This document discusses hypercoagulable states and thrombophilia. It covers the physiology and pathophysiology of congenital and acquired causes of hypercoagulability including deficiencies in natural anticoagulants, gain of procoagulant function due to mutations, and acquired conditions like cancer, pregnancy, oral contraceptives, and heparin-induced thrombocytopenia. It provides details on evaluation and testing as well as recommendations for anticoagulation therapy based on a patient's thrombophilia and clinical situation.

1. Hypercoagulable States
Dr Kiran G N

2.  INTRODUCTION - PHYSIOLOGY
 PATHOPHYSIOLOGY
 CONGENITAL
HYPERCOAGULABILITY
 ACQUIRED CAUSES OF HYPERCOAGULABILITY
 EVALUATION AND WORKUP OF HYPERCOAGULABLE STATES
 CHOICE AND DURATION OF ANTICOAGULATION THERAPY
Group 1 thrombophilia
Loss of Natural
Thrombosis Inhibition
Group 2 thrombophilia
Gain in Procoagulant Function
Antiphospholipid Syndrome
Solid or Hematologic Malignancies
Pregnancy
Oral Contraceptives and Estrogen
Replacement Therapy
Heparin-Induced Thrombocytopenia
Antithrombin III Deficiency
Protein C Deficiency
Protein S Deficiency
Factor V Leiden
Prothrombin Gene Mutation
Elevated Factor VIII Activity
Hyperhomocysteinemia
Dysfibrinogenemia

5. Fibrinolysis
Deficiency

8. Epidemiology of Inherited Hypercoagulable state

9. Congenital or hereditary hypercoagulability –
Loss of Natural Thrombosis Inhibition
• Crowther and Kelton

10. Antithrombin III Deficiency
Physiologic activity of AT3 is
enhanced 1000-fold with
naturally occurring or
administered heparin

11. Antithrombin III MOA- UFH vs LMWH

12. • AT3 deficiency 4% - 7.5% of patients.
• AD inheritance, > 250 mutations
• Nearly all patients are heterozygous for AT3 mutations
• Homozygosity is rarely compatible with life.
• Screening of first-degree family members is recommended after an
AT3 deficiency diagnosis is made in an individual with VTE.

13. Subtypes AT3 deficiency

14. Protein C Deficiency
• Protein C is a vitamin K-dependent
anticoagulation protein
When thrombin levels are
high, thrombin binds to the
endothelial protein receptor,
thrombomodulin(TM)

16. • The majority of people with protein C deficiency lack one copy of the
functioning genes leading to activity <60%
Rare
Qualitative
Quantitative
Qualitative

17. • Heterozygous for protein C mutations typically
• Homozygosity for protein C deficiency
Purpura fulminans
Present at birth
Diffuse micro vascular
thrombosis of the skin and
systemic organs
Immediate treatment with
heparin, plasma, or protein
C concentrates are
required to prevent
neonatal death
functional levels <20%

18. WISN 0.01-0.1%
• Protein C has short half life (5-8 hrs) compared to Vit- K
Dependant clotting factors
• Thus PC depleted more rapidly compared to Vit- K Dependant
clotting factors with Vit K administration

20. Protein S Deficiency
• Protein S is the vitamin K-dependent
cofactor
• Protein S deficiency - 0.7%
Protein S exists in two forms:
• free form -20% - 40%
• bound form- 60% t- 80%, bound to
complement binding protein C4b

21. Subtypes
• Type I and type III protein S deficiencies are the most common
forms
• Life-long anticoagulation should be considered in these
patients, who present with an event <40 years

22. Reduced protein S levels
• Protein S levels can also drop during 2/3
trimesters of pregnancy, and woman may have
fetal loss
• Low Protein S has also been reported in patients
with acquired conditions associated with
thrombosis, which includes
Active cancer,
Lupus,
APLA
syndrome,
sepsis,
IBD
AIDS

23. Congenital Thrombophilia –
Gain in Procoagulant Function

24. Factor V Leiden mutation (Activated Protein C Resistance)
Most common
inherited thrombophilia

25. Mutation in the 506 position
substitution of glycine for arginine
Makes factor V cleavage sites
resistant to the action of APC
leads to increased thrombin
generation

26. Rare
2% - 7% of individuals
19% of people with VTE and
in 30% to 50% of
individuals being evaluated
for thrombophilia
Rare
Heterozygous carriers - 6 x risk of VTE
Homozygous carriers – 20x risk of VTE

27. • Testing for factor V Leiden mutations should only be undertaken if it will
change patient management following an initial thrombotic event. Eg:
(1) History of an unprovoked VTE who are planning to stop
anticoagulation
(2) Female relatives of persons with a history of VTE or heritable
thrombophilia who are considering hormone therapy such as OCPs or HRT
(3) Female patients with a family history who are planning to get pregnant
and may need VTE prophylaxis.

