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Outline of Lecture


Most common cause of death and disability in the United States

Arterial thrombosis

Myocardial infarction: 600,000 deaths per year

Stroke: 200,000 deaths per year

Venous thrombosis

Pulmonary embolism: 50,000 deaths per year


Formation of a solid mass of platelets, RBCs, WBCs and fibrin within a living blood vessel or the heart.


Thrombus: intravascular, living vessel or heart

Blood clot: extravascular, hematoma, post-mortem, in vitro

Embolus: fragment of thrombus that moves to a new site

Arterial Thrombosis

High speed blood flow

High shear and turbulence

Thrombus primarily composed of platelets with smaller amounts of fibrin and other cells

Thrombus associated with vascular abnormalities (atherosclerosis) most often

Arterial Thrombosis

Venous Thrombosis

Slow blood flow

Low shear

Thrombus primarily composed of fibrin with layers of platelets and RBCs

Most often occurs in cases of stasis (inadequate flow) or biochemical abnormalities


Venous Thrombosis


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


Pathophysiology of Thrombosis

Injury or Activation of Endothelium

Alteration in Blood Flow

Alteration in Hemostatic System

Biochemical Abnormalities


Injury or Activation of Endothelium


Life style – smoking, obesity

Immune mediated

Heparin induced thrombocytopenia

Antiphospholipid Antibody Syndrome (Lupus Inhib)


Artificial Surface (vascular graft)


Alteration in Blood Flow

Arterial Thrombosis

Turbulence, shearing forces, platelet binding

Atherosclerosis, vascular graft

Venous Thrombosis

Stasis, slow flow

bed rest, sitting for long trip

Alteration in Hemostatic System

Coagulation System

Fibrinolytic System


Vessel Wall/Endothelium


Unusual or unexplained thrombosis – spontaneous, idiopathic, essential

Young age (20s, 30s, 40s)

No risk factors

Recurrent, unusual site (arm), multiple sites, extensive

Trigger – pregnancy, trauma, surgery

Coagulation Regulation

Accelerated Coagulation due to reduced inhibition of coagulation

Accelerated Coagulation due to elevated levels of coagulation factors


Coagulation Regulation – Strong Risk Factors

Antithrombin/Heparin Complex

Antithrombin/Endothelial Complex

Antithrombin Function

Regulates coagulation by inhibiting thrombin, FIXa, FXa

Forms 1:1 complex with active site of factor

Antithrombin is consumed in the process

Complexes are cleared by the liver

Activity increased 1000 fold by heparin

Hereditary Antithrombin Deficiency

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

Cause of decreased Antithrombin

Heparin therapy

Nephrotic syndrome

Asparaginase therapy


Hereditary deficiency

Reduced production

Abnormal molecule

Heparin and Antithrombin

Antithrombin Deficiency – Case 1

19 y/o woman with worsening abdominal pain, peritonitis, hematemesis

Surgery revealed small bowel infarction due to mesenteric vein thrombosis

Past History – three episodes of deep venous thrombosis

Family History – father had recurrent DVT, died of mesenteric vein thrombosis at age 29

Antithrombin Deficiency – Case 1

Laboratory evaluation

Antithrombin activity = 48%

Antithrombin antigen = 50%

Protein C antigen = 115%

Follow up

Died of hemorrhagic cerebral infarct

Protein C is activated by
Thrombin/thrombomodulin complex

Activated Protein C inactivates FVa

Protein C System

Protein C and Protein S are vitamin K dependent proteins

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

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

Autosomal dominant inheritance with incomplete penetrance

most patients heterozygous – 1 gene abnormal

rare severe homozygous – purpura fulminans

Incidence heterozygous – 1:200

Incidence symptomatic – 1:1000

Activity levels 50% of normal

Increased risk of venous thrombosis

Causes of decreased Protein C

Warfarin therapy

Ongoing thrombosis

Vitamin K deficiency

Liver disease

Post-operative state

Hereditary deficiency

Reduced production

Abnormal molecule

Protein S

Co-factor of Protein C, produced in megakarocytes and endothelium

Vitamin K dependent – activity reduced more than antigenic level

60% bound to C4B-binding protein (inactive)

