Condition

Platelet Disorders in Liver Disease

Editors: Elliot Tapper MD; Zbigniew Fedorowicz PhD, MSc, DPH, BDS, LDSRCS; William Aird MD

Next Section >

Background Information

Description

  • low platelet count (thrombocytopenia) or altered platelet function in patients with chronic liver disease (CLD)
  • thrombocytopenia in CLD is due to multiple causes; including hypersplenism, low thrombopoietin, bone marrow suppression, and reduced platelet survival; it is typically associated with cirrhosis, but may also occur as a result of specific triggers such as viral infection or alcohol
  • thrombocytopenia in CLD is typically mild or moderate in severity
  • altered platelet function may either increase or decrease clotting, depending on severity of cirrhosis (Hematology Am Soc Hematol Educ Program 2015;2015:243)

Definitions

  • thrombocytopenia defined as platelet count < 2.5th percentile of normal platelet count range
    • traditional cutoff for lower limit is 150 × 109/L
    • cutoff 100 × 109/L may be more appropriate to identify specific pathologic condition
    • cutoff < 150 × 109/L may be more appropriate in non-Western countries
    • Reference - Hematology Am Soc Hematol Educ Program 2012;2012:191
  • thrombocytopenia severity based on platelet count
    • mild - 70 to 150 × 109/L
    • moderate - 20 to 70 × 109/L
    • severe - < 20 × 109/L
    • Reference - Am Fam Physician 2012 Mar 15;85(6):612
  • compensated cirrhosis - absence of ascites, variceal hemorrhage, or encephalopathy (Child Pugh class A)
  • decompensated cirrhosis - presence of ascites, variceal hemorrhage, or encephalopathy (Child Pugh class B/C)

Epidemiology

Who is Most Affected

  • more common in patients with decompensated cirrhosis compared with compensated cirrhosis (Am J Gastroenterol 2000 Oct;95(10):2936)
  • hepatitis C virus-related immune thrombocytopenia more common in women

Incidence/Prevalence

  • thrombocytopenia is the most common hematological abnormality in patients with chronic liver disease (CLD), especially those with cirrhosis or fibrosis,
  • prevalence of thrombocytopenia depends on type of liver disease; reported in about,,
    • 6% of patients with chronic hepatitis
    • 77%-85% of patients with cirrhosis
      • 13% moderate thrombocytopenia
      • 1% severe thrombocytopenia
  • prevalence of thrombocytopenia depends on stage of cirrhosis
    • 5.5% in patients with stage 0–II fibrosis 64% in patients with stage III-IV fibrosis
    • Reference - Am J Gastroenterol 2000 Oct;95(10):2936
  • patients with cirrhosis - in cohort of 213 adult patients (< 75 years old) with compensated cirrhosis and portal hypertension, 197 patients (92%) had thrombocytopenia at median follow-up 54.9 months (78% at baseline and 16% developed); other baseline blood counts included
    • thrombocytopenia only in 46.5%
    • no cytopenias in 15.9%
    • thrombocytopenia and leukopenia in 15.5%
    • anemia and thrombocytopenia in 9.4%
    • thrombocytopenia, leukopenia, and anemia in 6.6%
    • anemia only in 4.7%
    • leukopenia only in 0.9%
    • anemia and leukopenia in 0.5%
    • Reference - Clin Gastroenterol Hepatol 2009 Jun;7(6):689
  • in persons with hepatitis C virus (HCV) infection, rate of immune thrombocytopenia is 30.2 per 100,000 person-years, compared to 18.5 per 100,000 person-years in persons without HCV infection

Associated Conditions

  • anemia and leukopenia (Semin Hematol 2013 Jul;50(3):216)
  • coagulopathy of liver disease (Hematology Am Soc Hematol Educ Program 2015;2015:243)

Etiology and Pathogenesis

Causes

General Causes of Thrombocytopenia
  • thrombocytopenia may occur as a result of
Causes of Thrombocytopenia in Liver Disease
  • in liver disease, causes of thrombocytopenia include,
    • decreased platelet production
      • reduced thrombopoietin (TPO) levels - occurs in patients with cirrhosis
      • bone marrow suppression
        • excessive alcohol ingestion
        • hepatitis C virus (HCV) and other viral infections
        • antiviral treatment-induced myelosuppression
      • other drugs
        • azathioprine
        • antibiotics
        • interferon
    • increased platelet destruction
      • antiplatelet antibodies
        • increased in patients with cirrhosis
        • ITP may occur in patients with
          • primary biliary cirrhosis
          • HCV
      • drug-induced thrombocytopenia
      • reduced ADAMTS13 levels - reported in patients with cirrhosis
      • consumption of activated platelets secondary to cirrhosis-related hypercoagulability (Hematology Am Soc Hematol Educ Program 2015;2015:243)
    • increased platelet sequestration - hypersplenism secondary to portal hypertension in patients with cirrhosis
Causes of Platelet Dysfunction in Chronic Liver Disease
  • impaired platelet activation
    • endotoxemia (, Hematology Am Soc Hematol Educ Program 2015;2015:243)
    • intrinsic platelet defect (Hepatology 1988 Nov-Dec;8(6):1620)
  • enhanced platelet activation
    • elevated von Willebrand factor (vWF) levels
      • acute phase response
      • reduced ADAMTS13 levels (synthesized by the liver; cleaves highly active vWF multimers)
      • Reference - World J Gastroenterol 2016 Jan 28;22(4):1541
    • endotoxemia (Hepatology 2017 Feb;65(2):571)

