hemostasis dysproteinemias

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Hemostatic Dysfunction in Paraproteinemiasand AmyloidosisMaurizio Zangari, M.D.,1 Francesca Elice, M.D.,1 Louis Fink, M.D.,2

and Guido Tricot, M.D., Ph.D.1

ABSTRACT

Thrombotic and hemorrhagic complications frequently have been observed inpatients with monoclonal gammopathy, Waldenstrom macroglobulinemia, amyloidosis,multiple myeloma (MM), and myeloma. Chemotherapy in combination with the use of

antiangiogenic agents can further enhance the risk of cardiovascular complications. Amalignancy-associated thrombophilic state (in particular, cytokine-induced high levels offactor VIII and von Willebrand factor) can also explain the high rate of thrombosisreported in these patients. Impaired fibrinolysis and a transient downregulation of theprotein C system are recently discovered pathogenetic mechanisms. At diagnosis, whenthe highest VTE risk is present, baseline coagulation tests such activated protein Cresistance may be helpful to identify patients who can benefit the most from anti-coagulation; with the emerging evidence of a positive effect on survival of low molecular

weight heparin, prospective trials are needed in this group of diseases.

KEYWORDS: Myeloma, paraproteinemia, amyloidosis, bleeding diathesis, thrombosis

INCIDENCE OF THROMBOEMBOLICCOMPLICATIONS

Thrombosis is now recognizedas one of the most commoncomplications faced by cancer patients. In addition to

common risk factors for venous thromboembolism(VTE) such as age, immobility, surgery, inflammatoryresponse, and chemotherapy,disease-specificmechanisms

are involved in the pathogenesis of the phenomenon. Theoverall incidence of VTE in the general population is 117per 100,000 person-years. Incidence rates for both deep

vein thrombosis (DVT) and pulmonary embolism (PE)

increase dramatically with advancing age among both menand women. Thromboembolic complications frequently

havebeenreportedinpatientswithparaproteinemias,asinmany other hematologic malignancies. Monoclonalgammopathy of undetermined significance (MGUS) has

been associated with an increased risk of VTE: the VTErate was 6.1% (1.3 per 100 patient-years) in a prospectiveanalysis of 310 MGUS patients1 and 7.5% in a retrospec-tive study with 174 patients observed during a 10-yearperiod.2 With the knowledge that specific interventioncan affect the hemostatic system differently, multiplemyeloma (MM) patients treated with vincristine 0.5 mg,doxorubicin (doxo) 10 mg/m2, and dexamethasone 40 mgdaily for 4 days (VAD) with or without radiotherapyshowed a VTE incidence of 10%.2,3 In a population

with a median age of 61 years, two recent large phase III

trials in the relapse setting have shown that single-agentdexamethasone is associated with a low rate of thrombosis(3.5% in theMM-009trial, 4.5% in theMM-010trial).4,5

Similar incidence (3%) has been observed with dexame-thasone in the newly diagnosed setting.6

1Myeloma Institute for Research and Therapy, University of Arkansasfor Medical Sciences, Little Rock, Arkansas; 2Nevada Cancer Institute,Las Vegas, Nevada.

Address for correspondence and reprint requests: Maurizio Zangari,M.D., Myeloma Institute for Research and Therapy, 4301 WestMarkham, 816 Little Rock, AR 72205. E-mail: [email protected].

Hemostatic Dysfunction in Malignant Hematologic Disorders; GuestEditor, Hau C. Kwaan, M.D., Ph.D.

Semin Thromb Hemost 2007;33:339349. Copyright # 2007 byThieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY10001, USA. Tel: +1(212) 5844662.DOI 10.1055/s-2007-976169. ISSN 0094-6176.

