Gervin Allen P.

de Guia

DISORDERS LEADING TO THROMBOSIS

Sometimes called the hypercoagulable state
Patients may present with laboratory abnormalities (such as antithrombin III or protein C deficiency) or with clinical conditions (such as
the postoperative state or malignancy) that have been associated with an
increased
incidence
of
thrombosis
or
thromboembolic
complications.

Two Types:
Primary Disorders usually inherited
Secondary Disorders more common
o Usually associated with more than one hemostatic abnormality

PATHOPHYSIOLOGY
Three natural anticoagulant mechanisms that control thrombus
formation
Antithrombin-III (AT-III) - neutralizes thrombin and the other activated
serine proteases in the coagulation cascade
o Heparin accelerates the formation of antithrombin-thrombin
complexes and neutralization of thrombin activity.
Protein C pathway
o Protein C - converted by thrombin to activated protein C (pCa)
o The rate of activation is greatly increased by Thrombomodulin
Fibrinolytic system
o Activates plasmin, which lyses the fibrin clot into fibrin
degradation products (FDP)

PRIMARY DISORDERS LEADING TO THROMBOSIS

Congenital conditions usually involving a single component of the

hemostatic system, generally a protein of the coagulation or
fibrinolytic system rather than a platelet abnormality

Gervin Allen P. de Guia

Patients suffer recurrent thrombosis, often starting at an early age.

It is important to recognize risk factors such as malignancy,
postoperative state, pregnancy, and lupus anticoagulant

Primary Disorders of Thrombosis

Antithrombin Deficiency
Protein C Deficiency
Protein S Deficiency
Fibrinolytic System Disorders
Dysfibrinogenemia
Homocystinuria

1.

Antithrombin III Deficiency

Best defined and understood of the primary thrombotic disorders
Principal inhibitor of thrombin in plasma
Heparin potentiates the action of AT-III in vitro and in vivo
Recent evidence indicates that a heparin-like substance (heparan) on the
endothelial cell surface plays an important part in regulating thrombosis.
First reported in 1965 in a family with recurrent venous
thromboembolism and approximately 40% of normal plasma AT-III
levels.
More common than is generally realized, with the estimated incidence in
the general population approaching 1 in 2000
Two to three percent of patients hospitalized for deep venous
thrombosis or pulmonary embolus have AT-III deficiency
Typically, the defect is inherited as an autosomal dominant trait with
males and females being affected equally
Heterozygous persons have AT-III levels between 25% and 60% of
normal
Homozygous state has not been reported

Clinical Findings
Recurrent lower-extremity thrombophlebitis
Pulmonary embolism
Thromboembolic events may occur at other anatomic sites

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o Thrombosis may be seen from the neonatal period to late in life,

although, the majority of affected persons manifest symptoms
before the age of 35 years
At least 85% of AT-III-deficient individuals will have a thrombotic event
by the age of 60
o Most thrombotic events are initiated by factors that may also cause
thrombosis in persons not deficient in AT-III, especially surgery,
trauma, pregnancy, oral contraceptive use, and infection
Laboratory Findings
Detected by measuring antigenic and functional levels of AT-III
Functional method - used to screen for the deficiency state
Immunologic measurement - confirm a molecular defect or decreased
protein level?
Immunologic assays (e. g., radioimmunodiffusion, radioimmunoassay)
have been used to measure antigenic levels of the molecule
Functional activity is determined by measuring the ability of AT-III to
inhibit thrombin. See Chapter 53 for details of these assays.
80% to 125% Normal range for functional AT-III in plasma
60% to 80% - indicate a moderate thrombotic risk
Below 50% to 60% - indicate significant risk.
Serum rather than plasma levels - preferred indicator of thrombotic
risk,
The normal range of serum AT-III is 70% to 125%

2. Protein C Deficiency
Vitamin K-dependent glycoprotein that inactivates factors Va and VIIIa,
Discovered in 1960
Initial report of a clinical deficiency was not made until 1981
Autosomal dominant trait
Homozygous deficiencies have been reported in infants with severe
thrombosis who have almost no measurable plasma protein
Heterozygous state is associated with venous thrombotic disease and
immunologic protein C levels of 40% to 50% of normal
Two Types of Hereditary Protein C Deficiency

