HEMOSTASIS DISORDERS IN LEUKEMIA

Zelly Dia Rofinda

ABSTRACT
Background: Abstract Leukemia is a malignancy of hematopoietic tissue which is
characterized by substituted of bone marrow element with abnormal blood cell or
leukemic cell. One of clinical manifestation of leukemia is bleeding that is caused by
several hemostasis disorders. Hemostasis disorders in leukemia such as
thrombocytopenia, platelet dysfunction, disseminated intravascular coagulation,
coagulation protein defect, primary fibrinolysis and thrombosis. Pathogenesis and
pathophysiology of thus hemostasis disorders in leukemia occur with different
mechanism.
Keywords: leukemia, hemostasis disorder

PRELIMINARY
Leukemia is a malignant disease of hematopoietic tissue characterized by the
replacement of normal bone marrow elements by abnormal blood cells or leukemic cells.
This is caused by uncontrolled proliferation of immature blood cell clones derived from
hematopoietic stem cells. Leukemic cells are also found in peripheral blood and often invade
reticuloendothelial tissues such as the spleen, liver and lymph nodes.
Leukemia is classified by cell type, both according to cell maturity and cell
derivatives. Based on cell maturity, leukemia is distinguished acute and chronic. If the cell is
malignant in part immaturity (blast), then leukemia is classified as acute, whereas if the
dominant cell is mature, then it is classified as chronic leukemia. Based on cell derivatives,
leukemia is classified for myeloid leukemia and lymphoid leukemia. Myeloid leukemia
groups include granulocytic, monocytic, megacryocytic and erythrocytic.
One clinical manifestation of leukemia is bleeding. The most common manifestations
of bleeding include ptekie, purpura or ecchymosis, which occurs in 40-70% of patients acute
leukemia at the time of diagnosis. Location of the eyes, nasal mucous membranes, gingiva
and gastrointestinal tract. Life-threatening bleeding usually occurs in the digestive tract and
the central nervous system, in addition to the lungs, uterus and ovaries. These bleeding
manifestations arise as a result of various haemostatic disorders.

