Thrombophilia

Hypercoagulable States

1. By
DR MONKEZ M YOUSIF
Professor of Internal Medicine
Zagazig University
2015
HYPERCOAGULABLE HYPERCOAGULABLE
STATES (THROMBOPHILIA)STATES (THROMBOPHILIA)

2. Objectives
•Revise hemostatic mechanisms
•Discuss hypercoaguable states
•Focus specifically on the inherited
hypercoaguable conditions
•Briefly describe the mechanism behind each of
the inherited thrombophilias
•Review the hypercoaguable workup and when
it is appropriately done

3. Case 1
•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).
•On physical examination, he has tachycardia with a heart
rate of 114 bpm, normotensive with a blood pressure of
102/76 mm Hg, and hypoxemic to 88% on room air.
•Contrast-enhanced chest computed tomogram demonstrated
bilateral segmental pulmonary embolism.
•Right lower-extremity venous ultrasound documented
femoral and popliteal DVT.

4. Case 2
•A 78-year-old woman with hypertension and
obesity developed acute left leg edema and
pain 2 days after open reduction and internal
fixation of a right hip fracture.
•On physical examination, the patient had
severe edema and tenderness of the left lower
leg and thigh.
•Left lower extremity venous ultrasound
documented left common femoral, distal
femoral, and popliteal DVT.

5. Definition of thrombophilia
A disorder associated with an
increased tendency to thrombosis.

7. VESSEL WALL
ENDOTHEL
PLATELETS
PLASMA
FACTORS
(procoagulation,
anti-coagulation)
HEMOSTASIS = the arrest of bleeding
from an injured vessel
Hemostatic abnormalities can result in procoagulation or/and anti-coagulation
conditions

8. HemostasisHemostasis
BV Injury
PlateletPlatelet
Aggregation
Platelet
Activation
Blood VesselBlood Vessel
Constriction
CoagulationCoagulation
Cascade
Stable Hemostatic Plug
Fibrin
formation
Reduced
Blood flow
Damage/contact.
Primary hemostatic plug
Neural
Contact

9. The Role of Platelets in Hemostasis
Collagen
Other
factors
TF
Thrombin
Activated
platelet
Activated
platelet
Activated
platelet
Adhesion
Aggregation
Contraction
Secretion
Primary
Hemostasis
=
Activated
platelet
Activated
platelet
Activated
platelet
Activated
platelet
This plug of activated platelets, localised to the site of injury, provides the
phospholipid surface upon which Secondary Hemostasis takes place

10. Coagulation Cascade
XII XIIa
XI XIa
IX
VIII VIIIa
X
Xa
Intrinsic Pathway Extrinsic Pathway
Endothelial activation or
exposure of subendothelium
Tissue Factor
VIITF/VIIa
Kallikrein
HMWK
Prekallikrein
IIaII
Ca2+
PL
Va V
Organized
Fibrin/Platelet
thrombus
Fibrinogen
Fibrin
Ca2+
PLCa2+
Cross-linked
fibrin polymer
XIIIa
Ca2+
IXa

11. The Cell-based Model of Coagulation
VIIIa
IXa
Hoffman M & Munroe DM. A cell-based model of hemostasis.
Thromb Haemost 2001; 85: 958-965
+ activates various
factors
Initiation
Amplification
Propagation

12. Coagulation Cascade:
Regulation
•Antithrombin (III)
–Regulates activity of all serine proteases
–Inhibitory activity enhanced by heparin
•Protein C and Protein S
–Regulate the activity of co-factors of coagulation
Va/VIIIa
•Fibrinolytic System

13. The Cell-based Model of Coagulation
VIIIa
IXa
+ activates various
factors
APC/PS
TFPI

Antithrombin
Plasmin

14. What is a Thrombus?
Intravascular mass of fibrin and blood cells
Arterial thrombi (White thrombi)
–High shear rates
–Primarily platelet aggregates + fibrin strands
–Thrombus associated with vascular abnormalities
(atherosclerosis) most often
Venous Thrombi (Red thrombi)
–Low shear rates
–Primarily red cells and fibrin strands (few platelets)
–Most often occurs in cases of stasis (inadequate
flow) or biochemical abnormalities

15. LDLLDL
LDLLDL
Mackness MI et al. Biochem J 1993;294:829-834.
EndotheliumEndothelium
Vessel LumenVessel Lumen
MonocyteMonocyte
Modified LDLModified LDL
MacrophageMacrophage
MCP-1MCP-1
AdhesionAdhesion
MoleculesMolecules
CytokinesCytokines
Pathophysiology of AtherosclerosisPathophysiology of Atherosclerosis
Foam Foam
CellCell
HDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux
IntimaIntima
HDL InhibitHDL Inhibit
OxidationOxidation
of LDLof LDL

17. Thromboembolism
•Arterial: often fragment of thrombus from
heart wall or heart valve, travels downstream
to smaller vessel - may lead to stroke or MI
•Venous: fragment of venous thrombus that
breaks off and travels upstream towards the
heart, may lead to pulmonary embolism

