**6. Treatment of venous thrombosis in APLS**

### **6.1 General treatment**

The standard of care for venous thromboembolism is continous infusion of intravenously delivered unfractionated heparin(UFH) and, more recently, subcutaneous low-molecular weight heparins(LMWH). DVT is associated with several possible complications, including recurrent nonfatal venous thromboembolism, postthrombotic chronic venous insufficiency, and nonfatal/fatal pulmonary embolism. The goals of therapy for DVT include the prevention of thrombus propagation, embolization, and early and late thrombus recurrence. Proper anticoagulation is the first critical step in the effective treatment of DVT. Complications can develop soon after thrombus detection, presenting a narrow window of opportunity for a safe and effective intervention. The secondary stage of treatment involves the maintenance of adequate anticoagulation to prevent the development of recurrent thromboembolism.

LMWH or fondaparinux is preferred for the initial anticoagulation of patients with deep vein thrombosis(Table 2). LMWH and fondaparinux are as safe and as effective as continuous unfractionated heparin (UFH). Suitable patients can be safely treated with LMWH and fondaparinux in the outpatient setting. Heparin/fondaparinux should be continued for at least five days after the initiation of warfarin therapy and until International Normalized Ratio (INR) is > 2.0 for two consecutive days. Warfarin should be initiated 5 mg on day 1.

predicting an initial venous thrombosis. Thrombosis is more frequent as the level of anticardiolipin antibody increases, and medium and high titers (>40 GPL and/or MPL units) are more frequently associated with thrombotic events. Although some investigators believe that elevated levels of IgG or IgA isotypes are more common than IgM in patients with thrombotic complications, this has not been clearly established. The lupus anticoagulant or increased levels of anticardiolipin antibody must be persistently present on more than one occasion at least 12 weeks apart because the incidence of thrombotic complications is almost the same in patients with transiently positive tests as in patients with negative tests at two different time intervals. The persistent presence of elevated levels of anticardiolipin antibody has been shown to be associated with indices of in-vivo coagulation activation. In a study of patients with SLE(Ginsberg JS 1993) who were persistently anticardiolipin antibody– positive versus patients who were transiently positive or persistently negative, anticardiolipin antibody–positive patients had a higher mean level of F1+2 and fibrinopeptide A than patients who were transiently positive, persistently negative, or on warfarin therapy. The differences remained significant even if patients with prior thromboembolism were excluded from the analysis. These results suggest that the presence of persistently elevated levels of anticardiolipin antibody in SLE patients is

Patients who are persistently positive for the lupus anticoagulant or who have persistently elevated levels of anticardiolipin antibody and suffer a thromboembolic event have a recurrence rate of approximately 50% within 2 years(Rosove MH 1992, Khamashta MA 1995). Recurrences tend to occur in most of the patients on the same side of the circulation as the initial event—venous recurrences after an initial venous event and arterial recurrences

The standard of care for venous thromboembolism is continous infusion of intravenously delivered unfractionated heparin(UFH) and, more recently, subcutaneous low-molecular weight heparins(LMWH). DVT is associated with several possible complications, including recurrent nonfatal venous thromboembolism, postthrombotic chronic venous insufficiency, and nonfatal/fatal pulmonary embolism. The goals of therapy for DVT include the prevention of thrombus propagation, embolization, and early and late thrombus recurrence. Proper anticoagulation is the first critical step in the effective treatment of DVT. Complications can develop soon after thrombus detection, presenting a narrow window of opportunity for a safe and effective intervention. The secondary stage of treatment involves the maintenance of adequate anticoagulation to prevent the development of recurrent

LMWH or fondaparinux is preferred for the initial anticoagulation of patients with deep vein thrombosis(Table 2). LMWH and fondaparinux are as safe and as effective as continuous unfractionated heparin (UFH). Suitable patients can be safely treated with LMWH and fondaparinux in the outpatient setting. Heparin/fondaparinux should be continued for at least five days after the initiation of warfarin therapy and until International Normalized Ratio (INR) is > 2.0 for two consecutive days. Warfarin should be

associated with an ongoing prothrombotic state.

**6. Treatment of venous thrombosis in APLS** 

after an initial arterial event.

**6.1 General treatment** 

thromboembolism.

initiated 5 mg on day 1.

