Antiphospholipid antibody syndrome (Hughes syndrome)

Antiphospholipid antibody syndrome (APS), also known as Hughes syndrome, is an acquired autoimmune thrombotic disorder characterized by venous and/or arterial thrombosis or obstetrical complications.

Although the exact pathophysiology is not known, the antiphospholipid antibodies are thought to activate endothelial cells, monocytes and platelets resulting in increased synthesis of tissue factor and thromboxane A2 causing thrombosis in the vascular bed. Complement activation is increasingly recognized as playing an important role in this disorder.

To meet the criteria for APS a patient must have both clinical and laboratory evidence of disease. The Sapporo criteria, developed to aid clinicians and researchers in making this diagnosis, were recently updated as follows:

Vascular thrombosis:

One or more clinical episodes of arterial, venous or small-vessel thrombosis in any tissue or organ. Thrombosis should be supported by objective and definitive radiographic or histopathologic findings.
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Pregnancy morbidity (one of the following):

One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation.

One or more premature births of a morphologically normal neonate before the 34th week of gestation due to eclampsia, severe pre-eclampsia or recognized features of placental insufficiency.

Three or more unexplained, consecutive, spontaneous abortions before the 10th week of gestation, with exclusion of maternal anatomic or hormonal abnormalities and parental chromosomal abnormalities.

Lupus anticoagulant present in plasma on two or more occasions at least 12 weeks apart. Whenever possible testing should be done off anticoagulation due to possibility of both false positive and false negative results.
Anticardiolipin antibody (immunoglobulin G (IgG) and/or immunoglobulin M (IgM) isotype) in serum or plasma, present in medium or high titers (greater than 40 IgG or IgM phospholipid units, or 99th centile) on two or more occasions at least 12 weeks apart, measured by a standardized enzyme-linked immunosorbent assay (ELISA).
Anti-β₂ glycoprotein I antibody (IgG and/or IgM isotype) present in medium or high titer (greater than 40 IgG or IgM phospholipid units, or greater than 99th centile) in serum or plasma, present on two or more occasions at least 12 weeks apart, measured by a standardized ELISA.

Disease activity tends to correlate with antibody titer and IgG isotype is generally more commonly associated with clinical events than IgM.

Symptoms can occur in all organ systems. A “typical” patient with APS is a young woman in her childbearing years with unprovoked first or recurrent venous thromboembolism (VTE). Venous thrombosis is the most common presentation of the disease, including deep vein thrombosis (DVT) and pulmonary embolism (PE), but mesenteric vein, renal vein, retinal vein, hepatic vein, adrenal vein, or cerebral vein thrombosis also occur.

Patients with APS may have arterial thrombosis including stroke or transient ischemic attack (TIA), digital gangrene, retinal artery thrombosis and myocardial infarction. Obstetrical complications are described in detail in the section above.

Other common findings in APS include livedo reticularis, thrombocytopenia, hemolytic anemia and heart valve disease (Libman Sacks valvulopathy). Less common manifestations include nephropathy, osteonecrosis, seizures, vascular dementia, pulmonary hypertension, cardiomyopathy, and adrenal hemorrhage.

Thrombosis while on anticoagulation occurs more commonly in patients with APS than those without the disorder. Thus it should be suspected in any patient with arterial or venous thrombosis despite therapeutic anticoagulation. In some patients this may be due to international normalized ratio (INR) overestimating effect of warfarin therapy as a result of antibodies interfering with assay results (see section D/E).

Catastrophic APS (CAPS) is a life threatening form of this disease with a distinct clinical presentation involving small-vessel thrombosis that can lead to or present with multi-organ failure. In contrast to APS, only about 20% of CAPS patients have large venous or arterial thrombosis. Fewer than 1% of APS patients develop CAPS, but mortality is high for those who do; mortality previously approached 50%, but has improved to 30% with more aggressive therapy.