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The recent introduction of effective antiangio-genic agents in cancer treatment has heightened themedical attention on this phenomenon. Thalidomide,the first antiangiogenic drug tested in MM, was associ-ated to an unexpected high rate of VTE (27%) whencombined with dexamethasone and chemotherapy.7Thiscomplication was not apparent when used as single agent:

VTE incidence was < 5% in 169 extensively pretreatedMM patients receiving single-agent thalidomide8; asimilar experience was reported by other investigators.9,10

Compared with single-agent thalidomide, a modest in-crease of the thrombotic risk was described in relapsed orrefractory patients treated with the combination of dex-amethasone and thalidomide (VTE rate 8%),11 but thisrisk became more prominent when the same regimen wasapplied to newly diagnosed subjects (VTE rate 20 to26%).6,12 The potential thrombogenicity of the thalido-mide/chemotherapy combination was confirmed furtherin a phase III trial with upfront random assignment to

chemotherapy with or without thalidomide: incidence ofthrombosis was statistically higher in the thalidomidearm (p 0.002).13 Among 232 MM patients treated withchemotherapy and thalidomide in two protocols thatdiffered only by the inclusion of doxo in one, VTEincidence was significantly different in the two groups(doxo 16 versus 3.5%; p 0.02).14

The synergistic prothrombotic effect of doxo/thalidomide combination was also confirmed in an ex-perimental model of thrombosis in rabbits.15 In a multi-

variate analysis of 535 patients treated with thalidomidein various trials, newly diagnosed status, thalidomide/doxo combination, and presence of chromosome 11abnormalities were the only independent risk factorsassociated with DVT development.16 The early onsetof thrombosis, when the highest tumor load is present(50% of cases within 2 months),12 indicates a possiblerelease of thrombogenic factors from cancer cells. LowVTE rate (8%) has been reported in the United King-dom Myeloma Forum T-VAD trial, in which thalido-mide was added to VAD chemotherapy (T-VAD) onlyafter an initial debulking with two chemotherapycycles.17 The low VTE incidence associated with thebrief delay in thalidomide administration suggests thatthe drug could act as a precipitating factor only in the

presence of a baseline prothrombophilic state. Theimmunomodulatory drug lenalidomide is a thalidomideanalogue that retains direct anticancer toxicity andimmunological activity of the parent compound but

with different toxicity profile. Deep venous thrombosiswas not a frequent event in phase I and II studies.18,19

However, grade 3 or 4 VTE were observed in 18% ofpatients enrolled in a phase II trial which comparedtwo different lenalidomide dexamethasone schedules.20

Preliminary reports of two multicenter double blindphase III trials which compared lenalidomide plusdexamethasone versus dexamethasone and placebo in

relapsed/refractory setting (MM-009 study in NorthAmerica and MM-010 study internationally) indicatestatistically higher DVT incidence in the lenalidomide/dexamethasone arms of both the studies (MM-009 15%

vs 3.5% & MM-010 8.5% vs 4.5%).4,5 Frequent throm-botic episodes were reported in an ongoing SWOG trial

which compared dexamethasone alone versus dexame-

thasone plus lenalidomide in newly diagnosed patients; 9of the first 12 patients (75%) enrolled in the lenalido-mide/dexamethasone arm without anticoagulation de-

veloped thrombosis, including one ischemic stroke,while no events were reported in 9 patients assigned tothe dexamethasone arm.21 The addition of aspirin (80mg or 325 mg) reduced such incidence to 19%. Morecontained DVT incidence was reported in a similarsetting by Rajkumar22 with aspirin prophylaxis (3%).

Among other paraproteinemias, venous and arte-rial thrombotic events have been frequently associated

with amyloidosis. In a group of 56 amyloidosis patients

with a median age of 67 years, 11% developed VTE.23

The presence of circulating monoclonal protein was nota risk factor for VTE development, whereas older age,immobility, and personal history of DVT were found toincrease the thrombotic risk. In patients with acuteleukemia and amyloidosis, a thrombotic event appearsto confer a substantial morbidity and mortality andcomplicates the management of an already complexclinical condition: median survival for patients witharterial and venous thrombosis was 3 and thrombosis

was 16 months respectively.24 Recent studies indicatethat cancer prothrombogenicity is involved intrinsicallyin tumor cell growth, angiogenesis, metastasis, andassociated with a poorer prognosis.25These observationshave led to the hypothesis that anticoagulant treatmentcould affect the survival of cancer patients.26 We haveanalyzed the prognostic impact of the development of athrombotic episode in newly diagnosed MM patients

who received chemotherapy either with or withoutthalidomide on our Total Therapy 2 protocol.27 Of668 patients enrolled, 155 developed VTE complicationduring treatment. The overall and event-free survival ofpatients who experience VTE was not inferior. Indeed,

we observed that patients who received intensive chemo-therapy without thalidomide and developed thrombosis

experienced a significantly longer event-free survivalcompared with those without VTE (p 0.02), suggest-ing a beneficial effect of low molecular weight heparin(LMWH) on disease progression.28

