antiphospholipid syndrome 7149

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the initial description of 10 cases in 1992 [17], additional case series reporting 50

[20] and now 80 [21] patients with CAPS have provided information regarding its

pathogenesis, clinical characteristics, and manifestations.

Pathology and pathophysiology

The predominant pathology in CAPS is a noninflammatory, thrombotic

microangiopathy of small vessels resulting in multiorgan failure [18]. The

pathophysiology of CAPS seems to involve derangements in the coagulation

process causing continued and widespread thrombosis within the microvascular

circulation. Antiphospholipid antibodies present in the serum of these patients

represent a group of immunoglobulins that bind plasma proteins (such as

b2-glycoprotein I [b2-GPI]), prothrombin, annexin, high and low molecular

weight kininogens) [22–25], or phospholipid microparticles in the circulation

[26]. Antibody binding to proteins on the cell surfaces of platelets, monocytes,

tumor cells, or endothelial cells can result in activation of these cells leading to a

procoagulant state. For example, endothelial cells, when activated, increase the

expression of adhesion molecules, promoting leukocyte adhesion to endothelial

surfaces and thus promoting thrombosis [27–29].

Antiphospholipid antibodies have also been implicated in promoting throm-

bosis by inhibiting the decreased expression of activated factors V and VIII,

causing increased thrombin production [18,30,31]. Also, during the process of

coagulation, the presence of fresh clots can potentiate coagulation activation

products in the plasma [32,33], resulting in depletion of antithrombin III, protein C,

or protein S. The term thrombotic storm has been used to describe this process in

an underlying hypercoagulable state [34].

The widespread, microvascular thrombosis seen in CAPS causes tissue

ischemia and necrosis, leading to a clinical picture similar to the systemic

inflammatory response syndrome (SIRS) seen in clinical settings such as trauma,

septic shock, and so forth [18]. SIRS is characterized by activation of cells (ie,

monocytes and macrophages, endothelial cells, neutrophils) with release of

inflammatory mediators that affect hemostasis through the extrinsic pathway,

inducing plasminogen activator inhibitor type-1, resulting in altered hemostasis,

increased coagulation, and microvascular fibrin deposition [35]. Possibly, by its

action on endothelial cells, aPL, alone or as a component of antibody-antigen

complexes, can induce a picture akin to SIRS.

Clinical presentation of CAPS

Patient history

Early recognition of CAPS is important for effective intervention and patient

survival. Knowledge of the patient’s history may be helpful. A previous diag-

nosis of APS with prior thrombotic episodes may be present. Previous symptoms

G.E. Westney, E.N. Harris / Crit Care Clin 18 (2002) 805–817 806



and signs of APS are reported to be present in 49% to 66% of patients presenting

with CAPS [20,21]. Most frequently, deep vein thrombosis (DVT), recurrent

fetal loss, and thrombocytopenia are reported in the history. Evidence of previousmajor venous or arterial occlusive episodes should be sought. Such episodes may

include pulmonary embolism (PE), superior or inferior vena caval thrombosis,

myocardial infarction, cerebrovascular accidents, adrenal and renal infarction,

and mesenteric and splenic artery thrombosis [20]. Other manifestations are

retinal artery occlusions, digital ischemic episodes, renal artery occlusion,

HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, livedo

reticularis, nonhealing leg ulcers, nasal septal perforation, heart valve lesions,

hemolytic anemia, and chorea [20,21].

Precipitating factors

Up to 22% of the patients may have identifiable precipitating factors [20].

Infections have been identified as dominant triggers in up to one third of pa-

tients. Organisms include Escherichia coli, Shigella, Salmonella, Streptococcus,

and Staphylococcus, with sites originating from the upper respiratory, urinary,

and gastrointestinal tracts, the skin, and central venous line sites [18]. Evidence

suggests that some infectious agents can induce antibodies to phospholipids and

b2-GPI [36,37], and production of these antibodies may in turn trigger CAPS[20,21].