18. Virchow’s thrombosis
model
Thrombosis
Vessel wall
injury
Slow blood
flow (Stasis)
Hypercoagulability

19. Injury or Activation of
Endothelium
•Atherosclerosis
–Life style - smoking, obesity
•Immune mediated
–Heparin induced thrombocytopenia
–Antiphospholipid Antibody Syndrome (Lupus
Inhib)
•Trauma
•Artificial Surface (vascular graft)
•Inflammation/Infection

20. Abnormal Blood Flow
Decreased mobility
Vessel Obstruction
Eccomomy class syndrome
Pregnancy
Malignancy
Estrogens
Myeloproliferative disorders
Hereditary Factors

21. Hereditary Risk Factors for
Venous Thrombosis

Antithrombin Deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden (FVL)
Prothrombin G20210A
Dysfibrinogenemias (rare)
Hyperhomocysteinemia

22. Site of Thrombosis vs. Coag. Defect
Abnormality ArterialVenous
Factor V Leiden - +
Prothrombin G20210A - +
Antithrombin deficiency - +
Protein C deficiency - +
Protein S deficiency - +
Hyperhomocysteinemia + +
Antiphospholipid syndromes + +

23. Protein C System
•Protein C and Protein S are vitamin K
dependent proteins produced in liver
•Protein C is activated by thrombin/
thrombomodulin on endothelial cells
•Protein S is a co-factor
•Activated protein C + protein S destroys factor
Va and factor VIIIa - blocking coagulation

24. Anticoagulant protein C pathway
Blood Flow
Thrombomodulin
Protein C
APC
Anticoagulant effect at
the downstream damage
ThrombinThrombin
Thrombus
Thrombosis occurring
at the vascular injury

25. VIIIai
The anticoagulant effects of protein C
Blood Flow
VIIIa
Va
Thrombus
Vai
APC
APC
PS
PS
Factor V Leiden

26. Protein C System - 3 abnormalities
•Protein C deficiency
•Protein S deficiency
•Mutation of factor V cleavage site (activated
protein C resistance)

27. Hereditary Protein C deficiency
•AD
–most patients heterozygous
–rare severe homozygous - purpura fulminans
•Activity levels 50% of normal
•Increased risk of venous thrombosis

28. Acquired Protein C deficiency
Warfarin therapy
Ongoing thrombosis
Vitamin K deficiency
Liver disease
Post-operative state

29. Protein S
•Co-factor of Protein C, produced in
hepatocytes, megakarocytes and endothelium
•Vitamin K dependent - activity reduced more
than antigenic level
•60% bound to C4B-binding protein (inactive)

30. Protein S deficiency
• AD
•Acquired deficiency
–Liver disease
–Renal disease
–Women – especially those on OCPs or
pregnant
–IBD

31. Clinical Picture
Increased risk of venous thrombosis (DVT,
mesenteric venous occlusion.
First episode - 20s to 40s, associated with
pregnancy, trauma, surgery
Warfarin associated skin necrosis
–occurs 24 - 48 hrs after starting warfarin

32. APC Resistance - Mutant Factor V
(Factor V Leiden)
•Activated Protein C (APC) destroys factor
Va by cleaving it at arginine 506
•Some patients have a mutated factor V with a
glutamine at position 506, this prevents APC
from cleaving factor Va and destroying it
•Defect is termed Factor V Leiden or APC
resistance
•Increased risk of venous thrombosis

33. APCR
aPC
A G
Cleavage site 506
Va
aPC
Point mutation 506
(Factor V Leiden)

34. APC Resistance Assay
•Determine aPTT in plasma before and after
addition of Activated Protein C.
•FVL Genetic assay (PCR)

35. Antithrombin deficiency
Ⅲ
•Synthesis in liver & endothelial cells
•Activated by binding to heparin-like
molecule
•Inhibits thrombin, factor a, a, XIa,
Ⅸ Ⅹ
XIIa
•Resistant to unfractionated heparin
•Must treat with low-molecular-weight
heparin (LMWH).

36. Cause of decreased Antithrombin
•Heparin therapy
•Nephrotic syndrome
•DIC
•Hereditary deficiency (AD)
–Reduced production
–Abnormal molecule

37. Antithrombin Clinical
•Increased risk of venous thromboembolism
•First episode typically in 20s to 40s associated
with pregnancy, trauma or surgery
•Most common sites for thrombosis
–Lower extremities
–Pulmonary embolus
–Mesenteric vein thrombosis
–Superior sagittal sinus thrombosis

38. Prothrombin G20210A Mutation
A Vitamin K-dependant protein synthesized in the
liver
Due to substitution of adenine for guanine
Results in 30% higher prothrombin levels
This promotes generation of thrombin and impairs inactivation of
Factor Va by APC
Seen in 6-10% of patients presenting with first
episode of unprovoked DVT

39. Type I (non immune mediated)
The more common form,
 May occur in up to 15% of patients receiving
therapeutic doses of heparin
 Benign and self limiting side effect.
 Rarely causes severe thrombocytopenia
 Usually doesn't require heparin discontinuation.
Heparin induced
thrombocytopenia (HIT)

40. Type II (immune type of HIT)

Pathogenesis involves the formation of antibodies
(usually IgG) against the heparin-platelet factor 4
(PF 4) complex. The HIT Abs trigger procoagulant
effect serious arterial and venous
thrombosis

41. J Thromb Haem 1,1471, 2003

42. The incidence of HIT is about 3-5% in
patients exposed to UFH, the incidence is
much lower with the use of LMWH.
In patients with de novo exposure to heparin a
fall in the platelet count in those with HIT
occurs between day 5 and 14.