Gervin Allen P. de Guia

Type I - both the antigen and the activity are below the normal range
o Incidence is about 5% in patients with venous thrombosis under
40
Type II - only the activity is below normal
Clinical Findings
Recurrent superficial or deep vein thrombophlebitis
Frequent pulmonary emboli
Approximately 50% experience a thromboembolic episode before 30
years of age
Laboratory Findings
Immunologic and functional assays
70% to 125% - normal reference for both assays
Both assays should be performed to distinguish type I from type II
deficiency
Because protein C is a vitamin K-dependent protein, levels will be low in
patients receiving warfarin
Congenitally deficient individuals will have a disproportionately low level
of protein C.
Treatment
Long-term warfarin therapy
Protein C supplementation appears to be useful
Factor IX concentrates are rich in protein C and have been effective in a
number of cases

3. Protein S Deficiency
Discovered in 1980
Cofactor that enhanced the in vitro inactivation of factor Va by Protein
Ca.

Clinical Findings
Heterozygous deficient individuals - recurrent venous thrombosis
together with immunologic protein S levels of 30% to 60% of reference
levels.
Laboratory Findings

Gervin Allen P. de Guia

Similar to that of protein C; however, the functional method is not

routinely available
70% to 125% - normal range
Warfarin will lower protein S levels, because protein S is vitamin K
dependent
Protein S is found free in plasma as well as bound to C4b-binding
protein
The C4b-binding protein must be removed from the plasma before
measuring protein S, as only the free protein S serves as a cofactor for
protein C.
Treatment
Warfarin

4. Fibrinolytic System Disorders

Plasminogen circulates in the blood in close association with fibrinogen

and is trapped in the forming fibrin clot
Plasminogen is activated by tissue or plasma activators. Regulation of the
activation to form plasmin is a complex process involving tPA release
from the vessel wall, plasma plasminogen activated by factor XIIa, and
the action of activated protein C to release tPA
o Inhibitors such as a2-antiplasmin retard or halt these processes.
Congenital and acquired disorders involving the fibrinolytic system can
impair the breakdown of fibrin, resulting in the buildup of fibrin and thus
thrombosis
Deficiencies in factor XII may result in reduced activation of plasma
plasminogen activator
Circulating inhibitors of plasminogen activator may also reduce the
activation of plasminogen

Functional (qualitative) and immunologic (quantitative) assays for

plasminogen are available

Functional levels are decreased more than immunologic

indicating a qualitative defect in the plasminogen molecule

levels,

Gervin Allen P. de Guia

5. Dysfibrinogenemia
Congenital disorders with clinically significant functional abnormalities of
fibrinogen (dysfibrinogenemia) have been reported occasionally in conjunction
with increased thrombosis. The functionally abnormal fibrinogen molecule
forms a rigid fibrin gel that is resistant to the fibrinolytic enzyme system.
6. Homocystinuria
Rare autosomal recessive disorder
Associated with a high incidence of arterial and venous thrombosis early
in life, resulting in a high morbidity and mortality rate
Endothelial cell injury apparently is responsible for the abnormal
platelet-vessel wall interaction.

SECONDARY DISORDERS OF THROMBOSIS

Associated with a high degree of thromboembolic complications. The

exact

Secondary Disorders of Thrombosis

Lupus Anticoagulant
Hemostatic Protein Abnormalities
o Postoperative state
o Malignancy
o Oral contraceptives and estrogens
o Other
Nephrotic syndrome
Coronary artery disease
Platelet abnormalities
o Diabetes mellitus
o Hyperlipidemia
o Myeloproliferative disorders
o Heparin-induced thrombocytopenia
Blood vessel and flow abnormalities
o Artificial surfaces
o Damaged vessels
o Abnormal blood flow

