Chapter 61: The Hypercoagulable State

Risk Factors for Venous Thromboembolism (VTE)

Evaluation of a Patient After a VTE: Routine Evaluation

1. History and examination to identify acquired risk factors (see above). This should include obstetric history in women because recurrent second- or third-trimester fetal loss may suggest antiphospholipid antibody syndrome or hereditary thrombophilia

2. Detailed family history with inquiry regarding female family members who have taken oral contraceptives or suffered any venous thrombotic events during pregnancy

3. CBC and peripheral smear to evaluate for underlying disease (eg, myeloproliferative disorder such as essential thrombocythemia, polycythemia vera or microangiopathic hemolysis)

4. Other laboratory tests as indicated (eg, antibody testing to evaluate for heparin-induced thrombocytopenia if applicable)

5. Extensive screening for malignancy not recommended. Perform age-appropriate screening as indicated. Lower threshold to search for malignancy based on symptoms or signs, especially in older patients with a smoking history, recurrent or bilateral VTE

6. Thrombophilia screen as outlined below for idiopathic deep vein thrombosis

Who should be tested for hereditary thrombophilia?

Yes

• VTE at age <50 years with positive family history (first-degree relatives)

• Cerebral venous thrombosis

• Portal/mesenteric vein thrombosis (rule out myeloproliferative neoplasms such as polycythemia vera, essential thrombocythemia, and paroxysmal nocturnal hemoglobinuria)

• Pregnancy loss (second and third trimester)

Reasonable

• VTE in association with oral contraceptives/hormone replacement therapy or pregnancy

• Patients >50 years with first spontaneous VTE

No

• Arterial thrombosis (except for paradoxical emboli)

• Asymptomatic patients with no personal or familial history of VTE

• Women using oral contraceptives with no familial history of VTE

• Venous thromboembolism in patients with active cancer

• Elderly patients with postoperative venous thromboembolism

• Retinal vein thrombosis

Laboratory Evaluation for Recurrent Arterial Thrombosis

1. Only the presence of a lupus anticoagulant/elevated cardiolipin antibody levels are risk factors for arterial thrombosis; the hereditary thrombophilias are not risk factors

2. Consider other disease states, including paroxysmal nocturnal hemoglobinuria, heparin-induced thrombocytopenia, occult malignancy, myeloproliferative disorders, and cocaine abuse

Acquired Risk Factors

1. Malignancy-Associated Thrombosis

General:

1. Accounts for approximately 20% of all cases of VTE

2. In some prospective studies, the incidence of malignancy in the first year after diagnosis of an idiopathic VTE is >7%. However, trials have not demonstrated improved patient outcomes and cost-effectiveness of extensive screening beyond age-appropriate or symptom-directed cancer screening

Pathogenesis:

1. Etiology not clearly established

2. May be related to tissue factor elaborated by tumor cells

Management of thrombosis:

1. Acute thrombosis: Heparin or low-molecular-weight heparin (LMWH)

2. Long-term therapy: Patients with cancer have a higher risk of recurrence than individuals who suffer an unprovoked VTE in the absence of cancer. Anticoagulate a minimum of 6 months and as long as the malignancy is active. Chronic anticoagulation can be considered with LMWH owing to high recurrence rates and potential for increased bleeding complications during anticoagulation with warfarin. In a randomized trial comparing LMWH (dalteparin) with warfarin, recurrence at 6 months was 17% in warfarin-treated patients compared with 8% in the dalteparin group (P = 0.0017), although there was no significant difference in major bleeding rates

Lee AYY et al. N Engl J Med 2003;349:146–153

Prandoni P et al. N Engl J Med 1992;327:1128–1133

2. Antiphospholipid Antibody Syndrome

General:

1. A clinical diagnosis characterized by a thrombotic event (venous or arterial thrombosis or recurrent fetal loss) in association with a persistent lupus anticoagulant (LA) in specialized coagulation assays and/or persistently elevated titers of cardiolipin antibodies (IgG and IgM)

2. LAs are rarely associated with bleeding, but confer an increased risk for recurrent thrombosis

3. Clinical manifestations include thrombocytopenia, recurrent fetal loss, and arterial or venous thrombosis

Pathogenesis:

