Dr Nico Lategan MBChB, MMed (Haematology) Thrombosis Dr Nico Lategan MBChB, MMed (Haematology)

General Coagulation/ Haemostasis: Blood clotting vs Fibrinolysis. Endothelium damage: release of TF (activates clotting) and tPA (activates fibrinolysis). Blood clotting: Virchow’s triad- vessel wall, blood flow, blood components. Vessel wall: Important, especially in arterial thrombosis. Blood flow: Stenosis, PV (RBC), CML (WCC), ET (PLT, acute leukaemia (Blasts).

Definition: Tendency to develop recurrent thrombosis at unusual sites due to enhanced thrombin generation started at a young age (<50 years).

Classification: 1. Familial – physiological 2. Non-familial (acquired) – physiological or pathological

Problems: Confirmation of diagnosis. Investigate, establish the cause. Therapy: Warfarin, Heparin, Disprin. Short term vs Long term.

Investigation: Good history. Family history (can be difficult). Medication (hormones). About recent TE. Thorough examination. Risk factors: previous episodes, immobilization, operations, trauma, pregnancy, obesity, younger than 40 years, homocysteinemia.

Always do basic tests: FBC, PLT, ESR PT, aPTT, TT, Fibrinogen

Remember: After acute episode, it is not recommended to do a full thrombotic profile to determine the cause: Fibrinogen, F VIII, and PAI are acute phase agents. Prot C and S, as well as AT III may be low. Can be difficult to distinguish between liver disease, acute DIC and Warfarin therapy. All clotting factors are produced by the liver except F VIII- probably from endothelium.

About Thrombophilia: Usually venous TE. Role in arterial Thrombosis? Autosomal dominant hereditary pattern: hetero- vs homozygous inheritance. Usually a risk factor needed in heterozygotes to be of clinical importance.

Familial: FV-Leiden (APCR: activated prot C resistance). Protein C (deficiency). Protein S (deficiency). Antithrombin III (deficiency). Abnormal Prothrombin (PT 20210 A). Sticky platelet syndrome.

1. FV-Leiden: One of the most common causes for thrombophilia – 20% of clinical disease (AT, PC and PS – 5%) + risk factor. Activated PC inhibits F Va and F VIIIa. Inability of APC to inhibit the above complex due to mutated FV. Heterozygous: 5-10 times increased risk for TE. Homozygous: 50-100 times.

2. Protein C Deficiency: Common cause (increasing TE with age). Needs TM from endothelium wall. Heterozygous: 50% of level of normal individuals. Homozygous: babies are born with undetected levels (thrombi in microvascular of skin DIC necrosis purpura fulminans).

3. Protein S Deficiency: Non-enzymatic co-factor for PC. Binds to TM-PC. Same properties as PC. Two forms: free in plasma and bound to C4b binding protein (60%). Only free fraction functions as co-factor for APC. Sometimes difficult to get accurate measures of PS because of the latter. Like PC can be acquired: liver disease, Warfarin, pregnancy, cancer, DIC and chemo.

4. Antithrombin III Deficiency: Common cause (incidence 1/2000 – 1/5000; heterozygotes; 50% DVT): Quantitative vs Qualitative disorder. (Acquired: DIC, cirrhosis, NS). Bind to and inactivate thrombin, Factors IXa, Xa, XIa and XIIa (AT/heparin complex - rate of inhibition 1000-fold increased). Not necessarily a risk factor to be involved in heterozygotes to give TE. Increased incidence with ageing: 80% at 55 years.

5. Abnormal Prothrombin (PT 20210 A): Common. Increased levels of prothrombin enhanced thrombin formation. Only way for diagnosis: DNA-PCR technique.

6. Sticky Platelet Syndrome: Especially in arterial thrombosis (MI, TIA) and development of recurrent TE while on Warfarin. 3 Forms. If on aspirin, it should be stopped 14 days prior to testing. Also remember: PC, PS and AT III are inhibitors of clotting.

Non-familial (Acquired): Antiphospholipid Syndrome: Antibodies directed against phospholipid cell membrane = APA (Antiphospholipid Ab). APA: ACA or LA. Primary (PAPS) or secondary (autoimmune disorders, e.g. SLE) ACA (Anticardiolipin Ab): IgM + IgG. IgG: the clinically important one. IgM: pregnancy, infection (viral), trauma and post-op. LA (Lupus anticoagulant): Ab which affect clotting tests (LA-PTT, RVV, Kaolin). PAPS = TE, miscarriage, IUD + ACA, LA.

Non-familial (Acquired) continued: TPA (Tissue Plasminogen Activator): decreased levels impaired fibrinolysis. PAI (Plasminogen Activator Inhibitor): increased levels decreased TPA. Dysfibrinogenemia. F XII deficiency: Hageman factor. Fibrinogen (increased). F VIII (increased). Plasminogen. Hyperhomocyteinemia – enzyme (folate).

Investigation (Thrombotic Profile): NB: Patients can be on Warfarin, but not Heparin! FBC, PLT & ESR PT, aPTT, TT & Fibrinogen PC & PS AT III APCR (if + screening, submit for PCR) PT 20210A (PCR) Lupus anticoagulant (RVVT, KT, LA-PTT) Cardiolipin antibodies (antiphospholipid syndrome) Sticky platelet syndrome (aspirin!) ANA screening PNH screening

When to test: Younger: < 50 years, recurrent TE, unusual sites, TE on Warfarin. Not ideal to test after acute episode (inhibitors of clotting may be low). Ideal: test after 6 weeks after settlement of hemostasis. Most patients are on Warfarin then (PC & PS are Vit K dependent, may be falsely low). My view: if long-term Warfarin is planned, do immediately/ according to duration of treatment it can be done after cessation of treatment.

When to test (continued): Practical (my experience): before treatment – if AT, PS, PC are low  repeat after Rx has been stopped. SPS: platelet aggregation studies (problem: sometimes aspirin cannot be stopped). Remember the effect of the vessel wall on clotting, especially in arterial thrombosis. Every woman on contraception, HRT?

Treatment: Heparin: unfractioned vs LMW. Heparin – PTT. LMW – anti FXa activity. NB: LMW does not affect PTT. Warfarin: venous, antiphospholipid syndrome. Warfarin: PT / INR (not % due to lab variation). Aspirin: arterial – SPS. Individualized patients: ex single episode of thrombosis in patient with FV-Leiden post-op lifelong treatment unnecessary (short to medium term). Lifelong: recurrent episodes, episodes on Warfarin, ? spontaneous episode with proven cause (DVT vs PE).

Duration of Treatment: 6 weeks 3 months 6 months INR Range: Single episode: 2-3 Recurrent episode: 3-3.5 PE: 2-3/ 3-3.5