Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

nonpregnant with acute thrombosis

1st line – low molecular weight or unfractionated heparin

Back
ACUTE
|
nonpregnant with acute thrombosis
1st line – 

low molecular weight or unfractionated heparin

Once the diagnosis is confirmed, most patients are initially anticoagulated with low molecular weight or unfractionated heparin, followed by oral anticoagulation with a vitamin K antagonist.[8][45]​​​ Low molecular weight heparin is preferred over unfractionated heparin.

If unfractionated heparin is the chosen treatment agent, activity is monitored using frequent activated partial thromboplastin time (aPTT) or anti-Xa measurements, with dose adjustment based on local protocols; those with lupus anticoagulant will have a prolonged aPTT so monitoring with anti-Xa levels is preferred.

Primary options

dalteparin: 100 units/kg subcutaneously twice daily, maximum 18,000 units/day

OR

enoxaparin: 1 mg/kg subcutaneously twice daily; or 1.5 mg/kg subcutaneously once daily

Secondary options

heparin: 80 units/kg intravenous bolus, followed by 18 units/kg/hour infusion

Plus – warfarin following low molecular weight or unfractionated heparin

Back
ACUTE
|
nonpregnant with acute thrombosis
Plus – 

warfarin following low molecular weight or unfractionated heparin

Treatment recommended for ALL patients in selected patient group

Patients with antiphospholipid syndrome have a high risk of recurrent thrombosis after cessation of anticoagulation, so the general recommendation is to continue anticoagulation long term if the thrombosis is unprovoked.[8][45]​​​[46]​​[47]​​​​

Guidance for patients with APS with provoked thrombosis is less clear because there is lack of evidence with regards to duration of anticoagulation in this setting. Consideration should be given to the nature of the provoking factor associated with the thrombotic event and bleeding risks associated with long-term anticoagulation.

Patients with a history of a venous thromboembolic event should be anticoagulated with a vitamin K antagonist (e.g., warfarin) at a target international normalized ratio (INR) of 2.5 (range 2-3). Warfarin should be started at the same time as low molecular weight heparin (or unfractionated heparin) and the treatments overlapped until the INR is stable, before stopping heparin (see your local protocols for more information). Evidence suggests that high-intensity warfarin is no better than regular-intensity warfarin.[48][49]​ However, patients with recurrent venous thromboembolic events on treatment were excluded from these studies.

Chromogenic factor X and factor II activity levels can be tested to guide therapy in patients with recurrent thrombotic events or abnormal PT/INR at baseline.[51]​ 

Optimal treatment for patients with previous arterial events remains controversial due to the lack of good prospective studies in this group. High-intensity warfarin therapy (INR range 3-4) or addition of low-dose aspirin to anticoagulation have been advocated for management of these patients. However, existing data have not been able to prove that these approaches are superior over the standard INR goal range of 2-3.

Management of recurrent events in patients who are already anticoagulated at a higher therapeutic INR is particularly difficult. Patients with recurrent thrombosis should have a thorough review to understand the factors involved. Patients with recurrent thrombosis despite therapeutic anticoagulation may need a target INR of 3-4 and may benefit from antiplatelet therapies.[50]

Primary options

warfarin: 2-5 mg orally once daily initially, adjust dose according to target INR

More

Plus – management of risk factors

Back
ACUTE
|
nonpregnant with acute thrombosis
Plus – 

management of risk factors

Treatment recommended for ALL patients in selected patient group

Optimization of other risk factors for thrombosis is strongly recommended, such as smoking cessation and treatment of hyperlipidemia, hypertension, diabetes, and obesity, as well as addressing factors of immobility and estrogen use.

pregnant

1st line – low molecular weight or unfractionated heparin

Back
ACUTE
|
pregnant
|
with acute thrombosis
1st line – 

low molecular weight or unfractionated heparin

Pregnant women with acute thrombosis should receive therapeutic anticoagulation with LMWH or unfractionated heparin for the duration of the pregnancy. They can be switched to warfarin post-delivery. Low molecular weight heparin is preferred in pregnant women over unfractionated heparin due to the risk of osteoporotic fracture seen with long-term use of unfractionated heparin in pregnancy.[75]

If unfractionated heparin is the chosen treatment agent, activity is monitored using frequent activated partial thromboplastin time (aPTT) or anti-Xa measurements, with dose adjustment based on local protocols; those with lupus anticoagulant will have a prolonged aPTT so monitoring with anti-Xa levels is preferred.

