acquired thrombophilic

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Acquired thrombophilic syndromes

31

Acquired thrombophilic

syndromes

Daniela Matei,1 Benjamin Brenner,2 Victor J. Marder1

1Vascular Medicine Program,Los Angeles Orthopaedic Hospital/University of

California at Los Angeles, Los Angeles,CA, USA

2Department of Hematology,Rambam Medical Center, Haifa, Israel

Abstract As the biochemical mechanisms of

hypercoagulable states are revealed, the syndromes of venous

thromboembolism have been increasingly associated with

specific aberrations. Most of these changes involve an increase

in procoagulant potential, for example, by activation of the

coagulation cascade, or by a defect or decrease in natural

inhibitors of clotting. Similar abnormalities of the fibrinolytic

pathways may contribute, as can loss of inhibitory mechanisms

of endothelial cells, as well as changes in vascular anatomy andrheologic patterns of blood flow.All of these factors can

directly influence thrombus formation and/or the physiologic

response to the thrombus.1 2001 Harcourt Publishers Ltd

INTRODUCTION

s with the hereditary thrombophilias, acquired dis-

orders vary widely in their propensity to cause

venous and arterial thrombotic disease. Certain

conditions such as the mucin-secreting adenocarcinomas

have very high potential for thrombogenesis and can cause

excessive thrombotic manifestations (arterial,venous,micro-circulatory, endocardial) in a given patient.The antiphospho-

lipid syndrome may manifest solely as a coincidental

laboratory derangement or cause venothromboembolic dis-

ease (VTED), stroke or obstetric complications. Patients

with myeloproliferative syndromes or paroxysmal nocturnal

hemoglobinuria may have significant clinical thrombotic

complications and can especially present with thrombosis in

unusual sites; while in patients with acute promyelocytic

leukemia the coagulation cascade can be triggered further

during cytolytic therapy.The hypercoagulable tendency man-

ifested in association with some medications leads mostly to

VTED, and can be enhanced by other prothrombotic envi-

ronmental factors such as smoking, obesity or by the pres-ence of on occult inherited thrombophilic trait.

ANTIPHOSPHOLIPID SYNDROME (APLS)

Antiphospholipid syndrome (APLS) has many clinical facets

and multiple manifestations, and is one of the more common

causes of acquired thrombophilia.2 The presence of acquired

circulating anticoagulants was first reported in patients with

systemic lupus erythematosus (SLE) in 1948.3 Fifteen years

later, Bowie et al. noted the occurrence of thrombosis in

patients with SLE who also had a circulating anticoagulant.4

This phenomenon was called the lupus anticoagulant (LA),

although it is now clear that the presence of LA is not

restricted to patients with SLE.

Several laboratory tests have been developed to detect

LAs including the partial thromboplastin time, the kaolin

clotting time,the dilute phospholipid test,platelet neutraliza-

tion tests, tissue thromboplastin inhibition tests, and anticar-

diolipin antibody.5,6 The concept supporting the detection of

the LA antibodies relies on the use of low concentrations of

phospholipid in phospholipid-based clotting assays to maxi-mize the inhibitory effect of the antibody. In the confirma-

tory phase, large amounts of phospholipid are added to the

liquid phase assay, overcoming the effect of the antibody.

While no single test can stand alone in the diagnosis of APLS,

multiple and persistently positive results anticipate more

thrombotic events.7,8 The Subcommittee on Lupus

Anticoagulants/Antiphospholipid Antibodies of the Scientific

and Standardization Committee of the International Society

on Thrombosis and Hemostasis has published criteria for LAs

that include prolongation of at least one phospholipid-

dependent assay, evidence of inhibitory activity on normal

plasma, and confirmation that the inhibitory activity is

dependent upon the presence of phospholipid.9

Perhaps themost instructive of the new assays that have been developed

for APLS is the one which detects antibodies against 2-

glycoprotein-I,10 especially in association with clinical throm-

botic events.11 An association between the degree of

elevation of the titer of a given test and the risk for thrombo-

sis has been proposed, but the titer may change sponta-

neously or may fall to undetectable levels at a time of

thrombosis.12,13 Recent studies reinforce the concept that

the diagnosis of APLS is not increased by simply expanding

the menu of assays,14 but more than one positive assay

results, for example, anticardiolipin and LA,may have greater

prognostic value for VTED and especially for arterial throm-

botic disease.