Treatment for venous thromboembolism with LMWH provides reliable anticoagulation levels when given subcutaneously on a weight-based dosing schedule. No laboratory monitoring of the intensity of anticoagulation is required for LMWH, except in special circumstances. Recent randomized controlled trials of the treatment of pulmonary embolism (PE) have shown LMWH to be as effective and safe as UFH. One randomized controlled trial of the treatment of venous thromboembolism (VTE) in 1,021 patients included 271 patients presenting with PE. In this study, there were no significant differences in outcomes following treatment with UFH versus LMWH. These studies used reviparin and tinzaparin. Two reviews agreed that LMWH may be efficacious in the treatment of PE, but cautioned that the LMWH products may not be equivalent to each other (Raskob 1999 ; Charland, 1998; Columbus Investigators, 1997; Simonneau, 1997).

LMWH may not be appropriate for patients with renal insufficiency (creatinine clearance less than 30 mL/min). Studies have shown modestly delayed clearance in patients with chronic renal failure. The clinician should weigh this evidence when considering outpatient therapy.

A high-loading dose of warfarin (greater than 10 mg) is of no clinical use and should be discouraged. A 10 mg initial dose of warfarin has been associated with early overanticoagulation and, when compared to a 5 mg initial dose, was no more effective in achieving a therapeutic international normalized ratio (INR) by day four or five of therapy. A therapeutic range of anticoagulation to keep the INR at 2.5 (range 2.0-3.0) is recommended for patients with venous thromboembolism. Heparin and warfarin may be started at the same time. The anticoagulant effect of warfarin is delayed until clotting factors already circulating are cleared. Although Factor VII has a shorter half-life in the blood (six to seven hours), peak anticoagulant activity is delayed for up to 96 hours until factors with longer plasma half-lives (II, IX and X) have cleared . Heparin (UFH or LMWH) and warfarin may be started at the same time. Heparin (UFH or LMWH) and/or fondaparinux should be given for a minimum of five days. Patient should continue heparin until INR >=2.0 for two consecutive days. In patients with suspected hypercoagulable state (Protein C or Protein S deficiency), the patient should be adequately anticoagulated with heparin (UFH or LMWH) and/or fondaparinux before warfarin is started at a low dose (2-5 mg). This is to avoid warfarin-induced skin necrosis or other transient hypercoagulable complications.

Recommendations for the management of thrombosis in the APLS have been based largely on retrospective case series. Recently, several clinical trials have been published on the management of thrombosis in APLS.These new clinical trials have challenged the previous dogma of a target INR of 3 to 4(high-intensity warfarin).

#### **6.2 Primary prophylaxis of thrombosis in patients with APL antibodies**

The therapeutic approach in asymptomatic carriers of APL without prior thrombotic events is still controversial. Present evidence-based knowledge does not support the widespread use of aspirin in all these aPL-positive patients. Annual thrombosis risk in asymptomatic APL-positive patients range from 0% to 3.8%( Finazzi G 1996, Shah NM 1998), being equivalent to that of major bleeding associated with the use of aspirin. The only randomized clinical trial (APLASA study) in which 98 asymptomatic persistently APL-positive individuals were randomized to recieve a daily dose of 81 mg of aspirin or placebo showed that these patients have a low overall annual incidence rate of acute

Antiphospholipd Syndrome and Venous Thrombosis 63

2005). In most reports the incidence of recurrence is highest in the first 6 months after discontinuing anticoagulant therapy. Although it was initially thought that prevention of venous recurrence required high-intensity warfarin with a target INR of 3.5, evidence has been accumulating from recent studies that standard intensity warfarin (INR 2 to 3) can almost completely abrogate recurrence of venous thromboembolic disease(Crowther MA 2003, Finazzi G 2005). The pooled data from these two studies revealed no difference in recurrent thrombosis between moderate-intensity warfarin (INR 2 to 3) and high-intensity (INR 3 to 4), nor was there a greater bleeding risk. As the data from several studies have demonstrated that patients with antiphospholipid syndrome have a high risk for recurrent venous thromboembolic disease after anticoagulation is discontinued, many feel that anticoagulation should be continued indefinitely. The American College of Chest Physicians recommends treatment for 12 months and consideration of indefinite therapy after an initial event(Ortel TL 2005, Buller HR 2004). Because of the efficacy of warfarin therapy in preventing recurrences, the use of corticosteroids and other immunosuppressive agents to suppress antibody production in the absence of






Table 2. Venous thromboembolism(VTE) treatment guidelines adapted from the American College of Chest Physicians Evidence –based clinical practice guidelines-8th edition

