https://www.uptodate.

com/contents/vitamin-k-and-the-synthesis-and-function-of-gamma-
carboxyglutamic-acid?source=see_link

https://www.uptodate.com/contents/pathogenesis-of-hepatic-
fibrosis?search=liver%20cirrhosis%20and%20platelet&source=search_result&selectedTitle=5
~150&usage_type=default&display_rank=5

https://www.uptodate.com/contents/pathogenesis-of-hepatic-
fibrosis?search=liver%20cirrhosis%20and%20platelet&usage_type=default&source=search_re
sult&selectedTitle=5~150&display_rank=5

https://www.uptodate.com/contents/clinical-and-laboratory-aspects-of-platelet-transfusion-
therapy?search=platelet%20transfusion%20guidelines&usage_type=default&source=search_
result&selectedTitle=1~150&display_rank=1

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

Coagulation factors are important in the mechanism of blood coagulation, and the liver is the
main source of production. In liver disease, the synthesis and post-translational modification of
the clotting factors may be impaired [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]

Many of the factors [II, VII, IV, X, Protein C, and Protein S] depend on vitamin K as an enzyme
cofactor in vitamin K-dependent gamma-glutamyl carboxylase – the enzyme needed for factor
synthesis

Patients with liver disease often have abnormalities in laboratory tests. Changes in primary
hemostasis in

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

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,

1
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'.)

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

2
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].

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http://www.journal-of-hepatology.eu/article/S0168-8278(11)00499-5/fulltext
Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction? - GOOD

F. Violi Correspondence information about the author F. Violi Email the author F. Violi

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

3
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.

Treatment of thrombocytopenia in liver cirrhosis

Thrombocytopenia may have a negative impact on clinical management of patients. Therapeutic platelet

transfusions are unequivocally indicated for patients with active bleeding associated with thrombocytopenia
[115]. There is consensus that the platelet count should not be allowed to fall below 50 × 109/L in patients
with acute bleeding.

According to the guidelines for the general use of platelet transfusions [115], a threshold of 10 × 109/L is as safe as

higher levels for patients without additional risk factors such as sepsis, concurrent use of antibiotics or other
abnormalities of haemostasis.

However, in patients with advanced liver disease there is a lack of consensus regarding the degree of

thrombocytopenia that may be associated with an increased risk of bleeding [[116], [117]]. Thus, specific guidelines in

LC are lacking to indicate the platelet cut-off below which procedures (as well as liver transplantation) should be
delayed and/or platelet transfusions or platelet-stimulating agents should be administrated.

Several therapeutic options (Table 2) are currently available to raise platelet count to a safe level for invasive
procedures or in case of active bleeding.

Therapeutic options
Jump to Section

4
Platelet transfusion (PT)
Platelet transfusion (PT) is the standard-of-care in general to temporarily increase platelet counts prior to

invasive procedures [115]. Current recommendations for PT [115] concerning liver biopsy, lumbar puncture,

epidural anaesthesia, or similar procedures in patients with chronic and stable thrombocytopenia suggest that the
platelet count should be raised to at least 50 × 109/L.

Recently, the American Association for the Study of Liver Disease guidelines [118] recommend that platelet

transfusion before liver biopsy, transcutaneously or transvenously, should be considered when levels of platelet count

are less than 50–60 × 109/L (Class 1, Level C i.e. without evidence from randomized studies). Thus, in LC

randomized controlled studies, assessing efficacy and safety of restrictive PT strategies in thrombocytopenic patients

during invasive procedures such as liver biopsy, are needed [119]. Moreover, PT seems to be inappropriate for long-

term management partially due to potential allo-immunization and also because shortened allogeneic platelet survival

due to sequestration in enlarged spleens. In addition, in liver transplant patients, platelet transfusions have been

associated with increased post-operative mortality, as a result of an increased risk of acute lung injury [120].
Additionally, there are no data to support benefit of PT strategies in subjects with TCP and variceal bleeding [121].

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https://www.ncbi.nlm.nih.gov/pubmed/28288507

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381832/

Clin Mol Hepatol. 2017 Mar;23(1):13-21. doi: 10.3350/cmh.2016.0110. Epub 2017 Mar 14.

Anticoagulation in cirrhosis: a new paradigm?

Leonardi F1, Maria N1, Villa E1.

