Keywords catastrophic thrombosis - thrombotic storm - antiphospholipid syndrome - PF4 antibodies
Catastrophic thrombosis, an acute and severe clinical manifestation of abnormal blood clotting, presents a significant challenge in contemporary medicine.[1 ]
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[4 ] This condition, also called “catastrophic thrombotic storm,” arises when blood clots form rapidly and extensively within blood vessels, leading to their critical obstructions that can profoundly impact organ function and patient outcomes. Not rarely, this progressive thrombosis involves unusual sites (i.e., cerebral venous sinuses and intra-abdominal veins), escalating in extension over a short time period (from a few days to a few weeks).[1 ] The intricate interplay of genetic predispositions, underlying medical conditions, and environmental factors underscores the multifaceted nature of catastrophic thrombosis, where not rarely multiple causes act in concert to produce an ultimately catastrophic clinical picture.[5 ]
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[8 ] From genetic thrombophilia mutations predisposing individuals to hypercoagulable states to acquired risk factors such as cancer, pregnancy, and autoimmune disorders, a comprehensive understanding of these contributing elements is essential for a timely and effective patient management (see [Table 1 ] for a summary of the main underlying disorders associated with catastrophic thrombosis). In some cases, however, no underlying prothrombotic disorders can be identified in patients with catastrophic thrombosis. It is also possible that in such idiopathic cases, the fulminant nature of the coagulopathy does not grant time to perform the diagnostic tests.
Table 1
Main conditions associated with catastrophic thrombosis
• Cancer
• Autoimmune disorders
• Extended period of immobility (at bed, prolonged flight)
• Pregnancy (HELLP syndrome)
• Surgical procedures
• Injury/trauma
• Infections/sepsis (e.g., SARS-CoV-2, CMV)
• Thrombotic microangiopathies
• Inflammation
• Hereditary thrombophilia (e.g., FV Leiden, FII G20210A, elevated protein C and protein S)[a ]
• Catastrophic antiphospholipid syndrome
• Drugs (oral contraceptives)
• Hyper-eosinophilic syndrome
• Disseminated intravascular coagulation
• Anti-PF4 immune disorders (HIT, VITT)
• Other conditions: PNH, Behcet's syndrome
Abbreviations: CMV, cytomegalovirus; HELLP, hemolysis, elevated liver enzyme, low platelets; HIT, heparin-induced thrombocytopenia; PF4, platelet factor 4; PNH paroxysmal nocturnal hemoglobinuria; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; VITT, vaccine-induced immune thrombotic thrombocytopenia.
a Homozygosity or double heterozygosity.
This review aims to elucidate the complex pathophysiology of catastrophic thrombosis, exploring its diverse clinical presentations and differential diagnostic challenges. Moreover, we will delve on the latest advancements in therapeutic strategies. Due to the complexity of this condition and the number of contributing factors, we will focus on selected disorders characterized by catastrophic thrombosis, including the catastrophic antiphospholipid syndrome (CAPS), thrombotic anti-platelet factor 4 (PF4) immune disorders (heparin-induced thrombocytopenia [HIT] and vaccine-induced immune thrombotic thrombocytopenia [VITT]), thrombotic microangiopathies (TMAs), cancer-associated thrombosis, disseminated intravascular coagulation (DIC), and the hyper-eosinophilic syndrome (HES). Coronavirus disease 2019 (COVID-19)-associated thrombotic storm will not be addressed here, as this is extensively described elsewhere.[9 ]
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[13 ] In addition, a diagnostic algorithm will be proposed to differentiate the various medical conditions associated with catastrophic thrombosis, in order to identify the actual associated condition and to start promptly the most appropriate treatment.
