A Case of Catastrophic Antiphospholipid Syndrome

An Electronic Roundtable Discussion from the Pulmonary Hypertension Clinicians and Researchers

Dear PHCR Colleagues:

I would like to have your advice on an interesting patient I recently evaluated. Briefly, he is a 35-year-old man with catastrophic antiphospholipid syndrome (CAPS) who was diagnosed with pulmonary hypertension by echo, RVSP estimated at 89 mmHg. He was empirically treated with sildenafil before being referred to me and had some response. However, he remains functionally limited. I classify him as WHO functional class III.

As per protocol, we would perform right-sided heart catheterization (RHC) prior to initiating pulmonary arterial hypertension (PAH) treatment. However, there are reported deaths in CAPS patients after surgery and/or instrumentation, including two reports of catastrophic tissue factor embolization associated with central line placement.

This has me worried about RHC, and I do not want to place the patient at unnecessary risk (risk of instrumentation itself and risk of altering anticoagulant therapy before instrumentation). He does have a history of systemic hypertension and may very well have some degree of diastolic dysfunction; however, with cardiopulmonary exercise testing (CPET), his gas exchange pattern during exercise fits that of typical pulmonary vascular disease. Thus, even if his PCWP is elevated, his PAP (at least by echocardiography) is elevated out of proportion and he could be considered a candidate for PAH treatment. I do not believe that partial success with sildenafil proves he will tolerate additional PAH therapy. However, I do believe that if catheterization places him at additional risk, one would be justified in empirically (and cautiously) adding an endothelin receptor antagonist (ERA) or even a prostanoid to his current PAH therapy. Please send questions, comments, suggestions.

I hate to ask the obvious, but I presume that he has had a negative V/Q scan?

I would repeat the echo-Doppler on sildenafil. If LA and LV size are normal and there is no element of LV diastolic dysfunction, there is no need to expose the patient to RHC. How did you do the work-up for chronic thromboembolic pulmonary hypertension (CTEPH)? I would have to be concerned about seronegative lupus and pulmonary venoocclusive disease (PVOD), but that doesn’t preclude avoiding catheterization.

I agree with repeat echo on sildenafil. Unless additional drugs are refused by company or insurance, you should be able to initiate based on the echo alone in this particular patient.

If this is truly CAPS, does he have other organ involvement, such as kidneys, etc? This may add to the risk. One would also have to factor in the fact that prognosis in these patients is not typically great and it may be reasonable to treat based on echo in this extreme case, especially since you have “typical“ CPET findings. However, to answer your question more directly, I don’t think there is an absolute contraindication to RHC in this situation (if you really need the numbers). Since this is a venous stick, you may consider doing the RHC on heparin, keeping in mind that sometimes PTT does not track and you may need to use heparin assay to monitor. Hope this helps.

I agree that between echo, which should give an idea of diastolic function, and presumed absence of reasons for major diastolic dysfunction, treating without RHC is the right thing to do. I would guess the V/Q scan shows mismatched defects? Subcutaneous treprostinil seems attractive in this setting. High resolution CT chest scanning could get at the question of PVOD if that remains an issue.

I think you have to do what you feel comfortable doing. If you are talking about an “in and out” RHC to accurately assess the hemodynamics along with nitric oxide testing, I think the risks would be acceptable. I have performed RHC on patients with antiphospholipid syndrome without incident. I have also had overestimation of PA pressures by echo, so I perform RHC in pretty much anyone I am considering for treatment. I can certainly understand if you would defer under the circumstances, however.

My preference is always to get a baseline cath, because when I haven’t, I have often regretted it later. I am not familiar with the two case reports you mentioned, but I wonder whether preexisting clot, prolonged access, or inadequate anticoagulation may have precipitated the embolizations. I also wonder whether covering the patient with intravenous heparin before and after the procedure might minimize the likelihood of catastrophe.

One consideration would be to perform the RHC on heparin or with a heparin bolus. Of course, there are the risks associated with this as well. I agree that you should be justified treating without confirmation by RHC given the risks.