Pathogenesis

Normal Platelet Production and Function
  • platelet production primarily regulated by thrombopoietin (TPO); other regulators include interleukin (IL)-3, IL-6, and IL-11
  • TPO,
    • stimulates differentiation of stem cells along the megakaryocytic pathway, leading to megakaryocyte maturation and platelet release into the circulation
    • produced mainly by hepatocytes, at a constant rate regardless of platelet count
    • circulating levels are regulated by a negative feedback mechanism in which TPO levels are inversely proportional to the platelet mass
      • binding of TPO to the TPO receptor (c-mpl) on platelets and megakaryocytes leads to the internalization and destruction of TPO
      • reduced TPO results in reduced stimulation of thrombopoiesis
      • the resulting elevation in platelet cell mass leads to increased removal of TPO, reducing its circulation level
  • normal platelet functions include
    • adhesion to the site of vascular injury by binding to the multimeric adhesive protein von Willebrand factor (vWF)
    • support thrombin generation by assembling activated clotting factors on their surface
    • Reference -
      • Hematology Am Soc Hematol Educ Program 2015;2015:243
      • Dig Liver Dis 2016 May;48(5):455
Hemostatic Balance in Chronic Liver Disease
  • chronic liver disease is associated with
    • reduced synthesis of procoagulants
    • reduced synthesis of anticoagulants
    • increased production of vWF
    • thrombocytopenia
    • impaired platelet function
    • Reference - Dig Liver Dis 2016 May;48(5):455
  • the net effect of these changes is rebalanced hemostasis
    • hemostatic equilibrium is unstable
    • can be altered towards either bleeding or thrombosis, depending on clinical conditions
    • Reference - Dig Liver Dis 2016 May;48(5):455
  • bleeding propensity with thrombocytopenia may be offset in part by
    • increased activation state of platelets
    • increased vWF levels
    • reduced ADAMTS13 levels
    • Reference -
      • World J Gastroenterol 2016 Jan 28;22(4):1541
      • J Hepatol 2013 Oct;59(4):889, commentary can be found in J Hepatol 2013 Oct;59(4):912
Pathogenesis According to Changes in Production, Destruction, and Sequestration
  • decreased production - in patients witch cirrhosis,
    • reduced mRNA levels of TPO in liver tissue, causing decreased circulating TPO levels and reduced platelet production
    • serum TPO levels decreased in patients with cirrhosis and thrombocytopenia compared to patients with cirrhosis and normal platelet counts
    • TPO levels are inversely correlated with liver function
    • TPO levels often undetectable in patients with cirrhosis prior to transplantation
      • TPO levels increase immediately after transplantation
      • platelet count and TPO levels normalize in most patients within 14 days
    • Reference - Hematology Am Soc Hematol Educ Program 2015;2015:243
  • hypersplenism,,
    • in the cirrhotic liver, liver cell dysfunction and scarring leads to reduced blood flow through the portal vein, causing portal vein hypertension and splenomegaly
    • splenomegaly results in platelet sequestration and subsequent thrombocytopenia
    • sequestered platelets bind and remove TPO from the circulation, resulting in lower TPO level, further accentuating thrombocytopenia
    • evidence for an association between platelet count and spleen size in patients with cirrhosis is conflicting
  • increased platelet destruction,,
    • autoantibodies
      • patients with chronic liver disease have autoantibodies against platelet surface antigens
      • hepatitis C virus (HCV)-induced cirrhosis associated with higher levels of antiplatelet antibodies
      • autoantibodies may increase platelet removal by the splenic and hepatic reticuloendothelial system, leading to thrombocytopenia
      • inconsistent evidence for association between the presence of antiplatelet antibodies and thrombocytopenia
      • autoantibodies may contribute to immune-mediated thrombocytopenia in patients with chronic liver disease; however, thrombocytopenia caused by liver cirrhosis is typically less severe than that in immune thrombocytopenia
    • levels and activity of ADAMTS13 are reduced in patients with advanced cirrhosis
      • low ADAMTS13 levels may lead to accumulation of ultra large von Willebrand factor multimers (UL-VWFM)
      • high UL-VWFM promotes high shear-stress-induced platelet aggregation
      • low platelet counts in cirrhosis are correlated with decreased levels of ADAMTS13 activity
Pathogenesis According to Underlying Disease
  • in cirrhosis, the primary mechanisms for thrombocytopenia include
    • decreased production of TPO in the liver
    • splenic sequestration of platelets
  • alcohol-induced thrombocytopenia,
    • alcohol has direct toxic effect on the bone marrow, leading to ineffective megakaryopoiesis
    • platelet life span is decreased by excessive alcohol exposure
    • after alcohol withdrawal, platelet counts typically rise within 5–7 days and normalize in a few weeks
  • virus-induced thrombocytopenia,,
    • viruses, such as HCV, are reported to have direct myelosuppressive effects
    • hepatitis A virus, hepatitis B virus, and HCV have been shown to inhibit the growth and differentiation of human bone marrow progenitor cells in vitro
    • decreased HCV viral load after interferon alfa treatment reported to significantly increase platelet count
    • HCV can directly bind to platelet membrane through cell surface receptors
      • anti-HCV antibodies then bind to the HCV-coated platelets, causing phagocytosis and increased clearance of platelets by the reticuloendothelial system
      • HCV can also induce neoantigens on the platelet surface or drive alterations in the platelet membrane glycoproteins (GPs), causing the formation of autoantibodies against platelet membrane GPs, such as GPIIb/IIIa, and subsequent development of immune thrombocytopenia
Platelet Dysfunction in Chronic Liver Disease
  • several platelet function defects in liver disease have been identified, but the clinical significance of these defects remains unproven (Hematology Am Soc Hematol Educ Program 2015;2015:243)
  • qualitative platelet defects in cirrhosis correlate with Child Pugh class
    • defective adhesion to the subendothelium of injured vessels (similar to uremia); this may be partially offset by
      • high levels of von Willebrand factor
      • increased ADAMTS13
    • impaired aggregation to stimuli (such as ADP, thrombin, collagen, epinephrine, or ristocetin)
    • reduced activation in response to appropriate stimuli owing to
      • abnormally low levels of prothrombotic signaling molecules (platelet factor 4, beta-thromboglobulin, and serotonin) in dense granules (storage pool defect)
      • excessive secretion of ATP, which antagonizes ADP-induced activation and desensitization of receptor P2Y12 resulting in lower intracellular ionized calcium levels
      • intracellular accumulation of cyclic nucleotides which result in lower concentrations of inositol phosphate and calcium and less production of thromboxane and serotonin
    • Reference -
      • J Hepatol 2013 Oct;59(4):889, editorial can be found in J Hepatol 2013 Oct;59(4):912
      • Hematology Am Soc Hematol Educ Program 2015;2015:243
  • qualitative platelet defects may be caused by endotoxemia secondary to portosystemic shunting and gut barrier disruption (J Hepatol 2013 Oct;59(4):889), editorial can be found in J Hepatol 2013 Oct;59(4):912
  • endotoxemia-mediated platelet activation may contribute to thrombotic complications occurring in cirrhosis (Hepatology 2017 Feb;65(2):571)
  • cirrhosis is associated with increased platelet-derived microparticles, which may contribute to hypercoagulability of early cirrhosis (J Hepatol 2013 Oct;59(4):889), editorial can be found in J Hepatol 2013 Oct;59(4):912
Next Section >