1. LAs result from antibodies that bind to phospholipids and plasma proteins (β₂-glycoprotein I, prothrombin) in vitro, and prolong clotting times (critically dependent on the amount of phospholipid in assay)

2. LAs are often associated with:

   1. Systemic lupus erythematosus

   2. Drugs (usually not prothrombotic)

   3. Cancer

   4. Idiopathic

   5. Infections (often transient)

Management of thrombosis:

1. Acute thrombosis: Unfractionated heparin or low-molecular-weight heparin (LMWH)

2. Long-term therapy: Warfarin administered orally. Retrospective studies suggested that patients with antiphospholipid antibody syndrome required a target INR >3 to obtain adequate antithrombotic protection. However, subsequent prospective studies showed that an INR = 2-3 is adequate in patients with venous thrombosis

Crowther MA et al. N Engl J Med 2003;349:1133–1138

Finazzi G et al. J Thromb Haemost 2005;3:848–853

3. Pregnancy-Associated Thrombosis

General:

1. Thrombosis is a leading cause of maternal mortality in developed countries

2. The risk of thrombosis increases 5- to 6-times during pregnancy and the increased risk persists up to 6 weeks postpartum

3. Most (80%) of DVTs are located in the left leg because of iliac vein compression by the right iliac artery

Management (antepartum):

Warfarin is absolutely contraindicated between the 6th and 12th weeks of pregnancy when the risk of warfarin embryopathy is greatest

1. Acute thrombosis:

   • LMWH are preferred for long-term anticoagulation over unfractionated heparin because of increased bioavailability, longer half-life, and a lower incidence of osteoporosis and heparin-induced thrombocytopenia

   • When therapeutic doses are used, monitor anti-Xa levels monthly to adjust for pregnancy-associated weight changes

   • With twice-daily dosing, therapeutic anti-Xa levels are between 0.6 and 1.0 unit/mL, and should be assessed 4–6 hours after LMWH administration

2. Prophylaxis: See Anticoagulant prophylaxis during pregnancy below

   Management (peripartum):

   Prepartum:

   • Discontinue LMWH at least 24 hours before delivery to minimize bleeding risks associated with epidural anesthesia and delivery

   • The decision to bridge with intravenous unfractionated heparin should be based on perceived risk of thrombosis during the time off anticoagulation

   • Intravenous unfractionated heparin should be administered if:

     • The time interval from the episode of thrombosis has been <1 month

     • Additional prothrombotic risk factors exist or the patient is otherwise perceived as having a high risk of thrombosis

   • Discontinue unfractionated heparin 4–6 hours before delivery (usually at the start of labor) to allow for normalization of aPTT

Management (postpartum):

1. Barring any bleeding complications, therapeutic anticoagulation can usually be resumed 12–18 hours after a vaginal delivery and 24 hours after cesarean section delivery

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   Restarting Anticoagulation Postpartum

   	Vaginal Delivery	Cesarean Delivery
   Prophylactic dosing	6 hours	12 hours
   Therapeutic dosing	12–24 hours	24–36 hours

2. Warfarin or LMWH, depending on patient preference

   • Anticoagulation is recommended for at least 6 weeks postpartum (minimum 3–6 months in total after a diagnosis of VTE)

Anticoagulant prophylaxis during pregnancy:

1. In women with a history of thrombosis associated with a transient risk factor, anticoagulant prophylaxis is generally not required antepartum because of the low rate of recurrent thrombosis. However, short-term anticoagulation for 6–8 weeks postpartum should be considered

2. In women with a history of thrombosis and a hereditary thrombophilic disorder (see below), the risk of recurrence without anticoagulation appears to be increased and anticoagulation antepartum is justified. However, the intensity of anticoagulation—therapeutic versus prophylactic—has not been established and should be based on perceived risk of thrombosis. During the postpartum period, therapeutic anticoagulation should be administered for 6–8 weeks

3. The management of asymptomatic carriers of hereditary thrombophilias is controversial. Considering that the estimated risk of thrombosis in women with the prothrombin G20210A mutation or factor V Leiden mutation is only 0.2–0.5% during pregnancy, prophylactic anticoagulation antepartum is generally not recommended but may be considered. During the postpartum period, anticoagulation likely needs to be considered only for high risk patients (eg, following cesarean section, complicated delivery with prolonged immobilization, pre-eclampsia) and can be administered for 6–8 weeks

