Trombophilia and Thrombosis
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Transcript of Trombophilia and Thrombosis
Components of Hemostasis Primary Hemostasis (Platelets &vWF)
Coagulation Cascade (Intrinsic & Extrinsic) Inhibitors of Coagulation (Natural & Acquired) Fibrinolytic System (Activators, Inhibitors &Degradation products)
Activated partial thromboplastin time (aPTT)Derives its name from use of a partial activated Component like the phospholipid cephalin and Negatively charged substance like kaolin for activation Expressed in seconds with normal range (27-40)
Prolonged:Heparin therapy Presence of anticoagulant (lupus like) Factor deficiency Massive blood transfusion. Liver disease High dose coumadin anticoagulation
Factor InhibitorsThe mixing study The patient's serum is mixed with normal serum and the aPTT of this mixture is measured. A 50:50 mixture will correct a factor deficiency (only 30% activity is needed for a normal aPTT). In the presence of an inhibitor, a 50:50 mix will not correct the abnormal coagulation test. If inhibition found, additional tests with diluted patient serum and normal serum will be applied and level of inhibitor will be determined (Bethesda units) by the dilution activity Factor VIII inhibitors IgG mostly, Occur primarily in haemophilia A patients who have received blood component transfusions. They develop a severe coagulopathy that is very difficult to manage May occur in a variety of unrelated conditions with a coagulopathy that is variable and usually disappears spontaneously.
Inhibitors of coagulation and fibrinolysis
Half life (hrs) Protein C Protein S Thrombo modulin 4 42 ND
Chromosome 2q13-14 3p11.1-11.2 20p11.2-cen
Function Protease (FV&FVIII) APC-cofactor Receptor for Thrombin/Prot.C Receptor for prot.C/APC Protease inhibitor Protease inhibitor Protease inhibitor
Protein C receptor Antithrombin TFPI Heparin Cofactor II
ND 70 ND 60
20q11.2 1q23-25 2q31-32.1 22q11
Activation by thrombin or FXa APC inactivates FVa FV-Leiden has Gln instead of Arg at 506, which confer APCR
sEPCR
Protein C pathwayAPCFVIIIa
sEPCR
PC T T TM PCEPCR EPCRsEPCR
FVIIIa
FVa APC FVa S
History 1965 Antithrombin (Egeberg) 1965 dysfibrinogenemia (Beck) 1981 - Protein C (Griffin) 1984 - Protein S (Comp) 1993- APCR (Dahlback) 1994 Factor V Leiden (Bertina) 1996 - PT G20210A mutation (Poort)
Large vessel - Death Medium vessel - Respiratory Failure Small vessel- asymptomatic repetition pulmonary hypertension
Block
Embolus
Lysed / Organized
Extend
Thrombus
40 35 30
of % VTE among autopsie s
25 20 15 10 5 035% 26 % 9 .4%
VTE PE Fatal PE Accountsfor about 10% of deaths in hospitalised patients11.Lindblad B, et al. BMJ 1991;302:70911 2. Dahl OE, Bergqvist D. Curr Opin Pulm Med 2002;8:3947
Venous Thrombosis Makes News in Washington Surgeon General nominated VTE Task Force
: Inherited Common- )Factor V G1691A )Leiden Prothrombin G20210A Increased levels of FVIII and Fibrinogen RareAntithrombin deficiency Protein C deficiency Protein S deficiency Very rare- Dysfibrinogenemia Homozygous homocystinuria ? Future risk factors
:AcquiredTrauma or surgery Immobilization Increasing age Malignant disorders Myeloproliferative disorders Previous thrombosis Pregnancy and puerperium Use of contraceptives or HRT Activated protein C resistance Mild to moderate hyperhomocystinemia Antiphospholipid syndrome
.. 64 . ( )DVT . , . : APS -01 , , - . 5 , , MRI .B.E - Laboratory findings )83-72 .71 (C )23 .54 (C )51 < 34 (C )3.1 < 2.9 (C 8.1 )52.1 < 2.14 (C ) 2 > 1.45 (C normal 75u/ml )51 < (C )002 < 417 u/ml (C )05 < 190 u/ml (C
Coagulation aPTT aPTT mixed with plasma CAI RVVT RVVT confirm TTI APCR Factor V Leiden Immunology anticardiolipin .anti-nuclear ab anti-DNA
Endothelial
cell mediated: injury to EC, receptor induction, increased TF expression, induction of apoptosis Protein C pathway related: aPL binds PC&S inhibition of PC activation, acquired APCR Inhibition of heparin-AT complexes Cross reaction with OX-LDL Increase PAI-1 Platelet activation
Clinical criteria
1.Vascular thrombosis )one or more ATE or VTE) 2. Pregnancy morbidity a. one or more IUFD >10th week b. one or more premature birth, preeclampsia, placental insufficiency, abruption, IUGR c. 3 or more early )10th week) abortions,) >2 late)
Laboratory criteria
1. Anti CL Ab )IgG/M), on two )6w) occasions 2. LAC on two )6w) occasions )aPTT, DRVVT) 3. Exclusion of other coagulopathies Definite aPLS is establish by at least one criterion of each category
Yield (%) 80 70 60 50 40 30 20 10 0
Selected Unselected until 1993 from 1993
Thrombophilia
Healthy subjects N affected % 0.2-0.4
Unselected patients N 2,028 2,028 affected % 3.7 2.3 1.9 18.8
Selected patients N 880 752 752 162 affected % 5.2 7.4 4.6 40
Protein C Protein S Antithrombin
15,070 ND 9,669
0.02 4.8 0.05 2.7 0.06
2,028 1,142
Factor V Leiden 16,1502,192
PT G20210A
11,932 1,811
2,884
7.1
551
16
Thrombophilia
Healthy subjects N affected %
Unselected patients N affected %
Selected patients N % affected
FVIII APCR Hcy
534 445 1,153
11.8 8.1 6.1
534 337 856
23.2 23.4 11.7
60
56.7
Priority for testing HighAPCR Factor V Leiden PT G20210A Homocysteine Factor VIII Lupus anticoagulant
IntermediateProtein C activity
LowFibrinogen
Free protein S antigen Thrombin time Antithrombin activity FIX activity Anticardiolipin Abs FXI activity C677T MTHFR
Risk of recurrence of thrombosis according to type of thrombophiliaHigh Antithrombin APL Abs Intermediate Increased Protein C Protein S FVIII Hcy None FVL FII
Prothrombin F1+2 and soluble fibrin in normal pregnancy
S Sarig )Fertility Sterility 2002(
Gris ( Thromb Haemost )1999
74, . , 81 ", . . , . , . , .
