Antiphospholipid Antibody Syndrome. Rare Diseases of the Immune System

15. Treatment of Thrombosis in Antiphospholipid Syndrome

Simon Braham , Paolo Bucciarelli  and Marco Moia 


Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Via F. Sforza 35, Milan, 20122, Italy

Simon Braham


Paolo Bucciarelli


Marco Moia (Corresponding author)


15.1 Introduction

Antiphospholipid syndrome (APS) is an acquired cause of venous thromboembolism (VTE), i.e., deep vein thrombosis and/or pulmonary embolism in patients with systemic lupus erythematosus or other autoimmune diseases, as well as in the general population. Antiphospholipid antibodies (aPLs), particularly lupus anticoagulant, are important thrombotic risk factors [1]. Growing evidence demonstrates that aPLs, particularly antibodies specific for β2glycoprotein I, are not merely a marker of thrombophilia but are pathogenic, directly contributing to hypercoagulability. Current management of VTE in patients with APS does not substantially differ from that in the general population of patients with VTE and without APS. However, a more problematic monitoring of the anticoagulant treatment, both in the acute and in the long-term management, and the high risk of recurrences makes the treatment of VTE in patients with APS more challenging and deserves some special considerations. The intensity and duration of anticoagulation with vitamin K antagonists (VKA) for longer-term secondary prophylaxis are therefore important issues.

The treatment of acute VTE in patients with APS is the same as for other patients with VTE. In the acute phase of VTE, anticoagulation with unfractionated heparin (UH) or low-molecular-weight heparin (LMWH), or fondaparinux, followed by VKA (i.e., warfarin, acenocoumarol, or phenprocoumon) is still the standard of care [2].

New oral anticoagulants, i.e., the direct inhibitor of coagulation factor IIa dabigatran etexilate and the direct inhibitors of factor Xa rivaroxaban, apixaban, or edoxaban, may be useful alternatives, but their efficacy and safety in patients with APS have still to be proven in proper studies. The main characteristics of these new drugs and their possible advantages and limits are addressed in the second part of this chapter.

15.2 Treatment of Acute VTE

15.2.1 Parenteral Anticoagulation

The vast majority of patients with APS and diagnosis of VTE should immediately receive parenteral anticoagulation, i.e., therapeutic doses of subcutaneous LMWH or fondaparinux or intravenous UH. Only patients with acute PE associated with hypotension (systolic blood pressure < 90 mmHg) who do not have a high bleeding risk should be systemically administered thrombolytic therapy, followed by heparins/fondaparinux. From studies in patients with VTE, LMWH or fondaparinux (administered at fixed, body-weight-adjusted, therapeutic doses) were at least as effective and safer than intravenous monitored UH [2]. Moreover, they have a lower incidence of side effects such as heparin-induced thrombocytopenia (HIT) and osteoporosis. The advantage of LMWH and fondaparinux over UH may be even more relevant in those patients with LA who have baseline prolonged activated partial thromboplastin time (aPTT), which makes UH monitoring cumbersome and unreliable.

The therapeutic doses of LMWH range from 125 to 200 anti-FXa units/die depending on the different molecule. Fondaparinux is administered at a single daily dose of 5.0 mg for body weight < 50 kg, of 7.5 mg for body weight between 50 and 100 kg, and of 10 mg for body weight > 100 kg. LMWH and fondaparinux are both cleared by the kidney. Renal insufficiency increases plasma levels of these drugs, thus increasing the risk of bleeding. In case of severe renal insufficiency (i.e., creatinine clearance < 30 mL/min), the use of LMWH or fondaparinux at therapeutic doses is generally contraindicated. LMWH doses could be empirically reduced or monitored by a chromogenic assay of anti Xa activity in patient’s plasma. However, since this laboratory test is not frequently available, patients with severe renal insufficiency are preferably treated with UH. When intravenous UH is chosen, an initial IV bolus (80 U/kg or 5,000 U) should be administered, followed by continuous infusion (initially at a dose of 18 U/kg/h or 1,300 U/h) with dose adjustment to achieve and maintain an aPTT prolongation that corresponds to plasma heparin levels of 0.3–0.7 IU/mL anti Xa activity. With the more commonly used reagents, this corresponds to an aPTT ratio from 1.5 to 2.5 times the baseline values. However, in patients with LA and baseline prolonged aPTT ratio, this hypothetical equivalence may be unreliable and therefore intravenous UH may result to being very difficult to manage even by experienced physicians.