We have seen that even if the echo does not reveal diastolic dysfunction, this won’t prevent you from finding elevated left-sided pressures. If you tell us that there is evidence of right heart involvement (eg, dilated right atrium and right ventricle with normal left atrial size), the pretest probability for PVH would certainly be low.

Thanks for sharing your case with us. Nice discussion. I think you have received extensive expert opinion already, so my comments might not add much. However, I would like to play devil’s advocate in this case. As some have mentioned (which you obviously know already), there is still plenty of information you might obtain from RHC that you could potentially miss later on to help determine how to modify your therapy.

Although I understand the increased risk you mention about potential complications for your patient, one wonders if the potential complications—not necessarily clotting related—of RHC are not the same or even higher for so many of the patients we currently bring to the cath lab (interstitial lung disease, hypoxemic patients, coagulopathies, unable to lay down flat, risk for hypoxemia or hypercapnea with sedation, tachyarrhythmias, risk of pulmonary edema with nitric oxide/epoprostenol, etc).

Hence, we could make a similar argument for many of these patients and treat them based on echocardiography. One could ask something like: Out of a group of pulmonary hypertension experts (clinicians working in pulmonary hypertension centers), in how many cases do the cath numbers and data end up significantly changing the pretest probability of PAH, pulmonary venous hypertension (PVH), presence of a shunt, etc? Overall, perhaps this number is low. However, in our experience there have been many cases in which a fluid challenge, an exercise challenge, a limited shunt run, a nitric oxide challenge (no vasodilator response, but increase in wedge v wave after this), or a nitroprusside challenge provided info that significantly changed patient management.

Given the potential cost, long-term prognosis, potential side effects, emotional implications to the patient, etc, perhaps one could argue that you need only a few patients in whom RHC changed your management to justify at least one baseline RHC in every patient who is going to get potentially treated with pulmonary hypertension-specific therapies.

Certainly, your pretest probability for PAH appears to be high in this case. For a pulmonary hypertension expert like yourself, the chances that he has another diagnosis (left heart disease) might be low but even so, missing the baseline RHC characteristics might have some implications down the road when you try to adjust your therapies (ie, stepping up the treatment to parenteral therapies), especially in a patient who is not naïve to pulmonary hypertension therapies and in whom you will be soon face additional treatment decisions.

Having said that, you do mention that this patient has a history of hypertension. We have seen that even if the echo does not reveal diastolic dysfunction, this won’t prevent you from finding elevated left-sided pressures. If you tell us that there is evidence of right heart involvement (eg, dilated right atrium and right ventricle with normal left atrial size), the pretest probability for PVH would certainly be low.

In our experience with patients with pulmonary hypertension “out-of-proportion” to left heart disease, the pulmonary diastolic gradient (PADG) appears to have better diagnostic properties to sort out PVH from PAH than a transpulmonary gradient. In cases where the PADG (PADPPCWP/LVEDP) is less than 10 (and certainly less than 5), we have found that regardless of how high the pulmonary systolic pressure is, the pulmonary hypertension can be explained with the elevation in left-sided pressures. We presented this a couple of years ago [Wendy ZK, Kleczka J, Marks D, et al. Nitroprus-side (NTP) in the assessment of pulmonary hypertension (PH) associated with elevated left ventricular (LV) filling pressures due to diastolic dysfunction. Chest Meeting Abstracts. 2005;128S (4):138S].

Furthermore, in this era of a high referral pattern of left heart disease as the ultimate cause of pulmonary hypertension, it would be nice to study if the RHC data can eventually and significantly change the management of a naïve “PH” patient even in the hands of a pulmonary hypertension expert (with high pretest probability before the cath). This might not have been the case 10 years ago where most of the patients seen in a PH center were likely to be PAH.