28. • Combining patient’s plasma with factor V deficient plasma and a heparin
neutralizer 100% sensitivity & specificity for diagnosing factor V
Leiden.
• The diagnosis can be confirmed by determining a Heterozygous or
homozygous variant in genetic testing

29. Prothrombin Gene Mutation G20210A
• Risk of VTE increases significantly
when the G20210A prothrombin mutation
+ environmental or congenital risk factors.
• Eg: women taking OC therapy with the G20210A mutation have a
significantly increased risk of VTE and are also at higher risk of
developing cerebral vein thrombosis.
• G20210A prothrombin mutation + Factor V Leiden mutation
VTE risk = x 2.6
Lifelong anticoagulation therapy mandatory

30. Rare
1% - 2% in the general
population
5% - 10% of patients
with a VTE event
Rare

31. Elevated Factor VIII Activity
An Acute phase
Reactant/protein

32. • With factor VIII activity >150%, VTE risk 4.8 x
• factor III levels contribute to approximately 4% of arterial thrombosis
• There is controversy as to whether increased levels of factor VIII are
independently associated with arterial thrombosis
• Factor VIII levels are increased during inflammation and thus likely
represent a cofactor in the development of thrombosis associated with
Infection
IBD
Cancer

33. • function assays used to measure factor VIII activity should be
performed following measurement of acute phase marker, such
as the ESR/CRP
• These diagnostic assays should be
repeated at least twice
at distant time intervals
An Acute phase
Reactant/protein

34. ElevatedfactorIX,XI
• Increased levels of factors IX and XI 2X increase in the risk
of VTE.
• These are relatively weak risk factors for thrombosis, but if
combined with other defects become significant

35. Hyperhomocysteinemia > 15 μmol/L
5%–10%
25% among those with
vascular diseases
MI, CVA 2-8 X *
Primary VTE 3 X

36. (1) a direct cytotoxic effect on
endothelium
(2) enhanced platelet activation
(3) Oxidation of LDL
(4) decrease in endothelial T Modulin
(5) an increase in vWF, factor VIII
Measurements are best performed
using freshly collected plasma,
preferentially with patients in the
fasting state.
It is reasonable to repeat the assay on
at least two separate occasions.
False values - comorbid conditions,
such as vitamin deficiency or CKD
With a high degree of suspicion, the
diagnosis of hyperhomocysteinemia
can be further confirmed based on the
MTHFR genotype.

37. 677C→T in MTHFR gene
methylenetetrahydrofolate reductase
Renal injury
or
worsening of CKD

38. Dysfibrinogenemia
In Dysfibrinogenemia
concentrations of circulating
thrombin are increased when
fibrinogen is deficient
• 40% no symptoms
• 50% bleeding disorder
• 10% hypercoagulable state.
Type 1
• Qualitative/ functional fibrinogen
• Abnormality in the fibrin molecule
resulting in defective fibrin clot
formation.
Type II
• Quantitative
• Reduced fibrinogen antigen levels.

40. ACQUIRED CAUSES OF
HYPERCOAGULABILITY

41. APLA Syndrome

42. • Characterized by the presence of antibodies that inhibit in vitro
coagulation reactions known as lupus anticoagulant and
antibodies that bind to anticardiolipin and β2-glycoprotein.
• Paradoxically, antiphospholipid antibodies prolong in vitro
coagulation tests, most commonly, the activated partial
thromboplastin time (aPTT)
• The mechanism(s) by which they result in thrombosis remains
unclear.

44. traditionally been treated with a vitamin K antagonist,
should be continued indefinitely
Rivaroxaban was safe to use in lower risk APS
Rivaroxaban may not be adequate in
treating high-risk APS patients
The 2006
Sydney
Consensus
At levels exceeding the 99th percentile, measured by
ELISA.
These tests should be confirmed by repeating them twice
at least 12 weeks apart

45. APLA Syndrome
Risk for DVT for individuals
positive for LA
3.6 X
Positive for both
the LA and either antiprothrombin
or anti-β2-glycoprotein-1
antibodies
10-fold increased risk of VTE.
After stopping oral anticoagulants
The risk of recurrent thrombosis may be as high as 50% in
retrospective studies
Prospective clinical trials have estimated
the relative risk of recurrence to be between 4- 8 X