15.2.2 Oral Anticoagulation

VKA act by inhibiting the vitamin K-dependent liver synthesis of four coagulation factors (II, VII, IX, and X) and two natural anticoagulant proteins (protein C and protein S). Hence, they are indirect inhibitors requiring few days to achieve their therapeutic effect. They should be started as soon as possible after parenteral anticoagulation, in order to reduce the time of administration of heparin/fondaparinux. As well known, VKA are ineffective as antithrombotic drugs during the very first days of administration, so that it is mandatory to continue the administration of the parenteral active anticoagulant drug for at least 5 days after the first dose of VKA. The parenteral anticoagulant drug can subsequently withdrawn provided that the International Normalized Ratio (INR), the test of choice for VKA monitoring derived from the prothrombin time, is >2.0 for at least two consecutive days. Several drugs as well as some dietary constituents and alcohol intake may interact with VKA and interfere with their anticoagulant intensity. Hence, a constant VKA monitoring with INR is required (at least every 4–6 weeks), preferably in specialized centers.

15.2.3 Regimen, Control, and Duration

Retrospective studies of APS patients suggested that high-intensity treatment with an INR ≥3.0 was more effective than less intensive regimens [3]. However, two more recent randomized controlled trials found that high-intensity treatment (INR 3.1–4.0) is no better than moderate intensity (INR 2.0–3.0) [45]. Since a moderate intensity treatment requires less frequent laboratory controls and has a lower risk of hemorrhage, this is now, in most cases, the standard of care. A higher target INR (>3.0) is suggested, on the basis of expert opinion, in case of recurrent VTE despite an INR in the therapeutic range [6]. It should be pointed out that most available retrospective and prospective studies included both patients with VTE and arterial thrombosis, so that it is not known if these different clinical manifestations of thrombotic APS may benefit from different treatment regimens.

INR results can be unreliable in a subset of patients with APS. In 6.5–10 % of patients with lupus anticoagulant, the antiphospholipid antibodies (aPLs) may prolong the prothrombin time assay leading to an unreliable INR value [79]. The reagents used to test the prothrombin time and to derive INR values may have different sensitivity to aPLs. A coagulation assay that is not affected by aPLs, for example, a chromogenic factor II activity assay, may be used to overcome this problem [10]. Therefore, in selected patients with APS, INR should be checked simultaneously to a chromogenic assay of factor II. This procedure may apply to patients with baseline prolonged prothrombin time, or with unexplained very unstable INR values, or with recurrent thrombosis and INR values apparently within the therapeutic interval. For INR within the therapeutic values, the chromogenic factor II level should range approximately from 15 to 25 %, while for factor II plasma levels above 30 %, the degree of anticoagulation is inadequate. In such patients, different reagents for INR determination should be tested and/or the INR therapeutic target individually chosen according with this procedure [1011].

The duration of anticoagulation for secondary prophylaxis of VTE in APS is also an important issue, which is closely related to the risk of recurrence. The risk of recurrent VTE in APS patients off anticoagulation is generally high. Previous reports found an incidence from 10 to 29 % per year [12] or of 50 % at 2 years and 78 % at 8 years [13]. Patients with APS can be divided in two categories: “high”-risk and “low”-risk patients (Table 15.1). Long-term anticoagulation is generally recommended in patients with APS and after a first unprovoked thrombotic event. Conversely, data about the optimal duration of anticoagulant treatment in patients with APS after a single thrombotic event provoked by a removable risk factor are lacking. Therefore, the duration of treatment should be individually planned. The acceptance and the cooperation of a patient are essential for such a demanding treatment as lifelong anticoagulation. For this reason, patients should always be involved in the decisions about long-term management of VTE, with adequate information about the presumed risk of recurrence without anticoagulation and on the risks and the burden of lifelong anticoagulation.

