Síndrome antifosfolípido catastrófico. A propósito de un caso, presentado en www.perlasclinicas.com, de una paciente femenina de 25 años con síntomas constitucionales, neurológicos y lesiones en piel.
6. INTRODUCCIÓN
Síndrome antifosfolípidos (SAF): Es una
enfermedad multisistémica autoinmune
caracterizada por trombosis venosas y arteriales
recurrentes y morbilidad gastacional (Hughes
1983).
SAF catastrófico: evidencia de compromiso
trombótico de múltiples órganos en un corto
periodo de tiempo (1 semana).
7. INTRODUCCIÓN
1992: Se adoptó el adjetivo CATASTRÓFICO para
definir una forma acelerada del síndrome
antifosfolípidos (SAF) o síndrome de Hughes.
Permanece incierto porque algunos pacientes
desarrollan trombosis recurrentes, principalmente
de grandes vasos (SAF clásico o simple) mientras
otros desarrollan rápidamente oclusiones
vasculares recurrentes de pequeños vasos (SAF
catastrófico).
8. EPIDEMIOLOGÍA
Títulos bajos de anticardiolipinas son detectados
en el 10%.
Títulos moderados-altos de anticardiolipinas o un
anticoagulante lúpico se encuentra en menos del
1%.
Donante
s sanos
9. EPIDEMIOLOGÍA
10-40% de los pacientes con LES y 20% con AR
tienen AFL(antifosfolípidos)
Pacientes asintomáticos con AFL tienen un 0-4% de
riesgo anual de trombosis.
ACS.
ANTIFOSFOLÍPIDOS
EDAD
10. EPIDEMIOLOGÍA
10% de los pacientes con un primer ECV tienen
AFL, especialmente si son jóvenes (hasta 29%)
20% de las mujeres que sufren 3 o más pérdidas
fetales consecutivas tienen AFL positivos.
12. SAF
CATASTRÓFICO
Trombosis de múltiples
órganos
Vasos pequeños y
parénquima
Órganos inusuales
SAF CLÁSICO
Trombosis de un solo vaso
(Arterial o venoso)
Mediano o gran calibre
Tasas de recurrencia baja
PERFÍL CLÍNICO
26. MANIFESTACIONES CLÍNICAS
Los riñones son el órgano más frecuentemente
afectado (73 %)
Insuficiencia renal: 74.5%
Hipertensión arterial: 22.2%
Proteinuria en diferente grado: 25%
Hematuria: 10.5%
27. MANIFESTACIONES CLÍNICAS
Los diferentes tipos de afectación renal:
trombosis de capilares glomerulares,
microangiopatía trombótica, necrosis cortical,
nefropatía mesangial, trombosis y estenosis de
la arteria renal y trombosis de la vena renal.
55. * Cuando el AcL y las anticardiolipinas (IgM, IgG) son negativas y se tiene
alta sospecha se debería realizar IgA anticardiolipinas y IgG, IgM e IgA
Anti-B2GPI.
56.
57. 2
1
1. ANTICOAGULANTE LÚPICO
2. ANTICUERPOS ANTICARDIOLIPINAS(ELISA)
3. ANTI-BETA-2 GLICOPROTEINA-I
LABORATORIO *
CLÍNICO
EVENTO VASCULAR O MORBILIDAD
GESTACIONAL
*EN DOS OCASIONES SEPARADAS POR AL MENOS 12 SEMANAS
66. TRATAMIENTO
Basado en series de casos
AC o GC no deberían ser usados solos (B)
AC + GC debería ser el “backbone” de la terapia (B)
Triple terapia (AC + GC + recambio plasmático y/o
IVIG) (B)
En infección: IVIG debería ser usado (D)
67. TRATAMIENTO
Tetra terapia (AC + GC + recambio plastmático y/o IVIG + ciclofosfamida):
para pacientes con LES u otra enfermedad autoinmune (D)
Ciclofosfamida: es el DMARD más usado; no hay suficiente evidencia de uno
sobre otro (D)
Rituximab:
Especialmente en anemia hemolítica microangiopática, un potencial
marcador de recurrencia.
Rol como segunda línea en pacientes refractarios a triple terapia
estándar.
Alternativa adyuvante en SAF-C en los cuales la AC esta contraindicada.
