Literature review.

 Pub Med
 NCBI
 Up to date. – get references

Look at studies done.

Mech of platelet dysfunction in liver cirrhosis…..

 Site reference…copy an paste info

Rough draft, and discuss what you learned into a rough draft…… 10days

 Paraphase
 Studies

Look at conclusions of those studies

 Copy paste parts of conclusion that it matters to you.

This study shows rat epithelium can can express this…if rats have it, we could have it.

Etc.

Doesn’t create vitamin K.

======================================================

Mech of platelet dysfunction in liver cirrhosis…..

The role of platelet transfusion in cirrhotic patients. Mainly we are looking to

address:
For: Tristan

1.focus on the background mechanisms of coagulopathy in liver disease.

https://www.uptodate.com/contents/pathogenesis-of-hepatic-
fibrosis?search=liver%20cirrhosis%20and%20platelet&source=search_result&selectedTitle=5~150&usag
e_type=default&display_rank=5
INTRODUCTION — Fibrosis is a wound healing response in which damaged regions are
encapsulated by an extracellular matrix or scar. It develops in almost all patients with chronic
liver injury at variable rates depending in part upon the cause of liver disease and host factors
[1-4].

Fibrosis occurs earliest in regions where injury is most severe, particularly in chronic
inflammatory liver disease due to alcohol or viral infection. As an example, pericentral injury is a
hallmark of alcoholic hepatitis; the development of pericentral fibrosis (also known as sclerosing
hyaline necrosis or perivenular fibrosis) is an early marker of likely progression to panlobular
cirrhosis [5].

Impaired hemostasis — Patients with liver disease are a heterogenous population, and
multiple abnormalities of hemostatic function may coexist in an individual patient.

Coagulation factor defects — The liver is the site of production of almost all of the numbered
coagulation factors including fibrinogen (factor I), thrombin (factor II), and upstream factors V,
VII, IX, X, and XI. Notable exceptions are factor VIII, which is produced in endothelial cells, and
the factor XIII A-subunit, which is produced in the bone marrow [3,16]. In addition to
synthesizing coagulation proteins, hepatocytes also make post-translational
modifications such as glycosylation and gamma-carboxylation of some factors. Both
synthesis and post-translational modification may be impaired in liver disease, affecting
coagulation factor abundance and function, respectively. (See "Vitamin K and the synthesis
and function of gamma-carboxyglutamic acid".)

In some patients with liver disease, particularly those actively using alcohol, vitamin K deficiency
can further exacerbate deficiencies of vitamin K-dependent factors (II [prothrombin], VII, IX, and
X) and/or lead to improper modifications (eg, under-gamma carboxylation of prothrombin) [4].
Dysfibrinogenemia may also contribute to the bleeding risk [4].

Thrombocytopenia and platelet dysfunction — Patients with liver disease may have normal
platelet counts (ie, ≥150,000/microL) or varying degrees of thrombocytopenia. Mild
thrombocytopenia (eg, platelet count between 100,000 and 150,000/microL) has been reported
in up to 75 percent of patients with chronic liver disease, and moderate thrombocytopenia (eg,
between 50,000 and 100,000/microL) has been reported in approximately 13 percent of
individuals with cirrhosis [5,17]. The correlation between platelet count and clinical bleeding is
weak, especially for counts >50,000/microL.

The mechanism of thrombocytopenia in liver disease may include impaired platelet production,
from decreased hepatic synthesis of thrombopoietin; bone marrow suppression, from hepatitis C
virus (HCV) infection or alcohol use, other infection, or antiviral or antibiotic therapy; and
increased platelet sequestration in the spleen, in the setting of portal hypertension and
hypersplenism [5]. (See "Biology and physiology of thrombopoietin" and "Extrahepatic
manifestations of hepatitis C virus infection" and "Approach to the adult with splenomegaly and
other splenic disorders", section on 'Hypersplenism'.)
In addition to thrombocytopenia, individuals with advanced liver disease may have reduced
platelet function due to coexisting uremia, infection, and/orendothelial abnormalities.
(See "Platelet dysfunction in uremia" and "Vascular endothelial function and fundamental
mechanisms of fibrinolysis (thrombolysis)".)

The overall incidence of infection in patients with liver disease has been estimated to be as high
as 30 percent [18]. Overt sepsis or low levels of endotoxemia can impair platelet function in
patients with cirrhosis. Moreover, infection has been associated with increases in endogenous
glycosaminoglycans known as heparinoids (eg, heparan sulphate, dermatan sulphate), which
can act as anticoagulants; these increases may result from changes in nitric oxide metabolism
or other endothelial changes [19,20].

Increased fibrinolysis — Fibrinolysis (dissolution of the fibrin clot) is often increased in

liver disease. Evidence of systemic fibrinolysis can be detected in 30 to 46 percent of
patients with chronic liver disease and parallels the degree of liver dysfunction. However,
clinically evident hyperfibrinolysis is less common and has been estimated to occur in 5 to 10
percent of those with decompensated cirrhosis [21-23]. Hyperfibrinolysis promotes
premature clot dissolution and interferes with clot formation due to the consumption of
clotting factors.