Catastrophic Antiphospholipid Syndrome
Catastrophic Antiphospholipid Syndrome
Initially described by Asherson in 1992 (and thus its initial description as Asherson's syndrome),[14 ] CAPS is a rare but severe form of antiphospholipid syndrome (APS) that affects approximately 1% of all APS patients.[15 ]
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[26 ] CAPS is characterized by multiple thromboses (microvascular and/or in large vessels) occurring in several vascular beds with clinical evidence of multi-organ involvement and laboratory confirmation of persistent antiphospholipid antibodies (aPLs; e.g., lupus anticoagulant, anti-β2 -glycoprotein I [anti-β2 GPI], and/or anti-cardiolipin antibodies confirmed on ≥2 occasions ≥12 weeks apart).[15 ]
[16 ] CAPS patients often experience both venous and arterial thrombotic events and approximately half of them were not previously diagnosed with APS before experiencing multiple and dramatic thrombotic events.[16 ]
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[21 ] Typically, the syndrome is triggered by factors such as infections, surgery, or obstetric complications and the most frequently involved organs include brain, lungs, heart, and kidneys, which undergo a structural and functional damage over a relatively short period (days).[27 ]
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[31 ] CAPS pathogenesis is mostly driven by complement dysregulation, caused by aPL or by a triggering stimulus (infection, pregnancy, cancer, etc.). In turn, activated complement (in particular C5a, a potent inflammatory mediator) damages vascular endothelial cells by exposing subendothelial collagen and tissue factor, causes activation of platelets and coagulation factors, and disrupts neutrophils by generating DNA extrusions with potent prothrombotic properties.[32 ]
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Although a high level of suspicion of CAPS should arise in any patient with rapidly progressing venous and/or arterial thrombosis, the diagnosis of CAPS is often challenging. A previous diagnosis of CAPS or of systemic lupus erythematosus (which, according to the CAPS Registry, occurs in approximately 30% of CAPS cases)[35 ] may further drive the clinical suspicion towards the correct diagnosis. The criteria for classification of definite or probable CAPS have been proposed at the International Congress on aPL antibodies.[36 ] The majority of our knowledge on CAPS is derived from the above-mentioned CAPS Registry, which is the largest published so far, reporting information on over 500 CAPS cases.[35 ] Based on these data, a panel of international experts published consensus-based guidelines on CAPS in 2018,[37 ] which recommended a combination of unfractionated heparin (UFH) at therapeutic doses, corticosteroids and therapeutic plasmapheresis or intravenous immunoglobulin (IVIG), also called triple therapy, as the first-line treatment for patients with CAPS (see [Table 2 ]).[37 ] Such therapeutic approach was independently associated with a higher survival rate among patients with CAPS.[38 ] While non-vitamin K antagonist (non-VKA) oral anticoagulants are generally not recommended in CAPS patients, low-dose aspirin is usually added to VKAs as long-term anticoagulation, unless the patient's bleeding risk outweighs the benefits.[38 ] Besides the triple therapy, which represents the cornerstone of the CAPS therapy, the treatment of the condition that triggered CAPS (if identified) is equally fundamental. Positive experiences have also been reported with rituximab (a monoclonal antibody against the B-cell antigen CD20) and eculizumab (a monoclonal antibody against the C5 component of the complement cascade involved in the pathogenesis of CAPS), but data are insufficient to recommend these biological drugs as first-line treatment, which thus are generally used as second-line options in refractory patients (see [Table 2 ]).[39 ]
Table 2
Current treatment of the catastrophic antiphospholipid syndrome
Drugs
Treatment option
Dose
Anticoagulants
First-line therapy
Intravenous heparin at therapeutic doses followed by long-term oral anticoagulation (VKA with INR target 2–3)
Corticosteroids
First-line therapy
Methylprednisolone 0.5–1 g/day IV, for 3 or more days, followed by oral prednisone 1 mg/kg/day with tapering initiated once the patient improves clinically
Therapeutic plasmapheresis
First-line therapy
Once daily procedure for five days (or longer if required)
IVIG
First-line therapy
400 mg/kg/day for 5 days
Low-dose aspirin
First-line therapy
100 mg/day (indefinitely)
Rituximab
Second-line therapy
375 mg/m2 /week for 4 weeks
Eculizumab
Second-line therapy
900 mg/week for 4 weeks
Abbreviations: INR, international normalized ratio; IV, intravenously; IVIG, intravenous immunoglobulin; VKA, vitamin K antagonists.