Monitoring anticoagulant therapy may be difficult in patients with lupus anticoagulants and a prolonged PTT. It is mandatory when using unfractionated heparin to monitor therapy using a specific heparin assay, such as the one dependent on factor Xa inhibition (therapeutic range, 0.3 to 0.7). In most instances, it is preferable to use low-molecular-weight heparin in therapeutic doses, which usually eliminates the need for monitoring. When using warfarin, the optimal INR for patients with lupus anticoagulants is controversial, because patients with lupus anticoagulants may have a variably prolonged prothrombin time,and various thromboplastins have a different sensitivity in the presence of a lupus


autoimmune disease is not recommended.





adjustment to achieve a therapeutic aPTT(1C).

or SC UFH(1A)

activity(1C)

inpatient(1A).

adjustment of dose(1C).

thrombosis, and develop vascular events when additional risk factors are present(Erkan D 2007). Therefore, according to the results of this trial, asymptomatic, persistently APLpositive individuals seem not to benefit from low-dose aspirin for primary thromboprophylaxis.

However, a more realistic approach with a lower degree of evidence would be to stratify these individuals according to some clinical features such as the presence of traditional congenital or acquired procoagulant risk factors, the APL profile(persistently positive aCL and or anti-β2GPI antibodies at moderate/high titers), and the coexistence of an underlying autoimmune disease, to consider primary prophylactic therapy with low-dose 75-100 mg aspirin daily. It is known that SLE represents a prothrombotic condition and acts as strong thrombophilic risk factor, primarily related to the chronic systemic inflammation and renal involvement. Furthermore, one study has shown that prophylactic aspirin should be given to all patients with SLE to prevent both arterial and venous thrombotic manifestations, especially in patients with APL(Wahl DG 2000). In the same study, the authors suggested that in selected patients with LA and a low bleeding risk, prophylactic oral anticoagulant therapy may provide higher utility. Therefore, there is currently consensus for primary thromboprophylaxis in these patients, mainly with low-dose aspirin.

An alternative to aspirin in SLE patients may be hydroxychloroquine. There are many evidences for the protective role of this old drug against the development of both venous and arterial thrombosis(Ruiz-Irastorza G 2006, Erkan D 2002).

All nonthrombotic APL-positive subjects should be encouraged to stop smoking. Cessation of oestrogen –containg oral contraceptive use and treatment of other vascular risk factors if present are additional recommended therapeutic measures.

At least half of patients with APLS with vascular events also have another reversible risk factors which are not related to APLS at time of thrombosis(Erkan D 2002). Therefore, identification and elimination of these risk factors and agressive prophylaxis during highrisk periods, are crucial for the primary thrombosis prevention in asymptomatic persistently APL-positive individuals. Serious perioperative complications including catastrophic antiphospholipid syndrome(CAPS) may occur despite prophylaxis in APL-positive individuals as they are at additional risk for thrombosis when undergoing surgical procedures. Therefore, perioperative strategies should be clearly identified before any surgical procedure, pharmacological, and physical antithrombosis interventions should be vigorously used; periods without anticoagulation should be kept to an absolute minimum(George D 2009).

#### **6.3 Therapy for acute thrombosis and secondary propylaxis of thrombosis in patients with antiphospholipid syndrome**

Therapy for thrombosis associated with the APLS should be guided by the knowledge that recurrence is common. In one study, patients who had discontinued oral anticoagulation had a 50% probability of recurrence in 2 years and a 78% recurrence in 8 years(Derksen RHWM 1993). Similar results have been published by others with a recurrence rate of 10% to 30% per year(Galli M 2003, Rosove MH 1992, Khamashta MA 1995). Three prospective studies reported that there was an increased risk of recurrence that varied from 10% to 67% per year(Lim W 2006, Schulman S 1998, Kearon C 1999, Kearon C 2003, Ortel TL

thrombosis, and develop vascular events when additional risk factors are present(Erkan D 2007). Therefore, according to the results of this trial, asymptomatic, persistently APLpositive individuals seem not to benefit from low-dose aspirin for primary

However, a more realistic approach with a lower degree of evidence would be to stratify these individuals according to some clinical features such as the presence of traditional congenital or acquired procoagulant risk factors, the APL profile(persistently positive aCL and or anti-β2GPI antibodies at moderate/high titers), and the coexistence of an underlying autoimmune disease, to consider primary prophylactic therapy with low-dose 75-100 mg aspirin daily. It is known that SLE represents a prothrombotic condition and acts as strong thrombophilic risk factor, primarily related to the chronic systemic inflammation and renal involvement. Furthermore, one study has shown that prophylactic aspirin should be given to all patients with SLE to prevent both arterial and venous thrombotic manifestations, especially in patients with APL(Wahl DG 2000). In the same study, the authors suggested that in selected patients with LA and a low bleeding risk, prophylactic oral anticoagulant therapy may provide higher utility. Therefore, there is currently consensus for primary thromboprophylaxis in these patients, mainly with