4. In recurrent adverse pregnancy outcomes, some evidence suggests that hereditary thrombophilia is a risk factor for recurrent fetal loss and prophylactic LMWH may result in improved pregnancy outcomes. Additional studies are required

Bates S et al. Chest 2008;133;844S–886S

Brill-Edwards P et al. N Engl J Med 2000;343:1439–1344

Dudding TE, Attia J. Thromb Haemost 2004;91:700–711

Freedman et al. Blood Coagul Fibrinolysis 2008;19:55–59

Gerhardt A et al. N Engl J Med 2000;342:374–380

Gris J-C et al. Blood 2004;103:3695–3699

Inherited Risk Factors

1. Antithrombin Deficiency

General:

Synthesized in liver and neutralizes thrombin, factors IXa, Xa, XIa, XIIa

Diagnostic assays:

Antithrombin–heparin cofactor assay to measure factor Xa inhibition (preferred); antithrombin antigen

Types of deficiency states:

1. Quantitative deficiency

2. Functional deficiency—reactive center or heparin-binding site defect

Acquired antithrombin deficiency:

1. DIC

2. Sepsis

3. Liver disease

4. Nephrotic syndrome

5. Occasionally, acute thrombosis

6. Heparin therapy

Management:

1. Acute thrombosis: Heparin, LMWH, rarely antithrombin concentrate with either heparin or LMWH

   • Heparin or LMWH. High doses may be required to achieve a therapeutic aPTT. Most individuals can be successfully treated with heparin or LMWH without the addition of antithrombin concentrate

   • Antithrombin (human) concentrate can be used to normalize antithrombin levels in chronically anticoagulated patients in special situations that present an unacceptably high risk of bleeding with concomitant anticoagulant use, such as neurosurgery, trauma, and obstetric intervention

   • Antithrombin (recombinant) concentrate produced by transgenic technology was recently approved for the prevention of perioperative and peripartum VTE in patients with familial antithrombin deficiency

   • Antithrombin (human) concentrate with either heparin or LMWH, in cases of extensive or life-threatening thrombosis

2. Asymptomatic carriers: Anticoagulation is not routinely recommended except in high-risk situations such as surgery and possibly pregnancy. Based on familial penetrance of VTE, long-term prophylactic anticoagulation can be considered

2. Protein C Deficiency

General:

Protein C: A vitamin K-dependent protein synthesized in the liver that exerts anticoagulant activity after activation by thrombin

Diagnostic assays:

1. Protac (Technoclone GmbH, Vienna, Austria) direct activation of protein C anticoagulant assay

2. Protac amidolytic assay to measure active site activity

3. Protein C antigen

Types of deficiency states:

1. Quantitative deficiency

2. Functional deficiency—based on abnormal amidolytic or anticoagulant activity

Acquired protein C deficiency:

1. Warfarin

2. Liver disease

3. DIC

4. Sepsis

5. Occasionally, acute thrombosis

Management:

1. Acute thrombosis: Heparin, LMWH, fondaparinux, or warfarin

   Warfarin can be used, but caution is necessary with the initiation of warfarin because of rare occurrence of warfarin-induced skin necrosis. Keep a patient fully anticoagulated with heparin when starting warfarin. The initial warfarin dose should be fairly low (2 mg for 3 days) with 2- to 3-mg increments until a therapeutic INR is achieved

2. Asymptomatic carriers: anticoagulation is not routinely recommended except in high-risk situations such as surgery

Griffin JH et al. J Clin Invest 1981;68:1370–1373

3. Protein S Deficiency

General:

Protein S: A vitamin K-dependent protein that enhances the anticoagulant effect of activated protein C

Diagnostic assays:

1. APC anticoagulant assay

2. Total and free protein S antigen quantification

Types of deficiency states:

Acquired protein S deficiency:

1. Warfarin

2. Pregnancy (>first trimester)

3. Oral contraceptives, DIC

4. Acute thrombosis

5. Liver disease

6. Inflammatory disorders

Management:

Standard therapy with heparin and warfarin

Comp PC, Esmon CT. N Engl J Med 1984;311:1525–1528

Schwarz HP et al. Blood 1984;64:1297–1300

4. Factor V Leiden

General:

Arginine-506 to glutamine substitution renders factor Va relatively resistant to activated protein C

