Molecular and Clinical Markers for the Diagnosis and Treatment of Type 1 VWD - PowerPoint PPT Presentation

1 / 58
About This Presentation
Title:

Molecular and Clinical Markers for the Diagnosis and Treatment of Type 1 VWD

Description:

Angelo Bianchi BONOMI Hemophilia Thrombosis Center ... Regina Elena Foundation & University of Milan. Via Pace, 9 20122 Milan. E.mail. ... – PowerPoint PPT presentation

Number of Views:175
Avg rating:3.0/5.0
Slides: 59
Provided by: molecular
Category:

less

Transcript and Presenter's Notes

Title: Molecular and Clinical Markers for the Diagnosis and Treatment of Type 1 VWD


1
THROMBOEMBOLIC EVENTS In Hematological
Malignancies
Augusto B. FEDERICI
Angelo Bianchi BONOMI Hemophilia Thrombosis
Center I.R.C.C.S. Maggiore Policlinico
Hospital, Mangiagalli, Regina Elena Foundation
University of Milan Via Pace, 9 20122
Milan E.mail. augusto.federici _at_ unimi.it XXIII
IATMO CONFERENCE, TRIESTE 19 OTTOBRE 2007
2
THROMBOEMBOLIC EVENTS (TEE) In Hematological
Malignancies (HM)
  • Incidence
  • Pathogenesis
  • Clinical conditions
  • Management

3
BACKGROUND (I) TEE IN HEMATOLOGICAL MALIGNANCIES
  • Thrombo Embolic Events are well
  • established complications of cancer.
  • Solid tumors increase the risk of
  • Venous Thrombo Embolism (VTE)
  • with an incidence as high as 50 in
  • autopsied findings

4
BACKGROUND (II) TEE IN HEMATOLOGICAL MALIGNANCIES
Recent surveys have indicated that TEE are
at least as common in hematological
malignancies (HM), if not more frequent, than
in solid tumors
5
THROMBOEMBOLIC EVENTS (TEE) In Hematological
Malignancies (HM)
  • Incidence
  • Pathogenesis
  • Clinical conditions
  • Management

6
TEE Hospitalized Cancer Patients Retrospective
Study in 66.106 Cases
  • Cancer Type Case N. of TEE
  • Leukemia 14,600 4.39
  • NHL 12,977
    5.01
  • Breast 5,197
    3.93
  • Lung 4,665
    7.00
  • Myeloma 4,527
    5.29
  • HD 2,042
    3,87
  • Khorana A et al JCO 2006 24484

7
THROMBOEMBOLIC EVENTS (TEE) In Hematological
Malignancies (HM)
  • Incidence
  • Pathogenesis
  • Clinical conditions
  • Management

8
BACKGROUND (III) TEE IN HEMATOLOGICAL
MALIGNANCIES
  • In patients with HM, the TEE can
  • be triggered by
  • Cancer per se
  • Chemotherapy Radiotherapy
  • Surgery CVC

9
Kwaan HC et al, Sem Thromb Hemost 2007 33 303-12
10
VTE and Cancer Pathogenesis
  • Hypercoagulability
  • Endothelial damage
  • Venous Stasis
  • Platelet activation

11
VTE and HM I) Hypercoagulability

Blood coagulation can be activated by cancer
cells A) DIRECTLY 1) Tissue Factor
(TF) 2) Cancer Procoagulant (CP) B)
INDIRECTLY 3) Mononuclear Cells Activation
4) Peptide Production
12

Tissue Factor (TF) in Patients with HM

TF does activate the extrinsic pathway of
blood coagulation through activated factor
VII (VII a) Elevated TF has been
demonstrated in acute leukemias and solid
tumors (kidney, stomach,ovary)
13

CANCER PROCOAGULANT (CP) in Patients with HM
CP is a protease of a 68 KDa MW which
directly activates the common pathway of blood
coagulation (Factor X ------gt X a) CP has been
demonstrated in acute leukemia as well as in
solid tumors (lung, colon, breast and kidney)