The antiphospholipid syndrome (APS) is a multi-system
autoimmune disorder characterized by recurrent arterial
and venous thromboses and pregnancy morbidity
Catastrophic APS is the most severe form of APS with: (a) clinical
evidence of multiple organ involvement developing over a short period
of time; (b) histopathological evidence of small vessel occlusions; and
(c) laboratory confirmation of aPL (lupus anticoagulant (LA) test;
anticardiolipin antibody (aCL) enzyme linked immunosorbent assay
(ELISA), and anti-β2-glycoprotein-I antibody (aβ2GPI) ELISA) [2].
In 1992, the adjective catastrophic was added to define an
accelerated form of the antiphospholipid syndrome (APS)
and to highlight a new subset of this syndrome, resulting in
often fatal multiorgan failure
Further, a precipitating event
(mainly infections) precede about 60% of catastrophic
episodes [3–5].
Although less than 1% of patients with APS develop
this complication, its potentially lethal outcome emphasizes
its importance in clinical medicine today
It is still unclear why some patients develop recurrent
thromboses, mainly of large vessels (simple or classic APS),
whereas others develop rapidly recurrent vascular occlusions,
predominantly affecting small vessels (catastrophic APS).
Low-titer, usually transient, anticardiolipin occurs in up to 10% of normal blood donors,4,5 and moderate- to high-titer anticardiolipin or a positive lupus anticoagulant test occurs in less than 1%. The prevalence of positive aPL tests increases with age. Ten percent to 40% of SLE patients5 and approximately 20% of rheumatoid arthritis patients6 have positive aPL tests.
Based on a limited number of uncontrolled and non– risk-stratified studies, asymptomatic (no history of vascular or pregnancy events) aPL-positive patients have a 0% to 4% annual risk of thrombosis; patients with other autoimmune diseases such as SLE are at the higher end of the range.7,8 The aPL profile (low vs. high risk for thrombosis) and patients’ clinical characteristics (presence or absence of other acquired or genetic thrombosis risk factors) influence the individual risk of thrombosis.9 Ten percent of first-stroke victims have aPLs,10 especially those who are young (up to 29%),5,11 as do up to 20% of women who have suffered three or more consecutive fetal losses.12 Fourteen percent of patients with recurrent venous thromboembolic disease have aPLs.13
It is still unclear why some patients develop recurrent
thromboses, mainly of large vessels (simple or classic APS),
whereas others develop rapidly recurrent vascular occlusions,
predominantly affecting small vessels (catastrophic APS).
Low-titer, usually transient, anticardiolipin occurs in up to 10% of normal blood donors,4,5 and moderate- to high-titer anticardiolipin or a positive lupus anticoagulant test occurs in less than 1%. The prevalence of positive aPL tests increases with age. Ten percent to 40% of SLE patients5 and approximately 20% of rheumatoid arthritis patients6 have positive aPL tests.
Based on a limited number of uncontrolled and non– risk-stratified studies, asymptomatic (no history of vascular or pregnancy events) aPL-positive patients have a 0% to 4% annual risk of thrombosis; patients with other autoimmune diseases such as SLE are at the higher end of the range.7,8 The aPL profile (low vs. high risk for thrombosis) and patients’ clinical characteristics (presence or absence of other acquired or genetic thrombosis risk factors) influence the individual risk of thrombosis.9 Ten percent of first-stroke victims have aPLs,10 especially those who are young (up to 29%),5,11 as do up to 20% of women who have suffered three or more consecutive fetal losses.12 Fourteen percent of patients with recurrent venous thromboembolic disease have aPLs.13
It is still unclear why some patients develop recurrent
thromboses, mainly of large vessels (simple or classic APS),
whereas others develop rapidly recurrent vascular occlusions,
predominantly affecting small vessels (catastrophic APS).
Menos del 1% de los pacientes con SAF desarrollan esta complicación, la cual es potencialmente letal.
Eventos precipitantes (principalmente infecciones) preceden en cerca del 60% de los episodios de SAF catastrófico.
Existe un registro europeo para el reporte de casos de SAF catastrófico (2000).
Antiphospholipid antibodies can stimulate endothelial cells, immune cells, and platelets. Binding of anti-B2GPI/B2GPI complex to various receptors on the surface of endothelial cells promotes a proinflammatory and prothrombotic phenotype mediated in part by p38 mitogen-activated protein kinase and nuclear factor kappa-B.
