Thrombosis

1
Thrombosis

• Dr Nico Lategan
• MBChB, MMed (Haematology)

2
General

• Coagulation/ Haemostasis Blood clotting vs
  Fibrinolysis.
• Endothelium damage release of TF (activates
  clotting) and tPA (activates fibrinolysis).
• Blood clotting Virchows 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).

3
Definition

• Tendency to develop recurrent thrombosis at
  unusual sites due to enhanced thrombin generation
  started at a young age (lt50 years).

4
Classification

• 1. Familial physiological
• 2. Non-familial (acquired) physiological or
  pathological

5
Problems

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

6
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.

7
Always do basic tests

• FBC, PLT, ESR
• PT, aPTT, TT, Fibrinogen

8
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.

9
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.

10
Familial

1. FV-Leiden (APCR activated prot C resistance).
2. Protein C (deficiency).
3. Protein S (deficiency).
4. Antithrombin III (deficiency).
5. Abnormal Prothrombin (PT 20210 A).
6. Sticky platelet syndrome.

11
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.

12
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).

13
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.

14
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.

15
5. Abnormal Prothrombin (PT 20210 A)

• Common.
• Increased levels of prothrombin enhanced thrombin
  formation.
• Only way for diagnosis DNA-PCR technique.

16
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.

17
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.

18
Non-familial (Acquired) continued

1. TPA (Tissue Plasminogen Activator) decreased
   levels impaired fibrinolysis.
2. PAI (Plasminogen Activator Inhibitor) increased
   levels decreased TPA.
3. Dysfibrinogenemia.
4. F XII deficiency Hageman factor.
5. Fibrinogen (increased).
6. F VIII (increased).
7. Plasminogen.
8. Hyperhomocyteinemia enzyme (folate).

19
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

20
When to test

• Younger lt 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.

21
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?

22
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).

23
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