The following is a list of the disorders that cause hypercoagulability
and their approximate incidences. Since these were derived from different
studies, percentages cannot be exact. Also, incidences may vary, depending
on the ethnic backgrounds of persons in a particular geographic area.
Antiphospholipid Antibody Syndrome
The antiphospholipid antibody syndrome is probably the most common of
the hypercoagulable disorders. It is caused by a heterogeneous family of immunoglobulins
that bind to plasma proteins that have an affinity for phospholipid surfaces.
These antigens include B2 glycoprotein I, prothrombin, high- and
low-molecular-weight kininogens, annexin V, activated protein C, and activated
protein S. It is usually acquired and can be divided into the lupus anticoagulant
syndrome and the anticardiolipin antibody syndrome. Both of these syndromes
may be associated with other disorders, such as collagen vascular diseases
or infections, but are more often primary. Antiphospholipid antibody syndrome
can also be associated with use of the following medications: phenytoin, quinidine,
hydralazine, procainamide hydrochloride, phenothiazines, interferon, cocaine,
quinine, and the combination product of pyrimethamine and sulfadoxine. Usually,
a patient will have one syndrome or the other but not both. Multiple mechanisms
as to the reason for hypercoagulability have been postulated, but the exact
cause is unknown at this time. The risk of thrombosis is 5.5% per year for
symptomatic patients.3
The lupus anticoagulant is directed against phospholipids, which then
causes an in vivo prolongation in the prothrombin time (PT), partial thromboplastin
time (PTT), or the Russell viper venom time. These values do not correct with
normal plasma. However, the addition of phospholipids will correct the abnormality.
Despite the prolonged coagulation times, thrombosis is the predominant feature
of this syndrome. The PT and PTT are not sensitive enough to be used as a
screening tool for the lupus anticoagulant. Instead, the Russell viper venom
time must be used. Venous thrombosis is much more common than arterial thrombosis
in these patients.4
The anticardiolipin antibody syndrome is 5 times more common than the
lupus anticoagulant syndrome.5 Antibodies can
be detected by enzyme-linked immunosorbent assay. Both IgG and IgM are associated
with thrombosis.4-5 A total of
1% to 7% of asymptomatic individuals have low titers of these antibodies.6 Even asymptomatic persons have a 1% risk per year
of thrombosis. This increases to 6% in those with high titers.7
This contrasts with a 0.1% risk per year in the general population. Venous
and arterial thrombi are equally common.4 Other
manifestations include valvular abnormalities, livedo reticularis, superficial
thrombophlebitis, ulcers, adrenal hemorrhage, fetal wastage, chorea, transverse
myelopathy, and thrombocytopenia.
The treatment of patients with antiphospholipid antibody syndrome who
have had thrombosis is long-term anticoagulation until the antibody has been
absent for at least 6 months.8 The drug of
choice is low-molecular-weight heparin sodium since in 65% of patients warfarin
sodium therapy fails8 and the international
normalized ratio is unreliable in monitoring the intensity of therapy. If
warfarin must be used, an international normalized ratio target range of 3
to 4 should be sought.9 The treatment of fetal
wastage syndrome is beyond the scope of this review. There is no clear indication
for therapy in asymptomatic persons; however, aspirin therapy would be reasonable
in this population because the risk of thrombosis is higher than normal. Other
treatments, such as corticosteroids, cyclophosphamide, and plasma exchange,
have been used for severely symptomatic disease, but their roles in routine
management are not well established.
