Hereditary Thrombotic Disorders

Inherited thrombophilia* should be suspected when:

• Patient has recurrent or life-threatening venous thromboembolism

• Family history of venous thrombosis

• Is younger than 45 years of age

• No apparent risk factors for thrombosis

• History of multiple abortions, stillbirths, or both.

Factor V Leiden

In Caucasians, factor V Leiden (activated protein C [APC] resistance) is the single most common inherited disorder predisposing to thrombosis. It results from a single G-to-A point mutation at nucleotide 1691 within the factor V gene; arginine is replaced by glutamine at position (R506Q), rendering activated factor V relatively resistant to inactivation by protein C. Approximately 95% of patients with activated protein C resistance test positively for factor V Leiden mutation. The remaining 5%

*In thrombophilia multiple gene defects often coexist with the clinical penetrance of the syndrome being the end result of the number of gene defects present in an individual. This has been shown for patients with inherited deficiencies of antithrombin, protein C, or protein S whose risk of developing thrombotic manifestations is enhanced when there is coexistence of factor V Leiden.

Table 11-32. Recommended Antithrombotic Regimens for Syndromes of Thrombosis Associated with Antiphospholipid Antibodies

Type I syndrome

Acute treatment with heparin/LMWH followed by long-terma administration of LMWH

Type II syndrome

Acute treatment with heparin/LMWH followed by long-term administration of LMWH

Type III syndrome


Long-term administration of subcutaneous LMWH Retinal

Long-terma self-administration of subcutaneous porcine heparin/LMWH

Type IV syndrome

Therapy depends on types and sites of thrombosis

Type V (fetal wastage) syndrome

Low-dose aspirin before conception and add fixed, low-dose LMWH every 12 hours immediately after conceptionb

Type VI syndrome

No indications for antithrombotic therapy

See Table 11-31 for a description of the various syndromes. Abbreviation: LMWH, low-molecular-weight heparin.

■•Antithrombotic therapy should not be stopped unless the ACLA has been absent for 4-6 months. bIn women with prior thromboembolism, higher doses of heparin are recommended for full anticoagulation. Modified from Bick RL. Antiphospholipid thrombosis syndromes. Hematol Oncol Clin North Am 2003;17:115-7, with permission.

of cases are attributable to oral contraceptive usage, presence of a lupus anticoagulant, or other rare mutations in the factor V gene.

The HR2 haplotype of the factor V gene causes resistance to APC and increases the risk of venous thrombosis when co-inherited with factor V Leiden. There is also a rare mutation in the second of the three sites in factor Va that activated protein C cleaves (Arg306Thr). Additional causes of resistance to APC, probably genetic but as yet unidentified, also increase the risk of venous thrombosis.

Three to 8% of Caucasians carry the factor V Leiden mutation and approximately 0.1% are homozygotes. In contrast this mutation is relatively uncommon in African and Asian populations with a prevalence of <1.0% (heterozygotes). Children with homozygous and heterozygous factor V Leiden usually have their first thrombotic event following puberty with an estimated annual incidence of 0.28%. Heterozygous factor V Leiden increases the risk of thrombosis 5- to 10-fold, whereas homozygous individuals have an 80-fold increased risk. APC resistance even in heterozygotes is a significant risk factor for thrombosis because >20% of patients presenting with a thrombotic event exhibit APC resistance. Forty-two percent of patients who sustain a first venous thrombotic event before 25 years of age and 21% of those between 54 and 70 years of age have APC resistance.

Both heterozygous and homozygous cases of factor V Leiden mutation have increased risk for either venous or arterial thrombosis throughout life but usually are asymptomatic in youth unless associated with other acquired or genetic pro-thrombotic conditions, including central venous catheters, trauma, surgery, cancer, pregnancy, oral contraceptives, deficient protein C, deficient protein S, or homocys-teinemia.

Factor V Leiden mutation has been associated with cerebral infarction and with venous thrombosis in children.

APTT-based assay (a screening test) can be used to obtain a diagnosis of APC resistance. Patients positive for APC resistance in the clotting assay should undergo genetic testing for factor V Leiden mutation by analyzing genomic DNA in peripheral blood mononuclear cells. This can be readily accomplished by amplifying a DNA fragment containing the factor V mutation site by polymerase chain reaction (PCR).

Prothrombin G20210A Mutation (FII G 20210 A)

The genetic defect is at nucleotide position 20210 in the prothrombin gene. The mutation results in abnormally high prothrombin levels and contributes to thrombotic risk by promoting increased thrombin generation. Prothrombin gene mutation is the second most common inherited thrombotic defect. The frequency of this mutation is about 2-3% in the Caucasian population and 4-5% in Mediterranean populations. The homozygous state is extremely rare. Homozygotes for the prothrombin G200210A mutation have less severe clinical presentations than homozygotes for antithrombin, protein C, and protein S deficiencies. The individual with this genetic defect usually presents with thrombotic episodes in adulthood. The diagnosis of this defect can be made by PCR testing.