Life-threatening bleeding is more common in acute leukemia and is a serious

problem. Bleeding is the main cause morbidity and mortality in acute leukemia especially in
acute myelocytic leukemia with monocytic differentiation and acute promielocytic leukemia.
Complications of bleeding result 7 - 10% mortality in patients with acute leukemia occur
within the first few days or weeks after diagnosis.
Leukemia that is most often associated with life-threatening bleeding is Acute
Promielocytic Leukemia (AML-M3 or APL), a subtype of acute myelocytic leukemia
characterized by reciprocal translocation of chromosomes 15 and 17. In Acute Promielocytic
Leukemia, almost 30% of premature deaths are due to bleeding complications. Bleeding that
occurs in Acute Promielocytic Leukemia is associated with disseminated intravascular
coagulation, hyperfibrinolysis and non-specific protease activity.
The most common cause of bleeding is on leukemia is thrombocytopenia. The
reduced platelet count in leukemia is usually a result of infiltration into bone marrow or
chemotherapy, but can also be due to disseminated intravascular coagulation, immunological
processes and hypersplenism secondary to spleen enlargement. In addition to
thrombocytopenia, bleeding can also result from platelet dysfunction, liver abnormalities and
fibrinolysis.
Disseminated intravascular coagulation (KID) frequently reported in acute leukemia
caused by the release of procoagulant material from leukemic cell blasts. Acute leukemia that
is often associated with KID is Acute Promyloocytic Leukemia (AML-M3), followed by
Acute Myelomonositic Leukemia (AML-M4) and Acute Myeloblastic Leukemia (AML-M1
and M2) and Acute Lymphocytic Leukemia (ALL). In chronic leukemia, KID is more
common in chronic myelocytic leukemia than Chronic Lymphocytic Leukemia.
Other hemostasis abnormalities can also be Leukemia occurs in thrombosis or
thromboembolism. Thrombosis can be one the symptoms found at diagnosis are at acute
promielocytic leukemia (AML-M3) 9.6%; on Non-M3 AML were 3.2% and at ALL 1.4%.
The pathogenesis of protrombotic conditions in leukemia is very complex and involves
various mechanisms such as activation of coagulation by the procoagulant substance released
by leukemic cells, failure of fibrinolytic pathways and changes endothelial.
This literature review will discuss regarding various hemostatic disorders that can
occur in leukemia. Knowledge about the pathogenesis and pathophysiology of hemostatic
abnormalities in leukemia is very important so that patient management can be carried out
optimally.
HEMOSTASIS ABNORMALITIES IN LEUKEMIA
Thrombocytopenia
Platelets must be in adequate amounts to maintain normal hemostasis. In normal
circumstances blood platelet counts range from 150,000 - 400,000 / mm3. Thrombocytopenia
is a term for platelet counts that are less than the normal value. Thrombocytopenia usually
does not have clinical manifestations of platelet count 100,000 / mm3, even up to 50,000 /
mm3. Spontaneous bleeding is usually only seen on platelet count < 20,000 / mm3.
Bleeding due to thrombocytopenia is the most frequent complication of acute
leukemia. Gaydos et al. (1962) who first reported an association between bleeding and
platelet count in acute leukemia. Manifestations of bleeding due to thrombocytopenia can be
ptekie or purpura, epistaxis, bleeding gums, gastrointestinal bleeding, menorrhagi until brain
hemorrhage. Webert et al. (2006) reported varying degrees of bleeding that occurred in
58.4% of patients with acute mieolocytic leukemia due to thrombocytopenia.
The reduced platelet count in acute leukemia is usually a result of bone marrow
infiltration or chemotherapy, but can also be caused by several other factors such as
disseminated intravascular coagulation, immunological processes and hypersplenism
secondary to enlargement of the spleen. Thrombocytopenia that occurs varies and almost
always found when leukemia is diagnosed.
The infiltration process in the bone marrow results in the bone marrow being filled
with leukemic cells resulting in a decrease in the number of megakaryocytes resulting in
decreased platelet production. Chemotherapy in leukemia can cause direct damage to the
bone marrow so that it will also cause reduced platelet production.
Disseminated intravascular coagulation that often occurs in acute leukemia, especially
acute promielocytic leukemia, causes platelets to be widely used in the coagulation process.
This excessive consumption of platelets also causes thrombocytopenia.
Thrombocytopenia due to immunologic thrombocytopenic purpura is found in 2% of
patients with chronic lymphocytic leukemia (20,21). This is related to the formation of
autoantibodies against platelets so that thrombocyte destruction results. The production of
autoantibodies together with infiltration of leukemic cells in the bone marrow and
hypersplenismus results in reduced platelet counts.
Patients with acute leukemia who are in treatment, often requires platelet transfusion
repeatedly. This situation creates a risk alloimmunization so that alloantibodies are formed
which can eventually cause platelet destruction. Thrombocytopenia can occur one week after
blood transfusion or blood products containing platelets. Platelet transfusion tends to fail in
patients who make these alloantibodies.
Corazza et al (2006) evaluated the serum thrombopoietin levels of ALL or AML
patients at the time of diagnosis. Increased levels of serum thrombopoietin that are adequate
in response to thrombocytopenia are found in ALL patients. In AML patients, thrombopoietin
levels are low, but immediately increase to the level expected during induction of
chemotherapy as soon as the blast cell disappears. Thrombopoietin levels are inadequate in
AML patients due to the presence of c-mpl thrombopoietin receptors on myeloid blast cells
that act as growth factors for myeloid leukemic cells and decrease apoptosis of these cells.
The risk of severe bleeding is inversely proportional to the platelet count. To prevent
the risk of severe bleeding in thrombocytopenia patients can be done with platelet
transfusion, but the optimal platelet count as a limit for prophylactic platelet transfusion is
still debated. The number of platelets used as a limit for platelet transfusion is below 20,000 /
mm3.
Platelet count can be done manually or by automatic devices. Platelet count with an
automatic device is affected by several things such as the presence of platelet aggregates due
to spontaneous aggregation, cold agglutinins or particles debris such as erythrocyte fragments
and leukocytes. For this reason it is important to do confirmation by inspection of the
peripheral blood erase preparation. A peripheral blood erase preparation can provide
information on platelet size and morphology and confirm platelet counts. A rough estimate of
platelet count with evaluation preparations remove peripheral blood under normal
circumstances there are about 10-20 platelets per field immersion (approximately one platelet
per 10-20 erythrocytes). If necessary, platelet count can be done with hemocytometer using a
phase contrast microscope.

