ThrombosisThrombosis

Dr Nico LateganDr Nico Lategan

MBChB, MMed (Haematology)MBChB, MMed (Haematology)

GeneralGeneral

Coagulation/ Haemostasis:Coagulation/ Haemostasis: Blood clotting vs Blood clotting vs Fibrinolysis.Fibrinolysis.

Endothelium damage: release of TF (activates Endothelium damage: release of TF (activates clotting) and tPA (activates fibrinolysis).clotting) and tPA (activates fibrinolysis).

Blood clotting:Blood clotting: Virchow’s triad- vessel wall, Virchow’s triad- vessel wall, blood flow, blood components.blood flow, blood components.

Vessel wall:Vessel wall: Important, especially in arterial Important, especially in arterial thrombosis.thrombosis.

Blood flow:Blood flow: Stenosis, PV (RBC), CML (WCC), Stenosis, PV (RBC), CML (WCC), ET (PLT, acute leukaemia (Blasts).ET (PLT, acute leukaemia (Blasts).

Definition:Definition:

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

Classification:Classification:

1. Familial – physiological1. Familial – physiological

2. Non-familial (acquired) – 2. Non-familial (acquired) – physiological or pathologicalphysiological or pathological

Problems:Problems:

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

Investigation:Investigation:

Good history.Good history. Family history Family history (can be difficult).(can be difficult). Medication Medication (hormones).(hormones). About recent TE.About recent TE. Thorough examination.Thorough examination. Risk factors: Risk factors: previous episodes, immobilization, previous episodes, immobilization,

operations, trauma, pregnancy, obesity, younger operations, trauma, pregnancy, obesity, younger than 40 years, homocysteinemia.than 40 years, homocysteinemia.

Always do basic tests:Always do basic tests:

FBC, PLT, ESRFBC, PLT, ESR PT, aPTT, TT, FibrinogenPT, aPTT, TT, Fibrinogen

Remember:Remember: After acute episode, it is not recommended After acute episode, it is not recommended

to do a full thrombotic profile to determine to do a full thrombotic profile to determine the cause: Fibrinogen, F VIII, and PAI are the cause: Fibrinogen, F VIII, and PAI are acute phase agents.acute phase agents.

Prot C and S, as well as AT III may be low.Prot C and S, as well as AT III may be low. Can be difficult to distinguish between liver Can be difficult to distinguish between liver

disease, acute DIC and Warfarin therapy.disease, acute DIC and Warfarin therapy. All clotting factors are produced by the All clotting factors are produced by the

liver except F VIII- probably from liver except F VIII- probably from endothelium.endothelium.

About Thrombophilia:About Thrombophilia:

Usually venous TE.Usually venous TE. Role in arterial Thrombosis?Role in arterial Thrombosis? Autosomal dominant hereditary pattern: Autosomal dominant hereditary pattern:

hetero- vs homozygous inheritance.hetero- vs homozygous inheritance. Usually a risk factor needed in Usually a risk factor needed in

heterozygotes to be of clinical importance.heterozygotes to be of clinical importance.

Familial:Familial:

1.1. FV-Leiden (APCR: activated prot C FV-Leiden (APCR: activated prot C resistance).resistance).

2.2. Protein C (deficiency).Protein C (deficiency).

3.3. Protein S (deficiency).Protein S (deficiency).

4.4. Antithrombin III (deficiency).Antithrombin III (deficiency).

5.5. Abnormal Prothrombin (PT 20210 A).Abnormal Prothrombin (PT 20210 A).

6.6. Sticky platelet syndrome.Sticky platelet syndrome.

1. FV-Leiden:1. FV-Leiden:

One of the most common causes for One of the most common causes for thrombophilia – 20% of clinical disease (AT, PC thrombophilia – 20% of clinical disease (AT, PC and PS – 5%) + risk factor.and PS – 5%) + risk factor.

Activated PC inhibits F Va and F VIIIa.Activated PC inhibits F Va and F VIIIa. Inability of APC to inhibit the above complex Inability of APC to inhibit the above complex

due to mutated FV.due to mutated FV. Heterozygous: 5-10 times increased risk for TE.Heterozygous: 5-10 times increased risk for TE. Homozygous: 50-100 times.Homozygous: 50-100 times.