Antiphospholipid antibodies can reduce the activity of endothelial nitric oxide synthase resulting in diminished nitric oxide production. Nitric oxide deficiency causes impaired vasodilation and promotes platelet adhesion to the endothelium. Antiphospholipid antibodies cause oxidative stress and stimulate expression of tissue factor on the surface of endothelial cells and monocytes. A membrane-bound lipoprotein, tissue factor is the cell surface receptor and cofactor for coagulation factor VII. Anti-B2GPI/B2GPI complex can induce platelet activation and aggregation via apolipoprotein E receptor 2’.
Antiphospholipid antibodies can inhibit anticoagulants. Endogenous anticoagulants include protein C, protein S, antithrombin, and annexin A5. An endothelial cell surface receptor, thrombomodulin binds thrombin and protein C, thereby facilitating protein C activation. A multifunctional serine protease, activated protein C inactivates coagulation factors Va and VIIIa with the aid of protein S. Antiphospholipid antibodies can inhibit the protein C pathway by: 1) inhibiting the assembly of protein C complex; 2) reducing protein C activation via thrombomodulin-thrombin complex; 3) suppressing protein C activity; 4) binding to and protecting coagulation factors Va and VIIIa from protein C-mediated proteolysis; and 5) enhancing clearance of protein C. Antiphospholipid antibodies disrupt annexin A5, a potent anticoagulant with high affinity for negatively charged prothrombotic phospholipids such as phosphatidylserine.
Antiphospholipid antibodies can impair fibrinolysis. The coordinated actions of the activators, inhibitors, cofactors, and receptors of the fibrinolytic system provide protection from the excessive activity of the coagulation system. Tissue plasminogen activator (tPA) and urokinase (uPA) convert plasminogen to plasmin, which degrades fibrin to its soluble degradation products. B2GPI serves as a cofactor for tPA. A cell surface receptor for tPA and plasminogen, annexin A2 facilitates tPA-mediated plasminogen proteolysis and plasmin generation. Plasminogen activator inhibitor-1 (PAI-1) inhibits the activity of both tPA and uPA. Antiphospholipid antibodies can interfere with fibrinolysis by: 1) inhibiting tPA; 2) blocking B2GPI; and 3) interfering with annexin A2.
Antiphospholipid antibodies can activate complements. Complements are activated through the classical, lectin, or alternative pathways (7). The classical pathway is strongly activated by immune complexes, which are recognized by the versatile pattern recognition molecule C1q. Complement activation results in C3 cleavage into C3a and C3b by the C3 convertases. Binding of C3a to its receptor on the surface of platelets causes activation, adhesion, and aggregation of platelets. C3b facilitates phagocytosis and participates in the assembly of the C5 convertases that cleaves C5 into C5a and C5b. C5a stimulates expression of tissue factor (monocytes, neutrophils, endothelial cells) and PAI-1 (mast cells, basophils). C5b participates in the assembly of membrane attack complex (C5b-9) on the surface of platelets and endothelial cells resulting in generation of negatively charged prothrombotic phospholipids. Membrane attack complex also triggers release of storage granules and tissue factor-bearing microparticles from platelets.
Proposed mechanism of antiphospholipid antibody (aPL)-related thrombosis and placental injury. The negatively charged phospholipid phosphatidylserine (PS, yellow circles) migrates from the inner to the outer cell membrane during activation or apoptosis of platelets and endothelial cells, and it is normally present on trophoblasts. The neutral phospholipid phosphatidylcholine (PC, red circles) is the major constituent of the outer layer of unactivated cells. Dimeric β2-glycoprotein I (β2GPI) then binds to PS (probably via β2GPI surface receptors such as apoER2′, annexin A2, or a Toll-like receptor), and aPL binds to β2GPI, activating the classic complement pathway and leading to the generation of C5a, which induces (1) expression of adhesion molecules (e.g., intracellular adhesion molecule-1) and tissue factor [TF]), and (2) activation of monocytes, polymorphonuclear (PMN) cells, and platelets, resulting in the release of proinflammatory mediators (e.g., tumor necrosis factor [TNF], vascular endothelial growth factor receptor-1) and initiation of the prothrombotic stage. Both nuclear factor κB (NFκB) and p38 mitogen-activated protein kinase (p38 MAPK) may play a role in the intracellular signaling cascade. Antiphospholipid antibodies also downregulate the expression of trophoblast signal transducer and activator of transcription 5 (STAT5), reducing the endometrial stromal cell production of prolactin (PRL) and insulin growth factor binding protein-1 (IGFBP-1).