Diagnostic assays:

1. Genotyping or

2. Activated protein C (APC) resistance assay with confirmation by genotyping

Management:

1. Acute thrombosis: Standard therapy with LMWH, fondaparinux, or unfractionated heparin and warfarin

2. Asymptomatic carriers:

   • 5% of white population are carriers of the mutation, but it is not found among native Asian and African populations

   • Chronic anticoagulation without a history of thrombosis is not recommended

   • Prophylactic measures should be considered during high-risk situations such as major surgery or trauma

   • Oral contraceptives containing estrogen are not recommended because of a 30-fold increased risk of thrombosis in asymptomatic carriers

   • Large-scale population screening for factor V Leiden is not cost-effective (approximately 8000 women would need to be screened to prevent a single DVT)

Bertina RM et al. Nature 1994;369:64–67

Dahlback B et al. Proc Natl Acad Sci U S A 1993;90:1004–1008

5. Prothrombin G20210A Mutation

General:

Mutation at position 20210 in the 3′-untranslated region of prothrombin leads to increased efficiency of prothrombin biosynthesis without affecting the rate of transcription

Diagnostic assay:

Genotyping

Management:

1. Acute thrombosis: Standard therapy with LMWH, fondaparinux, or unfractionated heparin and warfarin

2. Asymptomatic carriers:

   • Approximately 2% of the white population are carriers of the mutation, but it is not found among native Asian and African populations

   • Chronic anticoagulation for asymptomatic carriers not recommended (see Factor V Leiden above)

Poort SR et al. Blood 1996;88:3698–3703

Management issues:

Although case-control studies have demonstrated that hyperhomocysteinemia is a modest risk factor for arterial and venous thrombosis, prospective studies have failed to show a clinical benefit in reducing homocysteine levels. We do not recommend testing for hyperhomocysteinemia

Bønaa KH et al. N Engl J Med 2006;354:1578–1588

Ray JG et al. Ann Intern Med 2007;146:761–767

Treatment of Thrombotic Events

Acute Treatment of Acute Thrombosis

1. Initial management not generally affected by the presence of hereditary risk factors

2. Unfractionated heparin, low-molecular-weight heparin, fondaparinux for at least 5 days and until the INR is ≥2.0 for 24 hours

3. Unfractionated heparin should be administered in adequate dose-rates because failure to reach a therapeutic level of anticoagulation within the first 24 hours increases the risk for recurrence

   • Weight-based dosing for unfractionated heparin with an intravenously administered loading dose, followed by a continuous intravenous infusion

4. Warfarin can be started on day 1 with target INR = 2.0–3.0. Standard starting dose is 5–10 mg daily. Variants of CYP2C9 and VKORC1 genes contribute to variability in therapeutic warfarin dosing. Genotype-influenced warfarin dosing algorithms may offer benefit over standard dosing; however, its applicability in nonresearch settings has yet to be determined. (Klein TE et al. N Engl J Med 2009;360:753–764)

5. Rivaroxaban, an oral direct factor Xa inhibitor, is approved for initial treatment (3–12 months) of deep venous thrombosis and/or pulmonary embolism (N Engl J Med 2010;363:2499–2510, N Engl J Med 2012;366:1287–1297)

   • It does not require laboratory monitoring

   • Rivaroxaban use has not been adequately evaluated in prophylaxis or treatment for initial or recurrent episodes of DVT or PE in persons with creatinine clearance <30 mL/min (<0.5 mL/s)

   • Rivaroxaban is not specifically indicated for patients with malignancy-associated thrombosis

   • For initial treatment of acute DVT or PE: Rivaroxaban 15 mg, orally, twice daily with food for 21 days, then:

     Rivaroxaban 20 mg, orally, once daily with food at approximately the same time every day

   • For decreasing the risk of DVT or PE recurrence: Rivaroxaban 20 mg, orally, once daily with food at approximately the same time every day

Long-Term Therapy Following an Acute Thrombosis:

Balancing Risk of Recurrence Against Risk of Prolonged Anticoagulation

Risk of recurrence

1. Following an idiopathic event after discontinuing 3–12 months of anticoagulation: ~5–15% in the first year (25% at 5 years; 30% at 8 years)