Because of the change in referral pattern, at our institution we almost routinely measure LVEDP during the first catheterization of patients evaluated for pulmonary hypertension. We looked at data from 130 patients who underwent simultaneous LHC/RHC and found that in up to 38% of patients in whom the PCWP was found to be less than 15 mmHg (consistent with PAH based on current guidelines), the LVEDP was greater than 15 (median of around 8 mmHg for discrepancy between the two). The abstract citation is Soto FJ, Siegel R, Marks D, et al. Performance of pulmonary capillary wedge pressure (PCWP) vs left ventricular end diastolic pressure (LVEDP) in the diagnosis/classification of patients with suspect pulmonary arterial hypertension (PAH). Chest Meeting Abstracts. 2005; 128S (4): 137S.

In summary, I propose that despite the potential clotting risks present in this case, the short and long-term therapeutic and prognostic implications of knowing your baseline RHC data might still have a favorable risk/benefit ratio to justify doing it.

One consideration would be to perform the RHC on heparin or with a heparin bolus. Of course, there are the risks associated with this as well. I agree that you should be justified treating without confirmation by RHC given the risks.

Although you make some good points, I think the risk of stopping anticoagulants in this patient are too high. I have seen some horrendous sequelae in antiphospholipid patients who are taken off Coumadin (strokes in young patients are obviously tragic). I would make your treatment decisions based on clinical response, ECHO, MRI, BNP, etc. Not ideal, but prudent. I do disagree that other, sick pulmonary hypertension patients are also at higher risk from RHC. That has not been my experience.

I would agree with your approach. Our understanding here, based on very limited experience, is that these patients are at risk from more invasive procedures than RHC. More often surgical or prolonged nonsurgical procedures. I suspect RHC could be done safely and would consider it. Either way, I think your approach is the safer way to go. Even if there were evidence of diastolic dysfunction, with the PA out of proportion, or if measured there were a wide transpulmonary gradient, you would likely go down the same treatment path. I suspect the real issue is can you safely give the patient effective prostanoid therapy. Likely limited to inhaled in order to avoid a central line. I would absolutely agree with adding a selective ETRA to a PDE5 and observe his functional and echocardiographic response.

How is his antiphospholipid antibody syndrome being treated besides anticoagulation? Keep in mind that INR assays can be unreliable in these patients. You could consider aggressive treatment with plaquenil, high dose corticosteroids, apheresis followed by IVIG +/-rituximab before cath.

Thanks. I certainly don’t have the experience that you likely have in managing these patients and I am sure it takes seeing only one bad complication to make you reluctant to perform procedures or withhold anticoagulation in this population unless absolutely necessary.

To make this topic discussion even more complex, I came across an article that describes significant left ventricular relaxation impairment and diastolic dysfunction by echocardiography in patients with this syndrome (several etiologies suspected). There are a dozen or so similar articles in the literature. None of these studies confirmed echo findings with cath numbers, though.

Unfortunately, only a few of those articles described estimated PASP in their data so I am not sure what kind of PH numbers might be expected for the degree of diastolic dysfunction. In addition to LVDD, prevalence of leftsided valvular disease appears to be significant also. Such cardiac involvement appears to be independent of coexistent SLE.

Thank you all for your helpful advice. Because of the time involved and because I don’t want to subject you to reading individual answers to the questions that have been posed thus far, I will be brief and try to cover some of this with one e-mail.

Clearly, some of you advocate RHC, and I think it could be considered acceptable to do one, for reasons listed (I agree with the bridging heparin routine and the out-of-proportion comments on both sides). Similarly, a more conservative approach would also be reasonable.

I do suspect that CTEPH is the likely major contributor to his pulmonary hypertension, despite the negative (but not normal) V/Q; he does have some subsegmental contrast attenuation by CT, but no obvious large clot burden. Nevertheless, having now heard of successful pulmonary thromboendarterectomy (PTEA) in two cases similar to this one, I believe it would be best to better evaluate him for CTEPH, since fixing it is the one thing that can hugely affect his mortality.

