Blood Clots and Antiphospholipid Antibody Syndrome (APS)



Individuals with APS are at a far greater risk of developing blood clots in their arteries and veins.

 

Antiphospholipid antibody syndrome — just saying it is a test for our tongues (we’ll call it APS from here on). Unfortunately, having this blood clot producing syndrome means the health of those who live with it can also be severely tested.

We all have an abundance of phospholipids, which are complex fat molecules. “They exist in all mammals and are used in different places in the body for different functions,” said rheumatologist David Daikh, president of the American College of Rheumatology and professor at the University of California San Francisco Medical School. “Phospholipids are a component of cell membranes, as well as other structures, for example, blood vessels and other tissues throughout the body.”

Normally, we produce antibodies in response to foreign substances or infections in our body. But the antibodies in APS are attacking a normal structure. “The presence of an antibody against a normal phospholipid means that there is what we call ‘autoimmunity,’” Daikh said. “That is a situation in which abnormal antibodies, or other parts of the immune response, develop abnormally, when there really isn’t an infection and no reason for an immune response that we can tell.”

So far, no cause for this has been found. In fact, it was only identified as a syndrome in 1983 by Dr. Graham Hughes, an English rheumatologist; APS is also sometimes called Hughes Syndrome. There are two kinds of APS — primary and secondary. “Primary means there’s no other cause, no other reason to think that the person has an autoimmune condition. They just have these antiphospholipid antibodies,” Daikh said. “Secondary APS means that the individual already has an autoimmune disease, and as part of that, they develop antiphospholipid antibodies. By far the most common autoimmune disease in which APS is present is lupus (or systemic lupus erythematosus), also called SLE.”

Who is at risk?

APS occurs more commonly in women than men. When considering secondary APS, “If you look at lupus, women are at greater risk for developing it than men — it’s many times higher for women,” Daikh said, ”That being said, lupus is an uncommon condition, and since only a small percentage of patients with lupus ever develop APS, then secondary APS is an even more uncommon condition than lupus. Primary APS is also rare. In primary APS, we see a little bit of an increase in women compared to men, but it’s not as dramatic as we see in lupus. But aside from that, there really have not been well-described risk factors for developing APS.”

It is possible for someone to have antiphospholipid antibodies without developing APS, and even those individuals are at somewhat increased risk for developing blood clots. “In fact, the way it’s usually discovered that a person has the antiphospholipid antibodies is that they develop a blood clot and doctors are trying to figure out why,” Daikh said. “This is especially so when we see blood clots that occur in an unexpected location or in a person who doesn’t have other risk factors for blood clots, for example a young person who wouldn’t be expected to have the typical kinds of blood clots that occur with aging. That’s usually when a doctor will start investigating the possibility that there is APS present.”

Big Consequences

The risk for developing APS may be small, but the consequences of those blood clots can be huge and differ according to where the blood clot forms — in a vein or an artery. “Blood clots in arteries are usually not very subtle when they occur and include things like a stroke or an acute heart attack,” Daikh said. “Blood clots also occur in veins and include things like a deep venous thrombosis that occurs in the legs. Such clots sometimes develop as a result of someone sitting for a long time like on an airplane flight or occur after surgery if the person isn’t moving, but they are more likely to develop with APS. Another complication from APS is premature pregnancy loss: If blood clots form in the placenta during the development of a fetus, that can lead to loss of the fetus.”

Symptoms usually develop abruptly because these blood clots form abruptly. “Often, there is a trigger that sets off the blood clotting,” Daikh said. “Unfortunately, we don’t know all those triggers. One trigger is just having a lot of the antibody present in the system. We think that in many cases, if there’s damage to a blood vessel, like from surgery, it might trigger clotting in somebody who has APS. But we don’t know all the triggers.”

There appears to be something of a genetic component, at least for secondary APS where the patient has an underlying autoimmune disease, because there’s some genetic risk for developing those autoimmune diseases, such as lupus. “People who have a parent who had lupus are at somewhat higher risk,” he said. “There is some genetic component, but we certainly don’t understand all the genetic risks for developing APS.”