Trauma [38], surgical procedures such as biopsy [39], endoscopic retrograde

cholangiopancreatography (ERCP) [40], arterial manipulation [41], pregnancy,

and postfetal demise [42,43] have all been cited as precipitating CAPS. Induction

of autoimmune disease processes secondary to stress [44] and increased produc-

tion of tissue factors following invasive procedures [45] are possible explanations

for this association.

The association of malignancies with CAPS emerged from the most recent

case series and was implicated as a precipitating factor in 8% of patients [21].Some solid tumors have been associated with aPL positivity [46], contributing to

a procoagulant state that may be involved in CAPS development. Clinical

settings that cause formation of fresh clots (gangrenous limbs with major vessel

occlusions) in an underlying hypercoagulable state may incite the aforementioned

thrombotic storm [18,34].

Withdrawal of anticoagulation therapy or a decrease in the international

normalized ratio (INR) may lead to recurrent thrombosis and development of

CAPS [18]. The cessation of anticoagulation therapy in preparation for surgical

or dental procedures, administration of drugs affecting the metabolism of warfarin (barbiturates, carbamazepine, rifampin, phenytoin), or gastrointestinal

problems that result in poor absorption of anticoagulant medication are clinical

scenarios that may be implicated.

Additional situations cited as precipitating factors include SLE flares and use

of oral contraceptives and the drugs thiazide and captopril [20,21]. In approx-

imately 35% of patients, a causative factor was not identified [21].




Presentation

Progression to CAPS can occur within days to weeks [20]. The presentation is

one of simultaneous or rapidly progressing multiorgan failure. Although throm-

bosis of large cerebral and peripheral vessels (DVT causing PE) can occur, this

condition is present only in 15% to 20% of patients. Widespread thrombotic

microangiopathy seems to be the basic pathologic condition in whatever organ is

examined [18].

The patient progressing to CAPS should be evaluated for a wide range of

systemic signs and symptoms occurring simultaneously. In the series of

50 patients summarized by Asherson, renal involvement was present in 78%,

followed by lung (66%), central nervous system (CNS) (56%), skin and heart

(50%), gastrointestinal (38%), and adrenal gland (26%) involvement [20].

Involvement of the pancreas, spleen, thyroid gland, muscles, and peripheral

nerves has also been cited [47]. In the most recent series of patients with CAPS,

manifestations on initial presentation were cardiopulmonary (25%), CNS abnor-

malities (22%), abdominal pain (22%), and renal abnormalities (14%) [21]. It is

progressive cardiopulmonary failure, however, that brings patients to the ICU

needing acute life-saving intervention.

Organ involvement in CAPS

Pulmonary features and manifestation

Pulmonary complications described in patients with primary or secondary

APS include PE with or without infarction, pulmonary hypertension (PHT),

pulmonary arterial thrombosis, pulmonary in situ microthrombosis, alveolar

hemorrhage, and a case of fibrosing alveolitis [48]. These entities may be present

when CAPS develops, but the dominant feature in CAPS is the clinical picture of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS)

[18,20,21].

ALI and ARDS represent a spectrum of injury to the lung capillary endothelial

and epithelial surfaces resulting in pulmonary edema and hypoxemia. Criteria are

bilateral infiltrates seen on chest radiograph, absence of left atrial hypertension

(pulmonary artery wedge pressure 18 mm Hg) and a partial pressure of

arterial, oxygen to fraction of inspired oxygen (PaO2/FIO2) ratio of 300 mm Hg or

less (in ALI) or of 200 mm Hg or less (in ARDS) [49].

In the series of 50 patients with CAPS, 66% had some pulmonary symptomsor abnormality. In reported case series [20,21], 34% to 41% of patients developed

ARDS. Seven case reports provide some details regarding the features of ARDS

[14,50–53]. The typical scenario is worsening dyspnea and hypoxemia resulting

in the need for intubation and mechanical ventilation. Pulmonary examination

reveals localized or diffuse crackles, and chest radiographs show bilateral

infiltrates suggestive of pulmonary edema. Computed tomographic (CT) scan-




ning of the thorax may show evidence of PE, pleural effusions, basilar atelectasis,

and diffuse ground-glass opacities [53]. The development of ARDS may reflect

an acute increase in hydrostatic pressure from occluding pulmonary emboli or result from microvascular emboli causing vascular endothelial damage with

neutrophil influx and release of cytokines.