Antithrombin (AT) Deficiency

AT functions by forming a complex with the activated clotting factors thrombin, Xa, IXa, and XIa. The relatively slow formation of this complex is greatly accelerated in the presence of heparin or cell-surface heparin sulfate. The incidence of AT deficiency is about 0.2-0.5%. Congenital AT deficiency is a heterozygous disorder; homozygous deficiency, probably incompatible with life, has not been reported.

Two major types of AT deficiency have been described. Type I AT deficiency (low activity and low antigen level) is a quantitative defect caused by a mutation resulting in both decreased synthesis and functional activity of AT, whereas type II AT deficiency is a qualitative defect characterized by decreased AT activity and normal antigenic levels.

Thrombotic complications of AT deficiency usually occur in the second decade of life. However, few pediatric cases with venous thrombotic events have been reported with heterozygous AT deficiency. In affected individuals AT levels are about 40-60% (normal range, 80-120%). The risk of developing thrombotic complications depends on the particular subtype of AT deficiency and on other coexisting inherited or acquired risk factors. In children with heterozygous AT deficiency the relative risk of developing thrombotic episodes is increased 10-fold.


AT deficiency is usually treated with oral warfarin-type anticoagulants (Coumadin) to decrease the level of vitamin K-dependent procoagulants so that they are in balance with the level of AT. Heparin requires binding with AT to anticoagulate blood and, for this reason, heparin administration is usually ineffective in AT deficiency states. Because the administration of warfarin may take several days to decrease the vitamin K-dependent factors, acute thrombotic episodes are usually managed with AT replacement therapy, using either fresh frozen plasma or recombinant AT concentrates. Patients are initially treated with approximately 50 units/kg AT, which will increase the baseline level of AT by approximately 50%. AT levels should be maintained at 80% or higher. In patients with severe recurrent thrombosis who cannot be managed with oral anticoagulants, therapeutic or prophylactic replacement therapy can be monitored with AT concentrates.

5,10-Methylenetetrahydrofolate Reductase Mutation

In this condition there is a cytosine to thymine mutation at nucleotide 677 (C677T) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. This mutation is a risk factor for stroke in children, venous thrombosis in the young, and coronary artery disease in adults. MTHFR is essential for the remethylation of homocysteine to methionine and homozygosity for mutation of MTHFR is associated with hyperho-mocysteinemia. Hyperhomocysteinemia is a common risk factor for deep-venous thrombosis and increases the risk for DVT in patients with factor V Leiden. The mechanisms whereby excess homocysteine may be a risk factor in thrombosis are listed on page 336.

Protein C Deficiency

Protein C (PC) is a vitamin K-dependent plasma glycoprotein which when activated functions as an anticoagulant by inactivating factors Va and VIIIa. PC activity is enhanced by another vitamin K-dependent inhibitory cofactor, protein S.

PC deficiency is inherited in an autosomal dominant manner and is subdivided into two types. Type I PC deficiency (low activity and low antigen level) is a quantitative deficiency with decreased plasma concentration and functional activity to approximately 50% of normal. Type II PC deficiency (low activity and normal antigen level) is less common and is characterized by a qualitative decrease in functional activity, despite normal levels of PC antigen. Plasma levels of PC below 50% (normal range: 70-110%) are associated with the risk of thrombotic complications.

The population prevalence of heterozygous PC deficiency is estimated at 0.2%. The clinical manifestation of heterozygous PC deficiency is primarily venous throm-botic episodes during the second decade of life or young adulthood. Heterozygous deficiency of PC is not a significant problem during the neonatal period, but homozygous deficiency or compound heterozygous individuals with protein C deficiency may cause a fatal thrombotic disorder. It may present with neonatal purpura fulminans, DIC, progressive skin necrosis with microvascular thrombosis, and thrombosis of the renal veins, mesenteric veins, and dural venous sinuses. Several of the neonates with homozygous deficiency have been subsequently found to be blind.


Initially, affected neonates are treated for several months with replacement therapy with fresh frozen plasma (5-10 mL/kg q12h); later, they can usually be managed with long-term oral warfarin or protein C replacement (fresh frozen plasma or pro-thrombin complex concentrate).

Heterozygous PC deficiency is also one of the major causes of warfarin-induced skin necrosis. Because the half-life of PC is extremely short (2-8 hours), warfarin decreases PC more rapidly than factors IX, X, and prothrombin, resulting in a hemostatic imbalance with resultant microvascular thrombosis. Warfarin-induced skin necrosis is most likely to occur in these patients when loading doses of warfarin are used. This complication can usually be avoided by using low doses of warfarin.