Hyperfibrinolysis overlaps with a condition in cirrhosis that resembles disseminated

intravascular coagulation (DIC), called "accelerated intravascular coagulation and fibrinolysis
(AICF)," but it can be evident as a distinct clinical entity with intractable bleeding following
puncture wounds or dental extractions, or on occasion without any recognizable trauma [24].
However, the lack of a commonly available means to clearly identify this condition (such
as via the use of thromboelastography and thromboelastometry) impedes the evaluation
of hyperfibrinolysis in patients with cirrhosis. Even with these global tests of clot formation
and dissolution, widely accepted criteria for milder cases of hyperfibrinolysis are not yet
established.

Hepatocytes and Kupffer cells are also responsible for clearing coagulation factors and
products of fibrinolysis from the circulation [25]. Thus, chronically impaired liver function
in cirrhosis may be associated with multiple mechanism(s) of increased fibrinolysis:

●Increased levels of tissue plasminogen activator (tPA), which generates plasmin [26].

●Decreased levels of alpha 2 antiplasmin, coagulation factor XIII, and thrombin-activatable

fibrinolysis inhibitor (TAFI) [26].

●Elevated levels of fibrin degradation products such as D-dimer, which further interfere
with normal hemostasis.

●Fibrinolytic activity of ascitic fluid that may be delivered to the systemic circulation via the
thoracic duct [27].
//////////////////////////////////////////////////////////////////////////////////////////////////////////

What are the benefits of platelet transfusions in liver cirrhosis?

https://www.uptodate.com/contents/emerging-therapies-for-hepatic-
fibrosis?source=see_link

DOWNREGULATE STELLATE CELL ACTIVATION — Suppression or reversal of stellate cell

activation has inherent attractiveness as a therapeutic strategy because of the central role that
stellate cells have in fibrogenesis. (See "Pathogenesis of hepatic fibrosis".)

https://www.uptodate.com/contents/pathogenesis-of-hepatic-fibrosis?source=see_link

Kupffer cell infiltration and activation also contribute to stellate cell activation. Kupffer
cells stimulate matrix synthesis, cell proliferation, and release of retinoids by stellate cells
through the actions of cytokines (especially TGF-beta-1) and reactive
oxygen intermediates/lipid peroxides. On the other hand, activated Kupffer cells can also
lead to stellate cell apoptosis by different mechanisms [111].

World J Gastroenterol. 2017 May 14;23(18):3228-3239. doi: 10.3748/wjg.v23.i18.3228.

Platelets in liver disease, cancer and regeneration.

Kurokawa T1, Ohkohchi N1.

https://www.ncbi.nlm.nih.gov/pubmed/28566882; full
article: https://www.wjgnet.com/1007-
9327/full/v23/i18/3228.htm

https://www.wjgnet.com/1007-9327/full/v23/i18/3228.htm

Abstract
Although viral hepatitis treatments have evolved over the years, the resultant liver cirrhosis still
does not completely heal. Platelets contain proteins required for hemostasis, as well as many
growth factors required for organ development, tissue regeneration and repair.
Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD)
and cirrhosis, can manifest from decreased thrombopoietin production and
accelerated platelet destruction caused by hypersplenism; however, the relationship between
thrombocytopenia and hepatic pathogenesis, as well as the role of platelets in CLD, is poorly
understood. In this paper, experimental evidence of platelets improving liver fibrosis and
accelerating liver regeneration is summarized and addressed based on studies conducted in
our laboratory and current progress reports from other investigators. In addition, we describe our
current perspective based on the results of these studies. Platelets improve liver fibrosis by
inactivating hepatic stellate cells, which decreases collagen production. The regenerative
effect of platelets in the liver involves a direct effect on hepatocytes, a cooperative effect
with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on
these observations, we ascertained the direct effect of platelet transfusion on improving several
indicators of liver function in patients with CLD and liver cirrhosis. However, unlike the results
of our previous clinical study, the smaller incremental changes in liver function in patients with CLD
who received eltrombopag for 6 mo were due to patient selection from a heterogeneous population.
We highlight the current knowledge concerning the role of platelets in CLD and cancer and
anticipate a novel application of platelet-based clinical therapies to treat liver disease.

Core tip: Platelets improve liver fibrosis and accelerate liver regeneration;
therefore, patients with liver dysfunction due to chronic liver disease (CLD) and cirrhosis
can benefit from platelet transfusion. However, administration of the thrombopoietin
receptor agonist eltrombopag for 6 mo did not result in the improvement of liver function in
patients with CLD despite its long-term safety and ability to maintain an increased platelet
count. We believe that this difference is due to platelet aging. Therefore, we are pursuing
novel strategies with thrombopoietin receptor agonists and desialylated formulations to
treat liver diseases.

LIVER FIBROSIS AND PLATELETS

Liver fibrogenesis is triggered by destruction of hepatic cells and represents a wound-

healing process leading to excessive deposition of the matrix proteins collagens and elastin,
glycoproteins, proteoglycans and carbohydrates; in the context of chronic liver injury,
fibrosis ultimately results in the substitution of liver tissue with ECM, formation of scar
tissue, and gradual ceasing of hepatic functions[1,36]. Histologically, liver consists of
parenchymal hepatocytes (70%-80%) and non-parenchymal cells such as Kupffer cells,
sinusoidal endothelial cells and stellate cells. Hepatic stellate cells (HSCs) reside in the
perisinusoidal space of the liver, also known as the space of Disse, between hepatocytes
and sinusoidal endothelial cells and are the major fibrogenic cell type in the liver as they
produce a large number of ECM components and secrete transforming growth factor-β
(TGF-β), a key mediator of liver fibrogenesis[1,36].