An alternative to aspirin in SLE patients may be hydroxychloroquine. There are many evidences for the protective role of this old drug against the development of both venous

All nonthrombotic APL-positive subjects should be encouraged to stop smoking. Cessation of oestrogen –containg oral contraceptive use and treatment of other vascular risk factors if

At least half of patients with APLS with vascular events also have another reversible risk factors which are not related to APLS at time of thrombosis(Erkan D 2002). Therefore, identification and elimination of these risk factors and agressive prophylaxis during highrisk periods, are crucial for the primary thrombosis prevention in asymptomatic persistently APL-positive individuals. Serious perioperative complications including catastrophic antiphospholipid syndrome(CAPS) may occur despite prophylaxis in APL-positive individuals as they are at additional risk for thrombosis when undergoing surgical procedures. Therefore, perioperative strategies should be clearly identified before any surgical procedure, pharmacological, and physical antithrombosis interventions should be vigorously used; periods without anticoagulation should be kept to an absolute

**6.3 Therapy for acute thrombosis and secondary propylaxis of thrombosis in patients** 

Therapy for thrombosis associated with the APLS should be guided by the knowledge that recurrence is common. In one study, patients who had discontinued oral anticoagulation had a 50% probability of recurrence in 2 years and a 78% recurrence in 8 years(Derksen RHWM 1993). Similar results have been published by others with a recurrence rate of 10% to 30% per year(Galli M 2003, Rosove MH 1992, Khamashta MA 1995). Three prospective studies reported that there was an increased risk of recurrence that varied from 10% to 67% per year(Lim W 2006, Schulman S 1998, Kearon C 1999, Kearon C 2003, Ortel TL

and arterial thrombosis(Ruiz-Irastorza G 2006, Erkan D 2002).

present are additional recommended therapeutic measures.

thromboprophylaxis.

low-dose aspirin.

minimum(George D 2009).

**with antiphospholipid syndrome** 

2005). In most reports the incidence of recurrence is highest in the first 6 months after discontinuing anticoagulant therapy. Although it was initially thought that prevention of venous recurrence required high-intensity warfarin with a target INR of 3.5, evidence has been accumulating from recent studies that standard intensity warfarin (INR 2 to 3) can almost completely abrogate recurrence of venous thromboembolic disease(Crowther MA 2003, Finazzi G 2005). The pooled data from these two studies revealed no difference in recurrent thrombosis between moderate-intensity warfarin (INR 2 to 3) and high-intensity (INR 3 to 4), nor was there a greater bleeding risk. As the data from several studies have demonstrated that patients with antiphospholipid syndrome have a high risk for recurrent venous thromboembolic disease after anticoagulation is discontinued, many feel that anticoagulation should be continued indefinitely. The American College of Chest Physicians recommends treatment for 12 months and consideration of indefinite therapy after an initial event(Ortel TL 2005, Buller HR 2004). Because of the efficacy of warfarin therapy in preventing recurrences, the use of corticosteroids and other immunosuppressive agents to suppress antibody production in the absence of autoimmune disease is not recommended.


Table 2. Venous thromboembolism(VTE) treatment guidelines adapted from the American College of Chest Physicians Evidence –based clinical practice guidelines-8th edition

Monitoring anticoagulant therapy may be difficult in patients with lupus anticoagulants and a prolonged PTT. It is mandatory when using unfractionated heparin to monitor therapy using a specific heparin assay, such as the one dependent on factor Xa inhibition (therapeutic range, 0.3 to 0.7). In most instances, it is preferable to use low-molecular-weight heparin in therapeutic doses, which usually eliminates the need for monitoring. When using warfarin, the optimal INR for patients with lupus anticoagulants is controversial, because patients with lupus anticoagulants may have a variably prolonged prothrombin time,and various thromboplastins have a different sensitivity in the presence of a lupus

Antiphospholipd Syndrome and Venous Thrombosis 65

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anticoagulant.Therefore, it is possible that in various studies of therapy in patients with lupus anticoagulants that the degree of anticoagulation is overestimated, and the target INR of 3.0 noted earlier might be an overestimate because of the presence of the lupus anticoagulant(Donald I. Feinstein 2007). Rarely, patients may continue to have recurrent venous thromboembolic events despite INR values in the therapeutic range. Recurrent thrombotic events despite therapeutic anticoagulation require evaluation and modification of all non-APL thrombosis risk factors. Warfarin therapy is generally increased to highintensity(INR, 3.0-4.0). Other options include adding low-dose aspirin, hydroxychloroquine, and/or statins to warfarin or switching to low-molecular weight heparin. There are no randomized controlled studies investigating the effectiveness of any of these approaches.