46. Pregnancy
Hormone
related
elevations
of
fibrinogen,
factor VIII,
Hormone
related
reduction in
protein S
depressed
fibrinolysis
Patients with
congenital
deficiencies of AT-
III and proteins C
or S are 8X more
likely to have
thromboembolic
complications
during pregnancy
Factor V
Leiden was
the most
commonly
associated
thrombophili
a in
pregnancy Greer et al : acute
antepartum riskof
DVT to be 0.6 per
1000 in women
younger than 35
years and 1.2 per
1000 in women
older than 35 years

47.  Thromboembolism can develop any time during pregnancy; the
lowest - first trimester
 > 50% of pregnancy related VTEs is in Postpartum period accounts
for greater than
 The incidence is higher after CS
 The left leg is affected in 90% - due to a compressive
effect on the left iliac vein by the right iliac artery

48.  Pregnancy-associated thrombosis without documented
thrombophilia can have antepartum prophylactic
anticoagulation withheld, but to be followed closely and receive
prophylaxisin the immediate postpartum period
 With congenital deficiencies, such as antithrombin, protein C,
protein S, & APLA Syndrome considered for both ante &
postpartum prophylaxis, even if they have not had a previous
VTE
 Pregnant patients with active thrombosis should receive a full
dose of LMWH

49. Cancer(solid or hematologic malignancy)
 Incidence of clinically
significant VTE ranges from
10% - 43%
 Those patients receiving
chemotherapy /metastasis
are at a significantly higher
risk of VTE
Thrombosis
venous
arterial

50. Clinical- venous thrombus
CLOT trial- randomized patients to receive either LMWH agent
dalteparin or warfarin for 6 months and found a significant reduction
in symptomatic recurrent VTE associated with dalteparin with no
difference in bleeding risk.
CATCH trial- where recurrent VTE was reduced among cancerpatients
randomized to the LMWH agent tinzaparin relative to warfarin
Current guidelines recommend treating cancerrelated VTE with 3–6
months of LMWH therapy or potentially indefinite treatment with
active malignancy

52. Clinical – arterial thrombus

 Meta-analysis of 5 cancer trials chemotherapy + antiangiogenic
agent, bevacizumab, the incidence of arterial thromboembolic
events was 3.8%, 2X that seen in CT alone
 Most common cause of stroke in
patients with solid tumors due to a
cerebral emboli.
 Characterized by formation of
platelet and fibrin vegetation on
cardiac valves
 Transesophageal echocardiography
(TEE) has the greatest diagnostic yield

53. OCPs
 Estrogen alone as HRT is a well-documented risk
factor for venous thrombosis
 Third generation progestagen compounds were associated with a
doubling of the risk of VTE compared with second-generation
 Combination of OC use and inherited thrombophilia multiplicative effect
on the risk of VTE
 Transdermal estrogen replacement might be associated with a lower risk
of VTE

54. *
*

55. *

56. HIT

57. HIT is an
immunologic
disorder
Polyclonal IgG
antibody response
against
neoantigens
expressed on
platelet factor 4
(PF4) upon binding
to heparin- (heparin-
PF4 complexes).

58. • 1.1 % and 2.3 % of porcine and
bovine heparin respectively
• HIT-related thrombosis-HITT, has
been estimated to occur in 0.3% of
patients receiving therapeutic
doses of heparin

62. platelet factor 4
(PF4)

66. https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-03077-0#Fig3
Characteristic features of COVID-19-
associated coagulopathy.
The clinical and laboratory features of
COVID-19-associated coagulopathy (CAC)
partially overlap with sepsis-induced
coagulopathy (SIC)/disseminated
intravascular coagulation (DIC),
hemophagocytic syndrome
(HPS)/hemophagocytic
lymphohistiocytosis (HLH),
antiphospholipid syndrome (APS), and
thrombotic microangiopathy (TMA)

67. Evaluation of patients with suspected thrombophilias

70. CHOICE AND DURATIONOF ANTICOAGULATION THERAPY

71. Therapy for VTE in most cases should be the same regardless of whether a heritable
thrombophilia is present or not.
The majority of patients can be effectively treated with either a DOAC or VKA agent as
first-line therapy, and the recommendation for patients in the provoked setting would be
to treat for a 3-month period.
For patients who have an unprovoked VTE event, anticoagulant therapy should be
prescribed for an extended period of time or indefinitely unless their bleeding risk is
prohibitive.
If a patient is known to have cancer in the setting of a thrombophilia, the recommendation
is to use LMWH for initial anticoagulation.
If a patient has a recurrent event on either a VKA or a DOAC agent, then it is
recommended that the patient be transitioned to LMWH.

73. Thank you
Thank you