Activated Protein C Resistance
Activated protein C resistance (eg, factor V Leiden) is the most common
inherited disorder that causes hypercoagulability. Factor V Leiden is present
in 5% of whites but virtually absent in Africans and Asians. However, 1% of
African Americans have the mutation, reflecting racial mixing.10
It results from a point mutation in the factor V gene, which causes the substitution
of glutamine for arginine at position 506.11
(Several other rare factor V gene mutations that can lead to activated protein
C resistance have also been described.12-14)
Consequently, 1 of 3 activated protein C cleavage sites is lost. The result
is an impaired inactivation of factor V by activated protein C. Venous thromboses
and fetal wastage may occur. It is not an important risk factor for arterial
disease except in the presence of smoking or other known risk factors.15-16 Those with factor V Leiden have a
2- to 3-fold risk for venous thrombosis compared with healthy subjects. The
risk in homozygotes is 80-fold.17 Heterozygous
factor V Leiden is, therefore, a relatively mild risk factor for thrombosis.15, 18 The annual rate of thrombosis is
0.28%.19 Six percent of patients will have
a thrombosis by the age of 65 years.20 Sixty
percent of patients who experience thrombosis have a predisposing event, such
as oral contraceptive use or pregnancy.21 The
presence of this mutation does not appear to affect life expectancy, and many
patients will remain asymptomatic. Therefore, patients with no history of
thrombosis should not be treated prophylactically with long-term anticoagulation.22 Functional tests for activated protein C resistance
should be used to screen for the disorder, and positive results should be
confirmed with polymerase chain reaction for the genetic mutation. However,
patients with phenotypic resistance to activated protein C have an increased
risk of thrombosis even if it is not due to factor V Leiden.20
Functional tests may still be performed while patients undergo anticoagulation.
Elevated Coagulation Factor VIII Levels
Elevated coagulation factor VIII levels appear to be nearly as common
a risk factor for thrombosis as factor V Leiden. The Leiden Thrombophilia
Study found an 11% incidence in healthy controls and a 25% incidence in patients
with venous thrombosis. The odds ratio for thrombosis was 4.8 for subjects
with levels greater than 150 IU/dL vs those with levels less than 100 IU/dL.23-24 For every 10-IU/dL rise in levels,
the risk for a single episode of deep venous thrombosis (DVT) increases 10%
and the risk for recurrent DVT increases 24%.25
Levels of coagulation factor VIII are not elevated because of the acute-phase
reaction but appear to be constitutively increased in most patients with thrombosis,
since coagulation factor VIII levels are elevated independently of C-reactive
protein and fibrinogen, and 94% of patients continue to have high levels throughout
long-term follow-up.26-27 Pregnancy
and oral contraceptive use may also raise levels. The use of oral contraceptives
in patients with increased coagulation factor VIII levels raises the risk
of thrombosis 10-fold over patients with neither risk factor.28
The genetic basis for increased coagulation factor VIII levels is not well
understood at this time; however, one small study25
showed high concordance rates for first-degree adult family members.
Malignancy
Cancer is the second most common acquired cause of hypercoagulability,
accounting for 10% to 20% of spontaneous DVTs. Indeed, 15% of patients with
cancer have clinical thromboses and about 50% have thromboses on autopsy.29 Cancer not only causes hypercoagulability but may
also produce endothelial injury and venous stasis. Hypercoagulability is especially
frequent in mucin-secreting adenocarcinomas, brain tumors, acute promyelocytic
leukemia, and myeloproliferative disorders.
Arterial thrombosis is much less common than venous thrombosis and is
most often the result of nonbacterial thrombotic endocarditis or disseminated
intravascular coagulation. Ninety percent of patients with cancer have clotting
abnormalities, such as increased fibrinogen, clotting factors, fibrin degradation
products, and platelets.30-31
Overt disseminated intravascular coagulation is rare. There is no consensus
as to the value of measuring coagulation markers in predicting thrombosis
in individual patients with cancer.
Some cancers underlying spontaneous DVT are occult, early stage, and
curable. However, there is no proof that aggressive diagnostic testing leads
to improvement in survival. Most experts recommend a thorough history and
physical examination, routine blood tests, chest x-ray examination, urinalysis,
and age- and sex-specific screening, such as prostate-specific antigen, Papanicolaou
smear, lower endoscopy, mammography, and fecal occult blood testing. Suspicious
findings should be aggressively evaluated. In addition, patients without evidence
of cancer should be followed up closely for the ensuing 2 years, during which
time virtually all occult cancers will become clinically apparent.
