Although thrombotic and obstetric complications are the only clinical events included in the APS classification criteria, there are numerous ‘extra-criteria’ manifestations commonly observed in APS, including (but not limited to) nephropathy, cardiac valve lesions, neurologic complications (chorea, seizure, cognitive decline), skin manifestations (livedo reticularis, inflammatory skin ulceration), and cytopenias (hemolytic anemia, thrombocytopenia) . Of these, thrombocytopenia is likely the most common, with some APS cohorts demonstrating a higher prevalence of thrombocytopenia than obstetric complications [4,5]. Given this high prevalence, some early attempts at defining APS included thrombocytopenia as a clinical event warranting APS classification . Similarly, there have been more recent calls to consider the inclusion of thrombocytopenia as part of an updated classification strategy for APS .
Newer research, however, seems to be telling us something different. For example, a recent study found that the combination of aPL and thrombocytopenia (platelets <150 000/μl) increased the risk of future thrombosis two-fold over an average follow-up of 125 months [16▪▪]. Importantly the presence of an associated SLE diagnosis did not impact thrombotic risk [16▪▪]. Another recent study demonstrated similar results in a cohort of 138 patients with aPL; over an average 146 months of follow-up, patients with thrombocytopenia had elevated risk of thrombosis compared with patients without thrombocytopenia (29.4 versus 6.6%) . Furthermore, Radin et al.[19▪] recently published a manuscript that utilized a validated APS risk score – adjusted Global APS Score (aGAPSS)  – in a group of primary APS patients with or without additional extra-criteria APS manifestations (including thrombocytopenia). The 21% of patients with thrombocytopenia had a higher aGAPSS score than patients with no extra-criteria manifestations (10.6 versus 8.2). In summary, with the addition of recent literature, thrombocytopenia increasingly appears to be predictive of other APS complications. In our opinion, this is among the most pressing issues requiring further, and ideally prospective, interrogation.
As the presence of aPL ranges from 25 to 73% in ITP (the majority of publications pointing to the low end of that range) , there have been numerous recent studies exploring the relationship between aPL and clinical outcomes. For example, one study suggested that the presence of aPL can predict the severity of thrombocytopenia and future need for ITP-focused treatment [27▪]. Although ITP is classically characterized by bleeding events, a paradoxical increased risk of large-vessel thrombosis has also long been recognized . To this end, early research demonstrated a remarkable effect of aPL on thrombotic risk, including a 2001 study in which 60% of ITP patients with aPL experienced a thrombotic event as compared with just 2% of ITP patients without aPL . Similarly, a more recent cohort that consisted of 20% of all discharges from United States hospitals between the years of 2009 and 2014 revealed that the most significant risk factor for thrombosis in ITP was a concurrent APS diagnosis code . In summary, data published to date (all retrospective) suggest a higher thrombotic risk in ITP patients with aPL. Although prospective studies are obviously needed, when a patient with ‘ITP’ is seen in the rheumatology clinic, consideration should be given to testing for aPL. If nothing else, a positive test will emphasize the need for optimization of other cardiovascular and thrombotic risk factors.
When ITP-like physiology is felt to be at play, therapy is generally started once the platelet count is less than 30 000/μl (expert opinion). For a comprehensive review of this topic, we would refer the reader to the guidelines of the American Society of Hematology . It should be noted that these guidelines do not discuss APS beyond the recommendation that aPL testing not be routinely obtained in patients with idiopathic ITP (as above, we would argue that this rule may be less applicable to the rheumatology clinician).
Although thrombopoietin (TPO) mimetics are Food and Drug Administration (FDA)-approved for steroid-refractory ITP, they have not been systematically studied in APS patients . Early case reports and case series describing the use of TPO mimetics in SLE patients (including APS patients) largely showed that these agents were effective and without significant risk [39–45]; however, this was not universally seen . More recently, several reports have noted potential thrombotic risk of these agents in SLE and particularly APS patients [47–50,51▪▪]; two of these series, in particular, showed remarkably high rates of thrombotic complications in APS patients (33–60%) [50,51▪▪]. As the majority of thrombotic complications in these cases occurred at platelet counts greater than 100 000/μl, one can postulate that this risk may be minimized by dosing the TPO mimetics to maintain platelet counts around 50 000/μl. In summary, although TPO mimetics have excellent efficacy and are cost-effective (as compared with rituximab), caution should be exercised with use of these agents in the setting of aPL (especially in patients not receiving anticoagulation) until we have a better understanding of their risk/benefit profile. We have attempted to summarize the data available to date in Table 2.