Based on many cohort studies ,subgroup analysis and two randomized controlled studies, a recent review(Ruiz-Irastorza G 2007) suggests that patients with definite APLS with a first venous thrombosis should be treated with prolonged oral anticoagulation at a target INR of 2.0-3.0 and those with an arterial event at an 3.0-4.0.

So, the best secondary thromboprophylaxis in patients with definite APLS is long-term anticoagulation at a target INR of 2.0-3.0. Patients with recurrent venous thrombotic events despite optimal anticoagulation should be treated with warfarin at an INR of 3.0-4.0.

#### **7. References**


anticoagulant.Therefore, it is possible that in various studies of therapy in patients with lupus anticoagulants that the degree of anticoagulation is overestimated, and the target INR of 3.0 noted earlier might be an overestimate because of the presence of the lupus anticoagulant(Donald I. Feinstein 2007). Rarely, patients may continue to have recurrent venous thromboembolic events despite INR values in the therapeutic range. Recurrent thrombotic events despite therapeutic anticoagulation require evaluation and modification of all non-APL thrombosis risk factors. Warfarin therapy is generally increased to highintensity(INR, 3.0-4.0). Other options include adding low-dose aspirin, hydroxychloroquine, and/or statins to warfarin or switching to low-molecular weight heparin. There are no randomized controlled studies investigating the effectiveness of any of these approaches. Based on many cohort studies ,subgroup analysis and two randomized controlled studies, a recent review(Ruiz-Irastorza G 2007) suggests that patients with definite APLS with a first venous thrombosis should be treated with prolonged oral anticoagulation at a target INR of

So, the best secondary thromboprophylaxis in patients with definite APLS is long-term anticoagulation at a target INR of 2.0-3.0. Patients with recurrent venous thrombotic events

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**4** 

*USA* 

**Deep Venous Thrombosis in** 

*Orthpaedic Surgery, University of Texas Southwestern* 

Lawson A. B. Copley and Ngozi Okoro

**Children with Musculoskeletal Infection** 

Deep venous thrombosis (DVT) is rarely identified in children. However, there has been an increase in the reported association of DVT with pediatric musculoskeletal infection.1-13 The relationship appears to be tied to the rise of community-acquired, Methicillin-resistant *Staphylococcus aureus* (CA-MRSA).5-13 Children who are affected by musculoskeletal infection and deep venous thrombosis appear to share similar clinical features. They often require intensive care, surgical intervention, and prolonged hospitalization.5,6,9 Pulmonary involvement, including pneumonia and septic pulmonary emboli, is frequent.9,11 It is possible that the causative organisms have an underlying genetic makeup, such as Panton Valentine leukocidin, that potentiates the cascade of clinical features seen in these children.6,8,10 This chapter explores the relationship of DVT and pediatric musculoskeletal infection through meta-analysis of the medical literature from the past forty years. To the extent possible, risk factors and clinical characteristics are evaluated and evaluation and

The earliest case report of DVT associated with osteomyelitis was by Horvath et al. in 1971.14 Including that original case, 58 cases of pediatric DVT associated with musculoskeletal infection have surfaced in the medical literature (see table 1).1-19 A decade by decade review of the case occurrence reveals an exponential increase in the number of cases reported since 2000, during which time 51 new cases have been identified. This is compared to one case from the 1970s and 3 cases from each decade of the 1980s and 1990s. The largest series, to the present, was reported at a single institution, Children's Medical Center of Dallas, compiled from two separate reports with overlapping study periods and included 15 unique cases of children with DVT.5,9 Of the four studies that report the incidence of DVT within a series of children with musculoskeletal infection, the total number of children with DVT is 32 among a total of 430 children reviewed giving an estimated incidence of DVT associated with

Several trends can be derived from the reported cases in a descriptive manner. Children with DVT were noted to be male 34 times out of the 46 cases in which gender was identified

**1. Introduction** 

treatment strategies are discussed.

musculoskeletal infection of 7.4%.3,6,8,9

**3. Gender, age, type, and site of infection** 

**2. Review of literature** 

