Existence of a platelet-adhesion defect in patients with cirrhosis independent of hematocrit: studies under flow conditions.
Ordinas A,Escolar G,Cirera I,Viñas M,Cobo F,Bosch J,Terés J,Rodés J
Hepatology (Baltimore, Md.)
A defect in hemostasis has been repeatedly reported in patients with cirrhosis. However, the nature of this defect has not been fully characterized. We explored adhesive and cohesive functions of platelets from cirrhotic patients at different stages of disease development. The response of platelets to standard activating agents was tested by aggregometric procedures. The interaction of platelets with subendothelial components was explored in a perfusion system in which blood was exposed (shear rate, 800/s; 10 minutes) to denuded segments of rabbit aorta. Platelet interactions in these perfusions were analyzed morphometrically. Results were always compared with those obtained in similar studies using blood obtained from healthy subjects. Aggregation studies showed abnormal responses for single or several agonists. Abnormalities in aggregation were more evident in patients with severe disease (Child-Pugh class C), although they occasionally were abnormal for single agonists (ADP or U46619) in patients with less severe disease (Child-Pugh classes A or B). All the patient classes showed impaired platelet-subendothelial interactions (P < .01 vs. healthy subjects) that were not justified by the relative thrombocytopenia present in the more severely affected patients. Experimental increases in hematocrit in patients at stages B and C did not improve platelet-subendothelial interactions. Platelets from cirrhotic patients interact defectively with subendothelial components under flow conditions. The adhesion defect is more evident and consistent than the aggregation defects and may already be present in patients with mild liver failure. This adhesion defect may contribute to the defective hemostasis observed in cirrhotic patients.
Defective aggregation in cirrhosis is independent of in vivo platelet activation.
Laffi G,Cinotti S,Filimberti E,Ciabattoni G,Caporale R,Marra F,Melani L,Grossi A,Carloni V,Gentilini P
Journal of hepatology
BACKGROUND/AIMS:Platelet function abnormalities contribute to the hemostatic defect in patients with cirrhosis. In this study we evaluated the occurrence of in vivo platelet activation as a possible mechanism of defective platelet aggregation in patients with cirrhosis. METHODS:Nine patients with severe (Child B-C) cirrhosis and defective platelet aggregation were studied in comparison with age- and sex-matched healthy controls. The presence of activated platelets in the bloodstream was evaluated by fluorescence-activated flow cytometry using antibodies directed against activation-dependent platelet proteins and by measuring plasma levels of beta-thromboglobulin and platelet factor 4. Urinary levels of 11-dehydro-TXB2 and of 2,3-dinor-TXB2 were assayed by radioimmunoassay following chromatographic separation. RESULTS:In unstimulated platelets, the expression of both GMP 140 and GP 53 was not significantly different in patients with cirrhosis and in controls. After stimulation with ADP and epinephrine, expression of activation-dependent antigens was lower in platelets from patients (GMP 140: 0.64 +/- 0.09 vs 0.73 +/- 0.04, p = 0.02; GP 53: 0.41 +/- 0.13 vs 0.54 +/- 0.14). Plasma levels of beta-thromboglobulin and platelet factor 4, as indexes of in vivo platelet activation, were also comparable in the two groups of subjects. Urinary levels of 11-dehydro-TXB2 and of 2,3-dinor-TXB2, the major systemic metabolites of TXA2, were significantly higher in patients with cirrhosis (1807 +/- 518 vs 341 +/- 121 ng/pg creatinine and 693 +/- 512 vs 205 (93 ng/pg creatinine, respectively, p < 0.001). However, increased excretion of TXB2 metabolites was also observed in three patients with chronic autoimmune thrombocytopenia. CONCLUSIONS:These data indicate that circulating platelets are not activated in cirrhosis, and that defective aggregation is most likely dependent on the alteration of the transmembrane signaling pathways. The increased urinary excretion of systemic TXA2 metabolites may be related to increased intrasplenic platelet destruction.