The mortality rate in patients with CAPS was as high as 50% in early published series but has decreased over the last years due to earlier diagnosis and improved treatment options, being currently below 40%.[35 ]
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[41 ] Although mortality rates are still high, the majority of patients who survive an initial CAPS event do not experience recurrent symptoms when on long-term anticoagulant therapy.[42 ]
Thrombotic Anti-PF4 Immune Disorders
Thrombotic Anti-PF4 Immune Disorders
A subset of antibodies against PF4 (a highly cationic tetrameric protein), belonging to immunoglobulin G (IgG) class, is responsible for platelet activation, leading to a severe prothrombotic state with associated thrombocytopenia.[43 ]
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[46 ] Several disorders recognize this pathogenic mechanism, but primarily: the classical HIT, the HIT-like disorders (autoimmune HIT and spontaneous HIT), and the more recently described VITT.[46 ]
Heparin-Induced Thrombocytopenia
HIT is characterized by thrombocytopenia, hypercoagulability, and increased thrombotic risk.[47 ] First reported 50 years ago, it is nowadays well acknowledged that HIT encompasses a wide spectrum of prothrombotic disorders, including classical HIT, autoimmune HIT, and spontaneous HIT (see next section), all characterized by thrombocytopenia and both arterial and venous thromboembolic occlusions.[47 ]
[48 ] Anti-PF4 antibodies play a key role in the pathogenesis of HIT through the extensive activation of platelets, monocytes, neutrophils, and endothelial cells via FcγIIA receptors (FcRγIIA).[43 ]
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[49 ] Notably, being associated with a markedly increased thrombin generation, HIT may also be characterized by DIC.[44 ]
In the classic form of HIT, the pathogenic antibodies are directed against the immune complex formed by UFH, or more rarely low-molecular-weight heparin, with PF4. Other nonheparin polyanionic drugs, such as over-sulfated chondroitin sulfate and pentosan polysulfate, may alternatively be implicated.[44 ] Additional recent evidence has identified in von Willebrand factor (VWF) a new important cofactor through the formation of PF4–VWF immune complexes (PF4 binds to the A2 VWF domain) that induce and accelerate the thrombus formation in HIT.[50 ] In classical HIT, thrombocytopenia typically arises 5 to 10 days after the initiation of heparin treatment, but earlier in the case of previous heparin exposure (within 100 days). Venous thrombosis is more frequently reported than arterial thrombosis, with a ratio of 4:1.[47 ] The “4Ts” scoring system (thrombocytopenia, timing of platelet count decline, thrombosis or other sequelae, and other causes of thrombocytopenia), by enabling the calculation of a pretest clinical score, helps physicians in the diagnostic workup of HIT.[43 ] The combination of the “4Ts” score with the results of rapid PF4-dependent immunoassays with a very high diagnostic sensitivity (such as the latex immunoturbidimetric assay or the chemiluminescence immunoassay) improves the accuracy and speed of diagnosis.[51 ] The management of classical HIT includes the immediate cessation of heparin and its substitution with nonheparin parenteral anticoagulants (i.e., the direct thrombin inhibitors argatroban and bivalirudin, or the indirect factor Xa inhibitors fondaparinux and danaparoid). The VKA warfarin should not be used during the acute phase of HIT as it may cause progressive microvascular thrombosis due to the concomitant severe depletion of protein C.[43 ]
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HIT-Like Disorders
In autoimmune HIT, a severe HIT subtype, highly pathological anti-PF4 IgG antibodies are able to activate platelets through heparin-dependent and heparin-independent mechanisms.[52 ] The latter probably encompass the important role of nonheparin polyanions (chondroitin sulfate, polyphosphates) in the formation of immune complexes capable of activating platelets through their receptors (FcRγIIa). This variant, difficult to diagnose since there may not be any evident proximate heparin exposure, and thus likely under-recognized in its true incidence, is characterized by the persistence of thrombocytopenia, despite stopping heparin if present, and thus requires a particular treatment approach (usually high-dose IVIG to interrupt the immune-induced platelet activation or therapeutic plasma exchange in addition to nonheparin anticoagulants).[52 ]
[53 ] The more severe forms of HIT are characterized by severe thrombocytopenia (<20 × 109 /L) that can persist for weeks, often accompanied by DIC and microvascular thrombosis.[53 ] Paradoxically, the pentasaccharide fondaparinux is both a (rare) trigger of autoimmune HIT and a common anticoagulant used to treat HIT. Fondaparinux-associated HIT usually occurs 1 week later and recognizes a heparin-independent mechanism of platelet activation.[52 ] Actually, according to its clinical characteristics and onset, autoimmune HIT can be further classified in different subtypes (for a detailed description, see Greinacher et al[53 ]).