14
VTE and HM II) Endothelial damage

Vascular endothelium can be damaged A)
Directly by direct interactions of
cancer cell - platelets - endothelium
and/or B) Indirectly because of toxicity
produced by CT and/or RT
15
Chemotherapy and VTE Endothelial damage
  • Chemotherapy (CT) can induce endothelial
  • damage by the following mechanisms
  • DIRECT IMMEDIATE
  • (BCNU, Bleo, Carnim, Vincr)
  • DIRECT DELAYED (Adria)
  • INDIRECT by reduction of ATIII, aPC, PS
  • (Ciclof, MTX, 5-FU)

16

VTE and HM (IV) III) Venous Stasis

Venous stasis favor VTE because may reduce
the removal of activated coagulation factors
from the circulation and in cancer is due 1)
Bed rest (surgery) 2) External
compression of veins (tumor) 3)
Vascular invasion (type of cancer)
17
VTE and HM Factors Affecting Blood Viscosity
Kwaan HC et al, Sem Thromb Hemost 2007 33 303-12
18
VTE and HM IV) Platelet activation
Reactive Thrombocytosis in patients with
advanced cancer of the lung, breast, ovary,
stomach (Thrombopoietin ???) Increased
Platelet Adhesion due to generation of
activators (ADP, thrombin) by several types of
cancer
19
VTE and Cancer VTE related to Cancer Therapy
The risk of VTE may increase according to
invasive procedures and/or therapies during
the management of cancer patients VTE can be
associated with 1) Central Venous Catheter
(CVC) 2) Anti-Cancer Drugs - CT
agents - Hormones
20
VTE and HM Related to Anti-Cancer Drugs
1) L-Asparaginase 2) Hematopoietic Growth
Factors 3) High Dose POLY-CT or - B.M.T.
Venous Occlusive Disease of the liver (VOD)
21
Drug Related VTE L-Asparaginase
L-Asparaginase is mainly used in the
management of the ALL Mechanisms inducing VTE
Reduced synthesis of liver proteins,
including the physiologic inhibitors of
blood coagulation ATIII, APC, PS
22
Drug Related VTE Hematopoietic Growth Factors
Endothelial damage has been reported by the
use of Growth Factors GM-CSF - G-CSF A recent
metanalysis on the risk of V.T.E. in a large
number of patients treated with these Growth
Factors did show a VTE rate () - GM-CSF
962 cases -----gt 4.2 - G-CSF
884 cases -----gt 1.2 (Barbui et al - Thromb
Haem 1996 75368)
23
Drug Related VTE High Dose POLY-CT BMT
The association of more than one CT agent to
induce aplasia before BMT can induce a
prothrombotic state This prothrombotic state is
even higher when RT is associated with CT
Cyclofosfamide L-PAM TBI
24
VTE and Cancer Central Venous Catheter (CVC)
Data on the incidence of VTE in CVC Author
Journal Year of
VTE Lokich Cancer 1983
16 Conlan BMT
1991 33 Bern
Ann.Int.Med 1990 37.5 Monreal
Thromb Haem 1996
62 Prandoni Arch Int Med 1997
36 Karen JCO
2000 21
25
Lab Diagnosis of VTE Hypercoagulability

Pro-thrombotic State of cancer is due to the
simultaneous presence of a)
increased thrombin generation b) reduced
anticoagulant factors COMPENSATED CHRONIC
D.I.C.
26
Pathogenesis of DIC
  • DIC is characterized by the imbalance of pro-and
    anti-thrombotic activities
  • activation of coagulation (TF-FVII)
  • reduced anticoagulants (ATIII, PC/S,TFPI)
  • impaired fibrinolysis (PAI-1)
  • increased cytochines (TNF, IL-1, IL-6)
  • Depending on pro-thrombotic triggers and
  • underlying diseases, two forms can occur
  • ACUTE DIC -------gt Bleeding
  • CHRONIC DIC -------gt Thrombosis