Primary options

dalteparin: 100 units/kg subcutaneously twice daily, maximum 18,000 units/day

OR

enoxaparin: 1 mg/kg subcutaneously twice daily; or 1.5 mg/kg subcutaneously once daily

Secondary options

heparin: 80 units/kg intravenous bolus, followed by 18 units/kg/hour infusion

Plus – fetal monitoring + specialist multidisciplinary care

Back
ACUTE
|
pregnant
|
with acute thrombosis
Plus – 

fetal monitoring + specialist multidisciplinary care

Treatment recommended for ALL patients in selected patient group

Frequent prenatal exams and serial ultrasonography are recommended, owing to the risk of adverse pregnancy outcomes (preeclampsia, intrauterine growth restriction, and placental abruption).[58][76]​​

Fetal monitoring should include uterine artery Doppler scanning at 20-24 weeks to check for evidence of increased vascular resistance, which has been shown to predict placental dysfunction in women with antiphospholipid syndrome.[59] If this is abnormal, serial growth scans should be performed to monitor for intrauterine growth restriction.

Plus – warfarin post-delivery

Back
ACUTE
|
pregnant
|
with acute thrombosis
Plus – 

warfarin post-delivery

Treatment recommended for ALL patients in selected patient group

Pregnant patients are managed with heparin during pregnancy and can be switched to warfarin post-delivery. Patients with antiphospholipid syndrome (APS) have a high risk of recurrent thrombosis after cessation of anticoagulation, so the general recommendation is to continue anticoagulation long term if the thrombosis is unprovoked.[8][46]​​​[47] However, guidance for patients with APS with provoked thrombosis is less clear because there is lack of evidence with regards to duration of anticoagulation in this setting. Consideration should be given to the provoking factor associated with the thrombotic event and bleeding risks associated with long-term anticoagulation.

Patients should be anticoagulated with a vitamin K antagonist at a target international normalized ratio (INR) of 2.5 (range 2-3) postpartum. Two randomized clinical trials directly compared regular- and high-intensity warfarin therapy in patients with mainly venous thromboembolism and found that high-intensity therapy was no better than regular therapeutic-dose vitamin K antagonists and may be associated with increased bleeding.[48][49]​ However, patients with recurrent venous thromboembolic events on treatment were excluded from these studies: this group may need a target INR of 3-4.

Chromogenic factor X and factor II activity levels can be tested to guide therapy in patients with recurrent thrombotic events or abnormal PT/INR at baseline.

Primary options

warfarin: 2-5 mg orally once daily initially, adjust dose according to target INR

More

Plus – management of risk factors

Back
ACUTE
|
pregnant
|
with acute thrombosis
Plus – 

management of risk factors

Treatment recommended for ALL patients in selected patient group

Optimization of other risk factors for thrombosis is strongly recommended, such as smoking cessation and treatment of hyperlipidemia, hypertension, diabetes, and obesity, as well as addressing factors of immobility and estrogen use.

1st line – aspirin plus low molecular weight or unfractionated heparin

Back
ACUTE
|
pregnant
|
with APS and previous thrombotic event
1st line – 

aspirin plus low molecular weight or unfractionated heparin

Women with APS and previous history of thrombosis should receive anticoagulation with heparin/LMWH and aspirin throughout pregnancy and the postpartum period (6-8 weeks).[45]​​[56][57] [ Cochrane Clinical Answers logo ] ​​​​​​​

Some clinicians advocate increasing the dose of enoxaparin at 16 weeks of gestation, or adjusting with anti Xa levels.