Similarly, in the spontaneous forms of HIT, perhaps better characterized as a “HIT-like disorder,” anti-PF4 antibodies are detected in cases without heparin exposure. This rare HIT variant, characterized by the formation of immune complexes of PF4 and heparin-independent platelet-activating IgG antibodies, has been described in patients with previous acute infections, inflammatory events, and orthopedic surgery (in particular, total knee arthroplasty).[54 ] Both venous and arterial thromboses have been reported in spontaneous HIT. Notably, approximately 40% of patients with spontaneous HIT presented with cerebral venous thrombosis (CVT) and a further 20% developed acute stroke.[54 ] The cornerstone of treatment includes anticoagulation and immunomodulation (interruption of FcRγIIA-mediated platelet activation using high-dose IVIG). Although theoretically heparin could be safely used in spontaneous HIT, nonheparin anticoagulation is still recommended by most experts and international guidelines due to lack of sufficient evidence for heparin safety in these patients.[54 ]
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[Table 3 ] summarizes the main characteristics of the anti-PF4-related immune disorders.
Table 3
Summary of the main characteristics of the various forms of anti-PF4 immune disorders
Characteristics
Classic HIT
Autoimmune HIT
Spontaneous HIT
VITT
Trigger
Heparin
Heparin/nonheparin polyanions/fondaparinux
Total knee arthroplasty, infections
Adenovirus vector vaccines against COVID-19
Onset
5–10 days after starting heparin
Variable
5–10 days following orthopedic surgery or infection
5–30 days after the first vaccine dose
Thrombocytopenia
Mild to moderate Rapid recovery after stopping heparin
Severe
Often persists despite stopping heparin
Severe
It may last several weeks
Moderate to severe
It may last from days to weeks
D-dimer
Increased
Increased
Increased
Markedly increased
Thrombosis
Venous thrombosis more frequent than arterial thrombosis
Venous thrombosis more frequent than arterial thrombosis. High incidence of microvascular thrombosis.
Venous thrombosis more frequent than arterial thrombosis. High incidence of CVT and arterial stroke
Venous thrombosis more frequent than arterial thrombosis. High incidence of thrombosis at atypical sites (CVT, splanchnic thrombosis)
PF4-dependent tests
EIA (>90% sensitivity)
Rapid immunoassays (>90% sensitivity)
EIA (>90% sensitivity)
EIA (>90% sensitivity)
EIA (>90% sensitivity)
Low sensitivity for rapid immunoassays
Treatment
Nonheparin anticoagulation
Nonheparin anticoagulation; high-dose IVIG
Nonheparin anticoagulation; high-dose IVIG
Nonheparin anticoagulation; high-dose IVIG
Abbreviations: CVT, cerebral vein thrombosis; DIC, disseminated intravascular coagulation; EIA, enzyme immunoassay; HIT, heparin-induced thrombocytopenia; IVIG, intravenous immunoglobulin; PF4, platelet factor 4; VITT, vaccine-induced immune thrombotic thrombocytopenia.
Vaccine-Induced Immune Thrombotic Thrombocytopenia
First reported in 2021, VITT is the most recently recognized anti-PF4 antibody-mediated disorder.[57 ] VITT is now recognized as a very rare complication of vaccination with adenovirus vector vaccines employed against COVID-19, primarily ChAdOx1 nCoV-19 (Oxford University/AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson), although VITT-like symptoms have been reported with other vaccines.[58 ] VITT typically arises 5 to 30 days after the first vaccine dose. Similar to the other anti-PF4 disorders, in particular spontaneous HIT, the two-step pathologic mechanism of VITT includes the interaction between PF4 and polyanionic vaccine constituents and the formation of a cPF4/vaccine complex which triggers a B-cell response with the production of high-avidity anti-PF4 antibodies. The newly formed immune complexes in turn cause pan-cellular activation responsible for the severe clinical sequelae. However, the vaccine components causing the formation of such complexes have not as yet been fully characterized.[59 ]