2. After a provoked event such as surgery, pregnancy, or oral contraception, the rate of recurrence is lower (Christiansen SC et al. JAMA 2005; 293:2352–2361; Baglin T et al. Lancet 2003;262:523–266)

3. Generally considered increased in the following situations (increased risk of recurrence appended parenthetically):

   • Malignancy (~3 ×)

   • Antiphospholipid antibody syndrome (~2 ×)

   • Compound heterozygosity for factor V Leiden and prothrombin G20210A mutations (~2.5 ×)

   • Homozygosity for factor V Leiden or prothrombin G20210A mutations (~2 ×)

   • Selected kindreds with strong clinical penetrance for antithrombin, protein C, or protein S deficiency

   • The presence of 2 or more prothrombotic risk factors (eg, factor V Leiden and protein C deficiency)

      (Prandoni P et al. Blood 2002;100:3484–3488)

4. Not increased in heterozygosity for factor V Leiden or prothrombin G20210A mutation alone

De Stefano V et al. N Engl J Med 1999;341:801–806

Heit JA et al. Arch Intern Med 2000;160:761–768

Prandoni P et al. Ann Intern Med 1996;125:1–7

Bleeding risk with prolonged oral anticoagulation

1. Rate of major bleed is ~1–2% per year with a 0.4% per year fatality rate

2. The risk of bleeding is greater in patients with a history of GI bleeding, renal or liver failure, diabetes, or uncontrolled hypertension, or in those with advanced age (>75 years)

Beyth RJ et al. Am J Med 1998;105:91–99

Fitzmaurice DA et al. BMJ 2002;325:828–831

Palareti G et al. Lancet 1996;348:423–428

Factors that may identify individuals with a lower risk for recurrence include:

• Female sex (RR = 0.7)

• Isolated calf DVT (RR = 0.5)

• Normal D-dimer (usually <500 ng/mL using validated ELISA) measured 1 month following discontinuation of anticoagulation (RR = 0.4)

• Absence of residual deep vein thrombosis (RR = 0.7)

• Asian ethnicity (RR = 0.8)

Kearon C et al. Chest 2008;133:454S–545S

Notes: Duration and intensity of long-term therapy

Recent randomized trials evaluating strategies to prevent recurrent events after an initial idiopathic VTE have demonstrated:

• Efficacy of longer-duration therapy

• Lower intensity better than placebo but inferior to higher target INR anticoagulation after therapeutic anticoagulation for 3–6 months

• If patients prefer less frequent INR monitoring, low-intensity anticoagulation (INR 1.5–1.9) can be considered

Therapeutic Options for Venous Thromboembolic Events (VTEs): Regimen: Unfractionated Heparin Sodium

Hirsh J et al. Circulation 2001;103:2994–3018

Intravenous (unfractionated) heparin sodium

Loading dose:

Heparin sodium 80 units/kg by intravenous push, followed by:

Maintenance dose:

Heparin sodium, begin with 18 units/kg per hour; administer by continuous intravenous infusion, diluted in a convenient volume of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W)

Check aPTT every 6 hours until therapeutic range (1.5–2.3 × aPTT control) is sustained. When therapeutic range is achieved, check aPTT for 2 consecutive measurements 6 hours apart; then check aPPT every 24 hours

Note: Prepare heparin infusions in a standardized concentration that facilitates converting administration rates of “units/hour” to “volume/time (mL/hour)”; for example, heparin sodium 25,000 units in 250 mL 0.9% NS produces a concentration of 100 units/mL

Note: Intravenous (unfractionated) heparin sodium should be used with caution in patients who have baseline abnormal aPTT

Treatment Monitoring

Check aPTT 6 hours after starting continuous intravenous infusion and after each change in rate of administration. Maintain aPTT 1.5–2.3 × the upper limit of normal

Treatment Modifications

Adverse Effects

1. HIT: 1–3% of patients receiving unfractionated heparin for >1 week (see Chapter 59)

2. Non–immune-mediated, heparin-associated thrombocytopenia (HAT): 1–30%

   • Decreased platelet count usually mild and transient

   • Onset typically 2–4 days after start of heparin

   • Thrombocytopenia resolves despite continuing heparin administration

3. Osteopenia/osteoporosis

4. Hypoaldosteronism/hyperkalemia: 7–8% of patients

5. Increased serum free T₄ and T₃ with normal TSH

6. Increased hepatic AST and ALT

7. Increased serum triglycerides

8. Hypersensitivity reactions (rarely), including vasospasm, cutaneous effects around the injection site, conjunctivitis

9. Fever

Regimen: Low-Molecular-Weight Heparins (LMWHS): Enoxaparin Sodium, Tinzaparin Sodium

