New insights into the coagulopathy of liver disease and liver transplantation

INTRODUCTION The liver plays several key roles in blood coagulation being involved in both primary and secondary hemostasis[1]. It is the site of synthesis of all coagulation factors and their inhibitors except for von Willebrand factor (vWf)[2]. Liver da…     

Blood transfusion requirements after liver biopsy.

It is common practice to type and screen the blood before performing a percutaneous liver biopsy. Many practitioners think that this is unnecessary but do not have a reason to change their practice. The requirements for transfusion after biopsy were determined in a consecutive sample of cases at a tertiary care teaching hospital with the use of health record review and the anecdotal recall of gastroenterologists and others performing biopsies. One of 266 liver biopsies required a transfusion after biopsy over a two-year period. One other case of hemorrhage with a fatal outcome was recalled by several individuals. It is concluded that the incidence of significant hemorrhage after liver biopsy is low, and that it may not be necessary to type and screen the blood of low risk patients before biopsy.     

Coagulopathy and transfusion therapy in pediatric liver transplantation

Bleeding and coagulopathy are critical issues complicating pediatric liver transplantation and contributing to morbidity and mortality in the cirrhotic child. The complexity of coagulopathy in the pediatric patient is illustrated by the interaction between three basic models. The first model, developmental hemostasis, demonstrates how a different balance between pro- and anticoagulation factors leads to a normal hemostatic capacity in the pediatric patient at various ages. The second, the cell based model of coagulation, takes into account the interaction between plasma proteins and cells. In the last, the concept of rebalanced coagulation highlights how the reduction of both pro- and anticoagulation factors leads to a normal, although unstable, coagulation profile. This new concept has led to the development of novel techniques used to analyze the coagulation capacity of whole blood for all patients. For example, viscoelastic methodologies are increasingly used on adult patients to test hemostatic capacity and to guide transfusion protocols. However, results are often confounding or have limited impact on morbidity and mortality. Moreover, data from pediatric patients remain inadequate. In addition, several interventions have been proposed to limit blood loss during transplantation, including the use of antifibrinolytic drugs and surgical techniques, such as the piggyback and lowering the central venous pressure during the hepatic dissection phase. The rationale for the use of these interventions is quite solid and has led to their incorporation into clinical practice; yet few of them have been rigorously tested in adults, let alone in children. Finally, the postoperative period in pediatric cohorts of patients has been characterized by an enhanced risk of hepatic vessel thrombosis. Thrombosis in fact remains the primary cause of early graft failure and re-transplantation within the first 30 d following surgery, and it occurs despite prolongation of standard coagulation assays. Data, however, are currently lacking regarding the use of anti-aggregation/anticoagulation therapies and how to best monitor for thrombosis in the early postoperative period in pediatric patients. Therefore, further studies are necessary to elucidate the interaction between the development of the coagulation system and cirrhosis in children. Moreover, strategies to optimize blood transfusion and anticoagulation must be tested specifically in pediatric patients. In conclusion, data from the adult world can be translated with difficulty into the pediatric field as indication for transplantation, baseline pathologies and levels of pro- and anticoagulation factors are not comparable between the two populations.     

The coagulopathy of massive transfusion

Recently, the Groupe d'Intérêt en Hémostase Périopératoire reviewed the pathophysiology of coagulopathy in massively transfused, adult and previously haemostatically competent patients in both elective surgical and trauma settings. In this article, we focus on our main observations. First, in most cases, the onset and severity of coagulopathy associated with massive transfusion differs depending on whether haemorrhage occurs as a result of trauma or elective surgery. In trauma patients, tissue trauma is uncontrolled, the interval between haemorrhage and treatment can vary widely, hypovolemia, shock and hypothermia are frequent, and coagulopathy is often related to the development of disseminated intravascular coagulation. Monitoring of haemostasis occurs late, when coagulopathy is installed, and treatment can be very difficult. In elective surgery patients, the situation remains controlled and, in most cases, a decrease in fibrinogen concentration is observed initially while thrombocytopenia is a late occurrence. Monitoring of haemostasis is ongoing and treatment is usually much simpler. Second, blood products have changed over time and this has affected the management of the bleeding patient. Contrary to the recommendations of studies published at a time when whole blood was readily available, the first line of treatment (at least in elective surgery patients) ought to be with fresh-frozen plasma to correct decreased levels of coagulation factors. The role of recombinant activated factor VII to treat bleeding that cannot be controlled by conventional measures remains to be clarified. Coagulopathy associated with massive transfusion remains an important clinical problem. Treatment strategies must be adapted to the context and to the blood products available. Nevertheless, the level of evidence supporting specific treatment options is low and more studies are required to guide our management of massively transfused patients.     