Table 15.1

Risk of VTE recurrence in patients with APS

High-risk patients

Low-risk patients

Lupus anticoagulant presence

Isolated intermittently positive aCL or aβ2GPI at low titers

aCL at medium–high titers

Previous single venous thrombosis

Double or triple positivity (LA, aCL, aβ2GPI)

Removable risk factor

Presence of SLE

Presence of hereditary thrombophilia

Presence of coexistent cardiovascular risk factors

Previous arterial thrombosis

Recurrent thrombosis (arterial, venous, or both) during anticoagulation therapy

LA lupus anticoagulant, aCL anticardiolipin, 2 GPI anti-β2 glycoprotein I, SLE systemic lupus erythematosus

15.2.4 Other Treatments

Immunosuppressive drugs, such as corticosteroids and rituximab, are neither thought to be necessary in the acute phase of VTE in APS nor effective in preventing recurrent VTE associated with aPLs, except for resistant APS [1416], and in the case of catastrophic APS. Combined VKA and acetylsalicylic acid (ASA) have been proposed in patients with APS and arterial events [17]. However, since the evidence of an increased efficacy of this association is lacking and the increased risk of bleeding is proven, a careful assessment of the patients’ bleeding risk should be performed before starting this regimen. Statins, hydroxychloroquine, or LMWH has also been suggested in patients with recurrent thrombosis during VKA, provided that any possible attempt to optimize the quality of VKA treatment, in order to obtain a good time in therapeutic range, has been made (Table 15.2).

Table 15.2

Secondary thromboprophylaxis regimens for patients with established APS

Patients with definite APS and first venous event

Anticoagulant therapy with VKA to a target INR of 2.5 (range 2.0–3.0) indefinitely.

Duration of treatment can be limited to about 6 months in patients with low-risk aPL profile and provoked VTE

Patients with definite APS and arterial events

Anticoagulant therapy with VKA to a target INR of 3.0 (range 2.5–3.5) or VKA to a target INR of 2.5 combined with antiplatelet treatment (i.e., ASA 100 mg). Check the patient’s bleeding risk before starting the combined VKA-ASA regimen

Patients with recurrent refractory thrombosis

Consider statins, hydroxychloroquine, or LMWH in refractory cases

APS antiphospholipid syndrome, VKA vitamin K antagonist, ASA acetylsalicylic acid, INR international normalized ratio, LMWH low-molecular-weight heparin

15.3 New Oral Anticoagulant Drugs

The limitation and, in some cases, the difficulty to correctly manage VKA therapy have driven the search for new oral anticoagulant drugs (NOA). To date, three NOA have been licensed by FDA and EMA for the prevention of VTE in patients undergoing major elective orthopedic surgery and of stroke and systemic embolism in patients with atrial fibrillation: the direct inhibitor of coagulation factor IIa dabigatran etexilate and the direct inhibitors of factor Xa rivaroxaban and apixaban [18]. Other NOA are currently under investigation (edoxaban, betrixaban, others) and will probably be available in a few years. Rivaroxaban has already been licensed also for patients with VTE, both for the acute treatment and for the secondary prophylaxis. These agents represent a major advance as, unlike VKA, they do not interact with diet and alcohol intake and have few reported drug interactions affecting anticoagulant intensity. Furthermore, laboratory monitoring is not routinely required due to their predictable anticoagulant effects. Table 15.3 summarizes the main pharmacological characteristics of NOA already available in Europe for clinical use.

Table 15.3

Pharmacological characteristics of NOA






Factor Xa

Factor IIa

Factor Xa






>80 %

6 %

>50 %

Plasma protein binding

92–95 %

34–35 %

87 %

Time to peak

3 h

2 h

3 h


9 h

14–17 h

9–14 h


Fixed dose o.d.

Fixed dose b.i.d.

Fixed dose b.i.d.