Caution:

• Doses for LMWHs or unfractionated heparin cannot be used interchangeably

• Do not use any LMWH in a patient with heparin-induced thrombocytopenia

Enoxaparin sodium 1 mg/kg twice daily or 1.5 mg/kg once daily; administer only by subcutaneous injection

Tinzaparin sodium 175 anti-Xa units/kg; administer only by subcutaneous injection once daily

Dalteparin sodium 200 Units/kg (maximum daily dose = 18,000 Units); administer by subcutaneous injection

In patients with cancer treated long term:

• Days 1–30: 200 Units/kg once daily (maximum daily dose = 18,000 Units)

• Months 2–6: 150 Units/kg once daily (maximum daily dose = 18,000 Units)

• Dose recommendations for use beyond 6 months are not established

Toxicity

1. Increased risk of bleeding in patients who use drugs that may affect hemostasis and in those with comorbid pathologies that predispose to hemorrhage

2. Thrombocytopenia^✫

   Incidence of HIT is less than with unfractionated heparin

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   Platelet Count	Incidence	LMWH Implicated
   50,000–100,000/mm3	1.3%	Enoxaparin
   	1%	Tinzaparin
   <50,000/mm3	0.1%	Enoxaparin
   	0.13%	Tinzaparin
   ✫Discontinue LMWH if a platelet count decreases to <100,000/mm3

3. Pain at injection sites/injection site hematoma

4. Reversible increase in AST, ALT + alkaline phosphatase, LDH, and CK

5. Decreases in bone mineral density and osteoporosis (but less frequent than with unfractionated heparin)

Treatment Modifications

There is cumulative anti–factor Xa activity of LMWH in patients with renal impairment, which can increase the bleeding complications of therapy. In patients with severe renal failure, anticoagulation with unfractionated heparin is recommended. If LMWH is selected, close monitoring of anti-Xa activity is recommended

Notes

• Enoxaparin, Dalteparin, and Tinzaparin clearance is decreased in persons with creatinine clearance <30 mL/min and anti-Factor Xa concentrations are inversely increased

• Dose adjustments may be needed to maintain anti-Xa concentrations within a targeted therapeutic range

• LMWH doses in persons with severe renal impairment, extremes of body weight, and those at high risk for bleeding are guided by monitoring anti-Xa levels

Treatment Monitoring

In most patients, no monitoring is necessary. In some circumstances, such as pregnancy, renal dysfunction, obesity, and long-term therapy, a dose adjustment may be necessary. For twice-daily administration, the target therapeutic anti-Factor Xa concentration range is between 0.6 and 1.0 units/mL 4–6 hours after subcutaneous dose, but for once-daily dose the target range is less-well established (usually between 1.0 and 2.0 units/mL)

Notes

Advantages of LMWHs over unfractionated heparin:

1. Increased bioavailability

2. Lower incidence of osteoporosis

3. Lower incidence of heparin-induced thrombocytopenia

Regimen: Warfarin Sodium

Warfarin sodium; administer orally once daily, continually to maintain an INR of 2–3

Initiate therapy with an oral dose of 5–10 mg/day in the evening and increase doses in increments of 1–2 mg/day guided by laboratory values

Treatment Monitoring

Monitor INR initially 2 times per week. When stabilized, gradually reduce frequency to once per week. Less frequent testing can safely be performed in patients who are stable and/or receiving lower-intensity anticoagulation

Adverse Effects

1. Hemorrhage: Patients with a variant polymorphism for the cytochrome P450 CYP2C9 enzyme may have an increased risk of an exaggerated response to warfarin and hemorrhage

2. Warfarin embryopathy or fetal warfarin syndrome with congenital abnormalities after exposure in utero. Warfarin is absolutely contraindicated between the 6th and 12th weeks of pregnancy