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[62 ] The clinical picture of VITT is characterized predominantly by CVT (50–70% of cases) and splanchnic vein thrombosis (SVT; 10–20% of cases), thus resembling spontaneous HIT but differing significantly from classic HIT, where CVT and SVT are rare (approximately 5%).[63 ] Other studies, however, have recognized wider thrombotic forms in their VITT cohorts.[64 ] Like classic HIT, VITT patients develop venous thromboembolism more frequently than arterial thrombosis. Following the clinical suspicion of VITT, the laboratory diagnosis is based on the positivity of the anti-PF4 enzyme immunoassay, which has a high sensitivity and specificity, followed by the confirmation of the functional heparin-induced platelet activation assay or the serotonin-release assay.[65 ] The UK Hematology Expert Group developed consensus diagnostic criteria for VITT.[66 ] The mainstay of VITT treatment, which should be started immediately, includes high-dose IVIG, which inhibits FcRγIIA-mediated platelet activation, and a nonheparin anticoagulant (parenteral direct thrombin inhibitors such as argatroban or bivalirudin), which should be preferred to heparin, for which safety data are still insufficient ([Table 3 ]).[67 ]
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Thrombotic Microangiopathies
Thrombotic Microangiopathies
Other syndromes with features resembling thrombotic storm include the TMAs. A wide array of disorders, all characterized by thrombocytopenia, microangiopathic hemolytic anemia and organ injury, belongs to this category, including thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and pregnancy-related or transplant-related TMAs.[69 ]
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Thrombotic Thrombocytopenic Purpura
TTP is a rare hematologic disease characterized by microangiopathic hemolytic anemia (with the laboratory markers of reduced serum haptoglobin and increased serum indirect bilirubin, lactate dehydrogenase and reticulocyte count, and the detection of schistocytes in the peripheral blood smear), thrombocytopenia, fever, and various levels of organ damage, involving predominantly the kidney (renal failure) and the central nervous system (neurologic symptoms ranging from headache to focal signs, seizures, and coma).[73 ]
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[75 ] In the majority of TTP cases (70–80%), an inhibitor against a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) can be detected. As a consequence, the inhibited ADAMTS13 cannot cleave the ultra-large VWF multimers secreted by endothelial cells, which in turn activate (and consume) platelets forming microthrombi that disseminate, causing the mechanical destruction of red blood cells (hemolytic anemia) and, finally, the occlusion of the microcirculation with organ ischemia.[76 ] The measurement of the levels of circulating ADAMTS13 activity and anti-ADAMTS13 autoantibodies complete the diagnosis. Besides this autoimmune TTP form, a very rare congenital TTP (approximately 5% of all TTP cases), called Upshaw–Schulman syndrome, has been reported. This condition, caused by mutations in ADAMTS13 gene leading to significantly decreased VWF-cleaving protease activity, is characterized by relapsing TTP.[77 ]
The mainstay of the initial management of acute TTP includes plasma therapy by means of therapeutic plasma exchange, that is more effective than plasma infusion.[78 ] By replacing large volume of patients' plasma, plasma exchange replaces ADAMTS13 activity and, in autoimmune TTP cases, removes anti-ADAMTS13 autoantibodies. Immunosuppressive therapies for autoimmune TTP include corticosteroids and the anti-CD20 monoclonal antibody rituximab.[79 ] Caplacizumab is a nanobody that binds to the A1 domain of the VWF blocking its interaction with the GP1b glycoprotein on the platelet surface, halting the formation of small-vessel microthrombi and the consequent consumptive anemia and thrombocytopenia.[80 ] When added to standard treatment, a lower incidence of TTP-related complications, earlier platelet count normalization, a reduced number of plasma-exchange procedures, and a lower incidence of exacerbations were observed.[81 ] For this reason, caplacizumab was approved in 2019 by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of acute autoimmune TTP, together with plasma exchange and immunosuppression, and it is currently recommended as first-line therapy of immune TTP by several guidelines.[80 ] However, caplacizumab is not available everywhere, and so plasma exchange remains the preferred therapy in some geographic locations. Recombinant ADAMTS13 has been approved for treatment of congenital TTP.[82 ]
Other Thrombotic Microangiopathies
TMAs other than TTP predominantly include the typical and atypical HUSs, both of which are predominantly characterized by renal dysfunction. In addition, several other conditions, such as cancers, drugs, pregnancy, infections, autoimmune disorders, and hematopoietic stem cell transplants, may be complicated by clinical and laboratory signs resembling those of TMA (see later).
