This document discusses various hypercoagulable states and conditions that increase the risk of thrombosis. It covers the pathophysiology of thrombosis and describes several inherited and acquired hypercoagulable states including deficiencies of antithrombin III, protein C, and protein S. It also discusses factors such as factor V Leiden, prothrombin gene mutation, elevated factors VIII, XI, and IX, hyperhomocysteinemia, antiphospholipid antibody syndrome, cancer, pregnancy, oral contraceptive use, heparin-induced thrombocytopenia, and obesity as risk factors for thrombosis. It provides details on clinical presentation, diagnostic evaluation, and management of these various hypercoagulable conditions.

1. Hypercoagulable states
Dr Prashant Raman
MMC & RGGH, Chennai

2. • >6L/yr- USA
• 20% mortality
• Virchow’s triad

3. Pathophysiology
• Platelet activation- Plug- activation of coag
protein- thrombin- further platelet activation-
acts upon fibrinogen- insoluble fibrin clot
• Poorly understood mechanism-
hyperhomocysteinemia
Lp(a)

4. • Arterial thrombosis-
• Conditions affecting vascular wall and
endothelium
• Others- increased level of fibrinogen/ vWF-
enhances platelet function

5. Congenital hypercoag states
• Cowther & Kelton classified
• Type 1- Reduced natural anticoag
• Type 2- Gain of procoag(low risk, more
common)

6. Group 1
• Rare -<1%
• 30-50% heterozygote- symptomatic
thrombotic events <60 Y
• Routine prophylaxis in ambulant – No benefit
• Prophylaxis for known risk status

7. AT III
• Most Important inhibitor of thrombin and
other clotting factors (Xa, IXa & VIIa)
• Heparin potentiates- × 1000
• Rare <0.02%
• 4-7.5% in VTE pts
• >250 mutations
• Homozygosity – incompatible with life

8. • Types
• 1- function/Ag level
• 2-function
• 3-moderate  activity due to impaired
interaction with heparin
• Measurements:- Functional assay

9. • 60%- Type I &II- Thrombosis <60 Y
• Predominantly- lower extremity with/without
PE
• Recurrence
• Atypical events
• Preg- High risk- Heparin throughout preg and
cont. postpartum

10. • Breakthrough events- AT concentrates
• Acquired Form- Fatty liver of preg- Treatment
• Plasma
• AT concentrates

11. Protein C deficiency
• Vit K dependent anticoag protein- activated by
thrombin to APC
• thrombin binds with TMchanges the
specificity of thrombin from cleaving fibrinogen/
activating platelets to activating protein C
Protein C binds to its receptorAPCSerine
protease anticoagcleaves cofactor
VIIIa/Vamodulates thrombin generation/clot
formation

12. • 0.2%- general population
• 2.5-6%- VTE
• Types
• 1-  Function/ Ag
• 2-  Function
• Heterozygotes- activity level<60%

13. • VTE- Lower extremity
• Unusual sites same as AT III
• Life long anticoag- umprovoked/<40 Y
• Homozygotes- Neonatal disorder- Purpura
fulminans- Immediate Heparin/Plasma. Protein C
Concentrates
• Heterozygotes- higher dose of warfarin- similar
presentation.
• T/t: FFP/ Vit K/ Heparin

14. Protein S def
• Vit K dependent cofactor- necessary for the
inactivation of factor Va & VIIIa by APC
• Pathophysio- Same as Protein C def
• 2 forms
• Active and bound to complement binding C4b
• Functionally active free form- 20-40%

15. • Most pt with def- Activity level- 50-75%
• Types:
• 1. Function/Ag
• 2. function
• 3. free active protein S due to enhanced C4b
binding
• Type I & III- m/c

16. • Measurement confounded by-
• Preg- Level
• Active Ca/ SLE/ APLAS/ Sepsis/ Chr
Inflammatory disorders/ Active HIV

17. Clinical presentation
• VTE-frequently reported in association with
venous thrombosis in atypical site
• Neonatal purpura fulminans –also seen

18. Group 2
• Factor V Leiden (Activated Protein C
Resistance)
• Cofactor –that accelerates the conversion of
Factor IIthrombin(in presence of Xa)
• Normally degraded by serine protease
• Mutation- renders it resistant

19. • 2-7% of European ancestry
• Rare – Asian/African
• risk of thrombosis
• Homozygotes-80✕

20. Clinical Presentation/Mgmt
• Overwhelming Venous
• Rare- unusual sites
• Triggered by risk factors
• No  mortality
• No prophylaxis for carriers
• Antepartum – not recommended except for
previous h/o thrombosis/ recurrent fetal loss

21. Prothrombin Gene mutation
• Mutation affects 5’ end cleavage signal-
prothrombin mRNA stability
• Thrombotic risk- reatively low
• Rare- African/Asian
• Predominantly LL VTE
• Rare- unsusual sites
• risk in women on OCs

22. Elevated factor VIII, XI & IX
•  Factor VIII->150%- 4.8% RR
• No relation with Ocs
•  VTE
• Measurement confounded- APR/ bleeding/
inflammation
• Simultaneous- ESR/CRP

23. Clinical Presentation
• VTE- LL
• vWF- arterial
• Factor IX/ XI- 2✕

24. others
• Homocysteneimia- metab-
• 1. B6 dependent Cystathione beta synthetase
• 2. B12/ Folate – 5,10 MTHFR & methionine
synthase
• Folate supplementation- brings Normal range