_____
Although clinical findings are well defined, the pathological mechanisms
of CAPS are less understood. Nonetheless, the close association
between CAPS and classic antiphospholipid syndrome (APS) suggests
the presence of possible overlapping mechanisms. However, it is still
unclear why some patients will develop recurrent thrombosis mainly
affecting large vessels (classic APS), while others develop rapidly recurrent
vascular occlusions, predominantly affecting small vessels (CAPS).
In 1998, Kitchens introduced the new concept of “thrombotic storm”
to describe a peculiar event in the course of CAPS referred to the possible
ability of vascular occlusion to trigger itself additional thrombosis
[1]. According to such hypothesis, the author proposed that while
clots continue to generate thrombin, fibrinolysis is decreased by an
increase in plasminogen activator inhibitor (PAI) type-1 determining
a consumption of the natural anticoagulant proteins such as protein C
and antithrombin.
APS is considered to have a multifactorial etiopathogenesis and the
involvement of both adaptive immunity and innate immunity, supported
by the presence of a predisposing genetic background, is required
Other, less relevant antigens targeted by aPLs are prothrombin, annexin V, protein C, protein S, high- and low-molecular-weight kininogens, tissue plasminogen activator, factor VII, factor XI, factor XII, complement component C4, and complement factor H.19
APS affects all organ systems. Its principal manifestations are venous or arterial thromboses and pregnancy loss (see Table 82-1). Except for their severity, the youth of affected patients, and the unusual anatomic locations (Budd-Chiari syndrome; sagittal sinus and upper extremity thromboses), venous thromboses in APS do not differ clinically from thromboses attributable to other causes. Similarly, arterial thromboses differ from non–aPL-associated thromboses only by their recurrent nature, unusual locations, and occurrence in young patients. Deep vein thrombosis and stroke are the most common clinical manifestations of APS. Renal thrombotic microangiopathy, glomerular capillary endothelial cell injury, and thrombosis of renal vessels cause proteinuria without cells in the urine or hypocomplementemia and may lead to severe hypertension, renal failure, or both.
25 % DESARROLLAN CID
EN SAF EN GENERAL LA PROFILAXIS CON ASPIRINA:
APLASA STUDY (81 mg/día) y Physicians Health study (325 mg/día) no demostraron superioridad de esta profilaxis en comparación con el placebo para prevenir los eventos trombóticos. A pesar de estos datos contradictorios, opinión de expertos, y consensos, avalan su utilización especialmente en aquellos pacientes con anticuerpos persistentemente positivos -ESPECIALMENTE ANTICOAGULANTE LÚPICO- que cursan concomitantemente con Les y en pacientes obstétricas de alto riesgo.
LOS ANTIMALÁRICOS: han mostrado un efecto anti-trombótico moderado (ref 40 CAP SAF CIB: Ruiz-Irastorza G, et al. Clinical efficcacy an side effects…).
LAS ESTATINAS: también han demostrado en estudios RTC disminuir el riesgo de TVP y eventos cardiovasculares (ref.NEJM 2009, A Randomized trial of rosuvastatin in the prevention)
RECOMENDACIONES SOBRE PROFILAXIS SECUNDARIA:
La duración e intensidad de la anticoagulación son motivo de debate. El grupo de Lockshin propone INR 2-3 para primer evento trombótico venoso y entre 2.5-3.5 para los que tuvieron trombosis arterial.
La monitorización de INR debería ir acompañada de la medición de factor II -protrombina- en pacientes con riesgo de trombosis recurrente, ya que este valor de laboratorio reflejaría más precisamente la posible generación de trombina.
WARFARINA NO EN PRIMER TRIMESTRE NI DESPUÉS DE LA SEMANA 36. EN ESTE PERIODO DAR HEPARINA DE BAJO PESO.
ASA + HBPM a dosis de profilaxis: MATERNAS CON 2 O MÁS ABORTOS O PÉRDIDAS FETALES.