PATHOGENETIC MECHANISMS OF

THROMBOSIS IN PARAPROTEINEMIASMultiple and interdependent mechanisms are responsi-ble for the hypercoagulable state in patients withcancer. Tumor procoagulant activity, host inflammatoryresponses, and extrinsic factors, which frequently are

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iatrogenic, are involved. Classic risk factors such assurgery, prolonged immobilization, fractures, and useof oral contraceptives not only predispose apparentlynormal individuals to thrombosis but also are likely totrigger this condition in people with inherited andacquired thrombophilic abnormalities. Abnormallyhigh plasma levels of immunoglobulin and associated

increased blood viscosity can impair fibrin polymeriza-tion.29 The abnormally structured fibrin interferes withthe binding site for plasmin and factor XIII (FXIII).30

Defective binding with FXIII causes a deficit in clotretraction and bulky clot formation, which can moreeasily occlude small blood vessels.31 Abnormally as-sembled fibrin produces thinner and weaker strandsthat are more resistant to fibrinolytic activity of plasmin.In fact, fibrin structure is a major determinant of fibri-nolysis that can be impaired in a manner dependent onthe dose of immunoglobulin G (IgG).3234Yagci et al33

have observed a significant negative correlation between

global fibrinolytic capacity (GFC) with levels of plasmi-nogen activator inhibitor type 1 (PAI-1) and C-reactiveprotein (CRP), suggesting that decreased GFC is causedmainly by high PAI-1 activity. In MM, the increasedPAI-1 activity seems to be related to an increased CRPand interleukin-6 (IL-6) levels. These observations in-dicate that inflammatory cytokines associated with mye-loma (in particular, IL-6 and its downstream targetCRP) not only have a direct effect on coagulation, butcan also inhibit fibrinolysis.

The monoclonal paraprotein itself may have in-trinsic prothrombotic properties: several authors havedescribed monoclonal paraproteins with lupus antico-agulant activity in patients who developed thromboem-bolic events.35 Bellotti et al36 described three patients

with immunoglobulins against thromboplastin phos-pholipid that showed lupus anticoagulantlike activity:the strongest interaction was demonstrated in the patient

with the most basic antibody. Takamiya et al37 describedan IgG lambda paraprotein derived from a myelomapatient with lupus anticoagulantlike activity in mixingstudies; such immunoglobulin lost its activity whendegraded by pepsin, suggesting that the interaction

with coagulation factors and phospholipids was notimmunologically mediated. These observations indicate

that negatively charged immunoglobulins can interactwith acid phospholipid on the platelet surface by anelectrostatic mechanism. IL-6, CRP, and tumor necrosisfactor alpha (TNF-a) are acute-phase reactant proteinsfrequently elevated in patients with MM.

IL-6 plays is an important role as a survival andantiapoptotic factor for MM cells in the bone marrowmicroenvironment and has been implicated in both auto-crine and paracrine growth of the malignant clone.38 IL-6induces not only B lymphocyte differentiation into ter-minally differentiated plasma cells but also acts as asurvival and growth factor for MM. IL-6 is able to induce

the growth of plasma cells isolated from patients and toinhibit myeloma cell apoptosis induced by dexamethasoneand anti-Fas antibodies, but it cannot inhibit apoptosisinduced by irradiation.39 Serum levels of IL-6 and CRPhave been associated with the proliferative activity of thedisease and used as prognostic factors in MM patients.40