7

Mechanisms of thrombogenesis

Various mechanisms have been proposed to explain the

increased risk of thrombosis in patients with LA, including

inhibition of endothelial activation of protein C and inhibi-

tion of endothelial cell release or production of prostacy-

clin,15,16 while alterations in fibrinolytic mechanisms have

been discounted.17 Recent conceptual proposals on mecha-

nisms of lupus inhibitors include interference with the

action of2-glycoprotein-I,which blocks free protein S bind-

ing to C4b-BP,18 expression of tissue factor on circulating

monocytes,19 acquired activated protein C resistance20 and

endothelial cell activation.21 Of special note is the evidence

presented by Rand et al. on the LA antibody-induced reduc-

tion of annexin V levels in cultured endothelial cells and tro-

phoblasts.22 If this mechanism is indeed operating,23 it may

well explain the placental changes that underlie the fetal

wastage of APLS.

Clinical manifestations

Population studies indicate that 515% of patients present-

ing with VTED have LA,2426 in comparison with 02% of the

general population.2527While it is reasonable to assume that

co-existence of a hereditary thrombophilic marker could

contribute to thrombotic events in patients with APLS,28,29

epidemiological analyses to date indicate that the mutations

for factor V Leiden30 or prothrombin G20210A31,32 do not

A

2001 Harcourt Publishers Ltd Blood Reviews (2001) 15, 3148

doi: 10.1054/blre.2001.0148, available online at http://www.idealibrary.com on


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explain the thrombotic events in patients who have anti-phospholipid directed antibodies.

The primary APLS, also called Hughes syndrome, com-

prises a cluster of clinical and laboratory features in patients

with SLE or independent of SLE, including VTED with

recurrence,arterial occlusions, fetal wastage and thrombocy-

topenia3335 accompanied by a positive assay for antibody

against one or another of the phospholipid components.3638

The thrombotic manifestations of APLS are varied.The age

of distribution is wide and children can be affected.35,39 In a

series of 70 patients with APLS reported by Asherson et al.33,

38 had experienced deep venous thrombosis,18 pulmonary

embolism, one the Budd-Chiari syndrome, one portal vein

thrombosis,and one thrombosis of the inferior vena cava;31

had arterial thromboses, including 15 patients with transient

ischemic attacks, four with multi-infarct dementia, and five

with myocardial infarction. APLS has been associated with

thrombosis of the cerebral veins,cerebral sagittal sinus vein,

splenic vein, superior mesenteric vein, portal vein, hepatic

vein,renal vein, kidney and liver allograft thrombosis,subcla-

vian vein, retinal vein and other ocular vessels, inferior vena

cava, intracardiac thrombi, cutaneous necrosis and adrenal

gland hemorrhage and infarction.33,3952 Arterial events as

part of the APLS include both thrombotic strokes33,52,53 and

cerebral microembolicphenomena,54which may be related

to very elevated titers of anticardiolipin antibody.55

A malignant form of APLS, catastrophic APLS,5658 pre-

sents with sudden aggressive and fatal vascular occlusive

disease and can be marked by some or most of the follow-ing events, including renal failure, retinopathy, thrombotic

stroke, osteonecrosis, skin necrosis, acute MI, ischemic limb

syndrome,DIC and immune cytopenias.

Women with APLS are at increased risks for infertil-

ity, chorea gravidarum, preeclampsia, placenta previa, fetal

growth restriction, and fetal wastage59 which can be recur-

rent in 1540% of patients.60 The antibodies probably act by

interfering with the natural anticoagulant mechanisms of

endometrial and vascular annexin V22 and may lead to

extensive placental infarctions, the ultimate cause of fetal

wastage.60,61

Therapeutic considerations

Therapy for women with recurrent abortions due to APLS

has improved.Of 14 women who had experienced a total of

28 miscarriages due to placental infarctions, full-dose

heparin begun an average of 10 weeks into pregnancy and

continued through delivery was associated with a good out-

come in 14 of 15 pregnancies,with less evidence of placen-

tal infarction.62 The combination of subcutaneous heparin

(5000 U sub-cutaneous twice daily) or low molecular weight

heparin (20 mg enoxaparin/day) plus aspirin (75 mg/day)

has been advocated by Backos et al.63 based on a study of 150

such patients.However,higher doses of enoxaparin,40 mg/d

and 40 mg b.i.d.have been suggested by others.64 Two pilot

trials of intravenous immunoglobulin (IVIG) in 31 patients

used IVIG in addition to heparin plus aspirin,65,66 with

Matei et al.

32Blood Reviews (2001) 15, 3148 2001 Harcourt Publishers Ltd

Table 1 Mechanisms of thrombogenesis in the acquired thrombophilic syndromes

Mechanism Antiphospholipid Paroxysmal Myeloproliferative Acute promyelocytic Solid tumors Drugs

syndrome nocturnal disorders leukemia

hemoglobinuria

Coagulation, Reduced protein S18

Increased Promyelocyte Reduced protein C IncreasedNatural Acquired APCR 20 erythrocyte procoagulant or ATIII activity 214,215 coagulation

inhibitors prothrombinase activity 175,176 Acquired factors248250

activity 74,76 APCR 217,218 Acquired

APCR 259

Blood cells Loss of annexin V 22 Increased erythrocyte HIT-T294

and whole blood

viscosity 99101

Increased platelet count 108

and platelet activity 112,113

Vessel wall Endothelial cell HIT-T 297

activation 21

Loss of annexin V 22

Fibrinolysis Impaired Impaired Antifibrinolytic

fibrinolysis 77 fibrinolysis 128 treatment

of fibrinolysis 184186

Other Promyelocyte Release of

procoagulant microparticles 210213

activity 175,176

APCR: activated protein C resistance.