Platelet Dysfunction
Impaired platelet function can also cause bleeding even though platelet count is not so
low. This platelet dysfunction occurs in ± 30% of patients with chronic myelocytic leukemia
(LMK). Platelet function disorders that occur in the form aggregation disorders against ADP
and epinephrine, abnormalities in PF3 release, granular deficiency as well decreased release
of adenine nucleotides originating from platelets.
 Manifestations of bleeding that arise as a result impaired platelet function in
myelocytic leukemia chronic can be mucocutaneous bleeding, retinal hemorrhage and
hematuria. This is caused by reduced or absence of platelet aggregation in response to ADP,
epinephrine or collagen. In this patient there will be a lengthy bleeding time.
The pathogenesis of platelet dysfunction found in leukemia is still unclear. Several
factors are thought to cause functional changes of platelets such as abnormalities in the
interaction of hemostasis in the circulation at the time of activation and the reaction of
platelet release. Another possibility is platelet production abnormality which is primarily a
disruption of the structure and function of megakaryocytes.
Platelet transfusion must be given in dysfunction platelets even though the platelet
count is normal. Platelet sitaferesis can reduce bleeding when platelet dysfunction is related
to thrombocytosis ie platelet count> 700,000 / mm3.
Methods that can be used to judge Platelet function is bleeding time, platelet
aggregation test and automated functional analyzers. The bleeding time of the Ivy method is a
simple platelet function test by measuring the patient's bleeding time after a small incision is
made on the skin. This examination has many limitations including low reproducibility,
sensitivity is still questionable and unsuitable for serial examinations as well as weak
correlation with bleeding tendencies.
Platelet aggregation test is to measure the ability of platelets to bind to one another
and form a hemostatic plug automatically. This test can be done on platelet-rich plasma
(PRP) or whole blood. Aggregation-inducing agents that can be used are ADP, ristocetin,
collagen and epinephrine. This platelet aggregation test can be influenced by a number of
variables such as hemolysis samples because erythrocytes also contain ADP, lipemic samples
obscure changes in platelet aggregation and thrombocytopenia make evaluation of platelet
aggregation difficult to interpret. This test has a high cost and not all health facilities provide
it.
At present, automatic tools for assessing function The most widely used platelet is
Platelet Function Analyzer. This system uses membrane covered with collagen / epinephrine
or collagen / ADP to stimulate platelet aggregation. Blood samples are taken by a device
through a vacuum capillary which activates platelets by shear force. The time until the
formation of platelet blocks that block the device is recorded. The use of this technique is
increasing because time is fast, not too expensive and provides relevant clinical information.
Disseminated Intravascular Coagulation (Kid)
Disseminated intravascular coagulation (KID) is a syndrome characterized by
activation systemic intravascular coagulation in the form of formation and spread of fibrin
deposits in the circulation resulting in microvascular thrombus in various organs which can
result in multiorgan failure. Ongoing coagulation activation causing excessive consumption
of clotting factors and platelets resulting in complications of heavy bleeding. KID is not a
disease but a secondary occurrence of other underlying diseases.
KID is a pathophysiological term include the incidence of thrombosis and internal
bleeding body that occurs simultaneously. This term too known as consumption coagulopathy
because clotting factors in the plasma are used for freezing process. In addition, reduced
clotting factors can also be caused by plasmin degradation due to hyperfibrinolysis.
Leukemia and other malignancies are associated with hypercoagulable states that are
at high risk for thrombohemoragic complications. Clinical complications vary from
thrombosis that is local to severe bleeding due to KID.
Acute leukemia that is most often associated with KID is acute promielocytic
leukemia (AML-M3), followed by acute myelomonositic leukemia (AML-M4), as well as
acute myeloblastic leukemia AML-M1 and AML-M2. In acute lymphoblastic leukemia
approximately 10% of patients experience KID at the time of diagnosis. Chronic leukemia
which is more often experiencing KID is LMK compared to LLK.
In leukemia, complications of KID occur because of release of procoagulant