In the normal liver, HSCs have a star-like morphology corresponding to a quiescent state,
and their primary function is the storage of vitamin A as retinol ester in lipid
droplets[37,38]. In response to liver injury, HSCs undergo activation and change into
contractile myofibroblastic cells, which proliferate, secrete TGF-β, and increase matrix
production. As a result, collagens IV and VI in the space of Disse are progressively replaced
by fibrous collagens I and III and fibronectin, characteristic for ECM remodeling and
fibrosis[39,40].

In our previous study, we revealed a link between the activation of human HSCs and
platelets by showing that platelets and platelet-derived extracts suppressed
transdifferentiation of quiescent HSCs into the myofibroblast-like phenotype as
well as the production of collagen type I via cAMP signaling[31]. The underlying
mechanism is based on the increase of adenosine concentration in the HSC milieu due to
breakdown of ADP and ATP, which are abundant in platelet-dense granules[31]. As a result,
adenosine entering HSCs through its cognate receptors prevents their activation and down-
regulates their ability to secrete TGF-β and deposit the ECM. In addition, interaction
between HSCs and platelets promotes the release of platelet-derived HGF, which was shown
to inhibit the expression of type I collagen in cultured HSCs[41] and to attenuate liver
fibrosis in mice by decreasing hepatic TGF-β secretion and blocking myofibroblast
activation[42]. However, although these findings indicate that platelets can reduce hepatic
fibrogenesis through inhibition of HSC activation, it is unclear whether they can be
translated to the clinical situation, as the production of HGF by human platelets is lower
than that by rodent platelets[43].

TPO is the most important factor in the regulation of megakaryocyte proliferation and
differentiation into platelets through activation of its cognate receptor c-Mpl, also known as
TPO-R[44]. Several agonists of the c-Mpl receptor, such as eltrombopag and romiplostim,
are approved for clinical application as agents by which to increase platelet counts in chronic
immune thrombocytopenia[44,45]. Moreover, they are currently undergoing clinical trials as
treatment options to reduce thrombocytopenia in patients with CLD and liver cirrhosis[46-
48], as the increase in platelet counts could make these patients eligible for interferon-
based antiviral therapy[49,50].

The strategy to treat liver fibrosis in CLD through inhibition of thrombocytopenia

was proved feasible in studies showing that TPO improved both platelet counts
and liver fibrosis, even in conditions of hepatic cirrhosis[30,32]. Thus, in cirrhotic
rats with dimethylnitrosamine-induced liver fibrosis and 70% hepatectomy,
platelet increase by a single intravenous injection of TPO correlated with the inhibition of
HSC activation and decrease of the fibrotic area in the liver, while antiplatelet serum
attenuated hepatic regeneration[30]. In another study, mice with liver fibrosis
induced by carbon tetrachloride (CCl4) showed improvement after weekly
intraperitoneal administration of TPO for 5-8 wk[32].

Although mechanistic insights into the correlation of increased platelet counts with the
reversal of liver fibrosis are yet to be provided, it can be suggested that platelets may
promote hepatocyte proliferation by secreting HGF, which is a potent mitogen for
hepatocytes through activation of the MET receptor that is essential for organogenesis and
wound healing. Moreover, HGF may contribute to the resolution of fibrosis by modulating
levels of TGF-β and matrix metalloproteinases (MMPs), which are the main ECM enzymes
degrading collagen.

The suggested association between platelets, HGF, and hepatic fibrosis is supported by the
findings of Takahashi et al[51], who showed that transfused human platelets improved CCl 4-
induced liver fibrosis in severe combined immune deficiency mice by increasing HGF levels
in the mouse liver, which suppressed HSC activation, induced MMP-9 expression and
inhibited hepatocyte apoptosis.

Liver regeneration and platelets

Liver regeneration is provided by the proliferation of both parenchymal and non-

parenchymal hepatic cells, including hepatocytes, liver sinusoidal endothelial cells (LSECs),
biliary epithelial and Kupffer cells, and HSCs, which contribute to the restoration of
destroyed hepatic tissue[52]. Cell proliferation is triggered by several growth factors and
cytokines, such as HGF, TGF-α, tumor necrosis factor-α (TNF-α), epidermal growth factor
(EGF) and interleukin-6 (IL-6), which activate their cognate receptors and, consequently,
downstream signaling and transcription of the genes associated with cell cycle
progression[52-58]. Among the signaling cascades mediating platelet effects on the process
of liver regeneration, the most important are TNF-α/nuclear factor-kappa B (NF-κB), IL-
6/signal transducer and activator of transcription 3 STAT3, and phosphatidylinositol-3-
kinase (PI3K)/Akt.

Previous studies indicate that platelets can exert positive effects on liver regeneration
through cooperation with LSECs and Kupffer cells, and direct interaction with
hepatocytes.

