The document summarizes several cases of hypercoagulable states and deep vein thrombosis (DVT). It describes three cases: 1) A 36-year-old with recurrent DVT who presented with abdominal pain and bleeding, 2) A 33-year-old man with sudden dyspnea and chest pain along with leg edema, and 3) A 21-year-old woman referred for contraceptive evaluation given her family history of thrombosis. It then reviews hypercoagulable states, including definitions and classifications of congenital and acquired causes. Specific conditions discussed in detail include deficiencies of antithrombin, protein C, and protein S; factor V Leiden; prothrombin gene mutation; antiphosph

1. Hypercoagulable
States
Dr Fayazuddin Md
Nizam’s institute of medical sciences

2. Case #1
• 36-year-old Diagnosed case of Unprovoked Left lower limb DVT, who
completed course of anticoagulation 2 months back, Presented to ER with
generalized pain abdomen and Malena for 2days.
• Case referred to surgical gastro dept, They Evaluated the case and advised
CECT abdomen and pelvis

4. Case # 2
• A 33-year-old previously healthy man presented with sudden-onset dyspnea
and sharp right-sided chest pain. He had noted right leg edema and calf
discomfort a week earlier.
• He denied recent trauma, surgery, or immobility.
• His mother had a history of postpartum deep vein thrombosis (DVT).

5. On Evaluation
• Tachycardia with a heart rate of 114 bpm,
• O2 saturation was to 88% on room air.
• Rt lower limb edema
Investigations:
• Right lower-extremity venous doppler documented femoral and popliteal DVT

6. CTPA

7. Case # 3
A 21-year-old woman is referred for evaluation prior to initiation of oral
contraception. Her mother had a PE during her first pregnancy. Her older
sister had a DVT after ankle surgery in the setting of oral contraceptive use at
31 years old. The patient never had a thromboembolic event. Neither her
sister nor mother had undergone thrombophilia evaluation in the past.

8. Striking events
Unprovoked VTE
Age less than 50
Recurrent VTE
Unusual site VTE
Unusual presentation
Strong family history

9. Hypercoagulable
state????
What are the Hypercoagulable states?
When to suspect Hypercoagulability?
when to test?
why to test?
how to test?

10. Virchow’s triad

11. Hypercoagulable State
Definition:
A disorder associated with an increased tendency to thrombosis
Classification:
 Congenital
 Acquired
 Mixed/unknown

12. CONGENITAL HYPERCOAGULABILITY
Group -1
Deficiency of the natural anticoagulant
(“loss of inhibition”)
 Anti thrombin deficiency
 Protein C deficiency
 Protein S deficiency
Group -2
Inc levels or function of the coagulation factors
(“gain in procoagulant function”)
 Factor V Leiden(Activated Protein C resistance)
 Prothrombin gene G20210 A mutation
 Raised levels of VIII,IX,XI factors
 Dysfibrinogenemia's

13. Interesting
fact..,
• The risk of thrombosis is more in the group 1
thrombophilia patients
• But group 2 thrombophilia was detected at least five
times more frequently than group 1 disorders.
• Group 2 thrombophilia is known to be associated with
the first episode of DVT but may not be a risk factor for
the recurrent thrombotic attacks.

14. Antithrombin
Deficiency
• Antithrombin is the most important inhibitor of thrombin
and other activated clotting factors (e.g., factors Xa, IXa, and
VIIa).
• Its physiologic activity is enhanced 1000-fold by the binding
of naturally occurring or administered heparin.
• It is rare (0.02%), but it can be as high as 4–7.5% in patients
presenting with VTE.
• inheritance is autosomal dominant.
• Homozygosity is rare and appears to be incompatible with
life.

15. Types of
inherited
antithrombin
deficiency
Screening for antithrombin deficiency should always be undertaken
using a functional assay, because screening with an antigen assay may
fail to diagnose type II and III defects.
Type Antigen Activity
(No Heparin)
Activity
(With Heparin)
I (decreased
protein)
Low Low Low
II (active site
defect)
Normal Low Low
III (heparin-
binding site
defect)
Normal Normal Low

16. Protein C & protein S Deficiency

17. Diagnosis?

18. Purpura
fulminans
• Homozygosity for protein C & S deficiency
• characterized by diffuse microvascular
thrombosis of the skin and systemic organs.
• Immediate treatment with heparin, plasma, or
protein C & S concentrates can be lifesaving.

19. What is the Diagnosis???
What oral anticoagulation initiated?

20. warfarin
necrosis
• In heterozygous patients with protein C & S
deficiency treated with higher doses of warfarin,
usually without concomitant anticoagulation
with heparin present with skin necrosis.
• Results from the disproportional decrease in
protein C & S in comparison to other
procoagulant vitamin K-dependent coagulation
factors.
• Treatment: fresh frozen plasma, vitamin K, and
heparin.
• Prevention: initiation with lower doses of
warfarin and concomitant use of heparin.