Author information
Abstract
The liver plays a crucial role in coagulation cascade. Global hemostatic process is profoundly
influenced by the presence of liver disease and its complications. Patients with cirrhosis have
impaired synthesis of most of the factors involved in coagulation and fibrinolysis process due to a
reduced liver function and altered platelet count secondary to portal hypertension. Altered routine
tests and thrombocytopenia were considered in the past as associated with increased risk of
bleeding. These concepts explain both the routine use of plasma and/or platelets transfusion in
patients with liver cirrhosis, especially before invasive procedures, and why these patients were

5
considered "auto-anticoagulated". New recent evidences show that patients with liver cirrhosis have
a more complex hemostatic alteration. Despite the presence of altered levels of factors involved in
primary hemostasis, coagulation and fibrinolysis, patients with stable cirrhosis have a rebalanced
hemostatic, which however can easily be altered by decompensation or infection, both in
hemorrhagic or thrombotic direction. Patients with cirrhosis have an increased risk of venous
thrombotic events (namely portal vein thrombosis) while bleeding seems to be related to the grade of
portal hypertension rather than to a hemostatic imbalance. The use of anticoagulants both as
treatment or prophylaxis is safe, reduces the rate of portal vein thrombosis and decompensation,
and improves survival. Standard laboratory coagulation tests are unable to predict bleeding and are
inadequate for the assessment of hemostatic status in these patients, hence more comprehensive
tests are required to guide the management of thrombotic and bleeding complications.

CONCLUSIONS AND FUTURE DIRECTIONS

Patients with liver cirrhosis have a more complex coagulation state than previously believed.
They display a global hemostatic alteration, involving both pro- and anticoagulant factors.
However, compensated patients have a substantially normal coagulative performance
(“rebalanced hemostasis”)[3,4,40]. Decompensated patients present bleeding as a complication
of portal hypertension, mostly from gastro-intestinal varices. However, the contribution of
deranged hemostasis as a precipitating factor is poorly documented and the impact of
coagulation in this setting is not well established. What it is clear is that standard coagulation
tests are inappropriate to define the complex coagulation state of patients with liver cirrhosis and
dynamic tests like thromboelastography should be used instead [6].
The occurrence of thrombotic events, which are major contributors of variceal bleeding, has been
previously underestimated. A better knowledge of this complication and of its mechanisms has
changed the paradigm and the clinical management of the patients (i.e. the use of
anticoagulants). Anticoagulation should be started as soon as the thrombotic complication is
diagnosed and continued for at least 6 months. There are no strict indications on whether it
should be continued indefinitely.
The major challenge, however, is to define whether prophylactic anticoagulation should be
instituted in patients with cirrhosis and when. Data from a prospective randomized study [14]
showed that anticoagulation not only prevented the occurrence of portal vein thrombosis but,
most importantly, decreased the occurrence of decompensation and improved survival. Two
other studies with anticoagulants and with the same endpoints are currently ongoing
(Childbenox, NCT02271295, and Cirroxaban, NCT02643212). Their results are eagerly awaited.

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https://www.ncbi.nlm.nih.gov/pubmed/11110614

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Can J Gastroenterol. 2000 Nov;14 Suppl D:60D-66D.

Thrombocytopenia in liver disease.

Peck-Radosavljevic M1.

Author information
Abstract
Moderate thrombocytopenia is a frequent finding in cirrhosis of the liver and well tolerated in most
instances. The pathophysiology of thrombocytopenia in liver disease has long been associated with
the concept of hypersplenism, where portal hypertension was thought to cause pooling and
sequestration of all corpuscular elements of the blood, predominantly thrombocytes in the enlarged
spleen. The concept of hypersplenism was never proven beyond any doubt but was widely accepted
for the lack of alternative explanations. With the discovery of the lineage-specific cytokine
thrombopoietin (TPO) the missing link between hepatocellular function and thrombopoiesis was
found. TPO is predominantly produced by the liver and constitutively expressed by hepatocytes.
TPO production in humans is dependent on functional liver cell mass and is reduced when liver cell
mass is severely damaged. This leads to reduced thrombopoiesis in the bone marrow and
consequently to thrombocytopenia in the peripheral blood of patients with advanced-stage liver
disease. With recombinant TPOs in development, patients with liver disease and TPO seem to be
the ideal target population for this drug. Once the efficacy of thrombopoietin in patients with liver
disease is proven, a potent yet safe drug may be available to treat cirrhotic patients undergoing
invasive or surgical procedures, during bleeding episodes or when undergoing therapy with
myelosuppressive drugs such as interferon-alpha.