HIT-T: heparin-induced thrombocytopenia with thrombosis.


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inconclusive evidence of further benefit, but with a sugges-

tion of quantitative advantages to the fetus, for example, less

growth restriction and less use of the pediatric intensive care

unit. Prednisone is not of value in the management of these

patients.67

Therapeutic recommendations for non-pregnant patients

should be individualized appropriately.38 Active thrombotic

disease should be managed with anticoagulant and

antiplatelet agents as indicated, and long-term management

should be initiated if clinical judgment suggests that sponta-

neous recurrence is likely and that the risk of a bleeding com-

plication is sufficiently remote and non-life-threatening.

Thrombolytic therapy for serious VTED can be used as for

patients without APLS.68 While plasma exchange therapy is

not of proven use for long-term management of APLS, presen-

tation of the catastrophicform warrants such an approach,as

reported in the successful management of two cases.69 Long-

term anticoagulation with vitamin K antagonists can be con-

sidered in balance with the increased risk of bleeding.

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)

PNH is an acquired clonal hematopoietic stem cell disorder

characterized by hemolysis due to complement activation,associated predisposition to bone marrow failure and a

predilection for thrombosis.70 The molecular basis of com-

plement-sensitive hemolysis is a mutation of an X-

chromosome gene that controls biosynthesis of glycosyl

phosphatidylinositol (GPI) molecules, membrane proteins

that serve as receptors and/or anchors for many proteins.71,72

The red cell vulnerability to lysis stems from absent comple-

ment-regulatory membrane proteins CD59 (or membrane

inhibitor of reactive lysis, MIRL) and CD 55, the so-called

decay accelerating factor (DAF).73 Early reports of PNH

emphasized the presence of hemolytic anemia and hemoglo-

binuria,74 but also noted thrombosis in the cerebral and

visceral vessels more often than in peripheral veins.70 Of

interest,the initial complete description of PNH reported by

Strubing in 1882 included painful splenomegaly, which may

have been caused by visceral venous occlusion.75


Although there is no association between hemolytic and

thrombotic crises,76 in vitro studies of red cells suggest that

membrane vesicles77 possessing prothrombinase-promoting

activity76,78 presumably produced by complement-induced

lysis of the cells, circulate and induce thrombotic events at

various vascular sites of vulnerability.Additionally, it has been

proposed that monocytes have defective receptors for uroki-

nase (u-PAR), resulting in a reduced fibrinolytic capacity in

the face of incipient pathologic thrombi.79 That these or

other mechanisms are, in fact, due to a defect related to

hemolysis is supported by observations that knock-out mice

deficient in red cell spectrin are susceptible to thrombosis,

tendency that is perhaps related to red blood cell membrane

vesiculation.80

Thrombotic events could potentially be secondary to

inheritance of a second thrombophilic tendency but,as with

APLS noted above,there is no increased frequency of the fac-

tor V Leiden gene mutation in PNH patients that could

explain the VTED.81


For reasons that are not well understood, patients with PNH

have venous thrombotic events in unusual locations rou-

tinely, including cerebral or mesenteric veins,splenic,portal,

hepatic or renal veins and the inferior vena cava.74,8288

Purpura fulminans may occur, but arterial events such as

thrombotic stroke and myocardial infarction are only rarely

reported.89

Venous thrombosis is a prominent, enduring and life-

threatening part of the illness,as borne out by two long-term

follow-up studies of 80 patients at Hammersmith Hospital

(London)90 and 220 patients at Hpital St Louis (Paris).91 The


33 2001 Harcourt Publishers Ltd Blood Reviews (2001) 15, 3148

Table 2 Clinical manifestations in acquired thrombophilic syndromes

Mechanism Antiphospholipid Paroxysmal nocturnal Myeloproliferative Acute Solid Drugs

syndrome hemoglobinuria disorders promyelocytic tumors

leukemia

VENOUS THROMBOEMBOLICDISEASE (VTED)

DVT/PE + + + + + +

Unusual sites + + + +/ +

ARTERIAL THROMBOSIS

Peripheral + + + + +

Endocardial + + +

MICROCIRCULATORY OCCLUSION

Local

Placental + + + +

Erythromelalgia + + +

Systemic

DIC + + +

TTP + +


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frequency of significant thrombotic disease was 39% and

28%, respectively, and thrombosis contributed significantly

to mortality, causing death in 58% of known cases in London

and increasing the relative risk of death to 10.2 in the Paris

study.