The typical HUS, also known as Shiga toxin-associated HUS, is caused by Shiga toxin-producing enterohemorrhagic bacteria, mainly Escherichia coli (in particular the O157:H7 strain).[83 ] This syndrome usually occurs in children and, after a prodromal phase of bloody diarrhea lasting 5 to 7 days, it presents with the classic triad of TMA (thrombocytopenia, macroangiopathic hemolytic anemia, and severe renal insufficiency). The mechanisms by which Shiga toxin-producing E. coli causes TMA include a direct cell damage along with proinflammatory and prothrombotic properties, favored also by the induction of secretion of VWF from endothelial cells.[70 ] Patients with this disease have usually normal or only mildly reduced ADAMTS13 activity. The primary treatment of typical HUS is supportive (early hyperhydration and blood transfusions), while the roles of plasma exchange and anti-complement treatment remain uncertain.[83 ]
Atypical HUS is a rare condition, accounting for approximately 5 to 10% of all HUS cases, which differs from typical HUS because it is usually not preceded by diarrheal infection (negative stool test for Shiga toxin) and it has a worse prognosis (mortality up to 25%).[84 ] Atypical HUS is often caused by genetic mutations of the alternative pathway of the complement system (several mutations have been recognized so far, involving genes encoding for complement factors or complement regulatory proteins) or by autoantibodies against specific complement factors resulting in an over-activation of the complement system and formation of microvascular thrombi.[85 ] The development and marketing of eculizumab, a monoclonal antibody inhibitor of C5 complement factor, has revolutionized the therapeutic approach of atypical HUS, with rapid hematological responses and renal function improvement in most cases.[86 ]
[87 ] Finally, in the transplant-associated TMA, kidney is typically the primary site of microangiopathy, thus clinically resembling atypical HUS.[88 ]
Hyper-eosinophilic Syndrome
Hyper-eosinophilic Syndrome
HES is a rare condition characterized by an elevated peripheral eosinophil blood count (≥1,500/μL, measured on two occasions at least 1 month apart) with an eosinophilia-mediated organ dysfunction.[87 ] HES includes a heterogeneous group of disorders, which however can basically be restricted to three forms: a primary neoplastic/clonal form (several mutations have been reported so far), a secondary reactive form, and an idiopathic form, whose diagnosis is made on the basis of the exclusion of primary or secondary forms.[89 ] Weakness, cough, dyspnea, rash, fever, myalgia, and pruritus are the most frequently presenting symptoms.[89 ] The most common manifestations are, in order of frequency, dermatological, pulmonary, and gastrointestinal, but rheumatological and neurological manifestations have also been described.[90 ] Cardiac and thromboembolic complications are common causes of morbidity and mortality in patients with HES and several case reports have documented this evidence.[91 ]
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[95 ] In some cases, the dramatic clinical picture of catastrophic thrombosis may be observed.[96 ] In a retrospective cohort study of 138 patients with HES, thrombotic events were reported in 21%.[97 ] In another, more recent, retrospective cohort study assessing the association between HES and thrombosis in 71 patients, 25% had one or more thrombotic episodes, equally distributed between arterial and venous events, significantly associated with an increased risk of death.[98 ] Regarding the pathogenesis of thromboembolic complications, while the HES-related cardiac involvement has been attributed to a direct eosinophil-mediated endocardial damage leading to the formation of intramural thrombi,[88 ] other mechanisms potentially implicated have been reported in preclinical studies. These include an increased tissue factor expression in circulating eosinophils in patients with HES along with the degranulation of eosinophil granules containing inflammatory, oxidative, and prothrombotic substances, including the major basic protein and hydrogen peroxide.[99 ]
[100 ] In addition, a close interaction exists between platelets and eosinophils: the latter are stimulated by platelets to form extracellular eosinophil traps which in turn activate platelets through major basic protein.[101 ]
Besides the anticoagulation of possibly associated acute thrombosis, the mainstay of the treatment of HES is usually aimed at preventing organ damage from eosinophilic infiltration.[88 ] While the first-line treatment for idiopathic HES is represented by steroids, biologic therapies with humanized monoclonal antibodies, including the anti-interleukin-5 (anti-IL-5) (a cytokine involved in the eosinophil proliferation) agents mepolizumab and reslizumab, and the anti-IL-5 receptor agent benralizumab, have been shown to be effective and safe in treating HES, preventing further organ damage and avoiding the long-term side effects of steroid use.[102 ] In addition, as a high incidence of thromboembolic complication has been consistently reported in larger case-series on HES, possible antithrombotic prophylaxis should be always considered after a careful assessment of the patient's thrombotic risk.