25. • Reported mech
• Toxic
• platelet activation
• Oxidation of LDL
• Inflamm- d
•  endoth. TM
• vWF/ Factor VIII

26. • Measurement confounders
• Vit def
• Renal insufficiency
• Improper plasma collection
• Best performed: fastong state/ fresh sample

27. Lp(a)
• Consists of low density lipid particles with a
disulfide link to a polypeptide chain-
Apolipoprotein(a)
• Compete with tPA/plasminogen/plasmin for
binding to fibrin & endothelial annexin
• Inhibits fibrinolysis
• May  as APR

28. Sticky platelet syndrome
• AD
• Young- MI/PVD
• Precupitated with stress
• Hyperactivity to Epi/ ADP- but normal
response to thrombin/collagen/arachidonic
acid

29. • 3 types
• 1.  Activity to Epi/ADP
• 2. Epi only
• 3. ADP only
• Low dose ASA (81mg)

30. Idiopathic VTE
• Underlying inflamm. States
• IL-6/IL-8, Low levels of IL-10

31. Acquired
• APLAS
• Ca
• PNH-  Platelet activation and leukocyte
tissue factor
• MPS- unusual sites
• Esp with JAK-2 mutation

32. APLAS
• Art/Ven Thrombosis
• Presence of LA and titer IgG ACL Ab- 3.6✕
LA & either antiprothrombin or anti beta-2 GP-
10✕
Syndrome- paradox
aPTT
Complement C5a mediated inflammation has
been demonstrated- thrombosis/fetal loss

33. Diag
• Ig G/ IgM Ab - ACL
• Abti beta2 GP1

34. Clinical presentation
• Art/venous
• Unusual sites- NBTE
• Recurrence- 50%
• Moderate intensity warfarin
• Catastrophic APLA- prompt recog/ Heparin/
Plasmapharesis

35. Cancer
• Expression of tissue factor
• Malig induced inflammation
• Prothrombotic hemostatic changes
• fibrinogen/ Factor VIII & platelet count
• Mechanical and invasive
• Chemo induced
• With ca 7✕
• With mets20✕

36. • 3✕ recurrence/ risk of bleeding
• Against the use of warfarin/ in favour of
LMWH
• Arterial thrombosis: 10-30% of thrombotic
complications
• Chemo+ antiangiogenic(bevacizumab)- 2✕

37. • NBTE- m/c /c- stroke with solid tumors

38. Preg and OCs
• Preg- acquired prothrombotic state
• Hormone related elevation of fibrinogen,
Factor VIII, Protein S, depressed fibrinolysis
• Cong. Def- Protein C/S- more likely VTE
• Postpartum – 50% of all
• Lt leg- 90%

39. • Cong def- Ante/post partum prophylaxis
• Factor V- Peri/Postpartum(6wks) except for
previous events
• Active thrombosis- Full dose LMWH

40. OCs
• Estrogen alone/ with Progestrone
• 1st gen
• 2nd gen- Levonorgestrel/
norgestrione/norgestrel
• 3rd gen- Desgestrel/Gestodene
• 3rd gen ✕2

41. • Combination with inherited thrombophilia-
multiplicative

42. HIT
• Arterial/Venous
• No bleeding
• IgG Ab directed Hep-PF4 complex- Activation-
release membrane microparticles- Express P
selectin capable of activating monocytes and
inducing tissue factor expression- Coag
cascade
• V:A::4:1

43. Diag/Mgmt
• Thrombocytopenia/ thrombosis during or
immediately following heparin use- > 50% 
• Thrombotic sequelae- 30-70%
• Severe thrombocytopenia- <20% rare
• Median Nadir- 50-60K
• Development of new thrombosis/ progression
of existing in a pt receiving heparin

44. • In heparin naïve pt- platelet count every other
day beginning 5 days after starting Heparin
• With previous exposure- monitor with the
start of Heparin use
• Development of platelet activating, non-
complement fixing IgG Ab directed against the
complex of heparin+PF4 - hallmark

45. • Ab detection
• Functional assay- detects Ab capable of
inducing platelet activation (serotonin release
assay)- C14 SRA or heparin induced washed
platelet aggregation assay
• PF4- heparin immunoassay (ELISA)

46. • Prompt recognition
• Immediate cessation of all forms of heparin
• Rapid initiation of direct thrombin inhibitors-
such as Argatroban, Lepirudin or Bivalrudin.
• Essential for preserving – limb/ life
• Warfarin alone – not protective.

47. • Patients within 100 days of diag- should not
receive any form of heparin therapy
• Beyond 100 days- may receive if indicated
• Ideally daily platelet count monitoring

48. Obesity
• >25 Kg/m2: combination of tall stature/
obesity
• - presence of metab synd- abd
obesity/imapired gluc metab/ SHTN/
dyslipidemia

49. Evaluation
• Patients with VTE eho should be tested:
• <50 Y- unprovoked
• Unprovoked+ Recurrent
• Thrombosis including those associated with a
transient risk factor, if there is a strong family H/O
VTE
• In younger pts <50 Y – without DM- unprovoked
arterial thrombosis- screening evaluation can
identify prothrombotic risk factors.