Therapeutic considerationsProphylactic anticoagulant treatment is to be seriously con-

sidered in all patients with PNH. Occasionally the throm-

botic episode requires thrombolytic treatment,which can be

administered as for any patient with equivalent thrombotic

disease.92,93

PNH is particularly dangerous during pregnancy. In a

review of 20 women (31 pregnancies), there was a 43% inci-

dence of fetal wastage and a 74% incidence of maternal com-

plications,with a 10% incidence of maternal death, nearly all

of which were due to thrombotic events.94 One series of eight

pregnancies reported favorable results using subcutaneous

heparin prophylactically throughout the pregnancy, with full-

dose heparin following delivery,95

but a similar approach didnot prevent cerebral venous thrombosis in another case.96

MYELOPROLIFERATIVE DISORDERS (MPD)

The myeloproliferative disorders (MPD) encompass a group

of diseases characterized by clonal proliferation of bone mar-

row progenitors, with variable predisposition to thrombotic

and hemorrhagic complications.97 These are generally

divided into three clinical groups, which nevertheless may

merge or evolve one into another. Idiopathic myelofibrosis

(IMF) (agnogenic myeloid metaplasia) progresses to marrow

failure or may convert into leukemia and can manifest

venous thrombosis, especially of the portal system related tothe thrombocythemia that follows splenectomy.98 Essential

thrombocythemia (ET) and polycythemia vera (PV) are char-

acterized by a more striking association with thrombotic dis-

ease, and excess morbidity and mortality is often due to

arterial and venous thrombotic complications.99103 These

disorders can also evolve into acute myelogenous leukemia,

transformation that may be attributable in part to the use of

cytoreductive therapy.104107


The mechanisms implicated in the prothrombotic state asso-

ciated with these disorders are complex, with the exception

of the earliest and most clear association of vascular occlu-

sive episodes with high hematocrit (packed red blood cell

volume) and hyperviscosity.101103,108,109 The relation between

the platelet count and thrombosis is less precise,with a long-

held general feeling that patients with counts above 400

109 /L are 1.5-fold more likely to have venous thrombotic

complications than those with lower counts. Further evi-

dence that links a higher platelet count to thrombosis is pro-

vided by the study of cytoreductive therapy with

hydroxyurea in patients with ET. Patients with platelet

counts of about 500 109/L had fewer thrombotic events

than patients with persistent counts between 800 and

1000 109/L.110 However, severe thrombotic complications

at platelet counts below 500 10 9/L have been reported by

Regev et al. in 15% of patients.111 Furthermore, extremely

high platelet counts (>1500 109/L) are mostly associated

with hemorrhagic complications,112,113 especially when

aspirin therapy has been initiated.114 The underlying cause of

the increased platelet count is important, inasmuch as

patients with ET are significantly more likely to have throm-

botic events than are patients with thrombocytosis due to

non-clonal (reactive) disorders.115

Of interest, reactive poly-cythemia (smokers polycythemia) also has a significantly

lower, though still significant, risk of a thromboembolic

problem(41% versus 60%;p


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Identification of the susceptible patient who will develop a

thrombotic event is a challenge for the clinician.Age greater

than 60, history of a previous thrombotic event and pro-

longed duration of uncontrolled thrombocythemia have

been associated with increased risk for subsequent thrombo-

sis.133135

The Gruppo Italiano Studio Policitemia (GISP)133

fol-lowed 1213 patients with PV prospectively for 20 years, and

found an overall thrombosis rate of 3.4%/year, less for

patients who were younger than 40 and more for those over

age 70 (1.8% and 5.1%,respectively).The GISP reports subse-

quent thrombosis in 17.3% of patients without a history of

prior thrombosis,as compared to 24.6% for those with a pos-

itive history.A history of smoking or other risk factors for ath-

erosclerosis such as dyslipidemia,diabetes,and hypertension

were not predictive for thrombosis in some reports, 104,133 but

Watson and Key found an association of atherosclerotic risk

factors with arterial thrombotic complications in patients

with ET.136 Other studies document a direct relation between

thrombocythemia and thrombosis.137,138

These observations raise the question as to whether treat-

ment is warranted in all patients with MPD.Indeed, in a low

risk cohort of 65 patients with ET, younger than 60 years

of age and without a history of thrombosis, the incidence of

thrombosis after 4 years without treatment was the same as

in an age-and sex-matched control group (1.9% versus

1.5%).139

Most thrombotic episodes occur at presentation or

within 2 years preceding the diagnosis, suggesting that the

preclinical phase in MPD is associated with a latent pro-

thrombotic potential.133,140,141 Arterial events are common

and involve the cerebral, coronary and peripheral vessels,

whereas venous events often occur in the large mesenteric veins, the portal vein, the inferior vena cava and cerebral

veins.85,100,102,121,141153 Inherited thrombophilia, in particular

factor V Leiden, is often found in MPD patients manifesting

splanchnic vein thrombosis.154

Erythromelalgia is a typical manifestation of thrombo-

cythemia,first described by Mitchel in 1878,155 and is charac-

terized by red and painful extremities and progression in

some instances to ischemic acrocyanosis and gangrene.