CAPS is defined as thromboses in three or more organs developing in less than a week, microthrombosis in at least one organ and persistent aPL positivity. If 3 out of 4 of these are present the patient can be classified as probable CAPS. Renal, pulmonary, cardiac, cerebral, and dermatologic involvement is common. Precipitants include infection, anticoagulation withdrawal, and surgical procedures.

APS mainly affects young women in their childbearing years. The vast majority of patients will present prior to age 50 years. Those with APS over 50 years tend to be male and present with arterial thrombosis (cerebrovascular accident or coronary artery disease). While 30% percent of patients with lupus will develop the syndrome, 50% of patients with APS have primary disease not associated with systemic lupus erythematosus (SLE).

The following patterns should raise suspicion for APS:

Patients less than 50 years old presenting with VTE or stroke.
Recurrent thrombosis despite anticoagulation.
History of arterial and venous thrombosis.
Thrombosis at unusual sites.
Thrombosis in patients with SLE.
Thrombosis in patients with Raynaud’s or livedo reticularis.
Fetal loss after 10 weeks or multiple consecutive early miscarriages.
Thrombosis in multiple organs and evidence of multiorgan failure (catastrophic APS) particularly in patients with a history of APS who have recently interrupted anticoagulation, undergone surgery or have concomitant infection.

APS is a protean syndrome as it can affect any vascular bed and is commonly associated with hematologic and dermatologic abnormalities. It is helpful to think about the differential diagnosis in the context of the presentation:

Thrombosis and thrombocytopenia – consider disseminated intravascular coagulation (DIC), heparin-induced thrombocytopenia (HIT), or thrombotic thrombocytopenic purpura (TTP). Concomitant infection or sepsis with coagulopathy helps differentiate from DIC; recent exposure to heparin and appropriate timing of thrombocytopenia may favor HIT.
Arterial and venous thrombosis – consider malignancy, myeloproliferative disorders, sickle cell disease, hyperhomocysteinemia, vasculitis, and venous thrombosis with paradoxical embolism.
Thrombosis and aphthous ulcers – Behçet’s syndrome or inflammatory bowel disease.
Recurrent thrombosis despite anticoagulation – cancer; HIT or antithrombin deficiency (if recent/current heparin); protein C or S deficiency (if recent warfarin re-initiation without bridge); malignancy or Trousseau’s syndrome; and medication non-adherence.
Thrombosis in unusual location – myeloproliferative disorders, inflammatory bowel disease, nephrotic syndrome (renal vein thrombosis), paroxysmal nocturnal hemoglobinuria (PNH), and malignancy.

Diagnostic clues on physical exam include livedo reticularis, Raynaud’s, findings consistent with SLE (malar rash, aphthous ulcers, arthritis, photosensitivity, alopecia), leg ulcerations, varicose veins or signs of venous stasis, signs of DVT/PE, loud pulmonary 2 (P2), regurgitant murmur, digital gangrene, abdominal pain, or ascites (mesenteric or heparin vein thrombosis).

The presence of venous or arterial thrombosis should be confirmed radiographically; in patients with unexplained consecutive recurrent early miscarriage, efforts should be made to exclude maternal anatomical or hormonal abnormalities and paternal and maternal chromosomal causes. If biopsy is pursued, thrombosis should be present without substantial inflammation of the vessel wall.

To meet the criteria for APS there should be laboratory evidence of the disease on at least two assays, at least 12 weeks apart. ELISA for anticardiolipin antibody IgG and IgM and beta 2 glycoprotein IgG and IgM should be sent as well as at least one assay for lupus anticoagulant (LA). While the partial thromboplastin time (PTT) may be prolonged in patients with lupus anticoagulant it should not be used as a screening test for LA. Over 30% of APS patients have a normal PTT.

Caution must be taken when interpreting results of these tests. In the setting of acute thrombosis, anticoagulation or acute infection testing can be unreliable. Anticoagulation has been reported to cause both false positives and false negatives for LA. There is some suggestion that acute thrombosis may cause elevation in anticardiolipin antibodies as well, although this has not been widely demonstrated in the literature.

