METHODS OF ACQUIRING KNOWLEDGE IN NURSING.pptx by navdeep kaur
Thrombophilia
1. By
DR MONKEZ M YOUSIF
Professor of Internal Medicine
Zagazig University
2015
HYPERCOAGULABLEHYPERCOAGULABLE
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.
9. The Role of Platelets in Hemostasis
Collagen Other
factorsTF
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 LumenMonocyteMonocyte
Modified LDLModified LDL
MacrophageMacrophage
MCP-1MCP-1
AdhesionAdhesion
MoleculesMolecules
CytokinesCytokines
Pathophysiology of AtherosclerosisPathophysiology of Atherosclerosis
FoamFoam
CellCell
HDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux
IntimaIntima
HDL InhibitHDL Inhibit
OxidationOxidation
of LDLof LDL
16.
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
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 Arterial Venous
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
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
34. APC Resistance Assay
• Determine aPTT in plasma before and after
addition of Activated Protein C.
• FVL Genetic assay (PCR)
35. Antithrombin deficiencyⅢ
• 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
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.
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.
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
(β2GPI)
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
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.
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.
Homeostasis:The ability or tendency of an organism or cell to maintain internal equilibrium by adjusting its physiological processes
Hemostasis = the arrest of bleeding from an injured vessel - requires the combination of VASCULAR - PLATELETS - PLASMA factors counterbalanced by regulatory mechanisms to limit the accumulation of platelets and fibrin in the area of injury
Hemostatic abnormalities can lead to - in procoagulation or/and anti-coagulation (regulatory) mechanisms can lead to a bleeding or thrombosis disorders. Hemostasis is a integral part of inflammatory response
When a vessel wall is damaged, various signaling molecules are expressed / exposed, including tissue factor and collagen
The TF leads to the production of a small local amount of thrombin, which is the initiation step of the coagulation process
The exposed signaling molecules attract circulating platelets, which attach themselves to the exposed sub-endothelial tissue (mechanism to be discussed later): this is adhesion
These platelets become activated – principally through the presence of the thrombin – and release further attractant chemicals, which attract more platelets: this is secretion
These new platelets bind to the adhered platelets (mechanism to be discussed later) and themselves become activated: this is aggregation
Through the conformational changes inherent in activation, the loose platelet plug contracts to form a dense, adherent plug: this is contraction
Together these steps comprise primary hemostasis, which may well be sufficient to achieve hemostasis if the injury is relatively minor
The activated platelets also present a substantial area of negatively-charged phospholipid membrane at the site of the injury, upon which the subsequent processes of coagulation (secondary hemostasis) can occur, if needed
Initiation of coagulation occurs when sub-endothelial tissue is exposed to the circulation at a site of injury. These tissues express tissue factor at their surface, which binds to endogenous activated FVII
This complex binds small amounts of FX and FV to the exposed endothelial surface, which produce small quantities of thrombin
The thrombin activates platelets that are attracted to the site by the process, as well as other plasma-borne clotting factors
The activated factors (among them FVIII and FIX) enable the binding of activated FX and FV to the surface of platelets whose activation has produce conformational changes in their surface membranes to expose the ‘reaction sites’ necessary for continuation of the process
This leads to the ‘thrombin burst’ that is necessary for the large-scale production of fibrin and so the development of an effective clot
These three stages are called the initiation, amplification and propagation phases of coagulation
Initiation of coagulation occurs when sub-endothelial tissue is exposed to the circulation at a site of injury. These tissues express tissue factor at their surface, which binds to endogenous activated FVII
This complex binds small amounts of FX and FV to the exposed endothelial surface, which produce small quantities of thrombin
The thrombin activates platelets that are attracted to the site by the process, as well as other plasma-borne clotting factors
The activated factors (among them FVIII and FIX) enable the binding of activated FX and FV to the surface of platelets whose activation has produce conformational changes in their surface membranes to expose the ‘reaction sites’ necessary for continuation of the process
This leads to the ‘thrombin burst’ that is necessary for the large-scale production of fibrin and so the development of an effective clot
These three stages are called the initiation, amplification and propagation phases of coagulation
Pathogenesis - Virchow postulated thathrombi are formed as a result of the one or more abnormalities in:
blood vessels
blood flow
blood coagulability
Seen in heterozygotes when giving large loading doses of warfarin and heparin not given concomitantly
Occurs within days of starting therapy and develops over fatty tissue (thigh, buttocks, breasts) or extremities
Begins as a painful erythematous lesion and leads to necrosis
Occurs because of the shorter half life of Protein C verses the other vitamin K-dependent proteins
As a result, protein C levels decrease rapidly once warfarin therapy has been initiated (reduced to 50% of normal within one day)
This effect is even more pronounce in Protein C deficiency
Protein C is lost before the anticoagulant effects of warfarin are established and thrombosis develops
Treatment: stop warfarin, give heparin, Vitamin K, protein C concentrate
Can restart warfarin once skin lesions resolve, restart in low doses and give with heparin
It is named after the city Leiden (Netherlands), where it was first identified in 1994 by Prof R. Bertina