Routine drug monitoring





66 % renal

80 % renal

25 % renal

33 % fecal

55 % fecal

o.d. once daily, b.i.d. twice daily

awith normal creatinine clearance

The efficacy and safety of NOA in the prevention of stroke or systemic embolization in patients with non-valvular atrial fibrillation have been demonstrated in large phase III clinical trials, all showing that these drugs are as effective as warfarin, with a similar incidence of major bleeding [1921]. Of particular relevance is the lower incidence of intracranial hemorrhage in patients taking NOA than in those taking VKA. Conversely, the rate of GI bleeding is higher in the former group than in the latter.

Currently, rivaroxaban is the only NOA which is licensed for the treatment of VTE (both deep vein thrombosis and pulmonary embolism) in adults, following the results of the EINSTEIN-DVT and EINSTEIN-PE studies [2223], while both dabigatran and apixaban are under review for the treatment of acute VTE. Unfortunately, to date the safety and efficacy of NOA in children have not been established yet, so that they can be used in adult patients only. NOA are potentially teratogenic and must not be used in pregnancy and during breastfeeding, and women with childbearing potential must be warned about this problem.

As for all NOA, which are direct coagulation inhibitors, rivaroxaban can be started directly after the diagnosis of VTE, without bridging with heparins or fondaparinux. The initial dosage is 15 mg b.i.d for 3 weeks, followed by 20 mg o.d., and the tablets should be taken during meal.

15.3.1 Role of NOA in Patients with APS

Due to their better profile in comparison with VKA (no need of routine laboratory monitoring, no reported interactions with food or alcohol, few reported drug interactions), NOA are expected to result in improved quality of life in VTE patients with APS who require an indefinite period of anticoagulation [24]. Because aPLs interfere with a number of hemostatic mechanisms, a possible influence of these antibodies on the anticoagulant effect of NOA cannot be excluded. Therefore, the efficacy and safety of NOA in the treatment of VTE patients with APS might be different from those in VTE patients without APS. Despite aPL status was not documented in the available clinical trials, it is very likely that patients with APS were included in the study populations in phase III clinical trials of rivaroxaban (and other NOA) versus VKA for the treatment of VTE. Nevertheless, the results of ongoing prospective “ad hoc” trials of NOA in patients with APS, such as the RAPS (Rivaroxaban in AntiPhospholipid Syndrome) [25], are urgently needed. Until these results are not available, the use of rivaroxaban (and in future the other NOA) seems to be justified in selected patients with APS and scanty VKA management or with VTE recurrence during VKA treatment.

15.3.2 Cautions and Contraindications with NOA

Despite the fact that therapy with NOA does not require routine laboratory monitoring, NOA administration, as with other anticoagulants, should be implemented within a structured setting, where an experienced staff provides patients with clear information about the anticoagulant treatment and the risk and management of bleeding.

Renal impairment may necessitate dose reduction or avoidance of NOA. Dose adjustment of rivaroxaban is not required in case of mild renal impairment (creatinine clearance 50–80 mL/min), while a reduction of the dose from 20 mg o.d. to 15 mg o.d. should be considered for moderate renal impairment (creatinine clearance 30–49 mL/min). Rivaroxaban should be used with caution when creatinine clearance is between 15 and 29 mL/min and is not recommended in patients with severe renal impairment (creatinine clearance <15 mL/min). The recommendations in case of renal disease are more strict for dabigatran (contraindicated for creatinine clearance <30 mL/min) because it is predominantly excreted by the kidneys and less for apixaban (only a 25 % renal excretion). Periodic monitoring of renal function is particularly recommended in elderly patients or in situations potentially leading to renal impairment, such as infections and dehydration. Liver impairment is not a contraindication for rivaroxaban use, except in case of severe hepatic disease associated with coagulopathy and clinically relevant bleeding risk.

Laboratory tests in patients on NOA are desirable only in specific clinical settings, including patients at extremes of body weight, with renal impairment, and with poor compliance; in case of hemorrhagic or thrombotic complications; and when surgery or other interventions are required [26]. The diluted thrombin time or the ecarin thrombin time are the most sensitive tests for dabigatran, while a modified prothrombin time or an anti-factor Xa assay are the most suitable tests for monitoring rivaroxaban [27]. However, the experience with such tests, particularly in patients with APS, is very limited and requires a support by experts in blood coagulation.



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