13
A) Cabin related Cramped sitting position More in economy class 83% Non-aisle seats Lower air pressure, relative hypoxia differ among airlines Low humidity and dehydration
B) Passenger related Age over 40 Previous VTE Thrombophilia Hormonal Therapy Pregnancy Varicose veins Cancer Overweight
Coagulation activation in hypobaric chamber
Armand Trousseau (1801-1867)
When you are undecided about the nature of the disease of the stomach, when you hesitate among a chronic gastritis, a simple ulcer, and a carcinoma, a phlegmatia alba dolens (thrombophlebitis) occurring in the leg or arm will put an end to your indecision and you will be able to assert positivelythat a cancer is present.
Endothelial damage Shift to procoagulant endothelium Invasion of cancer cells into vessel wall
Stasis of blood Frequent immobilization, surgery Compression of blood vessels by tumor
Changes in the blood constituents Activation of clotting proteins and blood
cells
Tumor Cell Hemostatic Properties and Tumor BiologyTumor cell hemostatic properties Procoagulant ActivitiesTissue Factor
Mechanisms of malignancy
Fibrinolytic Activities(t-PA, u-PA, u-PAR, PAI)
Coagulationdependent
PROLIFERATION ANGIOGENESIS
TC-derived Cytokines(IL-1, TNF, VEGF)
Coagulationindependent
METASTASIS
Cell Adhesion Molecules
Tissue Factor/FV IIa Factor Xa Thrombin
Growth Invasion Metastasis
Fibrin generation plays additional roles in Angiogene these processes
Tumor cell TF FVIIa
FXProthrombin
FXaThrombin
Fibrinogen
VEGF Angiogenesis TF
FIBRIN
IL-8
Endothelial cellsRickles FR, and Falanga A. Thromb Res 2001
Tumour Cell- Host Cell Interactions at The Vascular Sitefibrin Localized clotting activation P PInduction of monocyte procoagulant activity
Induction of endothelial procoagulant and adhesive properties
TCP P
TC
TC
P P P
PMN fibrin P TC
Endothelial Cells
TC = tumor cell P = platelet PMN = polymorphonuclear leukocyte
Prandoni, Falanga, Piccioli, Lancet Oncology, 2005
The
bleeding diathesis of APL is most consistent with the diagnosis of DIC. Primary fibrinolysis is hard to document in APL and probably does not exist. Excessive fibrinolysis is probably secondary to thrombin generation. ATRA can improve the coagulopathy in patients with APL.
sEPCR
Protein C pathwayAPCFVIIIa
sEPCR
PC T T TM PCEPCR EPCRsEPCR
FVIIIa
FVa APC FVa S
Acquired activated protein C resistance is common in cancer patients and is associated with VTECancer with VTE Cancer without VTE VTE without Cancer Normal Controls
Patients FV Leiden APCR without FV Leiden
55 1 (2%) 29 (54%)
58 4 (7%) 9 (17%)
54 18 (33%) 7 (19%)
56 2 (4%) 0
Haim, Am J Med 2001
:HeparanaseHeparanase activity was implicated in cellular invasion ,angiogenesis, inflammation and cancer metastasis
Heparanase up-regulation was documented in an increasing number of primary solid and hematological .human malignancies Heparanase up-regulation correlated with reduced postoperative survival of pancreatic, bladder, gastric, .cervical and colorectal cancer patients Similarly, heparanase up-regulation correlated with increased lymph node and distant metastases,
Hepa
Hepa Hepa
Heparan sulfate
Considerations in planning treatment of patients with thrombosis Efficacy of treatment Rate of bleeding complications Rate of recurrence Complications due to recurrence
PT
correlates initially with FVII thus not reflecting actual AC Protein C fast drop creates initial hypercoagulability Initiation of coumadin should be covered by heparin
INR - International Normalized RatioISI
INR = R R = PT (sec) patient / PT control example: PT coumadin treated patient - 32 sec, PT control - 12 sec R = 2.6ISI = international standartization index
Intrinsic pathway Antithrombin ATIII ATIII ATII I
Extrinsic pathway
Xa
Xa
Pentasaccharide
IIFibrinogen
IIaFibrin clot
Adapted with permission from Turpie et al . N Engl J Med.2001;344:619
ORALTTP889 X TF/VIIa IX IXa VIIIa Rivaroxab an APIXABAN YM150 DU-176b Ximelagatran Dabigatran Fibrinogen Va Xa II AT
PARENTERALTFPI )tifacogin)
)APC (drotrecogin alfa )sTM )ART-123 Fondaparinux Idraparinux
DX-9065a IIa Fibrin
Adapted from Weitz & Bates, J Thromb Haemost2005