22. Factor V Leiden (Activated Protein C Resistance)
• Factor V is a cofactor that accelerates the conversion of factor II
(prothrombin) to thrombin by factor Xa.
• Factor V Leiden has a mutation in the 506 position that results in a
substitution of glycine for arginine. This renders one of the factor V cleavage
sites resistant to the action of APC.

23. Factor V Leiden (Activated Protein C Resistance)
• common mutation, present in 2% to 7% of individuals of European ancestry
but very rare in native Asians and Africans.
• Comprise 10% of people with VTE and in 30% to 50% of individuals being
evaluated for thrombophilia.
• Thrombosis is frequently triggered by transient risk factors, such as a
prolonged plane flight, OC use, or pregnancy

24. Factor V Leiden (Activated Protein C Resistance)
• No excess mortality
• No prophylaxis is recommended for carriers
• The risk of recurrent VTE after cessation of oral anticoagulation is not
greater than that observed in other patients with unprovoked VTE.

25. Prothrombin Gene Mutation G20210A
• It is an abnormality located at the untranslated 3′ end of the prothrombin
gene that results in increased plasma levels of prothrombin.
• The thrombotic risk is relatively low.
• The gene frequency in the European population is about 1% to 4%.
• very rare in Native Asians, Africans, and Americans.

26. Elevated Factors VIII, XI, and IX
• Patients with history of venous thrombosis have shown increased levels of
factors VIII, IX, and XI. But it is not clear how the elevated levels of
coagulation factors can increase the risk of thrombosis.
• It’s very weak risk factors for thrombosis.
• When there is combination of these of mutations, then there is higher risk
of thrombosis present during the childhood.

27. ACQUIRED
HYPERCOAGULABILITY
 Antiphospholipid Antibody Syndrome
 Cancer
 Pregnancy
 Oral Contraceptives
 Heparin-Induced Thrombocytopenia
 Obesity

28. Antiphospholipid Antibody Syndrome
• Most common causes of acquired hypercoagulability
Characterized by the association of:
• Thrombosis, obstetric complications and/or thrombocytopenia
• Antibodies against phospholipids or against proteins bound to phospholipids.
• increased risk of both arterial and venous thrombosis.

29. Etiology of APA Syndrome
• Primary:
 Idiopathic
• Secondary:
 SLE
 Infection
 Drug reaction
 Lymphoma

30. Antiphospholipid
Antibodies
10% of healthy donors, 30-50% of SLE patients
Lupus Anticoagulant (LA) Antibodies
Anticardiolipin (ACL) Antibodies
Anti-Beta 2 Glycoprotein I
Antibodies(β2GPI)
The syndrome is something of a paradox in that
this thrombotic disorder is characterized by
antibodies that prolong in vitro coagulation
tests, most commonly, the activated partial
thromboplastin time (aPTT).

31. Diagnosis - Clinical Criteria
Vascular thrombosis:
• arterial, venous, or small vessel, in any tissue or organ
Pregnancy morbidity:
- Unexplained fetal death
- Premature birth before 34 weeks gestation
- Three or more consecutive spontaneous abortions

32. Diagnosis -
Laboratory
criteria
Lupus anticoagulant,
Anticardiolipin antibodies (ACA)
Anti-beta-2-glycoprotein I antibodies
(anti-B2GPI),
• Present on at least 2 occasions, at least 12
wks apart

33. Mechanism of Thrombosis
• The mechanism(s) by which these antibodies result in thrombosis remains unclear.
• Activation of monocytes, platelets, and endothelial cells by antibody/β2-glycoprotein-1
complexes has been implicated in the etiology of thrombotic events.
• Antibodies to annexin II on endothelial cells, tissue plasminogen activator, and plasmin have
been proposed as additional antigenic targets.
• Complement (C5a)-mediated inflammation has been demonstrated to be associated with
increased thrombogenicity and recurrent fetal loss.

35. Management • Extended or indefinite anticoagulation
• CAPS is a life-threatening variant of the
disorder characterized by diffuse macro-
and microvascular thrombosis with
multiple organ involvement. Prompt
recognition and treatment with
corticosteroids and heparin, and in
refractory cases, plasmapheresis, can be
lifesaving

36. VTE in Cancer
• 20% of all first-time VTE events are associated with malignancy.
• 1 in 200 individuals with malignancy will develop either DVT or PE, a
fourfold higher risk than those without malignancy.
• 1 in 7 cancer patient who dies in hospital is due to PE .
• 5% to 11% of patients, malignancy appears within 1 to 2 years of
presentation for DVT.

39. VTE in Pregnancy & post partum
• Thromboembolism can develop any time during pregnancy
• The lowest risk occurs in the first trimester, but the risk does not
increase during the last 20 weeks of gestation.
• Occurrence of VTE postpartum period > pregnancy
• The incidence is higher after caesarean section than vaginal delivery.
• The left leg is affected in 90% of cases

40. VTE in
Pregnancy –
Risk factors

41. Full dose of LMWH
28-year-old lactating lady presented with Lt Leg DVT 2wks after caesarean
section, management?
UFH/LMWH/WARFARIN
28 wks of Pregnant patient presented with Lt Leg DVT, Management ?