27
Pathogenesis of DIC
28
Pathogenesis of DIC
29
CAUSES OF DIC
30
THROMBOEMBOLIC EVENTS (TEE) In Hematological
Malignancies (HM)
  • Incidence
  • Pathogenesis
  • Clinical conditions
  • Management

31
THROMBOEMBOLIC EVENTS In Hematological
Malignancies
  • Among the other hematological malignancies (HM)
    Thrombo Embolic Events (TEE) occur more
    frequently in
  • ALL and APL
  • NHL and MM
  • PV and ET

32
THROMBOEMBOLIC EVENTS Acute Lymphocytic
Leukemia

TEE in children with ALL are most commonly
reported after the initiation after the
initiation of certain anti-leukemic drugs
(L-asparaginase) , indicating a possible
interaction of the disease and therapy
33
Pathogenesis of TEE in ALL
34
TEE IN PEDIATRIC ALL A meta-analysis of 17
studies (1752 cases)
  • Rate of TEE is 5.2 (95CI4.2-6.4)
  • Most of events occurred during the
  • induction phase of therapy
  • Low dose L-ASP for long period are
  • associated with higher risk of TEE
  • The presence of CVC increases TEE
  • Caruso V et al, Blood 2006 1082216

35
Kieslich M et al, J Ped Hematol Oncol 2003 25
484-87
36
THROMBOEMBOLIC EVENTS Acute Promyelocytic
Leukemia

Patients with APL may experience TEE during
treatment with All-Trans-Retinoic Acid (ATRA)
37
(Barbui T and Falanga A)
38
Pathogenesis of Bleeds in APL
39
THROMBOEMBOLIC EVENTS Non Hodgkin Lymphomas

Among 1038 patients with NHL enrolled into a
retrospective study, TEE occurred in 7.7 ,
mostly in high-grade NHL during
treatment high-intensity CT can cause
this Increased incidence of TEE
40
THROMBOEMBOLIC EVENTS Multiple Myeloma

Patients with MM are at relatively high baseline
risk of developing TEE and certain treatment
regimens including Thalidomide may increase such
a risk
41
PATHOGENESIS OF TEE In Multiple Myeloma
  • Impaired fibrinolysis due to high IG
  • Pro-coagulant Auto-antibodies
  • Increased inflammatory Cytokines
  • Increased Acute Phase reactants
  • Acquired APC resistance no FV LEIDEN
  • These mechanisms can increase per se
  • at baseline the risk of TEE in MM

42
INCIDENCE () OF TEE IN MM Within the first 4
Mo of Therapy (I)
  • A) NO ANTITHROMBOTIC PROPHYLAXIS
  • THALIDOM (single agent) 2-3
  • DEXAMETH (single agent)
    3
  • VAD regimen
    5-10
  • B) THALIDOMIDE PLUS DEXAMETHASONE
  • No prophylaxis
    12-26
  • Low fixed-dose W (1 mg/Day) 24
  • Intermediate fixed-dose W
    13
  • Rajkumar AV. Mayo Clin Proc 2005 801549

43
INCIDENCE () OF TEE IN MM Within the first 4
Mo of Therapy (II)
  • C) THALIDOMIDE PLUS DOXORUBICINE
  • No prophylaxis
    27-30
  • Low fixed-dose W (1 mg/Day) 30
  • Aspirin
    19
  • Low molecular weight heparins 8-15
  • D) LENALIDOMIDE may have the same TEE risk
  • Rajkumar AV. Mayo Clin Proc 2005 801549

44
INCIDENCE () OF TEE IN MM Need of prospective
Trials
  • Three Drugs should be included in a prospective
    clinical trial to be designed to prevent TEE in
    patients with MM before and during therapies
  • WARFARIN (full intensityINR 2-3)
  • ASPIRIN
  • LMW heparins
  • Hirsh J. Chest 20076 131275

45
THROMBOEMBOLIC EVENTS In Mieloproliferative
Disorders

Among Myeloproliferative Disoders (MPD),
Polycythemia Vera (PV) and Essential
Thrombocythemia (ET) are frequently associated
with TEE
46
TEE IN PATIENTS WITH PV
47
(No Transcript)
48