IL-6 is produced not only by plasma cells, but mainly by

osteoblasts and stromal cells, resulting in paracrine stim-ulation of the malignant clone. This stimulation dependson both direct cellcell contact and on the release ofsoluble factors such as TNF-a, soluble IL-6Ra, and

vascular endothelial growth factor (VEGF).41 The pro-duction of VEGF in this cytokine loop is of particularinterest because VEGF enhances angiogenesis and upre-gulates the expression of tissue factor on endothelialcells,42 thus contributing to the disease-associated throm-bophilic state. Under normal conditions, the anticoagu-lant-to-procoagulant balance of the endothelium allowsblood cells and platelets to flow without adhering to vessel

walls. Excessive cytokine concentration during the in-flammatory- or acute-phase response states can alter thisfine balance, producing procoagulant endothelial condi-tions.43The cytokine network associated with MM also isan example of such an imbalance. In particular, elevatedIL-6 levels are able to increase fibrinogen, tissue factor,and FVIII plasma levels.44,45These in vitro observationsalso have been confirmed in the clinical setting, wherehigh levels of FVIII and von Willebrand factor (vWF)antigen have been associated with IL-6 levels in patients

with active disease.46

In this background of impaired fibrinolysis andcytokine-induced activation of the coagulation system,the deficiency of natural anticoagulant mechanisms canfurther alter the hemostatic balance in a thrombophilicdirection. In MM, an impaired activity of the protein Csystem has been suggested by the observation of abnor-mal resistance to activated protein C (APC) and by areduced protein S function.

Indeed, the presence of acquired resistance toAPC without FV Leiden mutation has been observedin cancer patients who experienced a thrombotic epi-sode.47,48 After reporting a high incidence (23%) ofacquired APC resistance in a group of 62 newly diag-nosed myeloma patients with active disease,49 we con-

ducted an analysis of 1178 newly diagnosed or newlytreated myeloma patients: APC resistance was detectedin 109 patients (9%) and in two thirds of them thealteration was not related to FV Leiden mutation.50

Patients carrying such an acquired abnormality developeda statistically higher incidence (p 0.008) of thrombosisduring treatment. Acquired APC resistance was notobserved in a series of 51 patients with MGUS that

were tested at our institution (unpublished data) support-ing the idea that cancer activity along with inflammatorycytokine release plays a crucial role in inducing abnor-malities in the APC system. Similar experiences have

HEMOSTATIC DYSFUNCTION IN PARAPROTEINEMIAS AND AMYLOIDOSIS/ZANGARI ET AL 341


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been reported by Hugo and Jeanet,51 who conducted aprospective study with 50 symptomatic MM patientstreated with thalidomide in combination with VAD(20 patients), dexamethasone (24 patients), or melpha-lan/prednisone (six patients).51 A transient acquired APCresistance was observed in 12% of patients and wasassociated with a high incidence (66%) of DVT.

Protein S is an important APC cofactor for theinactivation FVa and FVIIIa; levels of protein S areknown to be reduced in inflammatory conditions.52

Indeed, in a group of 78 newly diagnosed myelomapatients, we found a correlation between acquiredAPC resistance and decreased protein S activity(p 0.012), which was present in 27% of patients(Table 1).50 The binding of the IgG paraprotein withfree protein S, which resulted in a severe acquireddeficiency of protein S activity, has also been describedin a myeloma patient.53

The role of inherited thrombophilic factors seemsto be marginal in patients with neoplasia54 and inparticular with MM.55 In an analysis of 1178 myelomapatients conducted at our institution, 3% were carriers ofthe FV Leiden mutation.50 FV Leiden mutation is themost common thrombophilic mutation that is found in 1to 7% of a normal white population,56 and determines a

7-fold increase of VTE risk in heterozygous carriers,whereas this risk is up to 80-fold higher in homozygouspatients.57,58 In our series, patients carrying FV Leidenmutation appear to have higher VTE incidence com-pared with controls (22% v12%), but this difference didnot reach statistical significance.50 The prothromboticmutation 20210A of the prothrombin gene occurs in 2%of the general population, but it is more frequent inpatients with VTE.59 This mutation has been observedin 4% of newly diagnosed myeloma patients (Table 2).Methylenetetrahydrofolate reductase (MTHFR) gene

Table 1 Coagulation Factors at Baseline and during Therapy in Myeloma Patients

Baseline (% abnormal)