Arteriolar intimal thickening and microthrombosis have

been demonstrated,and clinical response to aspirin is usually

dramatic.113A transient neurologic syndrome manifesting by

sudden onset of symptoms, which include headache,

dysarthria,scotomata and hemiparesis,and lasting seconds tominutes,has also been ascribed to small vessel,platelet-medi-

ated microocclusions responsive to either aspirin or to

cytoreductive treatment.123 Finally, non-bacterial thrombotic

endocarditis (NBTE) has been detected by echocardiography

in over one third of patients with MPD.52


The treatment of PV and ET is geared towards prevention of

thrombotic phenomena, and must be balanced against the

risks associated with cytoreductive therapy, especially malig-

nant transformation. Mortality is mostly due to serious arter-

ial and thrombotic events and malignancies.The incidence of

malignancy is four times higher in patients who have

received myelosuppressive therapy than in those treated

with phlebotomy or with antithrombotic agents only.133,156

The classic study by the Polycythemia Vera Study Group156,157

compared phlebotomy with alkylating myelosuppressive

therapy and found that thrombosis was lower in the group

treated with chemotherapy despite a comparable reduction

in the hematocrit with both treatments. Because of the risk

of malignant transformation with alkylating agents, hydroxyurea is the preferred cytoreductive agent at present, and

alkylating agents and radiophosphorus treatment use is dis-

couraged. Direct comparison of results between hydrox-

yurea and phlebotomy has not been reported. Similarly,

patients with ET have lower rates of thrombosis with

hydroxyurea treatment and malignant transformation was

not noted during a limited follow-up of 27 months.110 New

agents such as interferon and anagrelide are being used

increasingly, especially in young patients with thrombo-

cythemia,158161with positive results to date for controlling

the platelet count and preventing thrombotic complications

without an added risk of leukemogenesis.

The role of aspirin in reducing thrombotic events hasbeen overshadowed by reports of increased rates of hemor-

rhagic complications.97,162 However, these reports and other

studies have been criticized because the dose of aspirin was

higher than needed (approximately 1 gm/day). For example,

dosages of aspirin as low as 100 mg/day reduce thrombox-

ane A2 production and alleviate erythromelalgic, neurologic

and vasomotor symptoms.113,124 Low-dose aspirin has been

shown to be tolerated and effective in preventing recurrence

of thrombotic complications in patients with ET.163165A large

prospective trial (European Collaboration on Low-dose

Aspirin in Polycythaemia vera-ECLAP) that will evaluate

safety and efficacy of low-dose aspirin is in progress.164 Until

results are available,it is reasonable to use aspirin in patientsconsidered at high risk for thrombosis, in addition to cytore-

ductive therapy.

ACUTE PROMYELOCYTIC LEUKEMIA (APL)

The high early mortality noted in patients with acute

promyelocytic leukemia (APL) is related to a coagulopathy

that can lead to hemorrhagic death.166 Since the introduction

of the differentiating agent all-trans-retinoic acid (ATRA)

which promotes maturation of promyelocytes,the remission

rate has reached 8090%.167169With aggressive hematologi-

cal support plus/minus the use of heparin, the rate of fatal

hemorrhage has been reduced to approximately 10% in spe-cialized centers.170 The microgranular variant of the disease,

characterized by a paucity of myeloid granules and a lobu-

lated monocytoid nucleus,171,172 is associated with thrombo-

sis, presumably due to the release of a procoagulant factor

from the leukemic cells that is capable of inducing intravas-

cular coagulation173 or massive fatal venous thrombosis, for

example,Budd-Chiari syndrome.174


The coagulopathy related to APL is profound and reflects a

dual disturbance of increased coagulation and increased fib-

rinolysis, both of which could be caused by the microgranu-lar contents. Enhanced procoagulant activity could be