2. Protein C Deficiency:2. Protein C Deficiency:

Common cause (increasing TE with age).Common cause (increasing TE with age). Needs TM from endothelium wall.Needs TM from endothelium wall. Heterozygous: 50% of level of normal Heterozygous: 50% of level of normal

individuals.individuals. Homozygous: babies are born with Homozygous: babies are born with

undetected levels (thrombi in microvascular undetected levels (thrombi in microvascular of skin DIC necrosis purpura of skin DIC necrosis purpura fulminans).fulminans).

3. Protein S Deficiency:3. Protein S Deficiency:

Non-enzymatic co-factor for PC.Non-enzymatic co-factor for PC. Binds to TM-PC.Binds to TM-PC. Same properties as PC.Same properties as PC. Two forms: free in plasma and bound to C4b Two forms: free in plasma and bound to C4b

binding protein (60%). Only free fraction binding protein (60%). Only free fraction functions as co-factor for APC.functions as co-factor for APC.

Sometimes difficult to get accurate measures of Sometimes difficult to get accurate measures of PS because of the latter.PS because of the latter.

Like PC can be acquired: liver disease, Warfarin, Like PC can be acquired: liver disease, Warfarin, pregnancy, cancer, DIC and chemo.pregnancy, cancer, DIC and chemo.

4. Antithrombin III Deficiency:4. Antithrombin III Deficiency:

Common cause (incidence 1/2000 – 1/5000; Common cause (incidence 1/2000 – 1/5000; heterozygotes; 50% DVT): Quantitative vs heterozygotes; 50% DVT): Quantitative vs Qualitative disorder. (Acquired: DIC, cirrhosis, Qualitative disorder. (Acquired: DIC, cirrhosis, NS).NS).

Bind to and inactivate thrombin, Factors IXa, Xa, Bind to and inactivate thrombin, Factors IXa, Xa, XIa and XIIa (AT/heparin complex - rate of XIa and XIIa (AT/heparin complex - rate of inhibition 1000-fold increased).inhibition 1000-fold increased).

Not necessarily a risk factor to be involved in Not necessarily a risk factor to be involved in heterozygotes to give TE.heterozygotes to give TE.

Increased incidence with ageing: 80% at 55 years.Increased incidence with ageing: 80% at 55 years.

5. Abnormal Prothrombin5. Abnormal Prothrombin (PT 20210 A): (PT 20210 A):

Common.Common. Increased levels of prothrombin enhanced Increased levels of prothrombin enhanced

thrombin formation.thrombin formation. Only way for diagnosis: DNA-PCR Only way for diagnosis: DNA-PCR

technique.technique.

6. Sticky Platelet Syndrome6. Sticky Platelet Syndrome::

Especially in arterial thrombosis (MI, TIA) and Especially in arterial thrombosis (MI, TIA) and development of recurrent TE while on Warfarin.development of recurrent TE while on Warfarin.

3 Forms.3 Forms. If on aspirin, it should be stopped 14 days prior to If on aspirin, it should be stopped 14 days prior to

testing.testing.

Also remember:Also remember:

PC, PS and AT III are inhibitors of clotting.PC, PS and AT III are inhibitors of clotting.

Non-familial (Acquired):Non-familial (Acquired):1.1. Antiphospholipid Syndrome:Antiphospholipid Syndrome: Antibodies directed against phospholipid cell membrane = Antibodies directed against phospholipid cell membrane =

APA (Antiphospholipid Ab).APA (Antiphospholipid Ab). APA: ACA or LA.APA: ACA or LA. Primary (PAPS) or secondary (autoimmune disorders, e.g. Primary (PAPS) or secondary (autoimmune disorders, e.g.