42. considered for both ante- and postpartum prophylaxis, even if they have not had
a previous thromboembolic event.
32-year-old diagnosed lady with antiphospholipid syndrome, now became
pregnant and came for advice on anticoagulation?
considered for both ante- and postpartum prophylaxis, even if they have not had
a previous thromboembolic event.
32-year-old diagnosed lady with group 1 congenital thrombophilia, now
became pregnant and came for advice on anticoagulation?

43. should receive prophylaxis in the peri- and postpartum periods (6 weeks)
32-year-old pregnant lady, diagnosed c/o factor V Leiden mutation, with h/o
VTE in last pregnancy, came for advice on anticoagulation?
considered for both ante- and postpartum prophylaxis
32-year-old pregnant lady, diagnosed c/o factor V Leiden mutation, with no
h/o VTE in last pregnancy, came for advice on anticoagulation?

44. Oral Contraceptives & HRT
• The first-generation OCs were associated with a 10-fold increased risk of VTE that
decreased to a 4-fold risk with the second-generation OCs.
• The third-generation OCs containing the newer progestogen compounds have a two-
to threefold increased risk of VTE over second-generation OCs.
• 2-4-fold higher risk of VTE among women taking HRT.
• Combination of OC use and inherited thrombophilia has a multiplicative effect on the
risk of VTE

45. Mechanism of thrombosis
• Estrogen is associated with alterations in the coagulation system that may
contribute to this thrombotic tendency.
• Such alterations include decreases in PAI-1 and increases in blood viscosity,
fibrinogen, plasma levels of factors VII and X, platelet adhesion and
aggregation and decreases in antithrombin and protein S inhibitor activity.
• The extent to which antithrombin and protein S are depressed is
significantly less with lower-estrogen preparations.

46. Diagnosis?
Vascular surgery referral was given
from CT ICU that 72-year-old male
pale pt who underwent CABG 6 days
back developed left upper limb
gangrenous changes. Doppler
showing both arterial and cephalic
vein thrombus. Nothing was
significant except platelet 1 lac.

48. Heparin-Induced Thrombocytopenia
• HIT is an antibody-mediated process triggered by antibodies directed against
neoantigens on PF4 that are exposed when heparin binds to this protein
• These antibodies(IgG) bind simultaneously to the heparin-PF4 complex and to
platelet Fc receptors. Such binding activates the platelets and generates platelet
microparticles.
• Circulating microparticles are prothrombotic because they express anionic
phospholipids on their surface and can bind clotting factors, thereby promoting
thrombin generation

49. Features of HIT
Features Details
Thrombocytopenia Platelet count of 100,000/µL or less or a decrease in platelet count of 50% or more
Timing Platelet count falls 5-10 days after starting heparin
Type of heparin
More common with unfractionated heparin than low-molecular-weight heparin;
almost never occurs with fondaparinux
Type of patient
More common in surgical patients than medical patients; more common in women
than men
Thrombosis Venous thrombosis more common than arterial thrombosis

50. • How to suspect HIT?
• How to investigate ?
• Management???

52. Diagnosis of
HIT
Immunoassays:
Enzyme-linked assays to detect antibodies against heparin-
PF4 complexes
Functional assays:
• Serotonin release assay (SRA)
• Heparin induced platelet aggregation

54. Management of HIT
Evaluate Evaluate for thrombosis, particularly deep venous thrombosis
Do not give
Do not give warfarin until the platelet count returns to its baseline level. If
warfarin was administered, give vitamin K to restore the international normalized
ratio to normal
Do not give Do not give platelet transfusions
Give Give an alternative anticoagulant, such as lepirudin, argatroban, bivalirudin,
fondaparinux, or rivaroxaban
Stop Stop all heparin

55. When to suspect
Hypercoagulability???
• Unprovoked VTE
• Age less than 50
• Recurrent VTE
• Unusual site VTE
• Unusual presentation
• Strong family history
• Unexplained neonatal thrombosis
• Skin necrosis particularly if on warfarin

56. why to test?? • To determine the risk of recurrent thrombosis, and, therefore, the duration
of anticoagulation.
• Testing of family members, who have not had a VTE, should be performed.
• This will allow asymptomatic carriers to be counseled regarding high-risk
situations of increased hemostatic stress, such as surgery, pregnancy, OC
pills, HRT, or prolonged travel.

57. How To Evaluate? Idiopathic, recurrent, VTE with age <40yr
(+) Family history (-) Family history
Lupus Anticoagulantd
Beta-2-glycoprotein-1 IgM, IgG
Fasting homocysteine
Age appropriate Cancer screening
Anti-thrombin activity/Antigena
Protein C activity/Antigenb
Protein S activity/Antigenb
Factor V Leiden genotype
Factor VIII activity/CRP/ESRc
Fasting homocysteine
Prothrombin gene mutation
G20210A
Negative

59. What Test to be
done?

60. Thank you