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chemotherapy or hormonal therapy, alteration of the vascu-

lar bed caused by tumor growth, direct extension of tumor

into a vein and disturbances of the coagulation pathway and

platelet number and/or function.Reactive thrombocytosis is

common in untreated cancer patients and abnormal platelet

aggregation in vitro, thought to be induced by material

released from tumor cells,208,209

may contribute to themetastatic spread of the malignancy.210212 Tumor cells can

activate the coagulation cascade by tissue factor expression

that activates factor VII172,213215 or through cysteine-contain-

ing proteases that are capable of directly activating factor

X.216 Natural anticoagulants (ATIII and protein C) are

reduced in some malignancies217,218 attributed by one group

to a decrease in hepatic synthesis rather than consump-

tion.219 Resistance to activated protein C that is unrelated to

a mutant factor V Leiden, perhaps due to elevated levels of

factor VIII or fibrinogen, may contribute to thrombosis.220,221

None of these abnormalities is predictive of thrombosis in an

individual cancer patient.222 Activation of fibrinolysis by

secretion of plasminogen activators may contribute to fibrindegradation around the tumor bed and to metastatic

spread.223 Chemotherapy may augment the risk for thrombo-

sis, for example, breast cancer treatment with or without

tamoxifen, especially in post-menopausal women.224,225 L-

asparaginase use,perhaps depleting asparagine that is essen-

tial for the synthesis of inhibitors of coagulation, is also

associated with thrombosis.226


The clinical spectrum of thrombotic events associated with

malignancy includes VTED, non-bacterial thrombotic (mar-

rantic) endocarditis, especially of valves on the left side of

the heart, and primary arterial thrombosis or embolic occlu-sions.227,228 Trousseau syndrome encompasses migratory

thrombophlebitis, unusual sites of thrombosis, intracardiac

thrombi,arterial thrombosis,DIC and markers of microangio-

pathic hemolytic anemia, elevated fibrin degradation prod-

ucts and hypofibrinogenemia.229231 Characteristically, the

thrombotic events are resistant to warfarin therapy and may

be devastating in the absence of heparin.231 Reports

describe patients with Trousseau syndrome treated success-

fully with low molecular weight heparin (LMWH), with last-

ing protection against recurrent thrombosis.232,233


As with other patients with VTED in the absence of con-

traindications, standard anticoagulation with heparin or

LMWH should be started immediately and continued as long

as the tumor presents a threat of recurrence,often resulting

in lifelong therapy.234 Greenfield filter placement should be

reserved for the minority of patients who have serious con-

traindications to anticoagulation or who fail anticoagulation

outright,235 especially considering that such patients have a

high rate of DVT extension, inferior vena caval thrombosis

and even pulmonary embolism after filter placement.236 In a

retrospective study, 64% of patients with cancer could be

managed with anticoagulation alone, 17% had filter

placement for standard indications and an additional 19%

underwent filter placement because of hemorrhagic compli-

cations or failure of anticoagulation. Serious complications

related to filter placement occurred in 17% of the patients.237

Given the high risk for thrombosis in cancer patients, pro-

phylactic therapy with LMWH is often initiated periopera-

tively and in high-risk medical situations.237,238

Anticoagulant therapy may have an antimetastatic poten-

tial and could potentially prolong survival when added toconventional chemotherapy.237 The mechanism involved in

this process is uncertain,but perhaps it is related to the pre-

vention of thrombus formation in distal capillaries where

migrant metastatic cells nest.239 The Veterans Administration

Study (#75) showed an improvement in survival (50 weeks

versus 24 weeks) in patients with small cell lung carcinoma

when warfarin was added to a combination chemoradiation

regimen240 and similar results were reported for heparin

added to standard chemotherapy for small cell cancer.241

However, these results were not replicated for patients with

other types of malignancy (colon,head and neck,prostate)242

and a randomized CALGB trial did not find a beneficial role

for anticoagulation in lung cancer patients.243

MEDICATIONS

The fine hemostatic balance can be affected by a number

of medications, most notably by hormonal preparations

that incorporate estrogens and by chemotherapeutic

agents.Theoretical considerations link the hematopoietic

growth factors to thrombosis, but to date these concerns

have not been translated into clinical proof of excess

thrombosis.

Oral contraceptives and hormonal replacement

therapy

The oral contraceptives (OC) have been linked to a throm-

bophilic state in direct relation with the estrogen con-

tent.244250 Invoked mechanisms include an increase in the

blood concentration of factors VII, VIII and XII, von

Willebrand factor and fibrinogen,251253 as well as complex

alterations of the platelet adhesiveness and aggregabil-

ity.254257 The synthetic estrogens affect the levels of the clot-

ting factors more than do the natural estrogen compounds

like estriol succinate.258,259 On the other hand,decreased lev-

els of PAI-1 have been noted in estrogen users, perhaps

underlying an augmented fibrinolytic activity and cardiopro-

tective effect.260,261An acquired resistance to activated pro-

tein C was documented in current OC users.262

The increased risk of VTED with OC use is dependent on

the dose of estrogen and the type of progestagen included in

the hormonal combination,with higher risk associated with

third generation progestagens than with first or second gen-

eration products (norethindrone and norgestrel respec-

tively).244247 The coexistence of an inherited thrombophilic

trait increases the susceptibility for thrombosis,a connection

that is particularly important for factor V Leiden, which is

present in up to 6% of the Caucasian population.Women that

carry the factor V R506Q mutation have a 35-fold increase in

VTED risk when using OC,compared to the control group.263

This observation raises the issue of screening for thrombophilic




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states, particularly for factor V Leiden, prior to initiating oral