Alcohol abuse and alcoholic liver cirrhosis leading to spontaneous muscle hematoma: an event fraught with danger.
Mangla Ankit,Hamad Hussein,Yadav Udit,Telfer Margaret
Case reports in gastroenterology
Alcohol abuse is associated with both potentiating and antagonizing hemostatic states. Liver cirrhosis is an independent causal factor for many bleeding complications. The long-term effects of alcohol abuse coupled with advanced liver cirrhosis are additive in favor of bleeding. We report the case of a patient with a history of alcohol abuse who presented with liver cirrhosis and nontraumatic muscle hematoma diagnosed as a spontaneous hematoma of the gastrocnemius muscle. He was managed conservatively with infusions of fresh frozen plasma and platelets, which resulted in resolution of the hematoma. The pathogenesis of 'spontaneous' muscle hematoma remains anecdotal, but since it is reported in patients on anticoagulant therapy or with hemostatic disorders, it is hypothetically related to severely deranged coagulation. Here we review the relevant literature pertaining to the pathogenesis, presentation and treatment options available for treating this often fatal complication of bleeding diatheses.
Review article: thrombocytopenia in chronic liver disease.
Alimentary pharmacology & therapeutics
BACKGROUND:Thrombocytopenia is a common finding in advanced liver disease. It is predominantly a result of portal hypertension and platelet sequestration in the enlarged spleen, but other mechanisms may contribute. The liver is the site of thrombopoietin (TPO) synthesis, a hormone that leads to proliferation and differentiation of megakaryocytes and platelet formation. Reduced TPO production further reduces measurable serum platelet counts. AIM:This paper describes the scope of thrombocytopenia in chronic liver disease and assesses the clinical impact in this patient population. METHODS:A medline review of the literature was performed pertaining to thrombocytopenia and advanced liver disease. This data is compiled into a review of the impact of low platelets in liver disease. RESULTS:The incidence of thrombocytopenia, its impact on clinical decision making and the use of platelet transfusions are addressed. Emerging novel therapeutics for thrombocytopenia is also discussed. CONCLUSIONS:Thrombocytopenia is a common and challenging clinical disorder in patients with chronic liver disease. New therapeutic options are needed to safely increase platelet counts prior to invasive medical procedures as well as to counteract therapies that further exacerbate low platelets, such as interferon. An ideal compound would be orally available and safe, with rapid onset of action.
Platelet activation in patients with chronic hepatitis C.
Fusegawa Hisae,Shiraishi Koichi,Ogasawara Fusao,Shimizu Mie,Haruki Yasuo,Miyachi Hayato,Matsuzaki Shohei,Ando Yasuhiko
The Tokai journal of experimental and clinical medicine
OBJECTIVE:To elucidate the mechanisms of thrombocytopenia in chronic hepatitis C (CHC), we investigated platelet activation in patients with chronic viral liver diseases. METHODS:Platelet activation was evaluated with flow cytometry in twenty-five patients with chronic viral hepatitis and 11 patients with liver cirrhosis of viral etiology. Liver biopsies were carried out in all patients. RESULTS:The platelet counts decreased significantly in patients with CHC and in patients with liver cirrhosis compared to controls, but not in patients with chronic hepatitis B (CHB). Patients with CHC had a significantly higher percentage of platelets positive for activation-dependent monoclonal antibodies (MoAbs), and also had a higher percentage of platelet microparticles (PMP), a marker of platelet activation, than patients with CHB. There was a significant correlation between the percentage of PMP and the levels of liver fibrosis markers, such as serum hyaluronate and N-terminal propeptide of type III procollagen (P-III-P), in CHC, suggesting the relationship between platelet activation and liver fibrosis. Platelet activation was markedly enhanced in CHC patients with high histological scores of liver fibrosis. CONCLUSION:Patients with CHC have increased platelet activation, which may contribute to the occurrence of thrombocytopenia in CHC. Liver fibrosis may play a role in activation of platelets in CHC.