LSECs mostly consist of sinusoidal cells which, through formation of a continuous thin layer
of the sinusoidal endothelium, create a structural barrier between the hepatic parenchyma
and blood flowing through the liver[59,60]. LSECs play an important role in the
maintenance of hepatic functions by providing exchange of nutrients between circulating
blood and hepatocytes because of the presence of open pores beneath the endothelium[61].
In addition, LSECs secrete immunoregulatory cytokines, including HGF, IL-1, IL-6 and
interferons, affecting liver regeneration. Thus, IL-6 secretion increased following
hepatectomy[62,63] triggers STAT3 phosphorylation in hepatocytes, which up-regulates the
synthesis of acute phase proteins as a part of the mechanism restoring the disturbed
physiological homeostasis[64]. The direct contact of platelets with LSECs stimulated LSEC
proliferation and accelerated DNA synthesis in hepatocytes by inducing IL-6 secretion,
possibly via sphingosine 1-phosphate (S1P), a major bioactive lysophospholipid released
from platelets[29]. S1P is known as a regulator of diverse cellular activities, including
migration, proliferation and cytoskeletal remodeling, and is known to induce STAT3
activation by stimulating IL-6 secretion[65]. Activated platelets secrete high amounts
of S1P which acts on endothelial cells in the processes involving platelet-
endothelial interactions, such as thrombosis, angiogenesis and
atherosclerosis[65,66].

Another type of non-parenchymal cell interacting with platelets is the Kupffer cells,
which constitute over 80% of the tissue macrophages found in the body and act against
gastrointestinal bacteria, microbial debris and endotoxins[67]. Upon activation, Kupffer cells
secrete important growth-stimulating cytokines that promote hepatocyte proliferation after
hepatectomy and induce processes involved in hepatic tissue restoration[68]. Kupffer cells
are the most important source of IL-6 and TNF-α; the latter is increased following
hepatectomy, suggesting that this cytokine as well as its producers (Kupffer cells) are
implicated in the restoration of hepatic function in pathologic conditions. This notion is
supported by the observations that anti-TNF-α antibodies suppressed hepatocyte
proliferation[69], while TNF-α receptor-deficient mice had delayed liver regeneration after
hepatectomy[70,71] because of decreased production of IL-6, which is a key target of TNF-
α receptor activation in the regenerating liver[52]. As Kupffer cells are the most active
producers of both TNF-α and IL-6 in the liver, it is not surprising that Kupffer cell-depleted
mice fail to up-regulate TNF-α and IL-6 secretion after hepatectomy[72].

However, the role of Kupffer cells in liver regeneration is controversial. It has been shown
that the interaction among platelets, Kupffer cells and leukocytes promote endothelial cell
apoptosis in the liver following ischemia/reperfusion[73]. Depletion of Kupffer cells
decreased platelet adherence in sinusoids in rats subjected to ischemia/reperfusion and
attenuated damage to liver endothelium[74], which is consistent with the findings that
platelets adhering to Kupffer cells during the early period of ischemia/reperfusion promoted
hepatocyte apoptosis[75]. Although Nakamura et al[76] reported that in lipopolysaccharide-
injected mice, platelets migrate to the space of Disse, which is mediated by their interaction
with Kupffer cells, and then enter hepatocytes, the role of this process in hepatic
regeneration is unclear. Further studies are needed to elucidate the mechanism underlying
the impact of platelet-Kupffer cell interaction in liver fibrosis. However, it is evident that the
contact between platelets and Kupffer cells cause activation of both cells.

Finally, platelets can induce hepatic regeneration by directly interacting with

hepatocytes. Thus, in thrombocytotic BALB/c mice, platelets accumulate in the liver shortly
after liver resection, causing the regeneration of hepatic tissue even following 90%
hepatectomy and preventing liver failure by promoting cell cycle progression and metabolic
pathways in hepatocytes[77]. Such stimulation of hepatocyte activity is likely a result of
platelet accumulation in the sinusoidal space, from where they flow into the space of
Disse and directly contact hepatocytes[26-28]. These findings suggest that following hepatic
injury, platelets quickly migrate to the liver where they, through direct interaction with
hepatocytes, activate cell cycle transition-related pathways and induce rapid hepatocyte
proliferation. This notion is supported by the study using a co-culture chamber system,
which showed that the contact between platelets and hepatocytes triggered the secretion of
growth factors, including HGF, IGF-1 and VEGF from platelets, which induced hepatocyte
proliferation[20].

We suggest the following mechanistic model explaining the effect of platelets on liver
regeneration. Platelets migrating to the injured liver translocate from the liver sinusoids to
the space of Disse, where, upon interaction with hepatocytes, they secrete HGF, IGF-1 and
VEGF, which induce hepatocyte proliferation, resulting in liver regeneration. However, this
model may not be fully applicable to humans, because human platelets do not secrete
sufficient amounts of HGF[43]; therefore, IGF-1 may be the most important platelet-derived
growth factor involved in the restoration of the human liver.

A recent study suggested an additional mechanism underlying platelet stimulation of liver

regeneration. Thus, Kirschbaum et al[78] showed that transfer of coding or regulatory RNA
could occur between platelets and hepatocytes, promoting hepatocyte proliferation.
However, the role of both mechanisms, i.e. the release of growth factors and/or RNA
transfer from platelets, in liver regeneration needs confirmation in vivo[79,80].

…… a lot more:

CONCLUSION
This editorial suggests the current perspective of novel treatments for liver cirrhosis by
using TPO-R agonists to increase platelet counts in a clinical setting.

There is significant evidence that platelets play a role in improving fibrosis. Upon their
release, the ATP and ADP within platelet dense granules are degraded by HSCs into
adenosine, which is incorporated into the HSCs.