Low molecular weight heparin is preferred in pregnant women over unfractionated heparin due to the risk of osteoporotic fracture seen with long-term use of unfractionated heparin in pregnancy.[75]

Primary options

enoxaparin: 40 mg subcutaneously once or twice daily

or

dalteparin: 5000 units subcutaneously once daily

-- AND --

aspirin: 81 mg orally once daily

Secondary options

heparin: 5000 units subcutaneously twice daily

and

aspirin: 81 mg orally once daily

Plus – fetal monitoring + specialist multidisciplinary care

Back
ACUTE
|
pregnant
|
with APS and previous thrombotic event
Plus – 

fetal monitoring + specialist multidisciplinary care

Treatment recommended for ALL patients in selected patient group

Frequent prenatal exams and serial ultrasonography are recommended, owing to the risk of adverse pregnancy outcomes (preeclampsia, intrauterine growth restriction, and placental abruption).[58][76]​​

Fetal monitoring should include uterine artery Doppler scanning at 20-24 weeks to check for evidence of increased vascular resistance, which has been shown to predict placental dysfunction in women with antiphospholipid syndrome.[59] If this is abnormal, serial growth scans should be performed to monitor for intrauterine growth restriction.

Plus – warfarin post-delivery

Back
ACUTE
|
pregnant
|
with APS and previous thrombotic event
Plus – 

warfarin post-delivery

Treatment recommended for ALL patients in selected patient group

Pregnant patients are managed with heparin during pregnancy and can be switched to warfarin post-delivery. Patients with antiphospholipid syndrome (APS) have a high risk of recurrent thrombosis after cessation of anticoagulation, so the general recommendation is to continue anticoagulation long term if the thrombosis is unprovoked.[8][46]​​​[47] However, guidance for patients with APS with provoked thrombosis is less clear because there is lack of evidence with regards to duration of anticoagulation in this setting. Consideration should be given to the provoking factor associated with the thrombotic event and bleeding risks associated with long-term anticoagulation.

Patients should be anticoagulated with a vitamin K antagonist at a target international normalized ratio (INR) of 2.5 (range 2-3) postpartum. Two randomized clinical trials directly compared regular- and high-intensity warfarin therapy in patients with mainly venous thromboembolism and found that high-intensity therapy was no better than regular therapeutic-dose vitamin K antagonists and may be associated with increased bleeding.[48][49] However, patients with recurrent venous thromboembolic events on treatment were excluded from these studies: this group may need a target INR of 3-4.

Chromogenic factor X and factor II activity levels can be tested to guide therapy in patients with recurrent thrombotic events or abnormal PT/INR at baseline.

Primary options

warfarin: 2-5 mg orally once daily initially, adjust dose according to target INR

More

1st line – aspirin + low molecular weight or unfractionated heparin

Back
ACUTE
|
pregnant
|
with obstetric APS
1st line – 

aspirin + low molecular weight or unfractionated heparin

Women with antiphospholipid syndrome and no thrombotic history should receive prophylactic low-dose aspirin, along with prophylactic low molecular weight heparin, during pregnancy and the postpartum period (6-8 weeks).​​​​​[45]​​[56][57] [ Cochrane Clinical Answers logo ] ​​​​​​ Low molecular weight heparin is preferred in pregnant women over unfractionated heparin due to the risk of osteoporotic fracture seen with long-term use of unfractionated heparin in pregnancy.[75]

Some clinicians advocate increasing the dose of enoxaparin at 16 weeks of gestation.