Protein S Assays

Total Protein S Antigen

Free Protein S Antigen – used at UW

Protein S Activity

Protein S deficiency

High C4B-binding protein – common

normal total, low free, low activity

Abn gene – low PS production – 1:2000

low total, low free, low activity

Abn gene – abnormal molecule – rare

normal total, ?free, low activity

Protein C/Protein S Clinical

Increased risk of venous thrombosis

First episode – 20s to 40s, associated with pregnancy, trauma, surgery

Warfarin associated skin necrosis

occurs 24 – 48 hrs after starting warfarin

Neonatal purpura fulminans

homozygous PC or PS deficiency – rare

Protein C and Protein S on Warfarin

Protein C and Protein S activity decrease along with Factors II, VII, IX and X

Protein C antigen falls to less than 50%

Protein S antigen falls to about 80%

Difficult to diagnose hereditary deficiency on warfarin

Protein C Deficiency – Case Study

APC Resistance – Mutant Factor V

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

Assay for Factor V Leiden

APC Resistance Assay

Determine aPTT in plasma before and after addition of Activated Protein C

Dilute sample in Factor V deficient plasma

Interpretation of ratio (PTTapc/PTT)

>2.1                         normal

1.5-1.8     heterozygous abn Factor V

<1.3                         homozygous abn Factor V

Probability of Factor V Abnormality

European/Hispanic Americans

3-5% of healthy subjects

20% of patients with venous thrombosis

30-50% of patients with venous thrombophilia

African Americans <1%

Asian Americans <1%

Summary of Protein C System

Protein C deficiency

decreased production

abnormal protein

Protein S deficiency

low free PS due to high C4B-binding protein

decreased production

abnormal protein

Factor V Leiden/APC Resistance


Coagulation Regulation – Mild Risk Factors

Prothrombin gene

Mutation of guanine to adenine at position 20210 in the 3’ untranslated region of prothrombin gene

Results in elevated levels of prothrombin in blood

Primarily leads to increased risk of venous thrombosis

Elevated Factor VIII

Other Coagulation Factors

Homocysteine Metabolism


Hyperhomocystinuria – homozygous CBS deficiency – severe atherosclerosis

Hyperhomocysteinemia – modest elevation of homocysteine in plasma

Endothelial injury

Increased arterial thrombosis – OR 2

Increased venous thrombosis – ?? – not recommended

Venous Thrombosis Risk Model

Venous Thrombosis Risk Model

Multiple Hit Hypothesis

Development of venous thrombosis requires multiple risk factors or a strong stimulus

Hip surgery

Antithrombin deficiency + plane ride

Prothrombin mutation + oral contraceptives

Combined Genetic Defects

Cerebral Venous Thrombosis and Oral Contraceptives

Risk of First Venous Thrombosis

Healthy subjects, no defects     0.05%/yr  age 60

Homocysteinemia                                    0.05%/yr (no change)

AT, PC, PS deficiency                             1.0%/yr    age 29

Increased FVIII, Pro, FVL                        0.2%/yr    age 40

Combined defects                                     2.5%/yr


Risk of bleeding on warfarin     2.0%/yr

Risk of Recurrent Venous Thrombosis

All patients                                              2.6%/yr

No Defects                                               1.3%/yr

Men vs women                                                         2.7x ­

Oral contraceptive use                                             2.2x ­

AT, PC, PS deficiency                                             4.0x ­

FVL, Prothrombin, FVIII                                         2.0x ­

Hyperhomocysteinemia                                           No change

Cancer, elderly                                                         ­ 


Bleeding on warfarin                                2.0%/yr

Incidence of Coagulation Abnormalities

Protein C and Thrombosis

Thrombosis in Children

On average children have fewer spontaneous thromboses than adults

Children and young adults may require 3 or 4 risk factors before thrombosis occurs:

Central Venous Catheters

Disease (cancer, heart disease, infection etc)

Hereditary deficiencies

Hereditary Risk Factors in Children

Venous Thrombosis Pediatric Risk Model

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