43. Suspicion
•Fall in platelet count by 50% following heparin
exposure
The clinical spectrum
•Isolated HIT
•HIT (T), that may be arterial (Stroke, MI, PAD)
or venous in nature.

44. Lab diagnosis
•Functional assays
---heparin induced platelet aggregation,
---serotonin release assay,
•Immunoassays
---Ab to heparin-PF 4 complexes.

45. Treatment
Stopping Heparin and
Direct thrombin inhibitors Argatorban
Platelet transfusion should be avoided
Once the platelet count is > 100.000/CC warfarin may be
started at low dose.

46. Bilateral foot ischemia secondary to HIT post open heart surgery

47. Bilateral foot ischemia secondary to HIT post open heart surgery

48. Arm ischemia secondary to HIT post open heart surgery

49. Antiphospholipid antibody
syndrome
Most common of hypercoagulable disorder
Characterized by the association of:
Thrombosis, obstetric complications and/or
thrombocytopenia AND
Antibodies against phospholipids or against proteins
bound to phospholipids.

50. Etiology of APA Syndrome
Primary: Idiopathic
Secondary: SLE
Infection
Drug reaction
Lymphoma

51. Antiphospholipid Antibodies
10% of healthy donors, 30-50% of SLE patients
Lupus Anticoagulant (LA) Antibodies
Anticardiolipin (aCL) Antibodies
Anti-Beta 2 Glycoprotein I Antibodies
(b
2GPI)

52. 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

53. 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

54. When to suspect
Hypercoagulability?
•Thrombosis < 50 years
•Family history
•Thrombosis in an unusual site (e.g. mesenteric
v. or cerebral v.)
•Idiopathic or recurrent thrombosis
•Unexplained spontaneous abortions
•Massive thrombosis

55. Stepwise Approach For
Management of Thrombophilia

56. •In fact, testing for an inherited hypercoagulable
state is costly & likely to uncover an abnormality
in more than 60% of patients presenting with
idiopathic VTEs.
•Although the remaining 40% will have
unremarkable test results, this does not imply a
true absence of a hypercoagulable state.
Diagnosis

57. •In the absence of validated guidelines,
testing for hypercoagulable states should
be performed only in selected patients,
and only if the results will significantly
affect the management.

58. Tips for Thrombophilia Testing
•Follow a stepwise strategy for thrombophilia
testing that considers:
–the clinical scenario (when to test),
–the implications of testing (why to test), and then
–the overall approach to testing (how to test).
•Use a selective strategy that focuses on the highest-
yield thrombophilia testing first.

59. •Defer testing for deficiencies of protein C, protein S,
and antithrombin because low levels do not
necessarily indicate true thrombophilia in the setting
of acute thrombosis and anticoagulation.
•Remind patients that a negative thrombophilia
evaluation does not exclude thrombophilia because
there are many hypercoagulable conditions that have
yet to be identified and for which testing does not
exist.

60. A stepwise approach to thrombophilia testing
Gregory Piazza Circulation. 2014;130:283-287
Copyright © American Heart Association, Inc. All rights reserved.

61. There are no specific therapies to reverse most
hypercoagulable states.
 Recombinant factor concentrates of
antithrombin and APC.
Gene transfer to correct a particular genetic defect.
Attempts to eliminate APA by plasmapheresis or
immunosuppressive therapy have not been very
successful.
Treatment

62. •Initiation of oral anticoagulation for
primary VTE prophylaxis in asymptomatic
carriers of any hypercoagulable state has not
been advised,

63. •However, aggressive VTE prophylaxis
should be prescribed to asymptomatic
carriers of hypercoagulable states during
high-risk situations such as major or
orthopedic surgery

64. Case 1
•Given the patient’s youth, family history of VTE, and
unprovoked event, thrombophilia testing was performed after
discharge from the hospital.

•A lupus anticoagulant was detected and subsequently
confirmed on a second test 6 weeks later.
•Because of a high risk of VTE recurrence in the setting of a
lupus anticoagulant and an unprovoked event, the patient was
maintained indefinitely on warfarin anticoagulation with
an international normalized ratio of 2 to 3.
•At the 1-year follow-up, he had recovered fully and had not
experienced another pulmonary embolism or DVT.

65. Case 2
•Given the patient’s age and the provoked
nature of her DVT, thrombophilia testing was
not performed. She was treated with 6 months
of anticoagulation with Warfarin.
•At the 1-year follow-up, she had recovered
fully and had not suffered a VTE recurrence.

66. 66
Monkez M Yousif