contraception.264266 Given the prevalence of OC use, cost

considerations suggest that screening should be reserved for

women with a personal or family history of thrombosis or

with other recognized prothrombotic risk factors.A propen-

sity for thrombosis has also been noted for hormonal

replacement therapy users.250

In the Heart and Estrogen/progestin Replacement Study (HERS), in which a hormonal

combination was used in women with known coronary dis-

ease, the risk of VTED was 2.7-fold higher in the treatment

versus the control group.249

Tamoxifen

Tamoxifen is used as an antiestrogen in the adjuvant setting

or as therapy in metastatic breast cancer, and is associated

with an increased risk of VTED, with significant contribu-

tions by the body mass index, age and smoking status of the

patient. A retrospective case control study of more than

10,000 women with breast cancer in the UK estimated a rel-

ative risk for VTED of 7.0 in current users of tamoxifen com-pared with controls.267 Higher risk for venous and arterial

thromboembolism was also noted in women taking tamox-

ifen for breast cancer prevention in the National Adjuvant

Breast and Bowel Project P1 study.268,269A randomized trial in

Canada observed a higher incidence and severity of VTED in

women with breast cancer undergoing concomitant adju-

vant therapy with tamoxifen and chemotherapy than among

those receiving tamoxifen alone (13.6% vs 2.6%).225Whether

decreases in the concentration of natural coagulation

inhibitors such as antithrombin III (AT III) and protein

C270,271 simply correlate with a thrombophilic predisposition

or reflect activation of coagulation is unresolved,with some

studies reporting no concomitant increase in markers ofthrombin generation (prothrombin fragments 1+2, throm-

bin-antithrombin complex or fibrin degradation products) in

association with decreases in AT III and protein C lev-

els.272274

Chemotherapy

The prothrombotic potential of chemotherapeutic agents

can be difficult to ascertain, as patients with malignancy

already have an underlying thrombophilic state, and in-

dwelling long-term catheters for delivery of the chemother-

apy probably represent foci for thrombi genesis as well.

However, some cytotoxic medications are associated with a

probably intrinsic prothrombotic tendency, such as L

Asparaginase,which causes AT III depletion,275 and estramus-

tine, which can lead to arterial, and VTED through an estro-

gen-like effect.276VTED may occur in 511% of children with

all treated L-asparaginase, and inherited thrombophilia may

substantially increase the risk.277A pilot study suggests that

low-molecular-weight heparin can prevent VTED in such

patients during L-asparaginase therapy.278

Hematopoietic growth factors

In vitro studies and occasional case reports have linked

recombinant hematopoietic growth factors to a throm-

bophilic state. For instance, erythropoietin causes an

increase in markers of endothelial cell injury (von Willebrand

factor, thrombomodulin and tissue factor pathway

inhibitor,279,280 a decrease in free protein S concentration281

and possibly enhances platelet aggregability.279,282,283 In addi-

tion, a rise in hematocrit secondary to erythropoietin could

predispose to thrombosis.284 However, short-and long-term

use of erythropoietin has not been associated with a signifi-

cant increase in thromboembolic complications.285289 There

are similar concerns regarding the use of thrombopoietinand granulocyte stimulating colony factor (G-CSF).290 Platelet

aggregation can be augmented by thrombopoietin120 and

platelets possess functional receptors for G-CSF.291,292 Rare

episodes of thrombosis have been reported in patients

receiving G-CSF.293 Clearly, definitive studies are needed to

prove a causal relationship.

Heparin and coumarins

Patients who develop thrombocytopenia secondary to anti-

body against platelet factor 4: heparin complexes (HIT) are

prone to both arterial and venous thrombosis (HIT-T).294 By a

similarly curious thrombotic complication of an anticoagu-

lant agent, coumarins can induce microvascular occlusionsleading to skin necrosis and venous limb gangrene in

patients with pre-existing protein C deficiency.295,296 These

clinical situations in which patients with evident thrombotic

disease or in need of prophylaxis against such events experi-

ence new and/or extended thrombotic complications may

be difficult to manage and present unusual therapeutic

dilemmas.Warkentin has reviewed the pathophysiology and

treatment of the conditions in detail.297

OTHERS

Acquired deficiencies of the natural inhibitors of the coagu-

lation pathway can be associated with a variety of disorders,sometimes related to a true hypercoagulable state. For

