ByDR MONKEZ M YOUSIF

Professor of Internal MedicineZagazig University

2015

HYPERCOAGULABLE HYPERCOAGULABLE STATES (THROMBOPHILIA)STATES (THROMBOPHILIA)

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

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.

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.

Definition of thrombophilia

A disorder associated with an increased tendency to thrombosis.

VESSEL WALL

ENDOTHEL

PLATELETSPLASMA

FACTORS (procoagulation,

anti-coagulation)

HEMOSTASIS = the arrest of bleeding from an injured vessel

Hemostatic abnormalities can result in procoagulation or/and anti-coagulation conditions

HemostasisHemostasis

BV Injury

PlateletPlateletAggregation

PlateletActivation

Blood VesselBlood Vessel Constriction

CoagulationCoagulation Cascade

Stable Hemostatic Plug

Fibrin formation

Reduced

Blood flow

Damage/contact.

Primary hemostatic plug

NeuralContact

The Role of Platelets in Hemostasis

Collagen OtherfactorsTF

ThrombinActivatedplatelet

Activatedplatelet

Activatedplatelet

Adhesion

Aggregation

Contraction

Secretion

Primary Hemostasis

=

Activatedplatelet

Activatedplatelet

Activatedplatelet

Activatedplatelet

This plug of activated platelets, localised to the site of injury, provides the phospholipid surface upon which Secondary Hemostasis takes place

Coagulation Cascade

XII XIIa

XI XIa

IX

VIII VIIIa

X

Xa

Intrinsic Pathway Extrinsic Pathway

Endothelial activation or exposure of subendothelium

Tissue FactorVIITF/VIIa

KallikreinHMWK

Prekallikrein

IIaIICa2+

PL

Va V

Organized Fibrin/Platelet thrombus

Fibrinogen

Fibrin

Ca2+PLCa2+

Cross-linked fibrin polymer

XIIIa

Ca2+

IXa

The Cell-based Model of Coagulation

VIIIaIXa

Hoffman M & Munroe DM. A cell-based model of hemostasis.Thromb Haemost 2001; 85: 958-965

+ activates various factors

Initiation

Amplification

Propagation

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

The Cell-based Model of Coagulation

VIIIaIXa

+ activates various factors

APC/PS

TFPI

Antithrombin

Plasmin

What is a Thrombus? Intravascular mass of fibrin and blood cellsArterial thrombi (White thrombi)

– High shear rates– Primarily platelet aggregates + fibrin strands– Thrombus associated with vascular abnormalities (atherosclerosis)

most oftenVenous 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

LDLLDL

LDLLDL

Mackness MI et al. Biochem J 1993;294:829-834.

EndotheliumEndothelium

Vessel LumenVessel LumenMonocyteMonocyte

Modified LDLModified LDL

MacrophageMacrophage

MCP-1MCP-1AdhesionAdhesionMoleculesMolecules

CytokinesCytokines

Pathophysiology of AtherosclerosisPathophysiology of Atherosclerosis

Foam Foam CellCell

HDL Promote Cholesterol EffluxHDL Promote Cholesterol EffluxIntimaIntima

HDL InhibitHDL InhibitOxidationOxidation

of LDLof LDL

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

Virchow’s thrombosis model

Thrombosis

Vessel wall injury

Slow blood flow (Stasis)

Hypercoagulability

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

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

Hereditary Risk Factors for Venous Thrombosis

Antithrombin Deficiency

Protein C deficiency

Protein S deficiency

Factor V Leiden (FVL)

Prothrombin G20210A

Dysfibrinogenemias (rare)

Hyperhomocysteinemia

Site of Thrombosis vs. Coag. Defect

Abnormality Arterial VenousFactor V Leiden - +Prothrombin G20210A - +Antithrombin deficiency - +Protein C deficiency - +Protein S deficiency - +Hyperhomocysteinemia + +Antiphospholipid syndromes + +

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

Anticoagulant protein C pathway

Blood Flow

Thrombomodulin

Protein C

APC

Anticoagulant effect at the downstream damage

ThrombinThrombin

Thrombus

Thrombosis occurring at the vascular injury

VIIIai

The anticoagulant effects of protein C

Blood Flow

VIIIaVa

Thrombus

Vai

APC APC

PSPS

Factor V Leiden

Protein C System - 3 abnormalities

• Protein C deficiency• Protein S deficiency• Mutation of factor V cleavage site (activated

protein C resistance)

Hereditary Protein C deficiency

• AD– most patients heterozygous– rare severe homozygous - purpura fulminans

• Activity levels 50% of normal• Increased risk of venous thrombosis

Acquired Protein C deficiencyWarfarin therapyOngoing thrombosisVitamin K deficiencyLiver diseasePost-operative state

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)

Protein S deficiency

• AD• Acquired deficiency

– Liver disease– Renal disease– Women – especially those on OCPs or

pregnant– IBD

Clinical PictureIncreased risk of venous thrombosis (DVT,

mesenteric venous occlusion.First episode - 20s to 40s, associated with

pregnancy, trauma, surgeryWarfarin associated skin necrosis

– occurs 24 - 48 hrs after starting warfarin

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

APCR

aPC

A G

Cleavage site 506

Va

aPC

Point mutation 506

(Factor V Leiden)

APC Resistance Assay• Determine aPTT in plasma before and after

addition of Activated Protein C.

• FVL Genetic assay (PCR)

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).

Cause of decreased Antithrombin

• Heparin therapy• Nephrotic syndrome• DIC• Hereditary deficiency (AD)

– Reduced production– Abnormal molecule

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

Prothrombin G20210A MutationA Vitamin K-dependant protein synthesized in the

liverDue to substitution of adenine for guanineResults 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

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)

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

J Thromb Haem 1,1471, 2003

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.

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.

Lab diagnosis

• Functional assays ---heparin induced platelet aggregation, ---serotonin release assay,

• Immunoassays ---Ab to heparin-PF 4 complexes.

TreatmentStopping Heparin and Direct thrombin inhibitors ArgatorbanPlatelet transfusion should be avoidedOnce the platelet count is > 100.000/CC warfarin may be

started at low dose.

Bilateral foot ischemia secondary to HIT post open heart surgery

Bilateral foot ischemia secondary to HIT post open heart surgery

Arm ischemia secondary to HIT post open heart surgery

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.

Etiology of APA SyndromePrimary: Idiopathic

Secondary: SLE Infection Drug reaction Lymphoma

Antiphospholipid Antibodies

10% of healthy donors, 30-50% of SLE patients

Lupus Anticoagulant (LA) Antibodies

Anticardiolipin (aCL) Antibodies

Anti-Beta 2 Glycoprotein I Antibodies (2GPI)

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

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

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

Stepwise Approach For Management of Thrombophilia

• 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

• 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.

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.

• 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.

A stepwise approach to thrombophilia testing

Gregory Piazza Circulation. 2014;130:283-287

Copyright © American Heart Association, Inc. All rights reserved.

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

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

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

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.

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.

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Monkez M Yousif