(thromboplastin-like substances) from blast cells. Procoagulant material is like a tissue factor
that will form a complex with factor VIIa so that it activates the coagulation cascade through
extrinsic pathways that form fibrin systemically. Ongoing coagulation will reduce
antithrombin levels Plasma III which is an important inhibitor for coagulation process.
Furthermore, fibrinolytic system inhibition occurs due to maximum coagulation activation.
This inhibition is caused by an increase in type 1 plasminogenactivator inhibitors (PAI-1) as
the main inhibitors for the fibrinolytic system.
In establishing the diagnosis of KID it is very important to assess the overall clinical
picture, pay attention to the patient's clinical condition, diagnosis of the disease basis and
laboratory results. There is no single routine laboratory test that is sensitive and specific
enough for the diagnosis of KID. Molecular markers for activation of coagulation or fibrin
formation are perhaps the most sensitive tests. The presence of soluble fibrin in plasma has a
sensitivity of 90-100% for the diagnosis of KID, but its specificity is low.
 Activation of the fibrinolytic system in KID can be identified by the presence of fibrin
degradation products (FDP) which can be detected by enzymelinked immunosorbent assay
(ELISA) techniques or by latex agglutination which can be performed as rapid bedside-test in
case of emergencies. But the tests available for FDP cross-react with fibrinogen degradation
products so that it messes up high yields. The specificity of high FDP levels is also limited by
several other conditions such as inflammation and surgery which can also increase FDP
levels.
Test specifically to detect the result of cross-linked fibrin degradation is D-dimer. D-
dimer levels increase in KID but also difficult distinguished from trauma or surgery patients.
The dynamics of KID can be determined by measuring coagulation activation markers that
are released when zimogen conversion of coagulation factors to proteases active like the F1 +
2 prothrombin fragment.
In general sensitive tests such as the F1 + 2 prothrombin fragment are not available in
public hospital laboratories. Although these tests are very helpful in clinical trials or other
research, they often cannot be done for routine examinations. For clinical practice, a
diagnosis of KID can be made by a combination of platelet count testing, APTT and PT
freezing time, measurement of 1 or 2 clotting factors and inhibitors (such as fibrinogen and
antithrombin III) and tests for fibrin degradation products (FDP or Ddimer). Serial
coagulation tests are more helpful in establishing the diagnosis of KID rather than the test
results just once.
The most important thing is to make sure that patients who have KID do not have it
liver disorders or vitamin K deficiency that can resembles the state of KID. Thrombin Time
(TT) seems useful for distinguishing abnormalities coagulation due to vitamin K deficiency
with KID, because TT is never abnormal in deficiency vitamin K.
Management of KID in patients with acute leukemia must be done individually. In
general, acute leukemia patients with KID can be heparinisasi.Bleeding must be monitored,
as well as factor V and fibrinogen to know the success of therapy. Heparin should not be
stopped or lowered the dose though bleeding has stopped, because KID has not really ended
until bone marrow aplasia occurs. In addition to the use of heparin, platelets can be given to
maintain platelet counts> 20,000 / mm3.
KID with thrombosis is often found in patients who experience sepsis, especially
those caused by Gram negative bacteria or fungi. If the diagnosis of thrombosis has been
established, the treatment of choice remains heparin. KID will be exacerbated by the
administration of antileukemia therapy, but with the availability of all-trans retinoic acid
(ATRA) for patients with acute promielocytic leukemia, the degree of KID can be reduced.
Rational approach to medicine acute leukemia patients with severe KID are by
starting induction chemotherapy as soon as possible to reduce the population of leukemia
cells that are thought to cause KID. If there is an infection, antibiotics must be given. In
addition, replacement therapy should be given if there is severe thrombocytopenia,
coagulopathy, or hypofibrinogenemia.
In patients at risk of KID, hemostasis examination should be done every day in the
first days of chemotherapy. Hypofibrinogenemia (fibrinogen <100 mg / dl) can be corrected
by giving cryoprecipitate, while the lengthening of PT and APTT can be corrected by giving
fresh frozen plasma (FFP).