There are three distinct mechanisms of liver regeneration induced by platelets: a

cooperative effect with LSECs; a cooperative effect with Kupffer cells; and a direct effect on
hepatocytes. Additionally, platelet transfusion improves liver function in patients with CLD
and cirrhosis. Despite its safety and maintenance in increasing platelet counts,
administration of the TPO-R agonist eltrombopag for 6 mo did not result in improvements of
liver function in patients with CLD. Therefore, we are planning a new approach to develop
novel strategies with TPO-R agonists and a desialylated formulation for treating liver
diseases for which there are currently no effective treatments except transplantation. Of
course, it is necessary to pay sufficient attention to the onset of thrombosis by excessively
increasing platelets.

https://www.wjgnet.com/1007-9327/full/v23/i18/3228.htm

//////////////////////// BENEFITS
https://www.uptodate.com/contents/clinical-features-diagnosis-
and-treatment-of-disseminated-intravascular-coagulation-in-
adults?sectionName=Prevention%2Ftreatment%20of%20bleeding
&anchor=H27&source=see_link#H27
Prevention/treatment of bleeding — Patients with DIC are at risk of bleeding due to
thrombocytopenia and depletion of coagulation factors. However, it is not possible to reliably
predict which patients will have bleeding. (See 'Pathogenesis' above.)

We do not routinely use prophylactic administration of platelets and coagulation factors in

patients who are not bleeding or who are not at high risk of bleeding, as long as the platelet
count is ≥10,000/microL. This practice is based on the lack of evidence that bleeding can be
prevented by these therapies; the likely transient nature of DIC if the underlying cause is
addressed; and the concomitant increased risk of thrombosis in DIC. One international
consensus group suggested using a platelet count threshold of 20,000/microL in the absence of
bleeding [31].

However, treatment is justified in patients who have serious bleeding, are at high risk for
bleeding (eg, after surgery), or require invasive procedures. Importantly, appropriate treatment
for bleeding should not be withheld for fear of "fueling the fire."

●Patients with serious bleeding or need for urgent/emergent surgery and a platelet
count <50,000/microL should be given platelet transfusions. Typically, we give one to two
units of random donor platelets per 10 kg of body weight, or one single donor apheresis
unit daily. Thresholds for specific surgical procedures are presented separately. The
increase in platelet count may be less than expected due to ongoing platelet consumption.
(See "Clinical and laboratory aspects of platelet transfusion therapy", section on 'TTP or
HIT' and "Clinical and laboratory aspects of platelet transfusion therapy", section on
'Preparation for an invasive procedure'.)

●Patients with a platelet count <10,000/microL should be given platelet transfusions due to
the increased risk of spontaneous bleeding. This degree of thrombocytopenia is rare in
DIC, with the exception of acute promyelocytic leukemia or other conditions associated
with severe bone marrow dysfunction. (See "Clinical and laboratory aspects of platelet
transfusion therapy", section on 'Prevention of spontaneous bleeding'.)

●Patients with serious bleeding and a significantly prolonged prothrombin time (PT) or
activated partial thromboplastin time (aPTT), or a fibrinogen level <50 mg/dL and serious
bleeding, should receive coagulation factor replacement. Options include Fresh Frozen
Plasma (FFP), related plasma products such as Plasma Frozen Within 24 Hours After
Phlebotomy (PF24), or cryoprecipitate. Cryoprecipitate provides a good source of
fibrinogen with significantly less volume load than FFP or PF24 (table 5). (See "Clinical use
of plasma components".)

The specific threshold for transfusion and amount of the product given are individualized to
the specific clinical setting and other patient factors such as volume status and severity of
bleeding. As an example, the following may be appropriate:

•If the plasma fibrinogen level is <100 mg/dL, we administer cryoprecipitate to

increase it to >100 mg/dL.

•If the plasma fibrinogen level is >100 mg/dL and the PT or aPTT remains significantly
elevated, we administer FFP or PF24. The goal is to reduce bleeding, not to normalize
the coagulation tests. Dosing is provided in the table (table 5).
 https://www.uptodate.com/contents/hemostatic-abnormalities-in-patients-with-liver-
disease?sectionName=Bleeding&anchor=H61498824&source=see_link#H61498824

RBCs and platelets – Monitor complete blood count (CBC) with platelet count.

•Transfuse platelets to maintain a platelet count >50,000

to 55,000/microL (>100,000/microL for active, severe, or central nervous system
bleeding).

•Platelet function defects (eg, due to uremia or drugs) may be assessed somewhat by
viscoelastic testing (eg, TEG, ROTEM); however, this has not been adequately
studied in patients with liver disease. If bleeding is severe and platelet function is
thought to be impaired, platelet transfusion may be appropriate. (See "Clinical and
laboratory aspects of platelet transfusion therapy", section on 'Platelet function
defects'.)

•Transfuse RBCs to maintain a hemoglobin level above 7 g/dL. The hemoglobin level
may be used to guide RBC transfusions in individuals without ongoing, active
bleeding. Higher target levels of hemoglobin may be appropriate in certain
circumstances such as with coexisting vascular disease. (See "Indications and
hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Acute
bleeding'.)