Ideally the LA tests should be sent prior to initiation of anticoagulation and antibody tests done outside of the setting of acute thrombosis. In cases where this disorder is strongly suspected however, testing should not be delayed. Up to 5% of healthy adults will have antiphospholipid antibodies. LA is more strongly associated with true disease than antibodies. Of the antibodies IgG is more strongly associated with clinical symptoms than IgM, and higher titers correlate with severity of disease. Patients who have “triple positivity” for LA, anticardiolipin antibodies, and beta-2 glycoprotein antibodies are at increased risk.

If any of the tests are abnormal they should be repeated after a minimum of 12 weeks to confirm persistent positivity. This includes test results that are mildly abnormal but do not meet criteria for APS diagnosis.

In cases of suspected catastrophic APS, titers of antiphospholipid antibodies may help direct immunotherapy.

Additional studies should be considered to rule out other disorders that are typically on the differential if clinically appropriate.

See above.

Thrombotic complications of APS should be confirmed with appropriate radiographic studies. Biopsy of dermatologic lesions may be helpful.

N/A

The mainstay of treatment in APS is anticoagulation, which after a thorough review for absolute contraindications, should be started immediately for patients with venous or arterial disease.

Initial therapy should be with heparin or low molecular weight heparin (LMWH), bridging to warfarin with a goal INR of 2-3. While the literature does not support a higher goal INR for all patients with APS, there are some exceptions.

A recent systematic review found high rates of recurrent events in APS patients with arterial disease or recurrent thrombosis when INR was 2-3 but not when INR was 3-4. Thus many experts recommend this higher goal INR for APS patients with arterial or recurrent thromboses and INR 2-3 for patients with first venous thromboemblism. However, recent guidelines from the American College of Chest Physicians recommend goal INR 2-3 for patients with either venous or arterial thromboses (grade 2B recommendation).

Treatment of obstetrical APS is beyond the scope of this review.

Catastrophic APS is treated with anticoagulation as well as immunosuppressive therapy such as high dose steroids, plasmapheresis and intravenous (IV) immunoglobulin.

See above.

The most dangerous complication of anticoagulation is bleeding, and the site with highest mortality is intracranial hemorrhage. The neurologic exam should be followed closely on all patients who start full dose anticoagulation. The practitioner should look daily for signs of bleeding, remembering to look on the abdomen and back for signs of retroperitoneal bleed and at extremities for spontaneous intramuscular bleeds.

Anticoagulant monitoring depends on the agent selected for treatment: INR for warfarin drawn daily, PTT for heparin drawn every 6 hours until stable, then daily, and anti-Xa levels for LMWH if the patient has compromised renal function or is very low or very high weight.

Platelet count should be monitored daily for HIT and hemoglobin/hematocrit (Hgb/Hct) for signs of bleeding. Renal function should be monitored if it is compromised or at risk for changing (recent exposure to contrast in high risk patient) or if the patient is on LMWH, as the dose may need to be adjusted or be replaced with unfractionated heparin.

Patients with APS and venous thrombosis are typically treated with anticoagulation indefinitely due to the high risk of recurrence if anticoagulation is stopped. Recurrence rates off anticoagulation are reported to be as high as 20-30% per year.

As the INR may overestimate the anticoagulant effect of warfarin (the antibodies can cause a false increase in INR) the reliability of the INR should be established. This is done by measuring chromogenic factor X or factor II levels simultaneously with the INR. If these values do not correlate (an INR of 3 roughly correlates to a factor X level of 40% while an INR of 2 correlates to a factor X level of 20%), then INR monitoring should be abandoned and chromogenic factor levels should be followed instead. If this type of monitoring is not available one can consider long-term parenteral anticoagulation. Although trials are underway as of this update, none of the new directly acting oral anticoagulants, including dabigatran, rivaroxaban, apixaban or edoxaban have been well evaluated in patients with APS, and they should not be used in this disorder.

Some experts choose to use aspirin or clopidogrel instead of warfarin for secondary prevention of non-cardioembolic stroke in patients with APS based on the results of a prospective trial that showed no benefit of warfarin over aspirin. However, the Sapporo criteria were not used to define APS in this study so there is concern that the results of this trial are not applicable to true APS patients.