Photochemically treated fresh frozen plasma for transfusion of patients with acquired coagulopathy of liver disease

An ex vivo photochemical treatment (PCT) process was developed to inactivate pathogens in fresh frozen plasma (PCT-FFP). A prospective, controlled, double-blinded, randomized study was conducted to evaluate the efficacy and safety of PCT-FFP compared with conventional FFP (C-FFP). Patients (n = 121) with acquired coagulopathy, largely due to liver disease, including hepatic transplantation, were transfused with either PCT-FFP or C-FFP for up to 7 days. Primary end points were changes in the prothrombin time (PT) and the partial thromboplastin time (PTT) in response to the first FFP transfusion. Secondary analyses compared changes in the PT and the PTT, factor VII levels, clinical hemostasis, blood component usage, and safety following FFP transfusions for up to 7 days. Following the first transfusion, correction in the PT and PTT adjusted for FFP dose and patient weight was not different. Changes in the PT were equivalent between treatment groups (P = .002 by noninferiority). Equivalence was not demonstrated for changes in the PTT. Following multiple transfusions, correction of the PT and the PTT was similar between groups. No differences were observed in use of blood components, clinical hemostasis, or safety. These results suggest PCT-FFP supported hemostasis in the treatment of acquired coagulopathy similarly to conventional FFP.     

Thrombocytopenia post liver transplantation. Correlations with pre-operative platelet count, blood transfusion requirements, allograft function and outcome.

This study reports that thrombocytopenia is a universal phenomenon post hepatic transplantation. In 53 consecutive adult patients undergoing liver transplantation the platelet count fell by a mean of 63% (157 x 10(9)/l to 50 x 10(9)/l). The platelet count reached a nadir at Day 5 post-transplant but returned to pre-operative levels by Day 14. Non-parametric regression analysis found that pre-operative platelet count, blood transfusion requirements and maximum post-operative ALT values were independent predictors of the percentage fall in platelet count. No correlation was seen with length of graft cold ischaemic time or the use of University of Wisconsin (UW) solution. The nadir day correlated with maximum post-operative bilirubin and ALT, graft ischaemic time and use of UW solution. Maximum post-operative ALT was also an independent predictor of nadir platelet count. It was observed that patients who did not survive the hospital admission had lower post-operative platelet counts and these did not return to pre-operative levels by Day 14. The percentage fall in platelet count was an independent predictor of survival. Severe thrombocytopenia was associated with cerebral haemorrhage in 3 patients. This report provides evidence that allograft dysfunction (maximum post-operative bilirubin and/or AST/ALT) was the most consistent independent predictor of the nadir platelet count, nadir day and percentage fall in platelet count post liver transplantation although the exact mechanism(s) of the platelet changes remain uncertain.     

Heparin‐like effect contributes to the coagulopathy in patients with acute liver failure undergoing liver transplantation

Introduction: Liver transplantation (LT) in cirrhotics is characterized by severe coagulopathy, associated with a well documented heparin‐like effect (HLE) seen by thromboelastography (TEG^?) after reperfusion. The amount of HLE present in patients with acute liver failure (ALF) and its role in their bleeding tendency before LT has not been investigated. Aim: To investigate the presence and extent of HLE in patients with ALF undergoing LT and to compare the extent of HLE in this group with a group of cirrhotics undergoing LT. Material and Methods: Ten consecutive ALF and 10 cirrhotic patients undergoing LT were included. TEG^? (with and without heparinase I), surrogate total thrombin generation (TTG) derived by TEG^? and haemodynamic variables were recorded for every stage of the LT. HLE was defined as a correction of r+k times on TEG^? of more than 50% by the addition of heparinase I. Results: Before incision, patients with ALF showed a significantly greater HLE compared with patients with cirrhosis (r+k time: 66 min corrected to 29 vs 45 min corrected to 32 min, P=0.001). After reperfusion, all the patients showed extensive HLE, without any difference between the two groups. Despite the greater HLE, patients with ALF showed similar TTG compared with the cirrhotic group. By the end of the operation, the extent of the HLE was greatly reduced in both the groups. Conclusions: Before transplantation, patients with ALF have a greater HLE than patients with liver cirrhosis. However, this did not affect the thrombin generation calculated by TEG^? and resolved after transplantation.     