Coagulation Protein Defects

Infiltration to the liver is often found in acute leukemia, followed by LLK and LMK,
which causes decreased coagulation factor synthesis which are dependent on vitamin K,
namely factors II, VII, IX and X. From several studies regarding F V found the decrease is
around 18 - 45%. In patients with AML-M3 more than 90% of patients experience factor V
deficiency.
Decreased fibrinogen and clotting factors others in acute leukemia can also be caused
by KID. In KID there is excessive consumption of factors the freezing. In addition, the state
of hyperfibrinolysis also causes degradation a number of clotting factors are increasingly
reduce the level of clotting factors mentioned at in blood.
Test to detect protein defects coagulation namely by examining APTT and PT and
measure the level of clotting factor itself. For disorders of the clotting factor synthesis which
is depending on vitamin K will be marked with PT lengthening, while for factor consumption
excessive freezing on the KID will be marked by extending both APTT and PT. Tests for
fibrinogen degradation due to hyperfibrinolysis can be detected in the presence of fibrinogen
degradation products.
Fibrinolysis Primer
Some researchers found that leukocytes in acute leukemia have fibrinolytic activity
which can cause primary fibrinolysis, especially in acute promielocytic leukemia. In primary
fibrinolysis, bleeding is caused by plasmin-induced clotting factors like fibrinogen, factor V
and factor VIII.
Acute Promyloocytic Leukemia (APL) is the most commonly associated leukemia
associated with life threatening bleeding due to primary fibrinolysis. This is caused by
abnormal promielocytes in leukemia that synthesize and secrete plasminogen activator. In
addition, also because of the high expression of annexin II in these leukemic cells which can
increase plasmin production resulting in degradation of fibrinogen.
Plasmin is formed from the meeting of plasminogen and tPA on annexin II on the cell
surface. The formed plasmin will be neutralized by its primary inhibitor, the plasmin inhibitor
produced in the liver. Once released, plasmin quickly forms an inactive complex with
reversible properties.
Annexin is a family of membrane and protein phospholipid binder regulated by
calcium. Annexin has the ability to interact with cell membranes so that they can influence a
number of events related to cell membranes such as receptors, effectors, regulators and
mediators of calcium signals.
Annexin II, which is expressed on the surface of endothelial cells and leukocytes,
functions as a plasminogen receptor and activator of tissue plasminogen activator (tPA).
Annexin II acts as a tPA cofactor in increasing the efficiency of plasmin formation.
Overexpression of annexin II on the surface of leukemic cells as in acute promielocytic
leukemia is associated with clinical manifestations of bleeding.
Systemic fibrinolysis in acute promielocytic leukemia causes a shortening of
euglobulin lysis time and a decrease in antiplasmin levels. Leukemic cells in acute
promielocytic leukemia as well synthesize proteolytic enzymes in the form of elastase.
Elastase has proteolytic activity and breaks down fibrinogen into fibrinogen degradation
products. The pattern of fibrinogen proteolysis by the elastase different from those produced
by plasmin. Besides granulocyte elastase can also destroy and inactivates factor IX. But now,
the inspection against these enzymes in plasma is difficult done.
Changes in the fibrinolytic system are reported more often in patients with acute
leukemia compared chronic leukemia. The role of fibrinolysis and its management in
bleeding in malignancies hematology is still controversial. The use of antifibrinolytic, amino
caproic acid or tranexamid acid is recommended if excessive fibrinolysis occurs, but this is
contraindicated in patients with KID.

