regimen.203,204

Homocysteine elevation is treated with folate supplements. Although the association between

hyperhomocysteinemia and VTE has been established, treatment to lower homocysteine levels and the

long-term effects of such treatment on procoagulant activity have yet to be validated.185

Other Disorders Associated with Thrombosis

Defective Fibrinolysis/Dysfibrinogenemia/Lipoprotein(a). Abnormal plasminogens

(dysplasminogenemias), although rare (<1%), have been described in cases of spontaneous arterial or

VTE.205 Both type I quantitative and type II qualitative deficiency states have been described. Other

defects in fibrinolysis may affect up to 10% of the normal population.206 Abnormal fibrinogens may

account for 1% to 3% of patients with VT and those presenting with digital ischemia.207 Numerous

molecular defects have been classified. Defective thrombin binding or resistance to plasmin-mediated

breakdown has been described.208 Although not clearly documented, defects in plasminogen activators,

tPA, or uPA may incite thrombotic events.209 Moreover, elevated PAI-1 has been associated with DVT

and myocardial infarction.205 Although the relationship between VTE and abnormal fibrinolysis is

debated, it is clear that in the postoperative period there is a connection between fibrinolysis and

VTE.205,210,211 Additionally, PAI-1 is upregulated by thrombin, endotoxin, and IL-1, explaining the

elevated circulating levels of PAI-1 during infections.212

Lipoprotein(a), associated with LDL, has both atherogenic and prothrombotic properties.213–215 It

prevents plasminogen from binding to cells or fibrin and inhibits fibrinolysis.216 Elevated levels of

lipoprotein(a) have been associated with VTE in childhood; it is a weak thrombotic risk factor in

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adults.217–219 When an individual with thrombosis presents with one of the previously mentioned

abnormalities, standard anticoagulation is necessary.220,221

Abnormal Platelet Aggregation. It has been recognized for some time that there are patients who

have thrombosis and may have hyperactive/hyperresponsive platelets but this entity is poorly defined.

Diabetes mellitus, which is known to be associated with hyperactive platelets and hyperlipidemic states,

may be a contributing factor. Hyperactive platelets have been noted during graft thrombosis in

peripheral vascular reconstructions.117 Although platelet aggregation assays may be helpful in making

the diagnosis, these assays are not commonly performed or standardized and, thus, the incidence and

importance of platelets to thrombosis are not well known. Bleeding time measurements are not specific,

and not recommended for making this diagnosis. This condition has been called “sticky platelet

syndrome” and both arterial and venous events have been reported.151

Standard anticoagulant treatment is recommended for this condition. Aspirin and the thienopyridine

derivatives such as clopidogrel may be useful, but their utility is unknown.222

Elevated Procoagulant Factors: VIII, IX, and XI

Elevated prothrombotic factors have only recently been associated with primary and recurrent

VTE.152,223 A dose–response effect has been observed; and elevated factor VIII has been best

studied.223–225 Factor VIII:C above the 90th percentile is associated with a 5-fold increased risk of

VTE.225,226 Factor VIII:C elevation is also affected by blood type and race. The risk is 6.7× after

adjusting for age, sex, factor V Leiden, prothrombin G20210A, and duration of Coumadin therapy.227 In

African American women, a statistically higher level of factor VIII has been found than in the white and

Asian populations.228 Elevation of factor XI above the 90th percentile is associated with a 2-fold

increase in VTE, independent of other hypercoagulability factors.229 Similar increases in VTE risk have

been observed with elevated factor IX.230 Acquired and environmental factors precipitate VTE in

patients with elevation of these factors, as opposed to inherited deficiencies of AT, protein C, and

protein S that confer higher VTE risk.231

The diagnosis is made by the direct measurement of these factors with activity assays. However, since

the carrier protein for factor VIII is vWF which is an acute-phase reactant, measurement of factor VIII

levels should be combined with an acute-phase reactant such as CRP or ESR. If VTE occurs with one of

these factor elevated, standard anticoagulant management should be undertaken.221

Disseminated Intravascular Coagulation

DIC is a primary form of acute thrombosis. Causes of DIC include sepsis, trauma, pancreatitis, obstetric

complications such as abruptio placentae or amniotic embolism, transplant rejection, malignant tumors,

certain snake bites, hematologic malignancies, and hepatic failure. Coagulation in DIC is activated by

the release of TF into the circulation causing unregulated activation of the coagulation cascade, leading

to massive thrombin production and fibrin generation. Fibrinolysis then becomes activated as well,

leading to bleeding in the later, hemorrhagic stages of the syndrome because of the consumption of

clotting factors, depletion of fibrinogen, and unchecked plasmin activity. The diagnosis of DIC is a

clinical one, which requires consideration of the gestalt of the patient. Laboratory values in DIC reveal a

downtrend in platelet count – even within the normal range, decreased fibrinogen level, prolonged PT,

and concomitant elevation in fibrin split products and the presence of a positive D-dimer test. The

treatment of DIC requires treatment of the underlying condition. The need for platelet or plasma

transfusion is based on the presence of hemorrhage, rather than on particular laboratory values.232

BLEEDING DISORDERS

Although the surgeon deals more often with procoagulant states than bleeding disorders, it is important

to recognize these disorders when they occur.