Other Causes
Many other conditions have been involved in the process of development of catastrophic thrombosis, the main ones being listed in [Table 1 ]. Several hematological cancers, including acute promyelocytic leukemia and myeloproliferative neoplasms, are associated with an increased thrombotic risk.[103 ] Thromboembolism is a leading cause of mortality in patients with cancer. Aggressive forms of Trousseau syndrome, which is characterized by migratory thrombotic events, resembling catastrophic thrombosis have been reported in patients with solid tumors, not necessarily related to the dimension of the cancer but being classified as part of a paraneoplastic syndrome.[4 ] As previously reported, cancer patients may also develop microangiopathic hemolytic anemia.[4 ] Massive thromboembolic events may occur in women under oral contraceptive or hormone replacement therapy, particularly in the presence of other congenital (i.e., inherited thrombophilia) or acquired (i.e., infections, prolonged immobility) prothrombotic factors.[104 ] Multifocal thromboembolic events have also been described in patients with the rare hematological condition paroxysmal nocturnal hemoglobinuria and, in the frame of the chronic inflammatory process, in patients with Behcet's syndrome.[4 ]
[105 ]
Massive thrombosis, particularly venous, is also associated with the severe homozygous deficiency of anticoagulant proteins C and S in pediatric and young adult patients.[4 ] Finally, infections such as severe acute respiratory coronavirus 2 infection, sepsis, and pregnancy-related syndromes (including hemolysis, elevated liver enzyme, and low platelet [HELLP] syndrome, pre-eclampsia, and eclampsia) may act as precipitating factors in catastrophic thrombosis.[4 ]
Management of Patients with Catastrophic Thrombosis
Management of Patients with Catastrophic Thrombosis
The correct diagnostic framework in a patient with sudden and rapidly evolving multiple thromboembolic events is very challenging for physicians because they have to rule out a number of possible triggering conditions in the shortest possible time. Apart from the obvious immediate start of anticoagulation, it is very important to carry out an accurate diagnostic workup in order to start quickly the most appropriate treatment, on which patient outcome depends. [Fig. 1 ] reports the proposed algorithm for the initial management of patients with the thrombotic storm. Before starting parenteral anticoagulation, it is important to collect from the patient multiple plasma samples to carry out functional coagulation tests for further verification or confirmation in order to avoid the interference with tests of anticoagulant therapy. During the differential diagnostic process, it is therefore important to consider the frequency of possible conditions associated with thrombotic storm (for example, cancers, rheumatologic disorders, and infections are certainly more frequent than congenital TTP). If the patient is a woman in reproductive age, a pregnancy-related complication or the use of oral contraceptives should be considered. A personal and/or family history positive for inherited thrombophilia should direct towards the laboratory investigation of thrombophilic mutations, which in turn could act as precipitating factors in association with other predisposing conditions. If a suspected HIT is considered, along with checking anti-PF4 antibodies, it is mandatory to immediately stop heparin and switch the patient to a nonheparin parenteral anticoagulant. The detection of clinical and laboratory signs of microangiopathic hemolytic anemia along with thrombocytopenia would favor a diagnosis of TTP or another TMA, while a diagnosis of CAPS should be considered in the case of confirmed presence of aPL antibodies according to the aforementioned classification criteria.[36 ] When a suspected diagnosis is not confirmed, other causes should be considered and ruled out. If all diagnostic-instrumental tests performed are inconclusive, in the absence of clinical symptoms leading to a specific associated disease, a diagnosis of idiopathic catastrophic thrombosis is finally made.
Fig. 1 Proposed algorithm for the management of patients with suspected thrombotic storm. aPL, antiphospholipid antibodies; CAPS, catastrophic antiphospholipid syndrome; HES, hyper-eosinophilic syndrome; HIT, heparin-induced thrombocytopenia; OC, oral contraceptive; VITT, vaccine-induced immune thrombotic thrombocytopenia. 1 In the case of suspected HIT, stop immediately heparin and start nonheparin parenteral anticoagulants. 2 If tests performed are inconclusive, a diagnosis of idiopathic catastrophic thrombosis is made. 3 Homozygosity or double heterozygosity. Thrombophilic mutations can contribute to trigger catastrophic thrombosis in association with other risk factors. 4 According to the classification criteria for CAPS. 5 Fulfilling the diagnostic criteria for HES (see text).
Conclusion
Catastrophic thrombosis is a severe medical emergency that warrants immediate intervention through anticoagulation and aggressive management to prevent life-threatening consequences and enhance patient outcomes. Because catastrophic thrombosis recognizes several triggering factors that may act separately or, more frequently, concomitantly in a synergic manner, their prompt recognition through a differential diagnosis process is essential to start the most appropriate treatment, having a favorable impact on patients' prognosis. Heightened awareness, early detection, and effective treatment modalities are mandatory in addressing this potentially fatal condition.