After

Treatment Therapy Reference

D-dimer Increased (63%) TCHT Elice et al50

PAI-1 Normal TD Corso et al60

Homocysteine Increased (56%) T and TD Weber et al61

Increased (814%) TCHT Elice et al50

Antithrombin Decreased (42%) In 19 of

20 patients

T or TD Weber et al61

Decreased (32%) TCHT Elice et al50

Protein C activity Decreased (18%) T and TD Weber et al61


Protein S activity Decreased (12%) T and TD Weber et al61


APC sensitivity ratio Decreased (9%) TCHT Elice et al50

Thrombomodulin Decreased # TD Corso et al60

von Willebrand antigen Increased (49%) TCHT Elice et al50

Increased TCHT Minnema et al46

Factor VIII:C Increased TCHT Minnema et al46

Anticardiolipin IgG Positive (3%) TCHT Elice et al50

Anticardiolipin IgA Positive (20%) Negative T and TD Weber et al61

VEGF Increased T and TD Weber et al105

Increased T Neben et al106

# in RP T Bertolini et al107

# in RP T Dmoszynska et al108

b-FGF # in RP T Bertolini et al107

# in RP T Dmoszynska et al108

T, thalidomide; CHT, chemotherapy; PAI-1, plasminogen activator inhibitor type 1; , no change; TD, thalidomide and dexamethesone; APC,activated protein C; #, decreased levels with therapy compared with baseline; C, coagulant activity; Ig, immunoglobulin; VEGF, vascularendothelial growth factor; RP, responding patients; b-FGF, basic fibroblast growth factor.



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Table2

StrategiesofThromboprophylaxisinMyelomaPatients

Status(N/R)

No

Prophylaxis

W

arfarin

11.2

5mg/d

LowMolecular

WeightH

eparin

Aspirin

%

VTE

No.

Reference

%

VTE

No

.

Reference

%

VTE

No.

Reference

%

VTE

No.

Reference(doseof

aspirin)

Thalidomide

dexamethasone

N

26

19

Cavoetal12

25

24

Weberetal68

7

42

Has

soun109

(81mg)*

20

102

Rajkumaretal

6

13

52

Cavoetal

12

R

2

120

Palumboetal110

8

47

Anagnotopoulosetal

11

Thalidomide

melphalan/

prednisone

N

12

124

Faconetal111

18

65

Palumboetal112

5

78

Palumboetal112

Thalidomide

chemotherapy

withdoxorubicin

N

34

87

Zangarietal

71

31

35

Zangarietal

71

15

68

Zangarietal

71

10

39

Zervasetal

113

10

211

Minnemaetal

73

12

16

Chanan-Khan

etal114

18

58

Baz

etal

75

(81mg)

R

16

192

Zangarietal49

Lenalidomide

dexamethasone

N

3

34

Rajkumaretal

22

(80325mg)

75

12

Zonderetal

21

19

32

Zon

deretal

21

(325mg)

R

8

351

Dimopoulosetal5

Lenalidomide

melphalan

andprednisone

R

2

38

Palumboetal

112

(100mg)

Lenalidomide

chemotherapy

withdoxorubicin

R

9

58

Baz

etal75

(82mg)

*Thalidomideanddexamethasonewerea

dministeredtonewlydiagnosedpatientsafteraninitialdebulkingchemotherapy.

R,relapsed/refractory;VTE,venousthrom

boembolism;N,newlydiagnosed.



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mutations have been described in up to 50% of MMindividuals and overall not different from general pop-ulation.60,61 In myeloma patients, inherited thrombo-philic factors seem to have a marginal impact on VTErisk. Prophylactic strategies, and selected testing (APC)rather than extensive screening for thrombophilic factorsare recommended in patients with paraproteinemias.