Coagulation Factor Deficiency

Coagulation factor deficiency states are important causes of bleeding and the most common are factor

VIII and IX deficiency states, termed hemophilia A and B, and type I von Willebrand disease (vWD).

6 Hemophilia A is inherited as a sex-linked recessive deficiency of factor VIII, with fewer cases

secondary to spontaneous mutation. The incidence of this abnormality is approximately 1 in 5,000

births.233 Clinical findings range from bleeding into joints and muscles, epistaxis, hematuria, and

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bleeding after minor trauma, to prolonged postoperative bleeding, retroperitoneal bleeding, and

intramural bowel hemorrhage. Laboratory screening tests usually reveal a prolongation of the aPTT

along with decreased factor VIII levels; other test results are normal. The minimum level of factor VIII

required for hemostasis is 30%, and spontaneous bleeding is uncommon with factor VIII levels greater

than 5% to 10% of normal. Levels less than 2% constitute severe, 2% to 5% moderate, and greater than

5% mild deficiency.234 Although the half-life of factor VIII is 2.9 days in normal subjects, the half-life of

factor VIII concentrates is only 9 to 18 hours.233 Levels between 80% and 100% of normal should be

attained for surgical bleeding or life-threatening hemorrhage. Acquired deficiency has been reported to

occur with the development of antibodies to factor VIII after therapy. Inhibitor antibodies develop in

approximately 10% to 15% of patients with hemophilia A, although the incidence of antibody formation

may be much higher in previously untreated patients and in those with severe hemophilia A.

Recombinant factor VIII preparation has been developed and tested in children and infants. Despite

the development of low levels of inhibitors in 20% of children at a mean 9 days after first

administration, these inhibitors either disappeared or remained at low levels.235

Factor IX deficiency (Christmas factor), known as hemophilia B, is transmitted as an X-linked

recessive trait. It may also be acquired because of enhanced factor IX clearance in states such as the

nephrotic syndrome, abnormal protein production in vitamin-K deficiency, and acquired specific

inhibitors to factor IX in various autoimmune diseases, such as SLE. It is clinically indistinguishable

from hemophilia A, and laboratory screening tests reveal a prolonged aPTT, with other test results

normal, although a greater proportion of patients have only mild or moderate deficiency.236 Severe

deficiency (approximately 30% of cases) is defined as a level of activity less than 4% of normal,

whereas moderate deficiency is reported with activity levels between 20% and 40%.234 Treatment

consists of plasma or factor IX concentrates and vitamin-K. It has been recommended that levels greater

than 30% be achieved for hemostasis.

vWF causes platelet adhesion to collagen, initiating platelet plug formation. It also forms a complex

with factor VIII in the blood. Produced in endothelial cells and megakaryocytes (compared with the

liver for factor VIII), it has a circulating half-life of 6 to 20 hours. vWD, a deficiency of vWF, is the

most common of the inherited coagulation disorder. A number of different subtypes have been

identified for its deficiency state, and the syndrome is transmitted as both autosomal dominant

(heterozygous) and autosomal recessive (homozygous) forms. Variants include types I and III

(quantitative decreases in normal-appearing vWF) and type II (qualitative abnormalities in structure and

function of vWF).237 vWF deficiency is probably as common as hemophilia A, although the true

incidence may surpass what is generally appreciated because many mild cases probably remain

undiagnosed.

The classic syndrome is caused by a reduction of factor VIII activity (although not as great as in

hemophilia A) and vWF (vWF–factor VIII complex). Clinical manifestations include easy bruisability,

mild to moderate epistaxis, gingival bleeding, menorrhagia, rare joint or muscle bleeding, prolonged

bleeding following surgery, and subcutaneous bleeding. Spontaneous bleeding is not as common as in

hemophilia A.

Abnormal laboratory tests include a prolonged bleeding time; a decreased level of factor VIII activity;

decreased immunoreactive levels of the vWF; and abnormal platelet aggregation response to ristocetin.

The most reliable source of vWF is cryoprecipitate, although many concentrates of factor VIII have vWF

present and show promise. Desmopressin acetate (DDAVP) is available for the treatment of mild cases

of type I vWD and type 2a and 2b, serum levels of 25% to 50% are needed for hemostasis. In other type

II states and type III vWD, factor VIII concentrates are necessary. Recombinant factor VIII/vWF

concentrates that avoid the infectious risks of transfusion are available.

Rare Factor Deficiencies

Other specific factor deficiencies are much less common and receive only a brief mention here. These

include factors II, XI, V, VII, and X. These can be measured by serum assays, although this is not

routinely available in many hospitals. The treatments are primarily FFP concentrates to give back the

clotting factors.

Deficiencies of fibrinogen can also lead to bleeding disorders. This is the only factor deficiency state

in which the TCT is prolonged. It is generally believed that a fibrinogen level of 100 mg/mL should be

achieved to stop bleeding related to fibrinogen abnormalities. Fibrinogen deficiency may also occur

from consumption during DIC and from primary fibrinolytic states.

Platelet Disorders

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