Many patients with APS will have an elevated PTT at baseline. This can make titration of heparin challenging. LMWH is a better choice in these patients. If this is not possible due to renal insufficiency or the need for the ability to immediately reverse the drug, heparin may be used. Heparin level should be used to guide dosing rather than PTT.

N/A

The choice of parenteral anticoagulant should take into account renal function. As LMWH is cleared renally, unfractionated heparin is the preferred agent if creatinine clearance (CrCL) is less than 30 milliliters/minute (ml/min).

Warfarin can be difficult to monitor in patients with liver disease due to elevated baseline INR. In these patients long-term injectable LMWH may be a better option.

No change in standard management.

Patients with APS have accelerated atherosclerotic disease. Aggressive treatment should be initiated for hyperlipidemia.

No change in standard management. Vitamin D deficiency should be treated aggressively since hypovitaminosis D has been associated with APS, although a causal association has not been firmly established.

No change in standard management.

Sign out should make it very clear that the patient is on full dose anticoagulation so that the following calls will register as “red flags” with the covering provider: headache, poorly controlled hypertension, fall, loss of IV access for heparin drip, change in level of consciousness. Providers should be aware of risk of thrombosis despite anticoagulation and rare progression to CAPS.

The length of stay varies by presentation.

Varies by presentation.

All patients discharged on anticoagulation should have close follow-up for monitoring, no more than a week after discharge but sooner in many cases. Detailed sign out to the anticoagulation provider is critical given the high-risk medication and the high rates of complications during times of transition.

Ideally monitoring is done by a dedicated anticoagulation clinic. Patients with APS should be referred to specialists with experience managing this condition, including hematology and rheumatology consultants.

See above.

If the patient is discharged on warfarin an INR should be done on the day of discharge as well as complete blood count (CBC).

The initial post hospital visit for anticoagulation monitoring will include a review of INR, CBC and creatinine (if renal function is impaired).

Prior to discharge the provider should confirm that the patient is not a fall risk, is able to get to follow-up appointments and can administer injections (if necessary). Failure to follow-up for anticoagulation monitoring can have devastating effects. If the patient is frail a physical therapy consult may be indicated. If the patient is thought to be a fall risk, a home safety evaluation with removal of obstacles should be considered.

Short-term rehabilitation may be considered if the patient is deconditioned. The provider should have a low threshold for arranging home nursing for medication teaching given the complexities of anticoagulation administration (LMWH) or the need for dietary stasis (warfarin).

APS is an acquired thrombotic disorder that typically results in recommendation for indefinite anticoagulation. Anticoagulation will provide excellent protection from recurrent thrombosis provided medication is taken regularly and monitoring is appropriate.

If there is a recurrence it tends to be in the same side of the circulation as the original presentation: patients presenting with venous thromboembolism have recurrent VTE while those with thrombosis in the arterial side of circulation have arterial events.

Comprehensive anticoagulation teaching should be completed prior to discharge including:

Signs and symptoms of thrombosis and bleeding.
The need to inform their provider immediately in the event of a serious fall, head trauma or new medications.
The need for strict medication adherence and follow-up with each scheduled anticoagulation monitoring appointment.
The need to alert anticoagulation providers about planned procedures that may necessitate interruption of anticoagulation therapy.
Importance of birth control for female patients in childbearing years who are on warfarin and the importance of seeking input from high risk obstetrics if they are considering pregnancy.
Nutrition counselling emphasizing dietary stasis (not elimination of greens).

There are no core safety measures specifically addressing APS, although there are core measures for VTE prevention and treatment that apply to APS patients. These include measures for appropriate overlap therapy during initiation or resumption of warfarin for VTE (patients on warfarin should receive overlap therapy with a parenteral anticoagulant for 24 hours after INR first reaches 2); appropriate drug dosing and platelet monitoring for patients receiving intravenous unfractionated heparin; and incidence of potentially preventable hospital-acquired VTE.

See the counselling chapter.

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