Engraftment and transfusion requirements after allogeneic marrow transplantation for patients with acute non-lymphocytic leukemia in first complete remission

This retrospective study analysed factors affecting engraftment and transfusion requirements of platelets and red blood cells in 303 patients transplanted for acute non-lymphocytic leukemia in first remission from HLA-identical or one-antigen mismatched donors. Multivariant analysis showed that the most important factors affecting the speed of engraftment were drugs used for graft-versus-host disease (GVHD) prophylaxis, the development of acute GVHD and HLA matching. Factors affecting only granulocyte recovery included patient age and sex. The radiation regimen used for preparing patients affected the time to platelet independence. Patients transplanted in laminar airflow rooms took longer to achieve red cell independence and required more units of red cells and platelets than patients transplanted in regular rooms. In addition, ABO incompatibility affected red cell transfusion requirements while GVHD prophylaxis and acute GVHD influenced both red blood cells and platelet support.     

原位肝移植患者围手术期成分输血探讨

目的:探讨原位肝移植围手术期成分输血疗效及手术前血液成分的准备,总结成分输血经验,降低用血量,减少输血反应。方法:44例肝移植患者来自不同的地区,其中1例来自韩国的患者,1例蒙古族患者;2例行肝肾联合移植的患者。部分受体与供体之间有血缘关系,ABO、RH血型相合。将44例肝移植患者按照病情诊断,分为肝硬化组18例(40.1%),男13例、女5例;肝恶性肿瘤组26例(59.1%),男24例、女2例。根据患者手术中、手术后的不同出血情况,给予不同的血液成分治疗,所用红细胞悬液均进行白细胞过滤。结果:肝硬化组成分用血量大于肝恶性肿瘤组(肝癌)。不同病情的肝移植患者需要的血液成分差异很大。讨论:术前明确患者的诊断及病程,探讨患者围手术期的出血量,提供安全、合理、有效的成分输血治疗,应用白细胞过滤技术,减少输血反应,降低输血总量是保障原位肝移植手术取得成功的关键环节。     

The effects of splenectomy on engraftment and platelet transfusion requirements in patients with chronic myelogenous leukemia undergoing marrow transplantation

Granulocyte and platelet recovery as well as platelet transfusion requirements following allogeneic marrow transplantation were analyzed in 67 patients with chronic myelogenous leukemia in the chronic phase. Twenty patients had splenectomy prior to transplantation. Forty-seven patients were transplanted without splenectomy, 21 of whom had splenic enlargement by physical examination. There were no differences in the proportion of patients with granulocyte recovery, but the recovery of peripheral granulocytes to levels of 200, 500 and 1,000/mm3 occurred more rapidly in the splenectomy group than in the no-splenectomy group. Patients with splenectomy received platelet transfusions for a mean of 10 (2-36) days as compared to 20 (3-82) days for patients without splenectomy (p less than .001). Eighteen (90%) patients with splenectomy became platelet transfusion independent at a median of 16 (2-32) days after transplantation as compared to 40 (85%) patients without splenectomy who became transfusion independent at a median of 28 (15-86) days (p less than .001). The proportion of patients achieving platelet levels of 50 and 100 X 10(3)/mm3 did not differ between the two groups (p = .07), but patients in the splenectomy group achieved these levels more rapidly following transplant (p less than .001). One of 17 evaluable patients in the splenectomy group and 31 of 46 in the no-splenectomy group became refractory to random platelets (p less than .001) and required platelets from family members or unrelated completely or partially HLA matched donors. In the no-splenectomy group, splenic size did not affect the speed of granulocyte or platelet recovery or platelet transfusion requirements.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epithelioid hemangioendothelioma of the liver associated with thrombocytopenia and coagulopathy