//////////////////////////////////////////////////////////////////////
2. What does available data support for threshold of platelets
requiring transfusion prior to procedures etc

2013 Mar;229(3):213-20.
Platelet transfusion improves liver function in patients with
chronic liver disease and cirrhosis. https://www.ncbi.nlm.nih.gov/pubmed/23459612
Platelets contain various growth factors and may play important roles in liver regeneration. Thus,
to investigate whether platelet transfusion improves liver function in patients with CLD
and cirrhosis, we conducted an exploratory clinical trial

/////////////////
Liver Int. 2013 Mar;33(3):362-7. doi: 10.1111/liv.12038. Epub 2012 Dec 11.

Global hemostasis tests in patients with cirrhosis before and after

prophylactic platelet transfusion.
https://www.ncbi.nlm.nih.gov/pubmed/23231699

Abstract
BACKGROUND/AIMS:
Cirrhosis presents with variable degrees of thrombocytopenia that might cause bleeding during
invasive procedures. Transfusion of one standard adult platelet dose is often employed to
prevent bleeding in thrombocytopenia, but the threshold platelet count that is clinically effective
is not well established because clinical studies and laboratory tools to judge on efficacy are
insufficient. However, in vitro studies showed that patients with cirrhosis generate as much
thrombin as healthy individuals provided that their platelet count is at least 100 × 10(9) /L.
CONCLUSIONS:
Infusing one standard adult platelet dose secures only a small increase in platelet count
without normalizing thrombin generation and thromboelastometry tests. To obtain greater
increases in platelet count and normalization of laboratory tests more
intensive platelet transfusions or treatment with non-transfusional drugs are probably
needed.
© 2012 John Wiley & Sons A/S.

//////////////////////
Cochrane Database Syst Rev. 2015 Dec 2;(12):CD011771. doi:
10.1002/14651858.CD011771.pub2.

Comparison of different platelet transfusion thresholds prior to

insertion of central lines in patients with thrombocytopenia.
https://www.ncbi.nlm.nih.gov/pubmed/26627708

Abstract
BACKGROUND:
Patients with a low platelet count (thrombocytopenia) often require the insertion of central lines
(central venous catheters (CVCs)). CVCs have a number of uses; these include: administration of
chemotherapy; intensive monitoring and treatment of critically-ill patients; administration of total
parenteral nutrition; and long-term intermittent intravenous access for patients requiring repeated
treatments. Current practice in many countries is to correct thrombocytopenia
with platelet transfusions prior to CVC insertion, in order to mitigate the risk of serious
procedure-related bleeding. However, the platelet count threshold recommended prior to CVC
insertion varies significantly from country to country. This indicates significant uncertainty
among clinicians of the correct management of these patients. The risk of bleeding after a central
 line insertion appears to be low if an ultrasound-guided technique is used. Patients may therefore
be exposed to the risks of a platelet transfusion without any obvious clinical benefit.

MAIN RESULTS:
One RCT was identified that compared different platelet transfusion thresholds prior to
insertion of a CVC in people with chronic liver disease. This study is still recruiting
participants (expected recruitment: up to 165 participants) and is due to be completed in
December 2017. There were no completed studies. There were no studies that compared
no platelet transfusions to a platelet transfusion threshold.

AUTHORS' CONCLUSIONS:
There is no evidence from RCTs to determine whether platelet transfusions are required
prior to central line insertion in patients with thrombocytopenia, and, if a platelet
transfusion is required, what is the correct platelet transfusion threshold. Further
randomized trials with robust methodology are required to develop the optimal transfusion
strategy for such patients. The one ongoing RCT involving people with cirrhosis will not be
able to answer this review's questions, because it is a small study that assesses one patient
group and does not address all of the comparisons included in this review. To detect an
increase in the proportion of participants who had major bleeding from 1 in 100 to 2 in 100
would require a study containing at least 4634 participants (80% power, 5% significance).

 Format: Abstract

Send to

Cureus. 2017 Oct 24;9(10):e1797. doi: 10.7759/cureus.1797.

Platelet Transfusion Thresholds Among Children Admitted to a

Pediatric Intensive Care Unit.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741280/
Alsheikh B1, Chegondi M2, Totapally B3.

Abstract
Objective To evaluate the threshold for platelet transfusion in children admitted to a pediatric
intensive care unit (PICU). This is a retrospective chart review study, conducted at our tertiary level
PICU and is related to critically ill pediatric patients who required platelet transfusion.
Results A total of 197 transfusion episodes in 64 patients were analyzed. The distribution of
transfusions episodes included hematologic 82% (n=161), surgical 7% (n=13), unstable 8% (n=16),
stable 3% (n=7). The mean standard deviation (SD) of pre-transfusion platelet count (x1000) in all
the patients and children in hematologic, surgical, unstable and stable groups were 29 (22), 29 (19),
47 (46), 28 (19), and 24 (14), respectively. The platelet count threshold for transfusion among the
surgical group was higher compared to hematologic and unstable groups (p <0.001; analysis of
variance (ANOVA) with multiple comparison tests). The mean platelet count during all episodes
increased from 29 (22) to 71 (57) (p <0.05; paired t-test). The post-transfusion increase
in platelet count was significantly higher among surgical and unstable patients compared to
hematologic patients (p <0.001; ANOVA with multiple comparison tests). Conclusion The most
common indication for platelet transfusion in the pediatric intensive care unit (PICU) is the underlying
hematologic condition. The platelet count threshold for transfusion varied with the clinical condition
and is higher among the surgical patients. The rise of platelet count after transfusion was higher
among the surgical and unstable patients.