SLE)SLE) ACA (Anticardiolipin Ab): IgM + IgG.ACA (Anticardiolipin Ab): IgM + IgG. IgG: the clinically important one.IgG: the clinically important one. IgM: pregnancy, infection (viral), trauma and post-op.IgM: pregnancy, infection (viral), trauma and post-op. LA (Lupus anticoagulant): Ab which affect clotting tests (LA-LA (Lupus anticoagulant): Ab which affect clotting tests (LA-

PTT, RVV, Kaolin).PTT, RVV, Kaolin). PAPS = TE, miscarriage, IUD + ACA, LA.PAPS = TE, miscarriage, IUD + ACA, LA.

Non-familial (Acquired) Non-familial (Acquired) continued:continued:

2.2. TPA (Tissue Plasminogen Activator): TPA (Tissue Plasminogen Activator): decreased levels impaired fibrinolysis.decreased levels impaired fibrinolysis.

3.3. PAI (Plasminogen Activator Inhibitor): PAI (Plasminogen Activator Inhibitor): increased levels decreased TPA.increased levels decreased TPA.

4.4. Dysfibrinogenemia.Dysfibrinogenemia.5.5. F XII deficiency: Hageman factor.F XII deficiency: Hageman factor.6.6. Fibrinogen (increased).Fibrinogen (increased).7.7. F VIII (increased).F VIII (increased).8.8. Plasminogen.Plasminogen.9.9. Hyperhomocyteinemia – enzyme (folate).Hyperhomocyteinemia – enzyme (folate).

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

When to test:When to test: Younger: < 50 years, recurrent TE, unusual sites, Younger: < 50 years, recurrent TE, unusual sites,

TE on Warfarin.TE on Warfarin. Not ideal to test after acute episode (inhibitors of Not ideal to test after acute episode (inhibitors of

clotting may be low).clotting may be low). Ideal: test after 6 weeks after settlement of Ideal: test after 6 weeks after settlement of

hemostasis.hemostasis. Most patients are on Warfarin then (PC & PS are Most patients are on Warfarin then (PC & PS are

Vit K dependent, may be falsely low).Vit K dependent, may be falsely low). My view: if long-term Warfarin is planned, do My view: if long-term Warfarin is planned, do

immediately/ according to duration of treatment it immediately/ according to duration of treatment it can be done after cessation of treatment.can be done after cessation of treatment.

When to test (continued):When to test (continued):

Practical (my experience): before treatment Practical (my experience): before treatment – if AT, PS, PC are low – if AT, PS, PC are low repeat after Rx repeat after Rx has been stopped.has been stopped.

SPS: platelet aggregation studies (problem: SPS: platelet aggregation studies (problem: sometimes aspirin cannot be stopped).sometimes aspirin cannot be stopped).

Remember the effect of the vessel wall on Remember the effect of the vessel wall on clotting, especially in arterial thrombosis.clotting, especially in arterial thrombosis.

Every woman on contraception, HRT?Every woman on contraception, HRT?

Treatment:Treatment: Heparin: unfractioned vs LMW.Heparin: unfractioned vs LMW. Heparin – PTT. LMW – anti FXa activity.Heparin – PTT. LMW – anti FXa activity. NB: LMW does not affect PTT.NB: LMW does not affect PTT. Warfarin: venous, antiphospholipid syndrome.Warfarin: venous, antiphospholipid syndrome. Warfarin: PT / INR (not % due to lab variation).Warfarin: PT / INR (not % due to lab variation). Aspirin: arterial – SPS.Aspirin: arterial – SPS. Individualized patients: ex single episode of Individualized patients: ex single episode of

thrombosis in patient with FV-Leiden post-op thrombosis in patient with FV-Leiden post-op lifelong treatment unnecessary (short to medium lifelong treatment unnecessary (short to medium term).term).

Lifelong: recurrent episodes, episodes on Lifelong: recurrent episodes, episodes on Warfarin, ? spontaneous episode with proven Warfarin, ? spontaneous episode with proven cause (DVT vs PE).cause (DVT vs PE).

Duration of Treatment:Duration of Treatment: 6 weeks6 weeks 3 months3 months 6 months6 months

INR Range:INR Range:

Single episode: 2-3Single episode: 2-3 Recurrent episode: 3-3.5Recurrent episode: 3-3.5 PE: 2-3/ 3-3.5PE: 2-3/ 3-3.5