Other medications that have been described (largely in the context of case reports) to improve platelet counts in APS include aspirin , warfarin , danazol , chloroquine , and dapsone . Splenectomy [57,58] and plasmapheresis  have also been reported. It is notable that some medications recently approved for ITP have yet to be characterized in the context of APS. For example, fostamatinib, a biologic therapy-targeting spleen tyrosine kinase , was approved in 2018 for the treatment of idiopathic ITP. Physicians will need to continue to follow the ITP literature, and pay close attention to any thrombotic-risk signal that emerges in that population.
Beyond antiglycoprotein antibodies, there is likely a role for aPL themselves in the pathophysiology of thrombocytopenia. Indeed, an emerging concept is that there may be parallels between thrombocytopenia in APS and that seen in heparin-induced thrombocytopenia (HIT). HIT is an acquired autoantibody-mediated condition associated – like APS – with increased thrombotic risk. In HIT, complexes of platelet factor 4 (PF4), heparin, and anti-PF4 antibodies engage the platelet surface where they both trigger platelet activation (via FcγRIIa), and ‘label’ platelets for removal by phagocytic cells in the spleen. A recent study by Gollomp et al.[61▪▪] characterized large-vein thrombosis in a mouse model of HIT, and suggested a previously unknown role for neutrophil–platelet crosstalk in HIT pathophysiology. First, the authors demonstrated PF4/anti-PF4 complexes were able to engage the surface of neutrophils (similar to the surface of platelets) and trigger neutrophil activation, adhesion, and extracellular trap (NET) release in FcγRIIa-dependent fashion [61▪▪]. NETs – extracellular tangles of chromatin and granule-derived proteins – subsequently formed complexes with PF4/anti-PF4 (potentially taking the place of heparin in the complex), leading to NET stabilization and thrombus propagation [61▪▪]. Interestingly, inhibition of both neutrophil adhesion and NET release were highly effective strategies for mitigating thrombosis in the HIT model [61▪▪]. Given reports of β2GPI/antiβ2GPI engagement with platelets [62,63], neutrophils [64,65], and even PF4 itself [66,67] – as well as striking similarities between the aforementioned HIT model and recently described models of APS [68,69]—one can postulate that crosstalk between platelets, neutrophils, NETs, and possibly even PF4 may play a role in the pathophysiology of both thrombosis and thrombocytopenia in APS.
As APS patients are exposed relatively frequently to heparin, HIT needs to be considered when such patients have an acute drop in the platelet count. At least one study showed a frequent co-occurrence of aPL and the pathogenic antibody in HIT (anti-PF4) , albeit with no follow-up functional assays performed. Additionally, a single-center case–control study found that autoimmune conditions (including APS) are commonly associated with HIT (55.9% of HIT patients compared with 10.8% of controls) [71▪].
Thrombotic microangiopathies can be directly or indirectly associated with APS and require prompt recognition owing to their highly associated morbidity and mortality. Thrombocytopenia in these diseases is driven by thrombosis-related platelet consumption or, more rarely, bone marrow infarction. APS-related microangiopathies include CAPS (catastrophic antiphospholipid syndrome), HELLP (hemolysis, elevated liver enzymes and low platelets), and TTP (thrombotic thrombocytopenic purpura). Other possibilities to consider in selected patients include severe infection, malignant hypertension, and disseminated intravascular coagulation. We will briefly summarize some of these potential diseases below.
