ANTITHROMBIN DEFICIENCY

ANTITHROMBIN DEFICIENCY - Marc JeffreyKahn, MD
BASICS
DESCRIPTION
Antithrombin is a protease that inhibits thrombin by forming an irreversible complex. Antithrombin can also inhibit factors Xa, IXa, and XIa. This process is catalyzed by the presence of heparin. Patients deficient in antithrombin have an increased incidence of venous thrombosis including venous thrombosis. Arterial thrombosis is much less common in patients deficient in antithrombin.
• System(s) Affected: Cardiovascular; Nervous; Pulmonary; Reproductive; Hemic/Lymphatic/ Immunologic
• Synonym(s): Antithrombin III deficiency
GENERAL PREVENTION
Patients with antithrombin deficiency without thrombosis do not require prophylactic treatment.
EPIDEMIOLOGY
• Predominant age: Mean age of 1st thrombosis is in the 2nd decade
• Predominant sex: Male = Female
Incidence
4% of patients with thrombophilia
Prevalence
0.16% of normal individuals
RISK FACTORS
• Oral contraceptives, pregnancy, and the use of hormone replacement therapy (HRT) increase the risk of venous thrombosis in patients with antithrombin deficiency.
• Patients with antithrombin deficiency and another prothrombotic state such as factor V Leiden or the prothrombin 20210 mutation have increased rates of thrombosis.
ALERT
Pregnancy Considerations
Increases thrombotic risk in patients with antithrombin deficiency
Genetics
• Autosomal dominant.
• Heterozygotes have an odds ratio of venous thrombosis of 10-20.
ETIOLOGY
Many mutations in the antithrombin gene have been identified.
• Type I deficiency is characterized by low levels of antigen. Type II deficiency is found when the antithrombin molecule is dysfunctional.
• Type II deficiencies are due to mutations in either the active center of antithrombin that binds the target enzyme or the heparin binding site.
• No patients homozygous for defects in the active center have been described, suggesting that this is a lethal condition. Patients heterozygous for mutations in the heparin binding site rarely have thrombotic episodes.

DIAGNOSIS
SIGNS AND SYMPTOMS
• Deep or superficial venous thrombosis
• Recurrence rate of thrombosis is 12-17% per year.
TESTS
Lab
• Antithrombin levels in the presence of heparin
• Anti-thrombin-heparin cofactor assay
• Drugs that may alter lab results: Heparin and asparaginase can lower antithrombin levels.
• Disorders that may alter lab results
- Liver disease, DIC, nephritic syndrome, and preeclampsia reduce antithrombin levels.
- Acute thrombosis can lower antithrombin levels.
DIFFERENTIAL DIAGNOSIS
• Factor V Leiden
• Protein C deficiency
• Protein S deficiency
• Dysfibrinogenemia
• Dysplasminogenemia
• Homocysteinemia
• Prothrombin 20210 mutation
• Elevated factor VIII levels
TREATMENT
STABILIZATION
Outpatient
GENERAL MEASURES
• Routine anticoagulation for asymptomatic patients with antithrombin deficiency is not recommended. (1)[A]
• Patients with antithrombin deficiency and a 1st thrombosis should be anticoagulated initially with unfractionated heparin followed by oral anticoagulation with warfarin. (1)[A]
• The role of family screening for antithrombin deficiency is unclear, because most patients with this mutation do not have thrombosis. Screening may be considered for women considering using oral contraceptives or for pregnant women with a family history of factor protein S deficiency. (1)[C]
Diet
No restrictions
Activity
No restrictions
MEDICATION (DRUGS)
First Line
• Heparin initial bolus of 80 U/kg followed by infusion of 18 U/kg/h. Frequent monitoring of the PTT is important as nearly 1/2 of patients deficient in antithrombin require more than 40,000 U of heparin daily to adequately prolong the PTT. (1)[C] After the INR is 2-3, heparin can be stopped after 5 total days of therapy. (1)[A]
• Oral anticoagulant following the initial administration of heparin. Warfarin (Coumadin) 5 mg PO per day and adjusted to INR of 2-3. Patients should be maintained on warfarin for at least 6 months. (1)[A]
• Recurrent thrombosis requires indefinite anticoagulation. (1)[A]
• Contraindications
- Active bleeding precludes anticoagulation; risk of bleeding is a relative contraindication to long-term anticoagulation.
• Precautions
- Observe patient for signs of embolization, further thrombosis, or bleeding.
- Avoid IM injections.
- Periodically check stool and urine for occult blood and monitor CBCs including platelets.
- Heparin-thrombocytopenia and/or paradoxical thrombosis with thrombocytopenia
• Significant possible interactions
- Agents that intensify the response to oral anticoagulants: Alcohol, allopurinol, amiodarone, anabolic steroids, androgens, many antimicrobials, cimetidine, chloral hydrate, disulfiram, all NSAIDs, sulfinpyrazone, tamoxifen, thyroid hormone, vitamin E, ranitidine, salicylates, acetaminophen
- Agents that diminish the response to oral anticoagulants: Aminoglutethimide, antacids, barbiturates, carbamazepine, cholestyramine, diuretics, griseofulvin, rifampin, and oral contraceptives
Second Line
• Argatroban 0.4-0.5 mcg/kg/min. Case reports describing the use of the direct thrombin inhibitor in patients with antithrombin deficiency have been published. (2)[C]
• Antithrombin III (ATnativ, Thrombate III) 50-100 IU/min IV titrated to antithrombin level desired. Precise role in therapy remains unclear. (1)[C]
• LMWH is difficult to manage in this population. (1)[C]
FOLLOW-UP
PROGNOSIS
The odds ratio of thrombosis in a patient with antithrombin deficiency is much higher than in patients with other thrombophilic conditions. The recurrence rate is similarly high. There is no difference in clinical severity between patients with type I defects and type II mutations.
COMPLICATIONS
Recurrent thrombosis (requires indefinite anticoagulation)
PATIENT MONITORING
Warfarin requires periodic (monthly after initial stabilization) monitoring of the INR.
REFERENCES
1. Vinazzer H. Hereditary and acquired antithrombin deficiency. Semin Thromb Hemost. 1999;25(3): 257-263.
2. Dager WE, Gosselin RC, Owings JT. Argatroban therapy for antithrombin deficiency and mesenteric thrombosis: Case report and review of the literature. Pharmacotherapy. 2004;24(5): 659-663.
3. Kottke-Marchant K, Duncan A. Antithrombin deficiency: Issues in laboratory diagnosis. Arch Pathol Lab Med. 2002;126(11):1326-1336.
MISCELLANEOUS
See also: Thrombosis; Deep Vein (DVT); Protein C Deficiency; Protein S Deficiency; Prothrombin 20210 (Mutation); Factor V Leiden