The initial treatment of thromboses is the same as in patients without
cancer. However, treatment should be continued indefinitely until the patient
is cured of the malignancy and is no longer receiving chemotherapy. If anticoagulation
is contraindicated as with cerebral or pericardial metastases, primary brain
tumors, or severe thrombocytopenia, an inferior vena cava filter may be placed.
Long-term treatment may be with low-molecular-weight heparin or warfarin,
although anecdotal evidence suggests that heparin may lead to fewer thrombotic
recurrences than warfarin.32 Certainly, warfarin
failure should lead to a switch to heparin. If heparin fails, an inferior
vena cava filter should then be placed. Thrombolytic agents should only be
used in patients with cancer who have a good prognosis and either pulmonary
embolism with hemodynamic compromise or severe iliofemoral thrombosis of less
than 4 days' duration. Of course, aggressive DVT prophylaxis with low-dose
subcutaneous heparin or low-molecular-weight heparin (depending on severity
and number of risk factors) should be carried out in patients with cancer
who are hospitalized, immobilized, or undergoing surgery.
Sticky Platelet Syndrome
The sticky platelet syndrome is an autosomal dominant disorder that
results in platelets that are hyperaggregable to epinephrine and/or adenosine
diphosphate. Venous or arterial thrombosis may occur.33
Episodes are more common during emotional stress. Retinal vascular thrombosis
appears to be associated with this entity. Fetal wastage may also occur. It
is diagnosed with platelet aggregation studies. Treatment is with low-dose
aspirin (81 mg). If platelet aggregability does not normalize, aspirin, 325
mg, may be tried.34 If there is still no response,
then clopidogrel (an adenosine diphosphate receptor antagonist similar to
but better tolerated than ticlopidine hydrochloride) may be used.
Protein C Deficiency
Protein C deficiency is an autosomal dominant trait that may be caused
by a decrease in absolute levels of protein C or a decrease in its function.
Deficiency of protein C occurs in 1 of 250 controls.35
Protein C is made in the liver and is vitamin K dependent. It acts to inactivate
factor V and factor VIII:C. It requires factor S as a cofactor and is activated
by thrombin, when thrombin is bound to thrombomodulin.
In families with thromboses and protein C deficiency, thromboses begin
in the late teens.36 Seventy-five percent of
affected individuals will have 1 or more events.38
The relative risk is 7.3.18 The annual incidence
is 1%.19 Seventy percent of episodes are spontaneous.37 Both DVT and pulmonary embolism are the most common
manifestations. Superficial thrombophlebitis is also common.38
Arterial events are rare.
The optimal time to investigate is at least 10 days after warfarin therapy
is stopped, since both warfarin and acute thrombosis decrease protein C levels.
Levels below 55% of normal are likely to be genetically deficient; 55% to
65% is borderline. Abnormal results should always be repeated for confirmation
and family studies performed.39
The short-term management of thrombosis is with heparin or low-molecular-weight
heparin. Warfarin may be used for long-term treatment; however, doses should
be started low and titrated upward slowly only after heparin is therapeutic
because of the risk of warfarin necrosis.40
In fact, one third of patients with warfarin necrosis have an underlying protein
C deficiency.
Protein S Deficiency
Protein S is vitamin K dependent and is synthesized by hepatocytes and
megakaryocytes. It acts as a cofactor for protein C. Fifty percent circulates
free and 50% circulates bound to C4b binding protein. Deficiency is transmitted
autosomally dominant and can be quantitative or qualitative.