Venous thromboembolism thromboprophylaxis with low molecular weight or unfractionated heparin should be given for 6 weeks postpartum.[45]​​[58] Patients may continue aspirin as primary thromboprophylaxis, but protective effects against thrombosis have not been demonstrated.​​

Primary options

aspirin: 81 mg orally once daily

OR

aspirin: 81 mg orally once daily

-- AND --

enoxaparin: 40 mg subcutaneously once daily

or

dalteparin: 5000 units subcutaneously once daily

or

heparin: 5000 units subcutaneously twice daily

Plus – fetal monitoring + specialist multidisciplinary care

Back
ACUTE
|
pregnant
|
with obstetric APS
Plus – 

fetal monitoring + specialist multidisciplinary care

Treatment recommended for ALL patients in selected patient group

Frequent prenatal exams and serial ultrasonography are recommended, owing to the risk of adverse pregnancy outcomes (preeclampsia, intrauterine growth restriction, and placental abruption).[58][76]​​

Fetal monitoring should include uterine artery Doppler scanning at 20-24 weeks to check for evidence of increased vascular resistance, which has been shown to predict placental dysfunction in women with antiphospholipid syndrome.[59] If this is abnormal, serial growth scans should be performed to monitor for intrauterine growth restriction.

1st line – aspirin

Back
ACUTE
|
pregnant
|
with incidental antiphospholipid antibodies
1st line – 

aspirin

Women with antiphospholipid syndrome (APS) antibodies alone (i.e., do not fit criteria for APS) are usually given aspirin alone during pregnancy, as well as thromboprophylaxis for 6 weeks postpartum.[58][66]

Attention should be paid to management of risk factors for cardiovascular and venous thromboembolic disease in all these patients. Patients should be assessed for the risk of thrombosis both prenatally and in the postpartum period in conjunction with local protocol and prescribed thromboprophylaxis as appropriate. Patients may continue aspirin as primary thromboprophylaxis, but protective effects against thrombosis have not been demonstrated.

Primary options

aspirin: 81 mg orally once daily

Plus – fetal monitoring + specialist multidisciplinary care

Back
ACUTE
|
pregnant
|
with incidental antiphospholipid antibodies
Plus – 

fetal monitoring + specialist multidisciplinary care

Treatment recommended for ALL patients in selected patient group

Frequent prenatal exams and serial ultrasonography are recommended, owing to the risk of adverse pregnancy outcomes (preeclampsia, intrauterine growth restriction, and placental abruption).[58][76]​​

Fetal monitoring should include uterine artery Doppler scanning at 20-24 weeks to check for evidence of increased vascular resistance, which has been shown to predict placental dysfunction in women with antiphospholipid syndrome.[59] If this is abnormal, serial growth scans should be performed to monitor for intrauterine growth restriction.

Plus – venous thromboembolism thromboprophylaxis post-delivery

Back
ACUTE
|
pregnant
|
with incidental antiphospholipid antibodies
Plus – 

venous thromboembolism thromboprophylaxis post-delivery

Treatment recommended for ALL patients in selected patient group

Venous thromboembolism thromboprophylaxis with unfractionated or low molecular weight heparin should be given for 6 weeks postpartum.[58][66] Patients may continue aspirin as primary thromboprophylaxis, but protective effects against thrombosis have not been demonstrated.

Primary options

enoxaparin: 40 mg subcutaneously once daily

OR

dalteparin: 5000 units subcutaneously once daily

OR

heparin: 5000 units subcutaneously twice daily

catastrophic APS (pregnant or nonpregnant)

1st line – unfractionated or low molecular weight heparin

Back
ACUTE
|
catastrophic APS (pregnant or nonpregnant)
1st line – 

unfractionated or low molecular weight heparin

Catastrophic antiphospholipid syndrome (APS) is a rare manifestation of APS. Patients present with multiorgan impairment due to widespread thromboses.[19][67]​ Thrombosis is commonly manifested as microvascular thrombosis rather than large-vessel thrombosis. There is an associated high mortality (up to 50%). 