Catastrophic APS

Catastrophic antiphospholipid syndrome or CAPS is what Daikh calls a dramatic form of APS. CAPS patients have widespread clotting in multiple organ systems at the same time. “Those are very sick patients, who require aggressive treatment,” he said. “Fortunately, CAPS is rare. In general, once you have determined that somebody has APS, then the main treatment is anticoagulation to prevent the blood from clotting.”

Treatment

“Warfarin has traditionally been the main anticoagulant for APS — aspirin was inadequate,” Daikh said. ”Now doctors have options for prescribing the newer DOAC (direct oral anticoagulants) drugs that are easier for patients to use. However, their effectiveness for APS is still being investigated. The early experience suggests that they will be effective. The largest study has been with rivaroxaban, and the indications are that it works. It is important, however, that a transition from warfarin to a DOAC for APS be done under the care of a hematologist and a rheumatologist to help ensure that effective anticoagulation will be maintained during the transition.”

Diagnosing APS

APS diagnosis is done by a blood test to identify antiphospholipid antibodies. “There are several different kinds of antibodies that can develop, and most people don’t have all of them, and some of the antibodies can be difficult to diagnose,” Daikh said. “The interpretation of the test results also requires a fair amount of expertise in this condition.”

Pouring a pill from bottle into hand
Warfarin or direct oral anticoagulants are often used to treat APS.

In addition to the presence of at least one antiphospholipid antibody, an APS diagnosis requires an arterial or venous clot or the loss of a pregnancy that cannot be explained by some other condition.

Strokes can result from APS, in which case the long-term treatment would involve a rheumatologist as well as the neurologist. Rheumatologists deal mainly with immune-mediated disorders of the musculoskeletal system, soft tissues, autoimmune diseases, vasculitis, and genetically inherited connective tissue disorders.

“Rheumatologists probably have the most familiarity with the condition and are trained in how to diagnose it,” Daikh said. “Hematologists are aware of the condition and can also help diagnose it. Frequently, the hematologists are involved in helping to manage the anticoagulation treatment, especially with these newer agents, or with patients who have complicated medical problems where you have to use different kinds of blood thinners. In these cases, having a hematologist involved is very helpful. For a woman who is either having trouble maintaining a pregnancy or has lost a pregnancy from APS, having a rheumatologist involved in their care during the time that they’re pregnant or trying to get pregnant is also very important.”

Belinda De La Rosa‘s Experience with APS

In 1997 a nagging pain in her left arm had been bothering Belinda De La Rosa for days. Thinking it was tennis elbow, the 41-year-old wife and mother of two from Victoria, Texas, made a doctor’s appointment to have it looked at. On her way there, she happened to be passing a hospital when the pain turned to numbness that spread from her left arm to her neck and face. She recognized it as a symptom of stroke and pulled in to the emergency room at the hospital.

Testing showed Belinda was, indeed, having an ischemic stroke. They treated her and she had no lingering deficits, but doctors could not find a cause for the stroke or the numbness that continued to come and go. “I was having a lot of episodes where my left side would go numb,” Belinda said. “We’d go out, take the kids to the movies or whatever, and all of a sudden, the numbness would hit me, and Joe, my husband, would have to take me to the emergency room. They would give me nitrate and it would subside. They considered a lot of things, including MS. But when they couldn’t come up with anything, I went to a neurologist here in town. He came up with ‘antilipidphosphous’ syndrome — I still can’t pronounce it.”

Indeed, antiphospholipid syndrome is difficult to pronounce, and in 1997 it would not have been at the top of anyone’s list of stroke causes as it was only identified in 1983. The neurologist prescribed warfarin, and the numbness stopped. Belinda relaxed and went back to taking care of her family.

Of course, the warfarin did complicate her life because of the constant monitoring and dose variation, but all was well for about a decade, until she was diagnosed with stage 3 colon cancer in 2006. That was successfully treated with chemotherapy and removal of part of her colon.

Then in 2015, she had another stroke and a third one this past June. The only deficits from those were a face tic and drooping eyelid and lip on her left side, most noticeable when she gets tired. She has returned to both physical and speech therapy, and she no longer takes warfarin, having transitioned to one of the newer direct oral anticoagulants, which has simplified her life considerably. She says neither of the more recent strokes were tied to her APS.