Alveolar hemorrhage is also reported but occurs less frequently. Diagnosis has

been by bronchoscopy, with hemosiderin-laden alveolar macrophages and

erythrocytes seen in bronchoalveolar lavage (BAL) fluid [53] or at autopsy [51].

Pulmonary artery catheter (PAC) measurements obtained in four cases sup-

ported the presence of PHT and showed normal cardiac output and pulmonary

capillary wedge pressures [50,52,53]. In one novel case [52], BAL fluid was

obtained after the development of CAPS in a patient with primary APS and wascompared with fluid from a control group. The percentages of BAL neutrophils,

total protein, and albumin were increased over those in controls. There were also

high levels of antiphosphatidylserine and antiphosphatidic acid IgG antibodies

and a quantitative and qualitative deficiency of surfactant phospholipids in the

BAL fluid [52].

Autopsy reports have described interstitial and alveolar hemorrhage without

evidence of vasculitis [51], diffuse alveolar damage with signs of chronic

interstitial inflammation [53], extensive infarction with thrombi in alveolar

capillary lumen, and interstitial fibrosis [54].

Cardiac features and manifestation

Cardiac involvement has been described in APS. Abnormalities include

valvular vegetations indistinguishable from Libman-Sacks endocarditis, other

valvular abnormalities that may be associated with hemodynamic abnormalities,

coronary artery occlusions resulting in myocardial infarction, and thrombus

formation within the cardiac chambers [55,56].

When CAPS develops, a range of abnormalities can be seen. Case reportsdescribe a presentation of acute and progressive dyspnea and radiographic

evidence of cardiomegaly and pulmonary infiltrates with or without pleural

effusions, consistent with decompensated congestive heart failure (CHF). Micro-

vascular thrombi involving the myocardium have been reported as the prominent

feature causing cardiac failure and circulatory collapse [20]. Left ventricle

dilatation with global hypokinesis has been shown by transthoracic echocardiog-

raphy (TTE) [57,58].

As more cases have been reviewed, a better picture of cardiac involvement in

CAPS has been obtained. In the series of 50 CAPS patients, 36% had myocardialinvolvement, and 32% had valve abnormalities with mitral, aortic, and tricuspid

valvular incompetence being noted [20]. In the later series of 80 patients, there

were episodes of valvular lesions in 31%, diagnosis of myocardial infarction in

20%, and diagnosis of heart failure in 16% of patients presenting with CAPS.

Pericardial effusions and atrial thrombi were described in 2 cases each, at CAPS

presentation [21]. These lesions may be seen together. The simultaneous occur-




rence of acute myocardial infarction, valvular marantic vegetations, and peri-

carditis was reported in one case [59]. Transesophageal echocardiography (TEE)

in this case revealed vegetations consistent with Libman-Sacks endocarditis that was missed on TTE.

There is interest in obtaining more information regarding the presence of aCL

and its effects on cardiac function. Some evidence suggests that aCL may be

associated with decreased left ventricular systolic and diastolic function [60], and

left ventricular diastolic dysfunction has been documented in CAPS [59].

A study of TTE patients with primary or secondary APS found more severe

right ventricular diastolic dysfunction, independent of valvular disease and

systolic dysfunction, in patients with primary APS. PHT (shown to be present

by PAC measurements during CAPS presentation) and primary APS were strongindependent predictors of more severe right ventricular diastolic impairment

[61]. PHT and myocardial ischemia are associated with a poor prognosis in

patients with APS [62]. The pre-existence of these clinical entities may influence

the manifestations of cardiac abnormalities in the patient presenting with CAPS.

Information gained from diagnostic procedures, such as echocardiography, may

become helpful in management.