Conclusion
The most common indication for platelet transfusion in the pediatric intensive care unit (PICU) is
the underlying hematologic condition. The platelet count threshold for transfusion varied
with the clinical condition and is higher among the surgical patients. The rise of platelet
count after transfusion was higher among the surgical and unstable patients.

////////////////////////
Nihon Shokakibyo Gakkai Zasshi. 2017;114(10):1853-1859. doi: 10.11405/nisshoshi.114.1853.

Avoidance of platelet transfusion with readministration of

lusutrombopag before radiofrequency ablation in
hepatocellular carcinoma:a case report.
https://www.ncbi.nlm.nih.gov/pubmed/28978885

[Article in Japanese]

Kotani S1, Kohge N2, Tsukano K2, Ogawa S2, Yamanouchi S2, Kusunoki R2, Aimi M2, Miyaoka
Y1, Fujishiro H2.

Author information
Abstract
Platelet transfusions are generally administered to patients with liver cirrhosis and associated
thrombocytopenia before radiofrequency ablation (RFA). Here, we describe a 77-year-old woman
who was diagnosed with hepatitis C, liver cirrhosis, and hepatocellular carcinoma (HCC) in 2006.
She underwent RFA in October 2014 and October 2015, with platelet transfusions. She was
admitted to our hospital in July 2016 to receive RFA for recurrence of HCC. To avoid platelet
transfusion before RFA, she was administered lusutrombopag. The platelet count increased,
and she did not need a platelet transfusion. In November 2016, computed tomography revealed
that HCC had recurred. Lusutrombopag was readministered to avoid platelet
transfusion before performing RFA. Subsequently, her platelet count increased, platelet
transfusion was avoided, with no side effects. The results obtained in this case are valuable
because there is little information on readministration of lusutrombopag.

PMID:28978885 DOI:10.11405/nisshoshi.114.1853

https://www.uptodate.com/contents/cirrhosis-in-adults-overview-of-complications-
general-management-and-
prognosis?search=liver%20cirrhosis%20and%20platelet&source=search_result&selecte
dTitle=2~150&usage_type=default&display_rank=2

Thrombocytopenia or elevated INR — Patients with cirrhosis frequently have low platelet
counts and elevated international normalized ratios (INRs). Because the liver makes
coagulation factors as well as anticoagulant proteins, liver disease can lead to a hypocoagulable
state or a hypercoagulable state. The relative balance or imbalance of these factors is not
reflected in conventional indices of coagulation, such as the prothrombin time, activated partial
thromboplastin time, or INR. (See "Hemostatic abnormalities in patients with liver disease",
section on 'Effects of hepatic dysfunction'.)

Patients typically only need treatment for thrombocytopenia if an invasive procedure that is
at moderate or high risk for bleeding is planned, or in the setting of active bleeding. It is
reasonable to aim for platelet counts of at least 50,000/microL during moderate-risk
procedures [40] or interventions and platelet counts closer to 100,000/microL in high-risk
situations or in the presence of active bleeding [41]. (See "Hemostatic abnormalities in patients
with liver disease", section on 'Invasive procedure'.)

Because conventional indices of coagulation are not helpful in determining a patient's bleeding
risk, patients who require an invasive procedure that is at moderate or high risk for bleeding or
who have active bleeding may need additional testing, such as a determination of fibrinogen
levels, thromboelastography, or thromboelastometry to guide management. While plasma is
commonly given to patients with chronic liver disease and an elevated INR, plasma infusion
may have adverse effects on portal vein pressures and collateral vessel flow. In addition, the
traditional dose of two units of plasma is unlikely to significantly alter coagulation factor levels.
(See "Clinical use of plasma components", section on 'Plasma products' and "Hemostatic
abnormalities in patients with liver disease", section on 'Common clinical problems'.)
The management of patients with chronic liver disease who require an invasive procedure that
is at moderate or high risk for bleeding, or who have active bleeding, is discussed in detail
elsewhere. (See "Hemostatic abnormalities in patients with liver disease", section on
'Bleeding' and "Hemostatic abnormalities in patients with liver disease", section on 'Invasive
procedure'.)

Preventing and identifying complications — Patients should be monitored for the

development of complications, and when possible, steps should be taken to prevent their
development. In particular, patients should be screened for esophageal varices and
hepatocellular carcinoma. If varices are present, prophylactic treatment with beta blockers or
esophageal variceal ligation is indicated.

Other measures to decrease the risk of complications include judicious diuresis and avoiding
proton pump inhibitors in patients without clear indications for their use (spontaneous bacterial
peritonitis); treating infections (spontaneous bacterial peritonitis, hepatic encephalopathy);
avoiding sedatives and treating hypokalemia and hyponatremia (hepatic encephalopathy);
avoiding nephrotoxic agents and aggressive diuresis (hepatorenal syndrome); and only using
urinary catheters, mechanical ventilation, and central lines when clearly indicated (secondary
infections). (See 'Major complications' above.)