EFFECT OF MYELOMA THERAPY ON

COAGULATION AND ANGIOGENIC

FACTORSActivation of coagulation system and fibrinolysis, in-creased angiogenesis, and reduction of natural antico-agulants has been observed in patients with myelomaduring the course of the disease (Table 1). Severalinvestigators reported transient elevations of FVIII and

vWF levels during therapy with thalidomide.46,62

Minema et al46 also described an association between

FVIII and vWF levels and VTE development. Clinicalevidence of an elevated plasma level of vWF and FVIIIwas described in a patient with hereditary von Willebranddisease type 2A, who experienced a temporary remissionof bleeding symptoms at onset of MM. The reappearanceof symptoms, after achieving remission, suggests that aneffective myeloma therapy can downregulate the levels ofthese factors.63 The knowledge of a correlation betweenFVIII levels and VTE risk64 could be important for theassessment of the thrombotic risk of patients receivingthrombogenic therapies. Levels of vWF and plateletaggregation tests were obtained in a group of individualsat baseline and after therapy with liposomal doxo, vin-cristine, dexamethasone, and thalidomide. Higher vWFlevels and increased platelet sensitivity to ristocetin dur-ing treatment suggest a possible interaction betweenplatelets and endothelial cells.65 The increased level ofsuch factors could be related not only to therapy, but alsocould be associated with disease activity, given that manypatients with active disease had elevated baseline FVIIIand vWF levels, irrespective of thalidomide treatment.Because vWF is synthesized by endothelial cells, the levelof vWF may indicate bone marrow neovascularization, orcould be the result of cytokines release. Indeed, interleu-kin-11 upregulates clotting factor levels.46 A group of 31

myeloma patients with acquired APC resistance had thetest repeated at least twice during treatment. Response totherapy was associated with normalization of APC valuesin two thirds of these patients. Disease status (activedisease versus partial or complete response) and level ofmonoclonal component were the two factors associated

with the presence of APC resistance.50

Reduction of thrombomodulin plasma concentra-tion and variation of angiogenic factors also have beenreported during thalidomide therapy60,66 (Table 2). Adecrease of VEGF and basic fibroblast growth factor (b-FGF) was only observed in responding patients. Similar

changes in angiogenic molecules were also described withconventional chemotherapy, indicating that tumor bur-den reduction rather than thalidomide-dependent inhib-ition of angiogenic cytokine secretion is the most likelyexplanation for this phenomenon. In a bone marrowendothelial cell system derived from active myelomapatients, thalidomide has been shown to downregulate

the expression of angiogenic genes such as VEGF, b-FGF, and hepatocyte growth factor. A similar effect wasnot observed on endothelial systems derived from inactiveMM or monoclonal gammopathy.67 It is conceivable thatthe antiangiogenic properties associated to thalidomideare depending on the disease and microenvironment,explaining the contrasting results obtained regardingthe antiangiogenic activity of thalidomide in vivo.

EFFECT OF ANTICOAGULANTS ON

THROMBOTIC COMPLICATIONS IN

PARAPROTEINEMIASThe best strategy to prevent thromboembolic complica-tions in paraproteinemias has not been established yet,mainly because of limited data available. Although it isdifficult to introduce a systematic thromboprophylaxis ina population of patients who are often thrombocytopenicand have an increased risk of bleeding, the high rate ofthromboembolic complications during the treatment

with new agents warrants the use of prophylaxis in thosepatients with the highest risk. Definition of the treat-ment-associated thrombotic risk in a specific cancerpopulation and identification of reliable markers forVTE development are fundamental for the evaluationof the riskbenefit ratio of an anticoagulant therapy.

Table 2 summarizes the strategies for thrombo-prophylaxis used in myeloma patients treated with tha-lidomide and lenalidomide in different combinations

with dexamethasone or chemotherapy. Effective anti-coagulation with warfarin has the advantage of oraladministration, but it requires regular monitoring tokeep international normalized ratio (INR) values withina defined range and it has many interactions with food orother drugs. With the use of therapeutic anticoagulation

with warfarin (INR range 2 to 3), thrombosis was a rareevent in newly diagnosed patients treated with thalido-

mide and dexamethasone.68 The use of fixed low-dosewarfarin derives from the experience in VTE prophylaxisfor patients with indwelling catheters or with atrialfibrillation. Although this strategy does not require bloodmonitoring, efficacy results were contrasting.69,70 Similaropposing results were obtained in MM: Although Cavoet al12 showed a significant reduction in VTE incidencein newly diagnosed patients treated with upfront thali-domide and dexamethasone, Weber et al68 and Zangariet al71 did not confirm this risk reduction. Different dosesof warfarin (1.25 versus 1 mg/d) or different patientpopulations may account for the discordant results.