EN SAF EN GENERAL LA PROFILAXIS CON ASPIRINA:
APLASA STUDY (81 mg/día) y Physicians Health study (325 mg/día) no demostraron superioridad de esta profilaxis en comparación con el placebo para prevenir los eventos trombóticos. A pesar de estos datos contradictorios, opinión de expertos, y consensos, avalan su utilización especialmente en aquellos pacientes con anticuerpos persistentemente positivos -ESPECIALMENTE ANTICOAGULANTE LÚPICO- que cursan concomitantemente con Les y en pacientes obstétricas de alto riesgo.
LOS ANTIMALÁRICOS: han mostrado un efecto anti-trombótico moderado (ref 40 CAP SAF CIB: Ruiz-Irastorza G, et al. Clinical efficcacy an side effects…).
LAS ESTATINAS: también han demostrado en estudios RTC disminuir el riesgo de TVP y eventos cardiovasculares (ref.NEJM 2009, A Randomized trial of rosuvastatin in the prevention)
RECOMENDACIONES SOBRE PROFILAXIS SECUNDARIA:
La duración e intensidad de la anticoagulación son motivo de debate. El grupo de Lockshin propone INR 2-3 para primer evento trombótico venoso y entre 2.5-3.5 para los que tuvieron trombosis arterial.
La monitorización de INR debería ir acompañada de la medición de factor II -protrombina- en pacientes con riesgo de trombosis recurrente, ya que este valor de laboratorio reflejaría más precisamente la posible generación de trombina.
WARFARINA NO EN PRIMER TRIMESTRE NI DESPUÉS DE LA SEMANA 36. EN ESTE PERIODO DAR HEPARINA DE BAJO PESO.
ASA + HBPM a dosis de profilaxis: MATERNAS CON 2 O MÁS ABORTOS O PÉRDIDAS FETALES.
EN SAF EN GENERAL LA PROFILAXIS CON ASPIRINA:
APLASA STUDY (81 mg/día) y Physicians Health study (325 mg/día) no demostraron superioridad de esta profilaxis en comparación con el placebo para prevenir los eventos trombóticos. A pesar de estos datos contradictorios, opinión de expertos, y consensos, avalan su utilización especialmente en aquellos pacientes con anticuerpos persistentemente positivos -ESPECIALMENTE ANTICOAGULANTE LÚPICO- que cursan concomitantemente con Les y en pacientes obstétricas de alto riesgo.
LOS ANTIMALÁRICOS: han mostrado un efecto anti-trombótico moderado (ref 40 CAP SAF CIB: Ruiz-Irastorza G, et al. Clinical efficcacy an side effects…).
LAS ESTATINAS: también han demostrado en estudios RTC disminuir el riesgo de TVP y eventos cardiovasculares (ref.NEJM 2009, A Randomized trial of rosuvastatin in the prevention)
RECOMENDACIONES SOBRE PROFILAXIS SECUNDARIA:
La duración e intensidad de la anticoagulación son motivo de debate. El grupo de Lockshin propone INR 2-3 para primer evento trombótico venoso y entre 2.5-3.5 para los que tuvieron trombosis arterial.
La monitorización de INR debería ir acompañada de la medición de factor II -protrombina- en pacientes con riesgo de trombosis recurrente, ya que este valor de laboratorio reflejaría más precisamente la posible generación de trombina.
WARFARINA NO EN PRIMER TRIMESTRE NI DESPUÉS DE LA SEMANA 36. EN ESTE PERIODO DAR HEPARINA DE BAJO PESO.
ASA + HBPM a dosis de profilaxis: MATERNAS CON 2 O MÁS ABORTOS O PÉRDIDAS FETALES.
However, mortality remains as high as 48% despite all attempts at effective therapy.75 No systematic studies have examined the treatment of catastrophic APS owing to the rarity of the condition.
LAS PRINCIPALES CAUSAS DE MUERTE SON POR ICTUS, HEMORRAGIA CEREBRAL Y ENCEFALOPATÍA O INFECCIONES. LA RECURRENCIA DE SAF-C <10 % (LIBRO CIB PAISAS - Erkan D, et al. Long Term outcome of catastrophic antiphospholipid syndrome survivors. Ann Rheum Dis. 2003; 62:530-3.)