, we have shown that thrombocytopenia has a relevant impact on the management of cirrhotic patients being evaluated for OLT who undergo invasive procedures. Expectedly, we observed that the prevalence of thrombocytopenia in this patient population is quite high (84%), and we also observed that more than half of the patients had severe thrombocytopenia.
      • Giannini E.G.
      Review article: thrombocytopenia in chronic liver disease and pharmacologic treatment options.
      • Liangpunsakul S.
      • Ulmer B.J.
      • Chalasani N.
      Predictors and implications of severe hypersplenism in patients with cirrhosis.
      • Qumar M.M.
      • Grace N.D.
      • Groszmann R.J.
      • et al.
      Incidence, prevalence, and clinical significance of abnormal hematologic indices in compensated cirrhosis.
      We found that a significant proportion of these patients (49%) underwent several invasive procedures, and this was associated with an increased risk of bleeding that was especially relevant in patients with severe thrombocytopenia. As bleeding may have a negative impact on patient prognosis, these findings have important implications for the clinical management of cirrhotic patients on the OLT waiting list.
      The results of this study show that the presence of severe thrombocytopenia is not perceived as a major obstacle to the performance of invasive procedures, as these are carried out even more frequently in thrombocytopenic patients with a severe decrease in platelet count as compared with patients with moderate thrombocytopenia. However, we found that patients with severe thrombocytopenia have a significantly greater likelihood of procedure-related bleeding as compared with patients with less severe thrombocytopenia. Noteworthy, among the variables that we assessed, platelet count seems to be the only determinant of bleeding, as in a posthoc analysis we were not able to identify any additional parameters associated with bleeding in patients with severe thrombocytopenia. In particular, the presence of significant coagulopathy was not associated with an increased risk of bleeding, thus further confirming recent findings that challenge the usefulness of this coagulation parameter in assessing the bleeding risk of cirrhotic patients.
      • Tripodi A.
      • Primignani M.
      • Mannucci P.M.
      Abnormalities of hemostasis and bleeding in chronic liver disease: the paradigm is challenged.
      • Lisman T.
      • Leebeek F.W.G.
      • de Groot P.G.
      Haemostatic abnormalities in patients with liver disease.
      • Tripodi A.
      • Mannucci P.M.
      Abnormalities of hemostasis in chronic liver disease: reappraisal of their clinical significance and need for clinical and laboratory research.
      Lastly, we also investigated the association between decreased hematocrit, a parameter that may represent an additive risk factor for bleeding in patients with cirrhosis due to the decreased rheologic effects of erythrocytes, and bleeding though we found none.
      • Ordinas A.
      • Escolar G.
      • Cirera I.
      • et al.
      Existence of a platelet-adhesion defect in patients with cirrhosis independent of hematocrit: studies under flow conditions.
      • Valeri C.R.
      • Cassidy G.
      • Pivacek L.E.
      • et al.
      Anemia-induced increase in the bleeding time: implications for treatment of nonsurgical blood loss.
      In this study series, we have pointed out that prophylactic platelet transfusions were performed in at least 14% of patients who underwent an invasive procedure. The invasive procedures performed in this study cohort reflect the “real world” conditions, and are those usually carried out in patients with advanced liver disease. However, the indications and transfusion triggers for platelet transfusions in this specific patient population and setting are not specifically addressed by current guidelines, and even among experts there is no general agreement on this topic.
      • Caldwell S.H.
      • Hoffman M.
      • Lisman T.
      • et al.
      Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management.
      • Slichter S.J.
      Relationship between platelet count and bleeding risk in thrombocytopenic patients.
      We observed that both platelet count and INR were not significantly different between patients who received prophylactic platelet transfusion and those who did not. Furthermore, platelet transfusion only minimally led to an increase in platelet counts in these patients, prophylactic platelet transfusions were more frequently administered to patients who bled after the procedure, and patients who bled despite receiving a transfusion received a greater number of platelet units per patient prior to the procedure as compared with patients who did not bleed. These findings seem to emphasize the fact that in this specific clinical setting patients may receive platelet transfusions without a meaningful increase in platelet count, and that current transfusion practice does not seem to be associated with a decreased risk of bleeding, suggesting that eventuality of legal concerns after treatment may drive the decision to transfuse patients.
      • Caldwell S.H.
      • Hoffman M.
      • Lisman T.
      • et al.
      Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management.
      Commonly, patients who are being considered for OLT, or are on OLT waiting list, undergo several invasive procedures that may increase their risk of bleeding, and of being transfused with platelets and red blood cells. In these patients, repeated transfusions may be associated with alloimmunization that may complicate further transfusions and OLT, and therefore detailed guidelines are particularly needed in this specific clinical setting.
      • Rebulla P.
      Platelet transfusion trigger in difficult patients [erratum in: 2002;9:109].
      • Pereboom I.T.A.
      • Lisman T.
      • Porte R.J.
      Platelets in liver transplantation: friend or foe?.
      This study undoubtedly has some drawbacks. The platelet count cutoff that we used to define a priori severe thrombocytopenia is derived from a previous study carried out in a similar setting that identified a platelet count <75,000/μL as a parameter associated with negative prognostic significance.
      • Liangpunsakul S.
      • Ulmer B.J.
      • Chalasani N.
      Predictors and implications of severe hypersplenism in patients with cirrhosis.
      We are aware that, despite a lack of consensus on this argument,
      • Caldwell S.H.
      • Hoffman M.
      • Lisman T.
      • et al.
      Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management.
      not every physician may agree with our definition of severe thrombocytopenia. Furthermore, we did not perform a detailed assessment of coagulation parameters in our patients in order to identify specific coagulation defects, and that a hyperfibrinolytic state has been described in some decompensated cirrhotic patients.
      • Lisman T.
      • Leebeek F.W.G.
      • de Groot P.G.
      Haemostatic abnormalities in patients with liver disease.
      • Tripodi A.
      • Mannucci P.M.
      Abnormalities of hemostasis in chronic liver disease: reappraisal of their clinical significance and need for clinical and laboratory research.
      However, we simply defined significant coagulopathy as the presence of an INR >1.5 as this is what generally happens in clinical practice, and we feel that this renders the study more similar to everyday clinical activity in centers evaluating cirrhotic patients for OLT.
      In summary, we found that thrombocytopenia is a frequent and relevant clinical problem in cirrhotic patients being evaluated for OLT. These patients frequently undergo invasive procedures that may increase their risk of bleeding and require platelet transfusions. The risk of procedure-associated bleeding is significantly greater in patients with a platelet count <75,000μL, and there seems to be no additional biochemical and clinical parameters that are associated with a greater likelihood of bleeding. Particular attention should be paid to patients with severe thrombocytopenia that require invasive procedures, while the presence of increased INR does not seem to be a clinically relevant problem.

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