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The superiority of LMWH compared with war-farin for recurrent VTE prophylaxis in cancer patients72

inspired the use of these drugs for thromboprophylaxisin MM patients with the highest VTE risk.

The prothrombotic effect of doxo-containingchemotherapy combined with thalidomide was abro-gated completely by the prophylactic use of enoxaparin

(40 mg/d) or nadroparin (2850 IU anti-Xa), as listed inTable 2.71,73 For the treatment of responding patientswho developed VTE, available data suggest that it isreasonable to resume the therapy with thalidomide whenfull anticoagulation has been established and continuedfor the total duration of therapy.71 The rate of VTErecurrence was overall 11% and not significantly differ-ent from the rate observed in other cancers (9 to 17%). 74

Recent data suggesting a possible role of plateletdysfunction in the pathogenesis of VTE have led to testaspirin as thromboprophylaxis in clinical trials.65

Although only a modest reduction of VTE incidence

was obtained with prophylactic fixed low dose aspirin inpatients treated with thalidomide, dexamethasone andchemotherapy,75 aspirin appears more efficacious inprotocols including lenalidomide/dexamethasone, asshown in Table 2.21,22

BLEEDING DIATHESIS IN

PARAPROTEINEMIASEvidence of bleeding, often confined to purpura, epis-taxis, or hematuria, manifests in less than 10% ofpatients with MGUS, MM, Waldenstrom macroglobu-linemia, and primary AL amyloidosis. Interactions be-tween plasma paraprotein, platelets, and coagulationfactors (reviewed by Liebman76) are the common path-ophysiologic mechanisms.

In a series of 62 patients with paraproteinemia,correlation between specific immunoglobulins and ab-normalities of the coagulation system or frequency ofbleeding episodes were described.77 Platelet count andthrombin time were more frequently altered in IgG andIgA paraproteinemias, whereas platelet adhesiveness test,FVIII levels, prothrombin time (PT), and partial throm-boplastin time (PTT) were often abnormal in IgA andIgM paraproteinemias. Bleeding episodes were more

frequent in Waldenstrom macroglobulinemia (36%) andIgA myeloma (33%). Mixing studies with normal plasmaindicated the presence of an inhibitory paraprotein thatcaused reduced levels of coagulation factors or prolonga-tion of thrombin time (TT), PT, and PTT times.

Bleeding diathesis is more commonly observed inpatients with amyloidosis: at diagnosis, 15% of patientsshow purpura, particularly in periorbital and facialareas.78 Severe hemorrhages are rare, but they can belife threatening. In a series of 36 patients with amyloi-dosis and monoclonal gammopathy, laboratory clottingabnormalities were found in most cases and hemorrhagic

manifestations were found in one third of patients (ninemild to moderate episodes of purpura or ecchymoses andfatal mucosa hemorrhage).79 Prolongation of TT, repti-lase time (RT), and Russel viper venom time (RVVT) arethe most common abnormalities found; low plasma levelsof FX are also common and do not correlate with RVVT.

The presence of a plasma inhibitor has been hypothesized

to be the cause of TT, RT, and RVVT prolongation butabnormal tests values can also be observed in the absenceof an abnormal paraprotein. Paraprotein can inhibit fibrinpolymerization, resulting in prolonged TT and abnormalclot formation.30 Inhibition of fibrin monomer aggrega-tion by the paraprotein also has been postulated in apatient with MM with prolonged TT and RT, where TTbut not RT was corrected by the mixing of patients andnormal plasma.80 Despite the relatively frequent abnor-mal TT time, clinical bleeding manifestations are ob-served only in a minority of patients, who possibly haveother associated hemostatic defects, such as a decreased

FX level, enhanced fibrinolysis due to a

2-antiplasmindeficiency,79 or vessel wall amyloid deposition.81 Theprimary role of plasma factors in the bleeding diathesisis also suggested by the clinical response observed withplasma exchange or large-volume plasmapheresis, inparticular in patients with Waldenstrom macroglobuli-nemia.82,83