[Coagulation management in patients with liver disease].
Bienholz A,Canbay A,Saner F H
Medizinische Klinik, Intensivmedizin und Notfallmedizin
BACKGROUND:End-stage liver disease is associated with complex alterations in hemostasis. Whereas prognosis is essentially affected by life-threatening bleeding complications in some patients, others, especially those with cholestatic liver diseases, suffer from thromboembolic complications. Standard laboratory values (SLVS; prothrombin time, activated partial thrombin time, platelet count) cannot sufficiently reflect the altered balance of pro- and anticoagulatory factors. Moreover, a couple of studies indicated that SLVS are not able to predict bleeding complications in patients with acute liver failure or decompensated liver cirrhosis. DIAGNOSIS AND THERAPY:Use of bed-side coagulation diagnostics such as thrombelastometry/-graphy, detection of thrombocyte function by multiple electrode aggregometry and selective measurement of single factors allows a targeted and causal therapy of hepatic coagulopathies especially in the context of bleeding complications or surgical interventions. In recent years, coagulation management guided by these new devices has contributed to a reduction in transfusion of allogenic blood products, which may be associated with undesirable side effects. DISCUSSION:The current review summarizes the complex pathophysiological alterations of hemostasis associated with advanced liver insufficiency and discusses recent upcoming diagnostics and coagulation management in this patient cohort.
Association of coagulopathy with the risk of bleeding after invasive procedures in liver cirrhosis.
Li Jing,Han Bing,Li Hongyu,Deng Han,Méndez-Sánchez Nahum,Guo Xiaozhong,Qi Xingshun
Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association
Background/Aim:Bleeding risk among patients with acute or chronic liver disease after invasive procedures is a common concern in clinical practice. This retrospective study aimed to explore whether the presence of coagulopathy increased the risk of major bleeding after invasive procedures in cirrhosis. Patients and Methods:A total of 874 cirrhotic patients underwent invasive procedures. Coagulopathy was defined as international normalized ratio (INR) ≥1.5 and/or platelets (PLTs) ≤50 × 10/L. Severe thrombocytopenia was defined as PLTs ≤ 50 × 10/L. Invasive procedures, major bleeding after invasive procedures, and in-hospital deaths were recorded. Results:In all, 296 patients (33.9%) had coagulopathy. Major bleeding after invasive procedures occurred in 21 patients (2.4%). Major bleeding after invasive procedures was more frequent in patients with coagulopathy than those without coagulopathy (4.1% vs 1.6%, P = 0.023). Major bleeding after invasive procedures was more frequent in patients with severe thrombocytopenia than those without severe thrombocytopenia (4.9% vs 1.6%, P = 0.008). Incidence of major bleeding after invasive procedures was not significantly different between patients with INR ≥ 1.5 and INR < 1.5 (4.5% vs 2.0%, P = 0.065). Patients with INR ≥1.5 had a significantly higher in-hospital mortality than those with INR < 1.5 (6.4% vs 1.3%, P < 0.001). Conclusion:Severe thrombocytopenia significantly increased the risk of major bleeding after invasive procedures in cirrhosis. INR ≥ 1.5 significantly increased in-hospital mortality.
Bleeding after invasive procedures is rare and unpredicted by platelet counts in cirrhotic patients with thrombocytopenia.