CAPS is a life-threatening form of APS reflecting a microvascular thrombotic storm afflicting multiple organs simultaneously . In one large series of CAPS patients, thrombocytopenia was detected in 65% of cases (whereas schistocytes were only detected in 22%) . In a recent study, the time course of thrombocytopenia in six patients with APS who developed CAPS was described [74▪]. All events were associated with platelet counts less than 100 000/μl (the majority <50 000/μl) and demonstrated a daily, step-wise decrease for 7 days preceding the clear recognition of CAPS manifestations – hinting that platelet activation and consumption may be integral to the emergence of CAPS, and that progressive thrombocytopenia must be carefully monitored in a patient with APS.
As above, schistocytes and frank evidence of hemolytic anemia are only detected in one out of four CAPS patients . In contrast, both HELLP and TTP are more likely to express a strong pattern of microangiopathic hemolytic anemia (MAHA). HELLP – which is considered to be on the spectrum of preeclampsia – is characterized by elevated blood pressure and proteinuria (i.e. signs of preeclampsia), as well as hemolysis, a microangiopathic blood smear, elevated liver enzymes, and a low platelet count. As compared with the general population, APS patients likely experience HELLP earlier in pregnancy, and with a higher degree of severity .
TTP is driven by deficiency or inactivation of ADAMTS-13, a metalloproteinase that cleaves von Willebrand factor (vWF). In TTP, abnormally large vWF multimers drive platelet aggregation in small vessels, resulting in end-organ damage and platelet consumption. A review of the literature reveals that definitive TTP is relatively uncommon in primary APS, with less than 10 case reports published [76–78]. Having said that, there has been an interesting body of work exploring the association of APS and ADAMTS-13, with several studies demonstrating no association [78,79]. A few studies, however, have found low ADAMTS-13 activity in APS patients [80,81], possibly mediated by antibeta-2 glycoprotein I antibodies directly antagonizing ADAMTS-13 activity [82▪].
Clinical manifestations significantly overlap between these conditions, likely due to a related pathophysiology that includes a prominent and pathogenic role for complement activation . We would direct readers to prior excellent review articles to assist with diagnosis [72,84,85]. From a practical perspective, we would argue that the clinician should not be overly concerned about nomenclature (i.e., CAPS versus HELLP versus TTP). In a patient with known APS who develops organ failure concerning for a thrombotic microangiopathy, traditional treatment for CAPS will likely be required – typically with the combination of corticosteroids, heparin, and plasmapheresis, as we and others have summarized [72,86].
In this difficult situation, treatment recommendations are based upon expert opinion or extrapolated from the cancer literature. Both bleeding and thrombotic risk need to be weighed before starting anticoagulation. In all cases, shared decision-making is essential, and treatment must be individualized. Generally, most experts feel that full anticoagulation can be provided in the setting of platelet counts greater than 50 000/μl. Unfortunately, as controlled studies of anticoagulants almost always exclude patients with platelet counts less than 50 000/μl, there is minimal prospective evidence to guide recommendations. A reasonable approach can be extrapolated from one institution's anticoagulation guidelines for thrombocytopenic cancer patients with history of VTE [87▪]. According to this protocol, full-dose enoxaparin is provided for platelet counts greater than 50 000/μl, half-dose enoxaparin for platelet counts between 25 000 and 50 000/μl, and no anticoagulation for platelet counts less than 25 000/μl [87▪]. Over 2 years of study, there were no recurrent thrombotic events or major bleeding episodes [87▪]. How the thrombotic risk of these patients compares with patients with aPL is of course hard to quantify; however, in the absence of additional evidence, our opinion is that this protocol would be reasonable to institute for APS inpatients with thrombocytopenia (while once again emphasizing the need for an individualized assessment).
Although APS is best known for its association with thrombotic events and pregnancy morbidity, thrombocytopenia is a common (perhaps the most common) ‘extra-criteria’ manifestation. Until the pathophysiology is better defined, the approach to when and how to treat will need to remain individualized. Furthermore, with the balance of evidence pointing to thrombocytopenia as a predictor of a more severe APS phenotype, we feel strongly that the cryptic conspirators of thrombocytopenia and APS warrant further investigation in animal models and prospective patient cohorts.
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