Prevention Therapy of TEE in Patients with HM
Sixth ACCP Consensus Conference on Antithrombotic
Therapy CHEST Volume 126 Sup Sep
2004 www.chestjournal.org
49
Recommendations (I) Primary Prevention of VTE
Cancer Pat Group - Method -
Duration Any cancer no V.T.E No
prophylaxis no active cancer therapy Cancer
Therapy Abdominal surgery
LMWH Until discharge
Gynecologic surgery LDH-
LMWH Until discharge Neurosurgery
LDH- LMWH Until
discharge Chemotherapy
Warfarin - LMWH Duration of CT CVC
Warfarin -
LMWH Until removal Radiotherapy Rectum
Warfarin (INR 2-3) 4 Months Post
Brain
Warfarin (INR 2-3) 12 Months Post
50
Recommendations (II) Secondary Prevention of VTE
Cancer Pat Group - Method -
Duration Any cancer established V.T.E.
Warfarin Until cancer is ambulatory
(INR 2-3)
active Brain tumors established V.T.E.
Warfarin Until cancer is
(INR
2-2.5) (Thodiyil et al, Acta Haem 2001 10673)
51
Prevention of VTE Clinical Approach in Surgery
Prevention of VTE in the surgery of
cancer patients should start 12 hours before
operation and maintained for 15 days or until
the patient is out of bed The following
regimens of prophylaxis A) UFH
5.000 U x 3/day (0.2 cc x 3) B) LMWH
2.000 - 6.000 U once/day
52
Prevention of VTE in Cancer Patients with CVC
Warfarin 1 mg die x 90 days (Bern et al -
Ann Int Med 1990, 112 423) LMW Heparins 2500 U
die x 90 days (Monreal et al - Thromb Haem 1996
7521)
53
Clinical Sites of the VTE DVT - PE - Superficial
Thrombosis
Deep Vein Thrombosis (DVT) - Proximal Lower
and Upper Limbs - Portal Venous Thrombosis -
Cerebral Veins Pulmonary Embolism (PE)
Superficial Thrombophlebitis (ST)
54
Management of VTE (I) Therapeutic Agents
1) Thrombolytic agents (t-PA, SK, UK) 2)
Unfractionated Heparin - sodium
-
calcium 3) Low Molecular Weight Heparins 4)
Oral Anticoagulant - Warfarin
- Acenocoumarol
4) Dermatan-sulphates
55
Management of VTE In Cancer Patients with CVC
A) Acute VTE Thrombolysis in the CVC -
UK 5.000-10.000 U (0.5 - 2 hrs) - t-PA
2 mg (2 hrs) B )Resistant VTE UK 40.000
U/h up to 6h
C) Chronic VTE - UFH with adjusted
dosage by PTT -
LMWH (bid) or Warfarin (dose by INR)
56
Management of VTE (II) in case of Acute VTE
A) I.v. UF Heparin with dosage bolus of
5.000 - 10.000 U continuous infusion
30.000 - 45.000 U/day B) S.c. UFH calcium (5000
U 0.2 ml) 5.000 - 12.500 every 8 -12
ore note dosage must be adjusted on APTT (ratio
2-3) C) LMW- Heparins 4.000 - 12.000
every 12 ore note dosage is not adjusted on
APTT but on body weight
57
Management of VTE (III) In case of Chronic VTE
A) Oral Anticoagulants - Warfarin (5
mg) - Acenocumarol (4 mg) note dosage
must be adjusted on the PT (INR 2-3)
following a loading dose of 8-10 mg B) LMW
Heparins 4.000 - 12.000 every 12 ore
note dosage is based on body weight, not on APTT
58
CONCLUSIONS TEE IN HEMATOLOGICAL MALIGNANCIES
Since TEE are so relatively frequent in patients
with HM, appropriate regimens of primary or
secondary prophylaxis and therapy should be
always planned in HM clinical conditions
Write a Comment
User Comments (0)
About PowerShow.com