THROMBOPHILIAS A practical Approach Akram Al-Hilali 2008
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COAGULATION VERSUS
THROMBOSIS The term Coagulation (or Clotting) of the blood is being used to describe the in vitro phenomenon, while Thrombosis describes intravascular in vivo process
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DEFINITION OF THE THROMBOPHILIC STATE
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Atheroma, vessel pathology and flow pathology are to be excluded from the definition of the condition. Thrombophilia may be just an additional factor on top of the vessel and flow problem. It is now believed that most thrombotic events are caused by multiple factors, rather than a single one. Discovering an abnormality should not end the search for others. 08/10/14
rFVIIa DDAVP
TRASYLOL TRANEXAMIC ACID EACA
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CLASSIFICATION OF THROMBOPHILIAS
Inherited –
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One or more anticoagulant factor activity deficiency Factor V Leiden mutation Excess PAI-1 Excess FVIII level
Acquired –
Deficiency of the activity of one or more factors inhibiting thrombosis/coagulation
An inherited factor deficiency may be coupled with an acquired factor deficiency. Multiple deficiencies of either or both are also possible
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INHERITED DISORDERS
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Protein C deficiency- various grades Protein S deficiency- various grades, total or free. Antithrombin III deficiency-Type I and typeII Factor V-Leiden mutation and allied mutations (aPC resistance) Prothrombin 20210 mutation PAI-1 excess due to gene polymorphism Factor VIII excess Plasminogen deficiency Inherited hyper-homocysteinemia (MTHFR deficiency) Some dysfibrinogenemias 08/10/14
RELATIVE RISK OF TE Factor Relative Risk ATIII 5 PC deficiency 6.5 PS deficiency 0.7 FV Leiden 8 Prothrombin G20210A 2.8 ↑ FVIII(>200%) 6 ▲ Homocysteine 1.5
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Actual Risk *<1% 2% <1% 25% 4% 16% 10%
ACQUIRED DISORDERS
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Pregnancy Oral contraceptives and HRT APL syndrome Increased homocysteine MPN’s
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PNH Cancer Nephrotic syndrome ?Smoking ? Lipemia ?DM Snake bites……..
MECHANISMS Pregnancy & Diminished protein C & S hormonal therapy
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APL
Platelet activation, damage & thromboplastin release
Cancer
Tissue damage and thromboplastin release
PNH
Intravascular hemolysis and thromboplastin release
MPD
Platelet activation and secretion 08/10/14
PREGNANCY & THROMBOPHILIA
It is only natural that blood becomes relatively hypercoagulable in pregnancy. Factor VIII and fibrinogen are raised. Protein C and Protein S are diminished. Platelets are more active So, if there is an inherited, or an acquired thrombophilia factor then pregnancy is the more favourable time for it to cause thrombosis
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THROMBOPHILIA IN PREGNANCY • • •
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Protein C and Protein S deficiencies will be exaggerated in pregnancy High Factor VIII will be further raised. Any inherited thrombophilia factor will get further enhanced by the physiological changes in pregnancy affecting coagulation. Antiphospholipid syndrome is a unique problem, since the condition is exacerbated in pregnancy. Thrombotic tendency of APL syndrome will find catalyst in the physiologic changes. 08/10/14
THROMBOPHILIA IN PREGNANCY
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Recurrent fetal loss is the commonest presentation. DVT is commoner than in general population One factor, or more, on top of pregnancy will raise the probability of TE and fetal loss. Management and prophylaxis of TE is more difficult in pregnancy. 08/10/14
Triggers for Investigation
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Unprovoked thrombosis. Repeated provoked thrombosis Coronary thrombosis at early age Strong family history in an otherwise normal individual Close relatives of a proven inherited thrombophilia case Repeated miscarriages: one in second or third trimester or more than one in 1 st trimester 08/10/14
SEQUENCE OF LAB TESTS
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All available in the laboratory Non-available coagulation-based tests to be done in reference laboratory Non-available genetic tests to be done in reference laboratory Do not stop if you get an abnormal test result. Always keep in mind acquired causes when investigating for an inherited ones. 08/10/14
PRECAUTIONS IN ORDERING TESTS
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Do not order PC and PS during 3rd trimester, or within 3 months of delivery/miscarriage. Do not order ATIII when patient is on heparin Do not order PC and PS on a patient taking warfarin APR test is better not done when patient is on warfarin Factor VIII assays should not be done during pregnancy, in inflammatory states or just after a bleeding episode. 08/10/14
Result Abnormal. What action?
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No action if no thrombotic event is recorded, unless patient is passing through an acquired predisposing condition. Oral anticoagulation in the presence of such conditions, other than pregnancy Heparin/ warfarin/ heparin in pregnancy, with an inherited disorder Life-long oral anticoagulation for those with an unprovoked thrombotic event & proven abnormality Same for those who get repeated thrombotic event, though an abnormality has not been confirmed. 08/10/14
ROLE OF LMWH
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In pregnancy from week 1 to week 12 and week 36 to delivery Throughout pregnancy in some centers Early in anticoagulation in Protein C and protein S deficiencies To replace warfarin in ignorant patients, incompliant patients and children 08/10/14
REPLACEMENT THERAPY
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Available recombinant products when necessary (ATIII, tPA) FFP as a general purpose product
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REMEMBER! 1-Persistent DIC in the neonate as a result of an inherited thrombophilic disorder
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2-Recurrent abortion as a result of an acquired thrombophilic state 08/10/14