Published by EBSCO Information Services. Copyright © 2025, EBSCO Information Services. All rights reserved. No part of this may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without permission.

EBSCO Information Services accepts no liability for advice or information given herein or errors/omissions in the text. It is merely intended as a general informational overview of the subject for the healthcare professional.

DynaMed Levels of Evidence

Quickly find and determine the quality of the evidence.

DynaMed provides easy-to-interpret Level of Evidence labels so users can quickly find and determine the quality of the best available evidence. Evidence may be labeled in one of three levels:

1Level 1 (likely reliable) Evidence
Representing research results addressing clinical outcomes and meeting an extensive set of quality criteria which minimizes bias.
There are two types of conclusions which can earn a Level 1 label: levels of evidence for conclusions derived from individual studies and levels of evidence for conclusions regarding a body of evidence.
2Level 2 (mid-level) Evidence
Representing research results addressing clinical outcomes, and using some method of scientific investigation, but not meeting the quality criteria to achieve Level 1 evidence labeling.
3Level 3 (lacking direct) Evidence
Representing reports that are not based on scientific analysis of clinical outcomes. Examples include case series, case reports, expert opinion, and conclusions extrapolated indirectly from scientific studies.

Grades of Recommendation

Guideline producers are now frequently using classification approaches for their evidence and recommendations, and these classifications are recognized and requested by guideline users. When summarizing guideline recommendations for DynaMed users, the DynaMed Editors are using the guideline-specific classifications and providing guideline classification approach when this is done.

Download the full version of Levels of Evidence