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ANTI PHOSPHOLIPID ANTIBODY SYNDROME

ANTI-PHOSPHOLIPID ANTIBODY SYNDROME - Christopher S.Manasseh, MD
BASICS
DESCRIPTION
• An autoimmune thrombotic syndrome characterized by the presence of antiphospholipid antibodies in association with either recurrent venous or arterial thromboembolic events or repeated fetal loss
• Types
- Primary
 Occurs in patients without clinical evidence of another autoimmune disease
- Secondary
 Occurs in association with another disease such as systemic lupus erythematosus (SLE)
- Catastrophic antiphospholipid syndrome
 Differs from primary and secondary types in the caliber of vessels affected. Venous or arterial thrombosis of large vessels is less common, and patients present with acute thrombotic microangiopathy, kidney being the most commonly affected organ.
 Disseminated intravascular coagulation which does not occur in primary or secondary forms is seen in up to 25% of patients with the catastrophic type.
• Synonym(s): Hughes syndrome
ALERT
Geriatric Considerations
Atherosclerosis and cancer are more frequent causes of thrombosis than is antiphospholipid antibody syndrome.
Pregnancy Considerations
• Increased frequency of recurrent fetal loss
• Increased risk of premature delivery due to pregnancy related hypertension and uteroplacental insufficiency
GENERAL PREVENTION
In pregnant women with h/o recurrent fetal loss, use low dose unfractionated heparin 5000 U SQ b.i.d.
In all women with the syndrome and previous pregnancy loss, aspirin 325 mg/day may provide protection against future thrombosis.
Modification of secondary risk factors for atherosclerosis include control of hypertension, diabetes, hyperlipidemia, and smoking cessation.
EPIDEMIOLOGY
1/2 of all patients with the syndrome have the primary form of the disease.
Incidence
• 15% of women with recurrent pregnancy loss have this syndrome
• 63% of patients have at least 1 valvular abnormality on echocardiogram
Prevalence
1-5% of otherwise young healthy adults have antiphospholipid antibodies
50-70% of patients with SLE who have the antiphospholipid antibodies may develop this syndrome
RISK FACTORS
• Smoking
• Oral contraceptive use
• Surgery
• Immobilization
• Pregnancy
PATHOPHYSIOLOGY
Any organ can be involved, and the extent of involvement depends on the
• Nature and size of vessel involved
• Acuteness or chronicity of the thrombotic process
ETIOLOGY
Antiphospholipid antibodies promote thrombosis by any of the following hypotheses
• Activation of endothelial cells
• Oxidant-mediated injury of the vascular endothelium
• Interference with the phospholipid binding proteins involved in the regulation of coagulation
ASSOCIATED CONDITIONS
• SLE
• Malignant hypertension
• Nephrotic syndrome