Seventy-four percent of patients develop DVT; 72% develop superficial
thrombophlebitis.41 The relative risk of thrombosis
is 8.5.18 The annual incidence is 1%19; 56% of episodes are spontaneous. Arterial events
are uncommon. One half of patients who develop thromboses do so by the age
of 25 years.41
Short-term therapy is standard. Long-term therapy is with warfarin or
low-molecular-weight heparin. Since warfarin necrosis may occur, therapy should
be started with warfarin at low doses and increased slowly after heparin has
been administered. While the patient is undergoing warfarin therapy, protein
C and S levels decrease by 50% within 48 hours and then increase to 70% of
usual levels after 2 weeks. Therefore, levels below 60% of normal while taking
warfarin in the long term are suspicious for deficiency.8
Homocystinemia
Elevated levels of homocysteine are known to be a risk factor for arterial
and venous thrombosis and fetal wastage. Homocysteine is an intermediate of
methionine metabolism and, therefore, elevated levels may result from cystathionine 
-synthase
deficiency, homozygous expression of the thermolabile form of methylenetetrahydrofolate
reductase, or from B12 or folic acid deficiency. Mild-to-moderate
increases in homocysteine occur in 5% to 10% of the population.42
The relative risk of thrombosis is 2.6.43
Elevated homocysteine levels are thought to cause thromboses via several
mechanisms, including (1) decreased protein C activation, (2) increased factor
V activity, (3) induction of endothelial cell tissue factor activity, (4)
inhibition of thrombomodulin expression and activation, (5) decreased antithrombin
activity, and (6) enhanced affinity of lipoprotein(a) and fibrin.44-46
Measurement of homocysteine levels is not well standardized, and acute
thrombosis may raise homocysteine levels. Dietary supplementation with vitamin
B6, B12, and folic acid can lower homocysteine levels.47 However, reduction of homocysteine levels has not
been shown to reduce thrombotic complications. Folate supplementation (400
µg/d) may decrease levels by 30% to 42%. B12 supplementation
(100 µg/d) may decrease levels by 15%. B6 supplementation
(3 µg/d) only reduces levels if there is a preexisting deficiency. Thrombosis
is treated in standard fashion in addition to vitamin supplementation.
Antithrombin Deficiency
Antithrombin is made in the liver and endothelial cells. It inactivates
thrombin and other serine proteases. Deficiency is an autosomal dominant disorder
and occurs in 1 of 5000 healthy blood donors.48
The protein may be absent or dysfunctional. The normal concentration is 150
µg/mL. Thrombosis may occur at less than 75% of this amount. Patients
may present with DVT or pulmonary embolism. Mesenteric vessels appear to be
particularly susceptible. Arterial events are rare. Fifty percent of patients
are asymptomatic. Thromboses occur early in life, with two thirds of patients
presenting by the age of 35 years. Forty percent of thromboses are spontaneous.49 The relative risk of thrombosis is 8.1,18
and the annual incidence of thrombosis is 1%.19
Acute thrombosis, heparin, and other systemic diseases may decrease
antithrombin levels.8 Warfarin may raise deficient
levels into the normal range.50 Therefore,
low levels in a patient during acute thrombosis or while taking heparin should
be confirmed when the patient is not undergoing therapy. Likewise, normal
levels while the patient is taking warfarin should be confirmed when the patient
is not undergoing therapy.
Treatment of acute thrombosis is with low-molecular-weight heparin because
deficiency may cause resistance to unfractionated heparin.51
In fact, heparin resistance may be a clue to the presence of this deficiency.
Lifelong therapy should be considered for spontaneous or recurrent thromboses.
Prophylactic treatment of asymptomatic individuals is controversial but usually
is limited to high-risk situations, such as pregnancy or surgery. Antithrombin
concentrate may be considered for situations in which both thrombosis and
bleeding may occur, such as labor and delivery, where anticoagulation might
be contraindicated.52
Dysfibrinolysis
There are 5 major forms of dysfibrinolysis: (1) congenital plasminogen
deficiency, (2) tissue plasminogen activator deficiency, (3) increased plasminogen
activator inhibitor, (4) congenital dysfibrinogenemia, and (5) factor XII
deficiency. Long-term treatment may be with warfarin or low-molecular-weight
heparin for all patients.
