Catastrophic antiphospholipid syndrome

Antiphospholipid syndrome is a state of autoimmune-induced hypercoagulability. The uncharacteristically hyperbolic term "catastrophic" is used to describe a case of antiphospholipid syndrome which involves both excessive clotting and excessive bleeding, with consumption of coagulation factors. Like most medical conditions with the words "catastrophic" in the title, the ICU trainee should have wanted to be familiar with this syndrome, even though it had previously never appeared in the fellowship exam papers. And then of course it did appear, as Question 11 from the second paper of 2022, and predictably only 9.6% of the trainees were able to pass this question (even with Angoff marking, which would have lowered the expected pass mark). Non-catastrophic antiphospholipid syndrome has also appeared as a third of Question 7 from the first paper of 2022.

If the time-poor trainee were going to devote any of their precious time to reading about this disease process, they may wish to limit thremselves to only one paper.

That paper should be the 2012 update by Cervera and Espinosa. Unless otherwise stated, everything that follows in this summary is a concentrated distillate of their wisdom. Other more recent resources include Garcia & Erkan (2018).

Pathophysiology of antiphospholipid syndrome

In brief:

• In lupus, antiphospholipid autoantibodies are produced which bind to negatively charged phospholipid surfaces normally involved in platelet aggregation (thus impeding clotting and increasing the APTT)
• Some of these antibodies also bind to open β2 -glycoprotein on endothelial cells
• This activates compliment, activates inflammatory cells, and promotes coagulation
• The net result is anticoagulation (because platelet aggregation is impaired) as well as thrombosis (because endothelial function is impaired).

Diagnosis of catastrophic antiphospholipid syndrome

One would confirm this diagnosis by ordering a lupus anticoagulant and an antiphospolipid antibody assays. Certainly, one could spend hours talking about esoterica like the Russel Viper Venom Time. Instead, I will point to the most recent consensus statement regarding the diagnostic criteria. One requires one clinical criterion (eg. thrombosis) and one laboratory criterion (eg. a positive anti-β₂-glycoprotein-I antibody) for a diagnosis of antiphospholipid syndrome, and a few other features to make it "catastrophic".

The complete list of criteria is as follows:

1. Evidence of involvement from three or more organ systems
2. Manifestations developing within the same week
3. Histopathological evidence of small vessel occlusion
4. Laboratory confirmation of antiphospholipid syndrome (eg. lupus anticoagulant)

"Definite" CAPS satisfies all 4 criteria, but one wonders whether histopathological confirmation is a sensible criterion to demand.  "Probable" CAPS satisfies criteria 1, 2 and 4.

Clinical features of catastrophic antiphospholipid syndrome

The antiphospholipid syndrome patient is prone to simultaneously clotting and bleeding. The specific list of complication and clinical features depends on the organs most affected. They may include the following:

• DVT
• PE
• miscarriage
• cerebral sinus thrombosis
• arterial thrombosis

The CAPS registry (consisting of 280 patients) records the following patterns:

• Renal disease (71%)
• Pulmonary disease, largely consisting of PE and ARDS (64%)
• CNS disease, including venous infarcts, seizures and encephalopathy (62%)
• Skin complications, eg. skin necrosis (50%)
• Cardiac disease (51% valvular, 25% ischaemic coronary)

Laboratory features, beyond the serology required for diagnosis, include the following:

• Thrombocytopenia (in 46%) and coagulopathy (15% have features of DIC)
• Features of haemolysis (30%)

Management of catastrophic antiphospholipid syndrome

Management strategies consist of anticoagulation and immunosuppression, with a stepwise escalation of therapies all the way up to weird stuff like ancrod and various mibs and mabs.

• Anticoagulation:  there appears to be an improvement in mortality with heparin; whether you choose unfractionated or LMWH does not seem to matter. Generally the heparinisation is continued for 7-10 days,  followed by oral agents (typically warfarin). Heparin also apparently has some sort of beneficial effect on complement activation, making it an effective choice for this condition.
• Use anti-Xa to monitor heparinisation. One interesting caveat of using heparin for CAPS is that it cannot be effectively monitored using the APTT. The APTT basically tells you nothing here because of the presence of lupus anticoagulant - at baseline it is already raised, so how do you know whether the heparin is working? Experts suggest you turn to using regular heparin anti-Xa measurements. Mehta et al (2011) recommend aiming for a range of 0.3-0.7. This is an indirect measure of heparin activity; it assesses the extent of heparin/antithrombin complex binding to Xa by detecting the amount of residual unbound Xa in the sample. 
• Corticosteroids:  Analysis of the CAPS registry revealed that steroids did not improve mortality (at least not on their own). However, a course of three days of 1000mg daily methylprednisolone seems to be the empirical steroid course.

Second line therapies:

• Plasma exchange:  there is a definite trend to improved mortality with plasma exchange, which makes one wonder why it is not a part of first line therapy. FFP seems to be the replacement fluid of choice, as it comes with some anticoagulants (eg. antithrombin)
• IV immunoglobulins:  There does not seem to be retrospective evidence of any survival benefit from the use of IVIG. There is a theoretical benefit (apprently it might improve the catabolism of the harmful circulating antibodies). The recommended dose is 0.4g/kg for 4-5 days.

Third line therapies:

• Cyclophosphamide:  there is little evidence for the use of this in CAPS; however Cervera and Espinosa make the recommendation that if you plan to use it, you should use it early.
• Rituximab:  There are a few case reports of this being helpful, but it is difficult to say exactly how helpful it was, because all those patients were also receiving all the other therapies.
• Prostacycline:  the recommendation for the use of this drug is largely theoretical, as it is both a vasodilator and an antiplatelet agent. In a severe SIRS state, the vasodilation may be undesirable, and there are probably safer antiplatelet drugs one could use.
• Defibrotide:  This is an alkali metal salt of single-stranded DNA and has
  antithrombotic properties. Elsewhere, its use in veno-occlusive disease is discussed in greater detail. In the CAPS registry, only one patient received it, with success.
• Ancrod: this is a rare defibrinogenating agent derived from the venom of the Malayan pit viper. As far as I know, it is not available anywhere. Cervera and Espinosa devote two lines to it.