Thrombosis
In acute leukemia patients, the risk of thrombosis cannot be ignored. Thrombosis can
constitute one of the symptoms found at the time of diagnosis is acute promielocytic
leukemia (AML-M3) 9.6%; in non-M3 AML 3.2% and in ALL 1.4%. Although the incidence
of symptomatic thrombosis when the diagnosis is relatively low in ALL patients, however
there was a significant increase of up to 10.6% during treatment. ALL patients who received
L-asparaginase therapy had an increased risk of thrombosis 4.9 times compared with those
who did not.
Asparaginase therapy in ALL causes the incidence of thrombotic complications
ranges from 2.4 - 11.5%. Asparaginase decreases antithrombin III biosynthesis, protein C and
hepatic S protein. Antithrombin III, protein C and protein S are coagulation inhibitors so that
protein deficiency causes thrombosis.
Ziegler et al (2005) in a cohort study of 719 acute leukemia patients reported venous
thromboembolism manifestations as much as 2.1% without any difference between AML and
ALL, while the incidence of thrombosis in APL as much as 6.5%.
Grace Ku et al (2006) reported incidents cumulative venous thromboembolism for 2
years on AML and ALL patients were 3.6%, of which half were diagnosed in the first 3
months of the disease course.
The pathogenesis of the protrombotic state in leukemia is very complex and involves
various mechanisms such as activation of blood coagulation through procoagulant substance
released by leukemic cells, failure of fibrinolytic pathways and endothelial changes in
thrombogenic conditions.
Laboratory tests to detect patients suspected thromboembolism is D-dimer which is
the result of the breakdown of cross-linked fibrin by plasmin. D-dimer examination can be
done by latex agglutination or by ELISA.
SUMMARY
Leukemia is a malignant disease of hematopoietic tissue characterized by the
replacement of normal bone marrow elements by abnormal blood cells or leukemic cells. One
of the clinical manifestations of leukemia is bleeding caused by various hemostatic disorders.
Thrombocytopenia in leukemia can be caused by infiltration of leukemic cells in the
bone marrow, bone marrow damage by chemotherapy, disseminated intravascular
coagulation, immunological processes or due to hypersplenismus secondary to enlargement
of the spleen. Impaired platelet function often occurs in chronic myelocytic leukemia, the
pathogenesis of platelet dysfunction is still unclear. Disseminated intravascular coagulation
that occurs in leukemia is caused by the release of material Procoagulants resemble
thromboplastin by cells leukemic. Coagulation protein defects in leukemia can be caused by
disorders of clotting factor-dependent synthesis of vitamin K due to infiltration to the liver
and due to excessive consumption during KID.

Primary fibrinolysis in acute promielocytic leukemia is caused by abnormal promielocytes

synthesizing and secreting plasminogen activators and high expression of annexin II in these
leukemic cells which increases plasmin production resulting in fibrinogen degradation.
Thrombosis in leukemia involves various mechanisms such as activation of blood
coagulation through the procoagulant substance released by cells leukemia, failure of
fibrinolytic pathways and changes endothelial.
Given the clinical manifestations of bleeding that can increase morbidity and
mortality in patients with leukemia, it is necessary to consider the existence of hemostasis
abnormalities for more optimal management.
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