Protein S Deficiency

Protein S deficiency is inherited in an autosomal dominant manner and has a prevalence of 1:33,000. Protein S (PS) is also a vitamin K-dependent anticoagulant that cir culates in the plasma in two forms: a free active form (40%) and an inactive form bound to C4b-free binding protein (60%). PS functions as a cofactor to PC by enhancing its activity against factors Va and Villa. Free PS levels (normal range: 44-92%) correlate clinically with thrombotic episodes. PS deficiency is classified into three subtypes according to a quantitative defect (type I) (low activity and low antigen level) or a qualitative defect (type II) (low activity and normal antigen level) in which PS activity is reduced as follows:

Total PS Free PS PS Function

Type IIa N N N

Type IIb N N N

The clinical presentation of protein S deficiency is indistinguishable from that of protein C deficiency. Heterozygous PS deficiency manifests in adulthood as either venous or arterial thrombotic events. Only a few cases with heterozygous protein S deficiency have been reported with thrombotic episodes during childhood. A small number of newborns with either homozygous or compound heterozygous PS deficiency have been reported. These infants, like those with homozygous PC deficiency, may present with purpura fulminans.


The acute episodes are usually treated with standard anticoagulation therapy with heparin, followed by oral warfarin administration for 3-6 months. Recurrent thrombosis or a life-threatening thromboembolic event in a patient with PS deficiency is usually managed with long-term oral anticoagulation. Asymptomatic patients are not usually treated but need prophylaxis for high-risk procedures, such as surgery. Pregnancy may be accompanied with a reduction in free PS. Oral contraceptives will also result in a reduction of PS and may precipitate thrombosis in a patient with heterozygous PS deficiency.


Approximately 45 different dysfibrinogenemias that predispose to thrombotic events have been described, with the majority due to single-point mutations. Dysfibrinogenemias are usually inherited as an autosomal recessive condition. Dysfibrinogenemia is a very rare condition: it is estimated to occur in 0.8% of adults presenting with thrombotic episodes. Impaired binding of thrombin to an abnormal fibrin and defective fibrinolysis occurs. Tissue plasminogen activator and plasminogen activation on the abnormal fibrin have been implicated in the development of thrombosis. Congenital dysfibrinogenemias may also be associated with abnormal interactions with platelets and defective calcium binding. Although dysfibrinogenemias are more often associated with bleeding, thrombosis occurs in 20% of cases. The clinical presentation is variable, consisting of venous thrombosis, pulmonary embolism, and arterial occlusion. Some cases of dysfib-rinogenemia may have an associated bleeding diathesis. Although it is very rare, intracranial hemorrhage is the most common cause of death in these patients. Homozygosity for dysfibrinogenemia is very rare and associated with juvenile arterial stroke, thrombotic abdominal aortic occlusions, and postoperative throm-botic episodes. Fibrinogen infusions may precipitate the thrombotic events. Slightly decreased fibrinogen levels with prolonged thrombin time (TT) may be indicative of dysfibrinogenemia.

Heparin Cofactor II Deficiency

Heparin cofactor II (HC-II) deficiency is inherited as an autosomal dominant trait. Clinical manifestations of HC-II deficiency are arterial and venous thrombotic events. HC-II deficiency seems to be a rare cause of unexplained thrombotic events.

Hereditary Defects of the Fibrinolytic System Type I Dysplasminogenemia

Homozygous deficiency of type I dysplasminogenemia clinically manifests as pseudomembranous conjunctivitis, hydrocephalus, obstructive airway disorder, and abnormal wound healing secondary to failure to remove fibrin deposits in various organs. Replacement therapy with plasminogen corrects these defects by allowing the lysis of fibrin deposits. Infants with homozygous deficiency do not seem to have a higher incidence of thrombotic events.

Type II Dysplasminogenemia

Type II dysplasminogenemia is inherited as a mutation at various loci in the plas-minogen molecule leading to functional abnormalities and failure of plasminogen activation. Type II defect is associated with increased incidence of thrombotic events.

Tissue Plasminogen Activator Deficiency

There are several families reported with t-PA deficiency with failure to release fibri-nolytic activity following venous thrombotic events.

Plasminogen Activator Inhibitor Deficiency

These polymorphic variations of human PAI-1 gene have been reported where specific alleles may be associated with decreased PAI-1 levels. PAI-1 genotype abnormality may represent a risk factor for venous thrombotic events in the setting of PS deficiency.

Prophylaxis in Relatives of Patients with Thrombophilia

First-degree relatives of index patients who are asymptomatic should be advised of the risk of venous thrombosis. Primary prophylaxis in these persons includes the administration of LMWH in high-risk conditions, such as during surgery, trauma, immobilization, and the 6-week postpartum period; maintenance of normal weight and homocysteine levels; and avoidance of contraceptives and hormone replacement therapy. Women with antithrombin deficiency, combined thrombophilia, or homozygosity for factor V Leiden or the G20210A mutation in the prothrombin gene should be treated throughout pregnancy and for 6 weeks postpartum with LMWH.

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