As for a possible hereditary component, both of her parents had strokes, but as far as she knows neither had APS.

Dr. Graham Hughes, the first to identify antiphospholipid antibodies
Dr. Graham Hughes, the first to identify antiphospholipid antibodies

Editor’s Note: Dr. Graham Hughes was the first to identify antiphospholipid antibodies in 1983. He is now the head of the London Lupus Centre at London Bridge Hospital in the UK. We asked him to share his thoughts about APS and stroke.

It has been reported that up to one in five of all young (under 45) stroke survivors have tested positive for antiphospholipid antibodies (aPL). A wider recognition of the link between aPL and stroke (especially in younger people) might lead to significant stroke prevention.

The antiphospholipid syndrome (APS) was first reported in 1983, and the detailed description recognised the risk of arterial as well as venous thrombosis. It also recognised the risk of neurological features including stroke.

Over the ensuing years, APS has been widely recognised as a cause of thrombosis and recurrent miscarriage, but recognition of some of the varied neurological features has lagged behind. One area where diagnostic progress has been made is in epilepsy. One recent review reported that individuals with positive aPL tests were found to be nearly 10 times more likely to have seizures than patients negative for these antibodies. Two other “neurological” features of APS are memory loss and migraine: indeed, migraine is such a common complaint in Hughes Syndrome patients that aPL could in part explain the known association between migraine and stroke.

The pattern of ischemic brain disease in APS covers the full spectrum of stroke, ranging from acute major cerebral thrombosis to problems of memory loss, visual disturbance, worsening headaches and of course, focal lesions on MRI.

Diagnosis

Although the three blood tests for aPL (anticardiolipin antibody, Lupus anticoagulant and anti-Beta 2 GP1) are highly specific, there are, undoubtedly, a number of patients whose clinical features strongly suggest Hughes Syndrome, but whose blood tests remain negative. Advances in aPL testing will undoubtedly make inroads into this group in time.

However, there are features in the history and examination of a patient which can help in diagnosis. These include:

  • Age under 45, female sex (APS is an autoimmune disease, most commonly affecting younger females.)
  • Family history of autoimmune disease (e.g. Sjogren’s, Lupus, Hughes syndrome, Hashimoto’s, Multiple Sclerosis and RA)
  • Worsening history of migraine
  • Past history of miscarriage (e.g., 20 years earlier)
  • Past history of “possible” thrombosis
  • Mottled skin

Treatment

The treatment of Hughes syndrome is geared towards preventing clots. For milder cases, low dose (25-100 mg daily) aspirin or clopidogrel are used. For more severe cases (including stroke), warfarin is required.

A common finding in APS is the effect of “higher” INR levels (a measure of clotting time) such as INR 3.5 or even higher (healthy INR is 1.1 or below). Interestingly, many patients know when their INR has fallen, say to 2, when headaches, balance problems and “brain fog” return. For this reason, I encourage patients, where feasible, to obtain a self-test INR machine, cross checking with their INR clinic or neurology department.

Microscopic view of antibodies
As many as one in five stroke survivors under the age of 45 have tested positive for antiphospholipid antibodies.

Of course, the clinical decision to move from aspirin to warfarin is a major one. For example, in our APS patients with increasing headaches despite aspirin, a practice we have found useful is a trial of two to three weeks of low molecular weight heparin (e.g., dalteparin injection 5000 units daily for two to three weeks). The practice came from observations in our lupus/APS pregnancy clinic where women on heparin during pregnancy often observed that (for example) the migraine headaches disappeared for the whole nine months.

Conclusions

Hughes syndrome is an important preventable cause of stroke. In addition to simple aPL blood tests, three clinical questions should prove a pointer towards the diagnosis — especially in a female under 45:

  • Do you have a past history of thrombosis or pregnancy loss?
  • Are you a migraine sufferer?
  • Do you have a family history of autoimmune disease?

If you answer yes to these questions, I would certainly suggest running the blood tests.

Visit the Graham Hughes International Charity for Hughes Antiphospholipid Syndrome for more information on Hughes Syndrome and lupus.

This information is provided as a resource to our readers. The tips, products or resources listed or linked to have not been reviewed or endorsed by the American Stroke Association.

 


 


 

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