3. Abdominal pain, cramping, flatulence, bloating, nausea, vomiting, diarrhea

4. Increased LFTs, cholestatic liver injury, jaundice

5. Nephritis with acute renal failure

6. Urolithiasis (calcium oxalate)

7. Increased liver enzymes, hepatitis, and a syndrome that mimics viral hepatitis

8. Skin necrosis (risk factors include protein C and heparin-induced thrombocytopenia; case reports of protein S deficiency and factor V Leiden)

9. Rash, dermatitis, bullous eruptions, urticaria, pruritus, and purpuric skin eruption

10. Alopecia

11. Osteoporosis

Notes

Numerous drug and food interactions can occur with oral administration of warfarin

Drug interactions:

• Antibiotics (eg, erythromycin, metronidazole, rifampin, fluconazole)

• Antiepileptics (carbamazepine, barbiturates)

• Lipid-lowering agents (eg, clofibrate, cholestyramine, lovastatin)

• Food interactions:

• Many vegetables contain high levels of vitamin K, but patients do not need to specifically avoid such foods

• Patients should be instructed to keep diet fairly uniform and adjust the warfarin dose according to INR

• Alcohol in small quantities is usually tolerated without affecting prothrombin time

Regimen: Antithrombin III (Human) (Thrombate III^®)

• Antithrombin III (AT-III units required^✫) intraVENously over 10–20 minutes, followed by:

• Antithrombin III (60% of initial dose) every 24 hours as needed (typically 2–8 days)

• Loading doses and maintenance intervals should be individualized for each patient

• Dose should be individually determined to increase plasma antithrombin III concentration (desired [AT-III]_plasma) to within a range of normal from the pre-therapy level (baseline [AT-III]_plasma)

  • Dosage may be calculated from the following formula:

     

    

     

• AT-III levels should initially be drawn at baseline and 20 minutes after AT-III administration

  • After an initial dose of THROMBATE III, plasma AT-III levels should be initially monitored at least every 12 hours and before the next dose with the goal of maintaining plasma AT-III levels >80%

• Subsequent doses may be calculated based on the level achieved with the first dose

ANTITHROMBIN III (RECOMBINANT) (ATryn^®)

• Dosage is individualized based on a patient's pretreatment functional AT-III activity level (expressed as percentage of normal) and body weight (kg), and using therapeutic drug monitoring

• The goal of treatment is to restore and maintain functional AT-III activity levels between 80 and 120% of normal (0.8–1.2 IU/mL)

• Administer a loading dose intraVENously over 15 minutes, immediately followed by a maintenance dose given by continuous intraVENous infusion

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  	Loading Dosage (International Units)	Maintenance Dosage (International Units/hour)
  Surgical patients
  Pregnant females

• Plasma AT-III activity monitoring is required for appropriate treatment. Check plasma AT-III activity once or twice daily with dose adjustments as suggested by the following table:

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  Initial Monitor Time	AT Level	Dose Adjustment	Recheck AT Level
  2 hours after initiation of treatment	<80%	Increase 30%	2 hours after each dose adjustment
  	80–120%	None	6 hours after initiation of treatment or dose adjustment
  	>120%	Decrease 30%	2 hours after each dose adjustment

  Recombinant antithrombin has a shorter half-life and more rapid clearance than plasma-derived antithrombin

• Mean elimination half-life (t_1/2) of antithrombin III products:

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  Antithrombin-III Product	Half-life
  Plasma-derived (Thrombate III®)	22 h (plasma t1/2) 2.5–3.8 d (biological t1/2)
  Recombinant (ATryn®)
  50 Int. Units/kg	11.6 h
  100 Int. Units/kg	17.7 h

The half-life of AT-III may be decreased following surgery, and in settings of hemorrhage, acute thrombosis, and during intravenous heparin administration

In such conditions, plasma AT-III levels should be monitored more frequently, and repeated AT-III doses administered as necessary

Adverse Effects

Infusion-related events:

1. Dizziness/light-headedness

2. Chest tightness or pain

3. Nausea

4. Dysgeusia

5. Chills

6. Cramps

7. Shortness of breath

8. Urticaria

9. Fever

Treatment Monitoring

1. Monitor peak antithrombin levels 20 minutes after infusion and trough levels just prior to next dose and adjust to keep levels above 80% of normal

2. Also recommended to check antithrombin levels 12 hours after the initial infusion

3. Simultaneous heparin administration can affect half-life and more frequent monitoring may be necessary