///////////////////////////////////////////////////////////////////////////////////////
3. What does available data support regarding complications
in these pts

https://www.uptodate.com/contents/clinical-and-laboratory-
aspects-of-platelet-transfusion-
therapy?sectionName=Antiplatelet%20agents&anchor=H262
0781574&source=see_link#H323107

Platelet transfusions can be helpful or even life-saving in patients with these conditions who are
bleeding and/or have anticipated bleeding due to a required invasive procedure (eg,
placement of a central venous catheter), and platelet transfusion should not be withheld
from a bleeding patient due to concerns that platelet transfusion will exacerbate
thrombotic risk. However, platelet transfusions may cause a slightly increased risk of
thrombosis in patients with these conditions; thus, we do not use prophylactic platelet
transfusions routinely in patients with TTP or HIT in the absence of bleeding or a required
invasive procedure.

Liver disease and DIC — Patients with liver disease and disseminated intravascular
coagulation (DIC) have a complex mixture of procoagulant and anticoagulant defects along with
thrombocytopenia, and therefore they are at risk for thrombosis and bleeding. There is no
evidence to support the administration of platelets in these patients if they are not
bleeding. However, platelet transfusion is justified in patients who have serious bleeding,
are at high risk for bleeding (eg, after surgery), or require invasive procedures.
(See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in
adults", section on 'Prevention/treatment of bleeding' and "Hemostatic abnormalities in patients
with liver disease", section on 'Bleeding'.)

/////////////
https://www.uptodate.com/contents/clinical-and-laboratory-aspects-of-platelet-
transfusion-
therapy?sectionName=Antiplatelet%20agents&anchor=H2620781574&source=se
e_link#H323107
COMPLICATIONS OF PLATELET TRANSFUSION (in general)— Platelet transfusion carries
several risks. The relative frequency of complications with apheresis versus whole blood-
derived, pooled platelets have not been studied in large randomized trials. A 2008 systematic
review and meta-analysis that evaluated several small randomized trials (mostly with fewer than
100 patients) found a greater incidence of reactions with whole blood-derived platelets;
however, this was no longer significant after controlling for the use of leukoreduction [54]. A
2016 study involving almost 800,000 platelet transfusions in France found that apheresis
platelets were associated with a greater frequency of adverse reactions (approximately 6 per
1000 for apheresis platelets versus 2 per 1000 for whole blood-derived platelets) [55]. In this
study, all platelets were leukoreduced (during collection for apheresis, and before storage for
whole blood-derived). However, comparison may be difficult due to the different size of
apheresis versus pooled platelet units and the challenges of calculating the incidence per unit
when multiple units are administered. Additional data are needed before a clear conclusion on
relative risk of complications can be made. (Seepla 'Dose' above.)

/////////////////
https://www.uptodate.com/contents/clinical-applications-of-thrombopoietic-
growth-
factors?search=liver%20cirrhosis%20and%20platelet%20transfusion&source=sear
ch_result&selectedTitle=5~150&usage_type=default&display_rank=5#H31

IMPACT ON PLATELET TRANSFUSION — There was much early enthusiasm for using
thrombopoietin (TPO) in the acute treatment of thrombocytopenia in lieu of platelet transfusions
[106]. However, since none of the thrombopoietic molecules hastens megakaryocyte
fragmentation into platelets and all take five days to start to increase platelet production [9],
TPO will not replace platelet transfusions in this acute setting. Nevertheless, there remains
interest in developing another substance (eg, SDF-1) that might stimulate platelet shedding from
existing megakaryocytes and possibly reduce the need for acute platelet transfusions.

It is unlikely that TPO receptor agonists will have a major impact on the need for platelet
transfusions. The TPO receptor agonists may be useful in modestly reducing the incidence of
 thrombocytopenia in nonmyeloablative chemotherapy. However, since this type of
thrombocytopenia is a rather uncommon event in routine oncology practice, there will probably
be little reduction in the overall use of platelet transfusions. For several newer chemotherapy
regimens (eg, use of bortezomib, lenalidomide, gemcitabine) in which thrombocytopenia is more
marked, thrombopoietic growth factors may be of greater, as yet untested, use.

////
https://www.uptodate.com/contents/clinical-applications-of-thrombopoietic-
growth-
factors?search=liver%20cirrhosis%20and%20platelet%20transfusion&source=sear
ch_result&selectedTitle=5~150&usage_type=default&display_rank=5#H31

SIDE EFFECTS AND RISKS — For any hematopoietic growth factor, potential adverse effects
must be carefully assessed. For the thrombopoietins a number of actual or potential toxicities
have been identified (table 3). Cost may also be limiting in some settings.

Potential adverse consequences of thrombopoietic growth factor

treatment
Thrombocytosis

Thrombosis

Stimulation of tumor cell growth

Stimulation of leukemia cell growth

Interactions with other cytokines

Autoantibody formation

Reduction in threshold for platelet activation

Increased bone marrow reticulin (positive reticulin stain)

Increased bone marrow collagen (positive trichrome stain)

Rebound worsening of thrombocytopenia upon stopping treatment

Graphic 74625 Version 2.0
https://www.uptodate.com/contents/image?imageKey=HEME%2F74625&topicKe
y=HEME%2F6671&search=liver%20cirrhosis%20and%20platelet%20transfusion&r
ank=5~150&source=see_link
///////////////////////////////////////////////////////////////////////////////////
4. Can these complications be correlated to platelet count of the patient

Lets touch base and discuss all data collected SUnday Night 10 pm. Jan 21
and then we will review your final version of your "rough" draft Wed night Jan 24th 9pm.

Thanks,
TJ

5. Is there any benefit of platelet transfusion in liver cirrhosis/what does data show? If benefit,
what is the mechanism?