Thus, I will try to get him down south to get formally evaluated, and defer the RHC to UCSD, not because I want to dump the risk on them, but because their comprehensive approach is better than mine. I don’t see enough to feel comfortable excluding operable disease, and once I find it, I can’t do anything about it at Harbor.

In the meantime, I plan to add an ERA and follow clinically with H&P, occasional echo, CPET, and/or 6-munute walk testing while I work on getting the records to UCSD, assuming they will consider PTEA. I suppose we could also add subcutaneous or inhaled prostanoids if need be. I don’t think the subcutaneous “instrumentation” will be a risk. Again, thank you for the advice.

Thanks. Let’s take a look at the scans. If the V/Q is really “near normal” and the CTA negative we would really have to think hard before cathing and PA-graming him. There is a high incidence of heparin-induced thrombocytopenia in these patients and in fact I have seen platelets bottom out just from stopping warfarin. We would probably put him on a heparinoid like argatroban at the time of warfarin discontinuation, and then get an HIPA study.

Quite an interesting discussion. If he has CAPS, it’s probably microvascular thrombi or infarcts accounting for your V/Q and CT angiographic findings. I’d be happy to look over the studies for the possibility of CTEPH. If it’s CAPS, we should keep him on warfarin and find reasons not to stop it. Did he also get ARDS with his CAPS? It’s definitely one of those miscellaneous pulmonary hypertension cases.

Sorry for joining late. I would be very wary of CAPS; we have seen some brutal presentations in recent years. Association with ARDS is remarkable, and as you all know, all organ systems are susceptible. I would be very cautious about withdrawing warfarin. This is a potentially very dangerous situation. If a cath/PA-gram is ultimately performed, I would absolutely, unequivocally, give intravenous steroids and keep him anticoagulated as much as is practically possible.

Difficult case. Excellent discussion from around the country. Nice to know that so many high-quality opinions are so readily available. We recently lost a patient with CAPS two years after he had open heart surgery to remove a clot from his aorta. I agree that RHC could be done with minimal risk using low-dose anticoagulation with intravenous unfractionated heparin. We have used ultrasound guidance to place most of our RHC via an internal jugular approach and believe we can really keep bleeding to a minimum this way. The other suggestion I have would be to consider a course of plasmapheresis prior to the procedure. Good luck.

Great discussion. Worthy of an Advances in Pulmonary Hypertension Roundtable.

One thought that occurs to me is that although RHC may be useful to precisely define the hemodynamic context, in this situation it would also be used to assess the effect of a vasoactive drug. The main outcome of relevance is not so much whether it would demonstrate a beneficial response, since CCB alone is probably not in the plans, but whether it may cause some degree of decompensation due to whatever diastolic dysfunction may be present. But this can probably be assessed without a catheter in place and thus avoid any potential higher risk; rather, just administer inhaled nitric oxide or peripheral intravenous epoprostenol with the patient under close observation (vital signs, exam, symptoms). If the patient tolerates this, then more aggressive long-term pulmonary vascular targeted therapy could be used and assessed in terms of long-term outcome targets. (If he doesn’t tolerate it, at least the effect would be brief).

I have had the same experience you are describing. My patient with CAPS had CTEPH and developed HIT on heparin. Despite heroic efforts over the following 1 to 2 years, she died of right heart failure. I agree that knowing the patient‘s hemodynamics at baseline is extremely important for prognosis and follow-up response to therapy. But this is one of those cases in which using noninvasive markers and imaging may be warranted.

To Everyone: I have really enjoyed the case on the patient with CAPS and the varying points of view, since I left the academic world in 2001. I like the idea proposed by Dr Channick of a case presentation. I hope it will continue to be presented in this format, from which all of us can learn.

A registry currently exists in an attempt to further elucidate this syndrome and increase the understanding of this rare but devastating process. The registry summary may be accessed on-line at http://www.med.ub.es/MIMMUN/ FORUM/CAPS.HTM.—Keith McCrae, MD, Division of Hematology and Oncology, Case University.