Napolitano Grazia,Iacobellis Angelo,Merla Antonio,Niro Grazia,Valvano Maria Rosa,Terracciano Fulvia,Siena Domenico,Caruso Mariangela,Ippolito Antonio,Mannuccio Pier Mannucci,Andriulli Angelo
European journal of internal medicine
BACKGROUND:In cirrhotics with low circulating platelets (PLT), restoration of normal cell counts has been traditionally recommended before invasive procedures. However, there is neither consensus on the PLT transfusion threshold nor evidence of its clinical efficacy. PATIENTS:In order to fill this gap of knowledge, we prospectively collected and analyzed data on circulating PLT counts [and International Normalized Ratio (INR)] values in a case series of 363 cirrhotics scheduled to undergo invasive investigations. PLT and/or fresh-frozen plasma (FFP) units were infused at the discretion of the attending physician, and the occurrence of post-procedural bleeding was related to pre-and post-infusion results. RESULTS:852 Procedures were carried out in 363 cirrhotics sub-grouped according to the Child-Pugh-Turcotte (CPT) classification (class A/B/C: 124/154/85). The infusion of PLT and/or FFP improved only marginally circulating PLT counts and INR values. Ten post-procedural bleeds occurred in the whole case series, i.e. 1 episode every 85 procedures or every 36 patients. Post-procedural bleeding was unrelated to the PLT counts, to the degree of INR abnormalities, nor to the CPT classes, but was more frequent in patients who underwent repeated investigations. In the 10 patients with the most profound alterations in PLT and/or INR values, no post-procedural bleeding occurred. CONCLUSIONS:In cirrhotic patients with low PLT and/or abnormal INR values undergoing invasive investigations, post-procedural bleeding was rare and unpredicted by PLT counts or abnormal INR values. In particular, the recommendation to infuse platelets when counts are <50×10/L is not substantiated by this case series of cirrhotic patients.
Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function.
Hayward C P M,Harrison P,Cattaneo M,Ortel T L,Rao A K,
Journal of thrombosis and haemostasis : JTH
BACKGROUND:Closure time (CT), measured by platelet function analyzer (PFA-100) device, is now available to the clinical laboratory as a possible alternative or supplement to the bleeding time test. AIM:On behalf of the Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH-SSC), a working Group was formed to review and make recommendations on the use of the PFA-100 CT in the evaluation of platelet function within the clinical laboratory. METHODS:The Medline database was searched to review the published information on the PFA-100 CT in the evaluation of platelet disorders and platelet function. This information, and expert opinion, was used to prepare a report and generate consensus recommendations. RESULTS:Although the PFA-100 CT is abnormal in some forms of platelet disorders, the test does not have sufficient sensitivity or specificity to be used as a screening tool for platelet disorders. A role of the PFA-100 CT in therapeutic monitoring of platelet function remains to be established. CONCLUSIONS:The PFA-100 closure time should be considered optional in the evaluation of platelet disorders and function, and its use in therapeutic monitoring of platelet function is currently best restricted to research studies and prospective clinical trials.
Evaluation of platelet kinetics in patients with liver cirrhosis: similarity to idiopathic thrombocytopenic purpura.
Kajihara Mikio,Okazaki Yuka,Kato Shinzo,Ishii Hiromasa,Kawakami Yutaka,Ikeda Yasuo,Kuwana Masataka
Journal of gastroenterology and hepatology
BACKGROUND:Thrombocytopenia is a common manifestation of liver cirrhosis (LC), but its underlying mechanism is not fully understood. The purpose of the present paper was to evaluate the platelet kinetics in LC patients by examining several non-invasive convenient markers. METHODS:Fifty-seven LC patients, 32 patients with idiopathic thrombocytopenic purpura (ITP), 12 with aplastic anemia (AA), and 29 healthy individuals were studied. Plasma thrombopoietin was measured by enzyme-linked immunosorbent assay. Absolute reticulated platelet (RP) count and plasma glycocalicin were used as indices for thrombopoiesis, and the indices for platelet turnover were the RP proportion and the plasma glycocalicin normalized to the individual platelet count (GCI). RESULTS:There was no difference in thrombopoietin levels between LC patients and healthy controls. The RP proportion and GCI were significantly higher and the absolute RP count and glycocalicin significantly lower in LC patients than in healthy controls. These markers in ITP and LC patients were comparable, but significantly different from those in AA patients. The bone marrow megakaryocyte density in LC and ITP patients was similar, and significantly higher than in AA patients. CONCLUSIONS:Cirrhotic thrombocytopenia is a multifactorial condition involving accelerated platelet turnover and moderately impaired thrombopoiesis. Thrombopoietin deficiency is unlikely to be the primary contributor to cirrhotic thrombocytopenia.
Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction?
Violi F,Basili S,Raparelli V,Chowdary P,Gatt A,Burroughs A K
Journal of hepatology
Patients with cirrhosis can have abnormalities in laboratory tests reflecting changes in primary haemostasis, including bleeding time, platelet function tests, markers of platelet activation, and platelet count. Such changes have been considered particularly relevant in the bleeding complications that occur in cirrhosis. However, several studies have shown that routine diagnostic tests, such as platelet count, bleeding time, PFA-100, thromboelastography are not clinically useful to stratify bleeding risk in patients with cirrhosis. Moreover, treatments used to increase platelet count or to modulate platelet function could potentially do harm. Consequently the optimal management of bleeding complications is still a matter of discussion. Moreover, in the last two decades there has been an increased recognition that not only bleeding but also thrombosis complicates the clinical course of cirrhosis. Thus, we performed a literature search looking at publications studying both qualitative and quantitative aspects of platelet function to verify which primary haemostasis defects occur in cirrhosis. In addition, we evaluated the contribution of qualitative and quantitative aspects of platelet function to the clinical outcome in cirrhosis and their therapeutic management according to the data available in the literature. From the detailed analysis of the literature, it appears clear that primary haemostasis may not be defective in cirrhosis, and a low platelet count should not necessarily be considered as an automatic index of an increased risk of bleeding. Conversely, caution should be observed in patients with severe thrombocytopenia where its correction is advised if bleeding occurs and before invasive diagnostic and therapeutic procedures.
Platelet Count Does Not Predict Bleeding in Cirrhotic Patients: Results from the PRO-LIVER Study.
Basili S,Raparelli V,Napoleone L,Talerico G,Corazza G R,Perticone F,Sacerdoti D,Andriulli A,Licata A,Pietrangelo A,Picardi A,Raimondo G,Violi F,
The American journal of gastroenterology
OBJECTIVES:Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS:We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years. RESULTS:A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child-Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800-1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50 × 10/μl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11-3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16-3.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS:Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients.
Chronic liver disease, thrombocytopenia and procedural bleeding risk; are novel thrombopoietin mimetics the solution?
Olson Sven R,Koprowski Steven,Hum Justine,McCarty Owen J T,DeLoughery Thomas G,Shatzel Joseph J
Chronic liver disease (CLD) alters normal hemostatic and thrombotic systems via multiple mechanisms including reduced platelet function and number, leading to challenging peri-operative planning. Hepatic thrombopoietin (TPO) synthesis is reduced in CLD, leading to several recent randomized, placebo-controlled trials examining the utility of TPO-mimetics to increase platelet counts prior to surgery. While these trials do suggest that TPO-mimetics are efficacious at increasing platelet counts in patients with CLD and have led to several recent drug approvals in this space by the U.S. Food & Drug Administration, it remains unclear whether these results translate to the relevant clinical endpoint of reduced perioperative bleeding rate and severity. In this article, we review several recently-published, phase 3 trials on the TPO-mimetics eltrombopag, avatrombopag and lusutrombopag, and discuss the clinical significance of their results.
The platelet and platelet function testing in liver disease.
Hugenholtz Greg G C,Porte Robert J,Lisman Ton
Clinics in liver disease
Patients who have liver disease commonly present with alterations in platelet number and function. Recent data have questioned the contribution of these changes to bleeding complications in these patients. Modern tests of platelet function revealed compensatory mechanisms for the decreased platelet number and function, the most prominent compensatory mechanism being substantially elevated levels of the adhesive protein von Willebrand's factor. Consequently, standard diagnostic tests of platelet functions seem to be of little use to predict bleeding complication in patients who have liver disease. This article outlines the role of platelet abnormalities and possibilities for platelet function testing in patients who have liver disease.
Platelet production and destruction in liver cirrhosis.