Epithelioid hemangioendothelioma of the liver is a rare vascular neoplasm with intermediate malignant potential. The prognosis is highly unpredictable. We report the case of a 59-year-old woman who had the tumor radically resected, but multiple metastases of the liver developed associated with thrombocytopenia and consumption coagulopathy, as observed in Kasabach-Merritt syndrome. The patient did not respond to any treatment and the behavior of the tumor was very aggressive. The patient died 15 months after radical resection of the tumor.     

The impact of donor type and ABO incompatibility on transfusion requirements after nonmyeloablative haematopoietic cell transplantation

We retrospectively analyzed transfusion requirements within the first 100 d among allogeneic haematopoietic cell transplantation (HCT) recipients with haematological malignancies given either myeloablative (n = 1353) or nonmyeloablative conditioning (n = 503). We confirmed that myeloablative recipients required more platelet and red blood cell (RBC) transfusions than nonmyeloablative recipients (P < 0·0001 for both). Myeloablative patients given peripheral blood stem cells required less platelet transfusions (P < 0·0001) than those given marrow while RBC transfusion requirements did not differ significantly. Subsequent analyses were restricted to nonmyeloablative recipients. Platelet and RBC transfusions were less frequent among related compared to unrelated recipients (P < 0·0001 for both), with comparable median numbers of transfused units. Major/bidirectionally ABO‐mismatched recipients required more RBC transfusions than ABO‐matched recipients (P = 0·006). Rates of graft rejection/failure, grades II–IV acute and chronic graft‐versus‐host‐disease (GVHD), 2‐year relapse, 3‐year survivals and non‐relapse mortality were comparable among ABO‐matched, minor‐mismatched, and major/bidirectionally mismatched recipients (P = 0·93, 0·72, 0·57, 0·36, 0·17 and 0·79, respectively). Times to disappearance of anti‐donor IgG and IgM isohemagglutinins among major/bidirectionally ABO‐mismatched recipients were affected by magnitude of pre‐HCT titres (P < 0·001 for both) but not GVHD (P = 0·71 and 0·78, respectively). In conclusion, nonmyeloablative recipients required fewer platelet and RBC transfusions and among them, both unrelated and major/bidirectionally ABO‐mismatched recipients required more RBC transfusions. ABO incompatibility did not affect nonmyeloablative HCT outcomes.     

Perioperative blood transfusion decreases long-term survival in pediatric living donor liver transplantation

BACKGROUNDThe impact of perioperative blood transfusion on short- and long-term outcomes in pediatric living donor liver transplantation (PLDLT) must still be ascertained, mainly among young children. Clinical and surgical postoperative complications related to perioperative blood transfusion are well described up to three months after adult liver transplantation.AIMTo determine whether transfusion is associated with early and late postoperative complications and mortality in small patients undergoing PLDLT.METHODSWe evaluated the effects of perioperative transfusion on postoperative complications in recipients up to 20 kg of body weight, submitted to PLDLT. A total of 240 patients were retrospectively allocated into two groups according to postoperative complications: Minor complications (n = 109) and major complications (n = 131). Multiple logistic regression analysis identified the volume of perioperative packed red blood cells (RBC) transfusion as the only independent risk factor for major postoperative complications. The receiver operating characteristic curve was drawn to identify the optimal volume of the perioperative RBC transfusion related to the presence of major postoperative complications, defining a cutoff point of 27.5 mL/kg. Subsequently, patients were reallocated to a low-volume transfusion group (LTr; n = 103, RBC ≤ 27.5 mL/kg) and a high-volume transfusion group (HTr; n = 137, RBC > 27.5 mL/kg) so that the outcome could be analyzed.RESULTSHigh-volume transfusion was associated with an increased number of major complications and mortality during hospitalization up to a 10-year follow-up period. During a short-term period, the HTr showed an increase in major infectious, cardiovascular, respiratory, and bleeding complications, with a decrease in rejection complications compared to the LTr. Over a long-term period, the HTr showed an increase in major infectious, cardiovascular, respiratory, and minor neoplastic complications, with a decrease in rejection complications. Additionally, Cox hazard regression found that high-volume RBC transfusion increased the mortality risk by 3.031-fold compared to low-volume transfusion. The Kaplan-Meier survival curves of the studied groups were compared using log-rank tests and the analysis showed significantly decreased graft survival, but with no impact in patient survival related to major complications. On the other hand, there was a significant decrease in both graft and patient survival, with high-volume RBC transfusion.CONCLUSIONTransfusion of RBC volume higher than 27.5 mL/kg during the perioperative period is associated with a significant increase in short- and long-term postoperative morbidity and mortality after PLDLT.     