instance, low levels of AT III,protein C and protein S can be

encountered in hepatic failure because of decreased synthe-

sis; however the hemostatic balance will reflect a concomi-

tant decrease in synthesis of the coagulation factors leading

to a bleeding tendency. Loss of ATIII is encountered in

nephrotic syndrome298 which is associated also with

decreased levels of free protein S to about 75% of normal. In

fact, the total level of protein S may actually be increased in

this circumstance,but the level of the C4b-BP, to which pro-

tein S is bound in plasma, is also increased to nearly twice

normal,accounting for a decreased level of free protein S.299,300

Low levels of protein S have been reported in multiplemyeloma301 orthotopic liver transplantation302 inflamma-

tory bowel disease303 and second trimester of the preg-

nancy, when the low protein S level may be related to an

increased C4b-BP or an increased affinity for C4b-BP in

plasma.304,305 Extensive thrombosis leads to rapid consump-

tion of these inhibitors, with subsequent reduced levels of AT

III,protein C and S.Protein S can be decreased in SLE, in asso-

ciation or not with APL antibodies.306,307 In one series,protein

S was reduced in nine of 36 patients with SLE and all patients

deficient in protein S had APL antibodies suggesting that the

thrombotic tendency was mediated through an acquired

deficiency in protein S.308A related case describes antibodies

against protein S in association with a thrombotic event. 309

Low levels of protein S have been reported in acute bacterial

Matei et al.



9/18

or viral illnesses that predispose to purpura fulminans,with

return of levels to normal after recovery.310312

HIV infection is associated with a prothrombotic state as

reflected by increased markers of thrombin activation (pro-

thrombin 1+2,FDP) and PAI 1 reported in a small series of 22

patients.313 Protein S is frequently decreased, sometimes in

association with a thrombophilic state.314317

The mechanismof these changes may be related to abnormal endothelial cell

function during HIV infection, and as yet there is no correla-

tion with clinical manifestations or duration of HIV infection

or with the CD4 count.

Behcet disease is a systemic disorder that occurs most

typically in males from the Mediterranean basin,and is char-

acterized by oral and genital ulceration and ocular inflamma-

tion. Vascular manifestations are primarily VTED of large

vessels,often in unusual sites including the inferior and supe-

rior vena cava, hepatic veins (Budd-Chiari syndrome), and

cerebral sinuses as well as intracardiac thrombosis and pul-

monary embolism.318321 Confounding and potentiating influ-

ences have been noted, for example, anti-endothelialantibodies, hyperhomocysteinemia and homozygosity for

MTHFR and the prothrombin 20210 and factor V Leiden

mutations,322324 although the latter observation has been dis-

puted as a contributing cause.325

Circumstantial risk factors which would otherwise repre-

sent an insufficient cause for a thrombotic episode may

unmask a prothrombotic predisposition as,for example,with

stasis, pregnancy or advanced age. There are well-docu-

mented reports that strongly relate VTED to prolonged

travel. Of interest,while air travel is increasingly but not uni-

versally recognized as a potential cause, automobile travel of

similar duration is less associated with VTED,326,327 perhaps

reflecting non-standardized evaluations of patients butpossibly related to environmental or physical factors present

during air travel.Bedridden patients are clearly at increased

risk for VTED,and a trial has demonstrated that such patients

with significant illness or with difficulty in ambulation have

objectively documented high rates of VTED, on the order of

15%, and that such events can be reduced significantly (to

6%) by treatment with low molecular weight heparin.328

The risk of VTED is increased four-fold duringpregnancy,

being particularly high during the postpartum period.Due to

anatomical considerations of the pelvic vessels, DVT is pre-

dominantly present in the left leg (80% of affected

women).329 Proximal DVT is common,often resulting in the

post-phlebitic syndrome,and the risk of VTED is increased in

patients with prior disease, positive family history, age over

35 years, Cesarean section, and gestational vascular com-

plications such as preeclampsia, placental abruption and

intrauterine growth restriction.330 The coagulation cascade is

activated during pregnancy as manifested by increased fac-

tor levels and activated peptides such as prothrombin frag-

ment 1.2 and fibrinopeptide A, as well as by soluble fibrin

and D-dimer.331 The natural anticoagulant systems may be

affected, for example, reduced activity of protein S and

increased APC-resistance332 and a reduced fibrinolytic

response may further exaggerate the situation.333 Thus, these

influences combine to produce a net effect that is prothrom-

botic. While inherited thrombophilia can be found in the

majority of women who experience gestational VTED,334

these acquired mechanisms contribute to its expression and

VTED may be manifest in women without inherited throm-

bophilia.

Acknowledgements

Supported by the Los Angeles Orthopaedic HospitalFoundation,Los Angeles,California,USA.

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Orthopaedic Hospital/UCLA, 2400 South Flower Street, Los Angeles, CA

90007,USA.Tel:+ (213) 742 1519; Fax: + (213) 742 6568; E-mail:

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