Pradella Paola,Bonetto Stefania,Turchetto Stefano,Uxa Laura,Comar Consuelo,Zorat Francesca,De Angelis Vincenzo,Pozzato Gabriele
Journal of hepatology
BACKGROUND & AIMS:Thrombocytopenia is common in liver cirrhosis (LC) but the mechanisms are not fully understood. The purpose of our work was to evaluate platelet kinetics in LC with different etiologies by examining platelet production and destruction. METHODS:Ninety-one consecutive LC patients (36 HCV, 49 alcoholics, 15 HBV) were enrolled. As controls, 25 subjects with idiopathic thrombocytopenic purpura, 10 subjects with aplastic anemia, and 40 healthy blood donors were studied. Plasma thrombopoietin (TPO) was measured by ELISA. Reticulated platelets (RP) were determined using the Thiazole Orange method. Plasma glycocalicin (GC) was measured using monoclonal antibodies. Platelet associated and serum antiplatelet antibodies were detected by flow cytometry. B-cell monoclonality in PBMC was assessed by immunoglobulin fingerprinting. RESULTS:Serum TPO was significantly lower in LC (29.9±18.1 pg/ml) compared to controls (82.3±47.6 pg/ml). The GC levels were higher in LC (any etiology) than in healthy cases. Conversely, the absolute levels of RP were lower in LC (any etiology) than in healthy controls. The platelet-associated and serum anti-platelet antibodies were higher in HCV+ LC compared to healthy subjects (p<0.0064), alcoholic LC (p<0.018), and HBV+ LC (p<0.0001). B-cell monoclonality was found in 27% of the HCV+LC, while it was not found in HBV+ or alcoholic LC. CONCLUSIONS:Patients with LC present decreased plasma TPO, accelerated platelet turnover, and reduced platelet production. This indicates that LC thrombocytopenia is a multifactorial condition involving both increased platelet clearance and impaired thrombopoiesis.
Blood platelet function abnormalities in cirrhotic patients with esophageal varices in relation to the variceal bleeding history.
Rogalski Pawel,Rogalska-Plonska Magdalena,Wroblewski Eugeniusz,Kostecka-Roslen Ines,Dabrowska Milena,Swidnicka-Siergiejko Agnieszka,Wasielica-Berger Justyna,Cydzik Mariusz,Hirnle Tomasz,Dobrzycki Slawomir,Flisiak Robert,Dabrowski Andrzej
Scandinavian journal of gastroenterology
The study aimed at assessing the effect of thrombocytopenia and platelet function abnormalities on the occurrence of variceal bleeding in patients with cirrhosis. The results of impedance aggregometry, von Willebrand factor antigen level and thromboelastometry (TEM) with and without the addition of a platelet inhibitor (FIBTEM, EXTEM test, respectively) were compared in two patient groups: Group 1 ( = 32) - patients with moderate or large esophageal or gastric varices, who had never had symptoms of acute gastrointestinal bleeding and Group 2 ( = 26) - patients with history of variceal bleeding. Standard clotting test indicated more hypocoagulable profile in Group 2 compared to Group 1. However, no differences in any TEM component were observed between groups in EXTEM test. The contribution of platelets to clot strength was significantly higher in Group 2 than in Group 1 [PLT% = 74.2 (67.5-80.4) versus 68.8 (63.7-76.5) %; = .039]. The aggregation index was also higher in Group 2 compared to Group 1, although not statistically significant [% of healthy = 96.9 (73.2-140.1) versus 67.6 (52.5-118.8) %, = .195]. No differences in vWF antigen levels were observed between groups. The results of thromboelastometry and aggregometry indicate increased contribution of platelets in clot formation in patients with a history of variceal bleeding compared to cirrhotic patients who never bled. Comparable effectiveness of hemostasis in both groups is most likely associated with the compensatory role of platelets. Increased platelet activity in this group of patients is probably due to a mechanism independent of the von Willebrand factor antigen level.