Hydroxyurea can eliminate transfusion requirements in children with severe beta-thalassemia

Hydroxyurea (HU) enhances fetal hemoglobin (Hb) production. An increase in total Hb level has been repeatedly reported during HU treatment in patients with sickle cell disease and in several patients with beta-thalassemia intermedia. Effects in patients with beta-thalassemia major are controversial. We now report a marked elevation of total Hb levels with HU that permitted regular transfusions to be stopped in 7 children with transfusion-dependent beta-thalassemia. The median follow-up was 19 +/- 3 months (range, 13-21 months). We conclude that HU can eliminate transfusional needs in children with beta-thalassemia major, which could be particularly useful in countries such as Algeria, where supplies of blood or chelating agents are limited.     

自体输血在Rh(D)阴性患者肝移植术中的应用

目的探讨自体输血在Rh（D）阴性患者接受Rh（D）阳性供肝在肝移植术中的应用。方法总结我院实施的3例Rh（D）阴性患者的肝移植围手术期备血、输血经验。结果3例患者肝移植手术均获成功，无一例在围手术期出现溶血反应，3例患者均治愈出院，目前仍在随访中。结论自体输血安全、经济，Rh（D）阴性血型患者不应因为血源不足等原因而失去肝移植的机会。     

HIV-HCV RNA loads and liver failure in coinfected patients with coagulopathy.

BACKGROUND AND OBJECTIVE: The aim of this study was to measure contemporaneously HCV-RNA load, HIV-RNA load and CD4+ lymphocyte count in HCV/HIV coinfected patients with coagulopathy and to examine the relationship between these parameters and the liver failure. DESIGN AND METHODS: A cross-sectional study was performed on 54 patients with severe coagulopathy: 39 HCV/HIV coinfected and 15 HCV+/HIV- comparable for age and HCV exposure time. HCV-RNA and HIV-RNA load, CD4+ lymphocyte count, biochemical and ultrasonographic parameters were evaluated at the time of entry to the study. RESULTS: Mean HCV-RNA load was significantly higher in coinfected patients (643,872 717,687 copies/mL) than in HCV+/HIV- (mean 161,573 276,896 copies/mL) (p = 0.01). The 39 HCV/HIV coinfected patients had a mean HIV-RNA load of 205,913 456,311 copies/mL (range 4,000-2,500,000) and a mean CD4+ lymphocyte count of 206.5171/microL (range 5-693). Five of the 39 (12.8%) coinfected patients had liver failure. In these five patients the mean HCV-RNA load (770,200 996,426 copies/mL) was high but not significantly different from that in the 34 HCV+/HIV+ patients (623,496 682,239 copies/mL) without liver failure (p = 1.0). Coinfected patients with liver failure had a significantly higher HIV-RNA load (mean 764, 599 978,542 copies/mL) and lower CD4+ lymphocyte count (mean 52.655. 6/microL) than those observed in coinfected patients without liver failure (p = 0.007 and p = 0.03, respectively). A significant inverse correlation was found between CD4+ lymphocyte count and HIV-RNA load (r = -0.37, p = 0.01). INTERPRETATION AND CONCLUSIONS: HCV-RNA load is significantly higher in HIV+ than in HIV- patients with coagulopathy. Liver failure was found only in the HCV/HIV coinfected patients with severe immunodepression, expressed either by low CD4+ lymphocyte count or by high HIV-RNA load.