DIAGNOSIS
SIGNS AND SYMPTOMS
• Arthralgia
• Livedo reticularis
History
• Family history of rheumatic illness
• Personal history of thrombosis
Physical Exam
Look for deep vein thrombosis of the legs.
Most common manifestation of the syndrome
TESTS
• ELISA test for anticardiolipin antibodies
• Clotting test for lupus anticoagulant
Lab
• Thrombocytopenia
• Leukopenia
Diagnostic Criteria
• The presence of at least ONE of the following clinical criteria
- Vascular thrombosis
 1 or more clinical episodes of arterial, venous, or small vessel thrombosis, occurring within any tissue or organ
- Complications of pregnancy
 1 or more unexplained deaths of morphologically normal fetuses at or after the 10th week of pregnancy OR
 1 or more premature births of morphologically normal neonates at or before the 34th week of pregnancy OR
 3 or more unexplained consecutive spontaneous abortions before the 10th week of pregnancy
• AND presence of at least ONE of the following laboratory criteria
- Anticardiolipin antibodies
 Anticardiolipin IgG or IgM antibodies present at moderate or high levels in the blood on 2 or more occasions at least 6 weeks apart
- Lupus anticoagulant antibodies
 Detected in the blood on 2 or more occasions at least 6 weeks apart
Pathological Findings
• Acute changes
- Capillary congestion
- Non-inflammatory fibrin thrombi
• Chronic changes
- Ischemic hypoperfusion
- Atrophy and fibrosis
DIFFERENTIAL DIAGNOSIS
• Other conditions that cause thrombotic microangiopathy, such as
- Hemolytic-uremic syndrome
- Thrombotic thrombocytopenic purpura
• Other thrombophilic conditions, such as
- Deficiency of protein C, protein S
- Deficiency of antithrombin III
- Mutation of factor V Leiden
- Prothrombin gene mutation
- Homocysteinemia
MEDICATION (DRUGS)
First Line
Warfarin treatment of moderate intensity (to achieve an international normalized ratio (INR) of 2-2.9) significantly reduces the rate of recurrent thrombosis.
• Duration of treatment is lifelong.
Second Line
Corticosteroids and azathioprine for treatment of symptoms of lupus in patients with secondary form of the syndrome
SPECIAL THERAPY
In patients who develop new thromboses despite moderate intensity anticoagulant therapy and for patients with catastrophic antiphospholipid syndrome
• Plasmapheresis
• IV immune globulin
FOLLOW-UP
PROGNOSIS
• Pulmonary hypertension, neurologic involvement, myocardial ischemia, nephropathy, gangrene of extremities, and catastrophic APS are associated with a worse prognosis.
• Most patients experience recurrences months or years after the initial event.
• Mortality rate is ~50% in patients presenting with the catastrophic type, and death is due to multi-organ system failure.
COMPLICATIONS
Discontinuation of warfarin results in increased risk of thrombosis (even death), particularly in the 1st 6 months after stopping treatment.
PATIENT MONITORING
As warfarin therapy is lifelong, patients need to have regular monitoring to maintain INR in the therapeutic range (between 2 and 2.9).
REFERENCES
1. Lockshin M. Antiphospholipid antibody syndrome. In: Ruddy S, Harris ED, Sledge CB, ed. Kelley's Textbook of Rheumatology. Philadelphia: Saunders Company; 2001;1145-1152.
2. Erkan D, Yazici Y, Sobel R, Lockshin MD. Primary antiphospholipid syndrome. Functional outcome after 10 years. J Rheumatol. 2000;27:2817-2821.
3. Levine JS, Branch DW. The antiphospholipid syndrome. N Eng J Med. 2002;10:752-759.
4. Crowther MA, Ginsberg JS, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with antiphospholipid syndrome. N Eng J Med. 2003;12:1133-1138.
ADDITIONAL READING
The decade of autoimmunity: edited by Y. Shoenfeld, publication date 1999.

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