The presence of circulating paraproteins withvWF or FVIII inhibitory activity have been describedin patients with MGUS,84 MM, Waldenstrom macro-globulinemia, lymphoma, chronic lymphocytic leuke-mia, and amyloidosis.85,86 The presence of such factors

was associated with clinical symptoms of acquired vonWillebrand disease or hemophilia.87,88

The addition of purified paraprotein to platelet-rich plasma can impair platelet aggregation and release ofplatelet factor 3.89,90 A lambda dimeric protein purifiedin a patient with IgD/lambda myeloma, who rapidlydeveloped a subcutaneous hematoma after puncture ofthe inguinal artery, retained the ability to prolong PTTand RVVT and to inhibit ristocetin-induced plateletaggregation.91 This lambda dimer showed both lupusanticoagulant activity and inhibitory effect on vWFglycoprotein Ibabinding on the platelet surface, induc-ing an acquired von Willebrand state.91The coexistence

of these two hemostatic alterations caused by the samemonoclonal protein is rare, but it has been observed inseveral cases of paraproteinemias.84

Other paraprotein-independent mechanisms candetermine laboratory or clinical hemostatic abnormalities.Heparin-like anticoagulants have been identified in pa-tients with MM with a prolonged TT, which was cor-rected by addition of heparinase or protamine sulfate; thelatter was also able to control bleeding in one patient.92,93

Excessive fibrinolysis has been reported in severalcases of MM and amyloidosis that manifested bleed-ing diathesis and abnormal coagulation tests, such as



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shortened clot lysis and elevated fibrin/fibrinogen deg-radation products.94 The pathogenesis of hyperfibrinol-

ysis could be related to a reduced levels ofa2-antiplasminor may be secondary to complex formation with plasmin;increased urokinase-type plasminogen activator activityalso has been observed in a few other cases.95Treatment

with e-aminocaproic acid was efficacious in controlling

bleeding symptoms in some patients.96

Accelerated clearance of coagulation proteins canexplain the hemostatic abnormalities in same cases. Anincreased binding of vWF with monomeric IgM on thesurface of malignant cells has been described to induceacquired von Willebrand disease in a patient with

Waldenstrom macroglobulinemia.97 Bleeding symptomsassociated to acquired deficiency of FX is a relativelycommon feature in amyloidosis.98 No evidence of a FXinhibitor was demonstrated, but a rapid clearing fromcirculation of I131-labeled FX and accumulation in areasinvolved by amyloid deposits were shown by Furie

et al.99

Quantitative affinity chromatography analysisdemonstrated that FX binds frequently to amyloid fibrilsin the spleen.100,101 Splenectomy can produce resolutionof bleeding diathesis in some cases.102,103

Hemorrhagic symptoms, in particular retinalhemorrhages, epistaxis, and gingival bleeding, are char-acteristic of the hyperviscosity syndrome, frequentlyobserved in Waldenstrom macroglobulinemia and lesscommonly in MM.104 Plasma exchange is an effectivetreatment to reduce plasma viscosity and bleeding.

CONCLUSIONSHemostatic dysfunctions leading to thrombotic or hem-orrhagic complications are common in patients withparaproteinemias and amyloidosis. The use of antian-giogenic agents in combination with steroids or chemo-therapy further enhances the thrombotic risk.

The inflammatory response associated with theseconditions and reduced natural anticoagulant mecha-nisms are important factors that determine the thrombo-philic state, even though specific paraprotein-linkedeffects (such as lupus anticoagulant activity or inhibitionof fibrin polymerization) also are involved in several cases.

The coagulation abnormalities that are more frequently

observed in the presence of active disease can normalizewith effective treatment. Emerging data indicate that theeffect of LMWH in cancer and in MM is not confined tothe anticoagulant activity but extends to survival.

ABBREVIATIONSAPC activated protein Cb-FGF basic fibroblast growth factorCRP C-reactive proteindoxo doxorubicinGFC global fibrinolytic capacity

IL-6 interleukin 6LMWH low molecular weight heparinMGUS monoclonal gammopathy of undetermined

significanceMM multiple myelomaPT prothrombin timePTT partial thromboplastin time

TNF-a tumor necrosis factor alphaTT thrombin timeVAD vincristine/ adriamycin/dexamethasoneVEGF vascular endothelial growth factorVTE venous thromboembolism

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