Gervin Allen P. de Guia

1. Lupus Anticoagulant
Acquired immunoglobulin directed against phospholipids
Associated with an increased risk of thrombosis, possibly secondary to
prostacyclin inhibition
Can be present in Patients with systemic lupus erythematosus, other
autoimmune disorders, or neoplasms; during certain drug therapy
Can cause prolonged APTT and occasionally, a prolonged PT

2. Hemostatic Protein Abnormalities

There may be increases in one or more coagulation factors (I, II, V, VII,
VIII, IX, and X) or decreases in AT-III, protein C, or fibrinolytic activity.
Increased thrombin generation
Hypercoagulability attributable solely to increased levels of coagulation
factors is not a universally accepted cause of thrombosis
a. Postoperative State

The postoperative state, particularly after orthopedic procedures, is a

complex example of secondary hypercoagulability.
50% with a high incidence of pulmonary embolus - frequency of deep
venous thrombosis in patients undergoing hip surgery
o Contributing risk factors include immobilization, advanced age,
obesity, malignancy, oral contraceptive use, pregnancy, and the
increase in platelets that often follows surgical trauma.

b. Malignancy
Related to the release of coagulation activating factors by the neoplastic
cells
Trousseaus report more than a century ago
5% to 15% generally and as high as 50% in certain malignancies
incidence of thrombosis in cancer patients
Patients with adenocarcinomas seem to be especially susceptible to
thrombosis
Typically, hemostatic abnormalities are corrected by elimination of the
malignancy
c. Pregnancy

Gervin Allen P. de Guia

Placenta - rich in tissue thromboplastin

Other potential etiologies
o Decreased blood flow (stasis)
o Increased levels of coagulation proteins (especially factors VII, VIII,
and fibrinogen)
o Decreased levels of AT-III
There is a definite increase in the incidence of thromboembolic
complications during the antepartum period.
During the first month after delivery, a 20to 50-fold increase exists in
the risk of phlebitis and thromboembolism

d. Oral Contraceptive or Estrogen Use

Increases the risk of cardiovascular, cerebrovascular, and venous
thromboembolic
o Other complications
Renal artery thrombosis, peripheral artery occlusion,
mesenteric vascular insufficiency, aorto-iliac arterial
thrombosis, and Budd-Chiari syndrome.

Estrogen - used to treat prostate cancer or arterial disease and to prevent

lactation has likewise been associated with an increase in
thromboembolic disease
o Alters the rate of blood flow and blood viscosity

e.

Other Causes
Nephrotic syndrome
Coronary artery disease
Stroke
In addition to plasma protein abnormalities, these patients frequently
exhibit hyperactive platelet function and elevated levels of von
Willebrand factor
Decreased levels of AT-III in morbidly obese or severely burned

3.

Platelet Abnormalities
Elevated numbers
Increased aggregation response to ADP, collagen, and epinephrine
Increased levels of beta-thromboglobulin and platelet factor

Gervin Allen P. de Guia

o Clinical conditions in which these abnormalities are frequently
observed include:
Diabetes mellitus
Hyperlipidemia
Myeloproliferative disorders
Heparin-induced
platelet
agglutination
and
thrombocytopenia
4. Blood Vessel and Flow Abnormalities
a. Artificial Surfaces
Situations in which circulating blood is exposed to artificial surfaces
create a substantial risk of thrombosis
o Vascular graft
o Prosthetic heart valves
o Hemodialysis or hemoperfusion procedures
The foreign surface activates platelets, causing increased adhesion and
aggregation with activation of the coagulation system
b. Abnormal Vascular Surfaces
Disrupting the normal antithrombotic function of endothelium
o Vasculitis
o Scleroderma
o Systemic lupus erythematosus
o Kawasaki disease
o Chronic occlusive arterial disease
o Behcets disease
Increased levels of von Willebrand factor
Decreased fibrinolytic activity
c. Abnormal Blood Flow
Venous stasis - probably causes vascular endothelial damage through
local hypoxia and slow removal of activated clotting factors from a site of
vascular injury
Immobilization is an important contributor to venous stasis, as is hyper
viscosity, because of the elevated numbers of cells, increased cell rigidity,
or elevated plasma protein concentrations.