Congenital plasminogen deficiency is a rare autosomal dominant disorder
caused by either absent or dysfunctional plasminogen. Clinically, it mimics
protein C and S deficiencies. Symptoms usually begin in the late teens. Most
commonly, it presents with DVT or pulmonary embolism. Arterial events are
uncommon. Events usually occur when plasminogen levels are less than 40% of
the normal values. The results of routine coagulation studies are normal.53 Treatment is standard.
Congenital deficiency of tissue plasminogen activator and congenital
increases of plasminogen activator inhibitor are exceedingly rare. Acquired
abnormalities are more common. They may occur with diabetes mellitus, inflammatory
bowel disease, and coronary atherosclerosis.54-56
Most congenital dysfibrinogenemias occur in asymptomatic individuals
(55% of patients) or cause mild hemorrhagic disorders (20%). Only 20% are
associated with thrombosis.57 Venous thrombosis
is most common but arterial events may occur. They are usually autosomal dominant.
They may be detected with abnormal thrombin times or reptilase clotting times.
Treatment of thrombosis consists of heparin or low-molecular-weight heparin
followed by warfarin.
Factor XII deficiency is inherited in autosomal dominant fashion. It
is involved in plasmin generation. Thus, patients will have a prolonged PTT,
yet have a thrombotic diathesis. Arterial and venous thromboses and fetal
wastage are common. Approximately 8% of deficient subjects develop thromboses.58 Factor XII deficiency should be suspected when a
patient with thrombosis has a prolonged PTT that corrects with the addition
of normal plasma. A factor XII assay should then be performed. Treatment is
with low-molecular-weight heparin followed by warfarin or continuation of
low-molecular-weight heparin. Standard unfractionated heparin should not be
used because of difficulties in monitoring the PTT.
Prothrombin G20210A
Prothrombin G20210A mutation is a relatively recently discovered defect
in which there is a G to A transition at nucleotide position 20210. This mutation
increases prothrombin activity and levels.59
It is found in 2.3% of healthy controls. The incidence is twice as high in
people from southern Europe than from northern Europe, and it is rare in Africans
and Asians.60 It may be detected through DNA
analysis. At this time, it must be considered a very mild risk factor for
venous and arterial thrombosis. The relative risk is approximately 2 to 3
times that of individuals without the mutation.61-63
Other Hypercoagulable Syndromes
Heparin cofactor II inhibits thrombin by mimicking the cleavage sites
of thrombin and forming a stable complex with it, thus acting as a "suicide"
substrate. Deficiency is rare and could theoretically cause thrombotic potential,
but its exact role is controversial. Heparin is effective in the presence
of heparin cofactor II deficiency.
Tissue factor pathway inhibitor is a plasma component that binds and
inhibits factor Xa directly. This complex then binds to the tissue factor–factor
VIIa complex, blocking its activity as well. Unstimulated plasma levels do
not appear to be related to thrombosis. However, plasma levels measured 10
minutes after intravenous heparin, 7500 U, is administered correlate with
venous thrombosis.64 The role of tissue factor
pathway inhibitor and its incidence in thrombophilia are currently unknown.
Thrombomodulin mutations have also been implicated in thrombophilia
but prevalence and degree of risk are unknown.65
The Wein-Penzing defect is an extremely rare deficiency of the lipoxygenase
metabolic pathway that results in the compensatory increase of the cyclooxygenase
pathway and, therefore, elevated thromboxane levels. Thus, platelets are in
a state of increased activation.
INVESTIGATION OF HYPERCOAGULABILITY
2 spontaneous episodes, 1 spontaneous life-threatening thrombosis,
1 thrombosis at an unusual site, or 1 thrombosis in the presence of >1 defect)
and moderate risk (asymptomatic individuals or 1 thrombosis in response to
a prothrombotic stimulus). In the high-risk group, he recommends indefinite
anticoagulation. In the moderate-risk group, he recommends vigorous prophylaxis
only for high-risk situations. Since no long-term studies have been performed
comparing lifetime anticoagulation treatment with short-term anticoagulation
therapy, definitive recommendations cannot be made at this time. Until these
studies are performed, 