Anticoagulation with heparin is recommended until the patient's condition is stabilized.[19]

If unfractionated heparin is the chosen treatment agent, activity is monitored using frequent activated partial thromboplastin time (aPTT) or anti-Xa measurements, with dose adjustment based on local protocols; those with lupus anticoagulant will have a prolonged aPTT so monitoring with anti-Xa levels is preferred.

Primary options

heparin: 80 units/kg intravenous bolus, followed by 18 units/kg/hour infusion

OR

dalteparin: 100 units/kg subcutaneously twice daily, maximum 18,000 units/day

OR

enoxaparin: 1 mg/kg subcutaneously twice daily; or 1.5 mg/kg subcutaneously once daily

Plus – immunosuppressive therapy

Back
ACUTE
|
catastrophic APS (pregnant or nonpregnant)
Plus – 

immunosuppressive therapy

Treatment recommended for ALL patients in selected patient group

Patients may require aggressive management and treatment is tailored according to the extent of disease involvement. Guidelines recommend combination therapy with heparin, corticosteroids, and plasma exchange or intravenous immunoglobulin over single agents.[45]​ Specialist consultation is necessary.

In refractory cases, some case reports suggest rituximab, eculizumab, or daratumumab may be of benefit.[70][71][72]

Primary options

prednisolone: see local specialist protocols

-- AND --

plasma exchange: see local specialist protocols

or

immune globulin (human): consult specialist for guidance on dose

Secondary options

rituximab: consult specialist for guidance on dose

OR

eculizumab: consult specialist for guidance on dose

OR

daratumumab: consult specialist for guidance on dose

Consider – fetal monitoring + specialist multidisciplinary care

Back
ACUTE
|
catastrophic APS (pregnant or nonpregnant)
Consider – 

fetal monitoring + specialist multidisciplinary care

Treatment recommended for SOME patients in selected patient group

Frequent prenatal exams and serial ultrasonography are recommended, owing to the risk of adverse pregnancy outcomes (preeclampsia, intrauterine growth restriction, and placental abruption).[58][76]​​

Fetal monitoring should include uterine artery Doppler scanning at 20-24 weeks to check for evidence of increased vascular resistance, which has been shown to predict placental dysfunction in women with antiphospholipid syndrome.[59] If this is abnormal, serial growth scans should be performed to monitor for intrauterine growth restriction.

ONGOING

incidental antiphospholipid antibodies

1st line – management of risk factors

Back
ONGOING
|
incidental antiphospholipid antibodies
1st line – 

management of risk factors

Patients who have antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibody, and anti-beta2-glycoprotein I) but no thrombotic or related obstetric complications (i.e., do not fit criteria for antiphospholipid syndrome) are considered to have incidental antiphospholipid antibodies (aPL).

Such patients may be at increased risk of thrombosis, but it is not possible to identify which specific patients are at risk.[60]

Thus, attention should be paid to management of risk factors for cardiovascular and venous thromboembolic disease in all these patients. Routine management of other risk factors for thrombosis is also strongly recommended, such as smoking cessation and management of hyperlipidemia, hypertension, diabetes, and obesity, as well as addressing factors of immobility and estrogen use.

Evidence is conflicting regarding the use of aspirin in patients with incidental aPL. Some retrospective studies suggest a protective effect against thrombosis, while a placebo-controlled trial showed no such benefit.[61][62][63] Meta-analysis based on limited data concluded that patients with aPL who were treated with aspirin had a lower risk of thrombosis.[64] European League Against Rheumatism guidelines recommend using aspirin in patients with triple positive aPL or in patients with aPL associated with systemic lupus erythematosus.[45]​​

There are additional concerns regarding the use of aspirin; trials among healthy individuals have suggested that the benefit of reducing thrombosis is less than the bleeding risk, and, among individuals with diabetes, evidence suggests the use of aspirin is ineffective in reducing the risk of nonfatal myocardial infarction or cardiovascular death and may still increase the risk of major bleeding.[65]

back arrow

Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

Use of this content is subject to our disclaimer