Renal features and manifestation

There seems to be a strong association between intrarenal thrombosis and APS

with or without accompanying autoimmune disease (such as SLE). In patients

with SLE, up to 32% of renal biopsies show thrombi [63], and in a series of

patients with primary APS, 31% of biopsies had thrombotic microangiopathy

with fibrin thrombi in arterioles and glomeruli [47,64].

In CAPS, renal abnormalities are reported as the initial presentation in 14% of

patients. Renal abnormalities during CAPS are quite common, however, and

represent 72% of thrombotic manifestations [21]. Laboratory abnormalities that

can be encountered on initial presentation include elevated blood urea nitrogenand creatinine levels, with the urinalysis showing hematuria, proteinuria, hyaline,

or granular casts in the urine sediment. Renal failure may initially be nonoliguric

but can rapidly progress to oliguria with development of edema and the need for

urgent dialysis [11,20,21,47].

The usual histopathologic picture is renal thrombotic microangiopathy of

the glomerular capillaries and small renal arteries [18,47]. Changes of prolif-

erative [11,20] and crescentic glomerulonephritis [47] have been reported in

autopsies, suggesting that aCL may be involved in causing glomerular wall

damage [47,65].Systemic hypertension is also a prominent feature in APS, being present in

93% of patients [64]. With the development of CAPS, there is often the

presentation of malignant hypertension that requires management, along with

further worsening of renal function [21]. If CAPS presentation is dominated by

myocardial failure or by infection with sepsis, however, hemodynamic support

with vasopressor and inotropic agents is required.




CNS features and manifestations

A range of CNS findings have been reported in CAPS. Altered mental status

causing stupor and coma, or seizures (with status epilepticus, uncommonly) can

compromise respiratory function, resulting in the need for intubation and mech-

anical ventilation [20]. The predominant pathology is microthombi or micro-

infarctions in the brain, reported in 26% of patients in one series, with large vessel

infarctions seen less frequently (in 13%) [20]. Other reported manifestations

include retinal artery thrombosis [58], mononeuritis multiplex, and pituitary gland

necrosis [20].

Intra-abdominal features and manifestationAbdominal pain (with or without nausea and vomiting) is a common

presenting symptom. Diffuse abdominal tenderness may be elicited on examina-

tion [18,20,21]. Hepatic involvement is reported in 34% to 37%, splenic

involvement in 17% to 20%, and pancreatic involvement in 12% of CAPS

manifestations. Liver and pancreatic enzyme levels may be elevated. [20,21].

Vascular occlusions (of hepatic, splenic, bowel, or pancreatic vessels) seem to

be common, and arterial occlusions may result in bowel gangrene or splenic

infarctions [20]. Esophageal perforation with mediastinitis, ischemic colitis, and

acalculous ischemic necrosis of the gallbladder have also been reported [20].Adrenal gland involvement is reported in APS [66], but complications in CAPS

seem to be higher than anticipated. In the 2001 series of 80 CAPS patients, 10% of

thrombotic episodes involved the adrenal glands [21], and 26% of patients from the

1998 series had adrenal involvement [20]. Autopsy findings have reported multiple

adrenal thrombi, bilateral hemorrhagic necrosis, and adrenal infarction [20].

Adrenal gland involvement seems to be frequently missed in the ICU CAPS

patient. Sudden collapse in a patient receiving heparin therapy for PE may be

mistakenly attributed to recurrent embolism [21]. Patients presenting with CAPS

may often already be taking steroids as part of their management, and adrenalinsufficiency may be unmasked only as steroid use is being discontinued [20].

Abdominal and flank pain, hypotension poorly responsive to vasopressor

agents, and laboratory findings of hyponatremia with or without hyperkalemia

suggest adrenal hypofunction. Evaluating the cortisol level, performing an adre-

nocorticotropic stimulation test, and CT imaging of the abdomen can provide a

timely diagnosis [20,21,50].

Skin and extremity features and manifestation

Skin involvement is common in CAPS and has been reported in 50% to 52%

of patients [20,21]. Manifestations include livedo reticularis, digital ischemia,

splinter hemorrhages, ulcerations, and superficial gangrene in the lower limbs,

cheeks, and ears [20]. Evidence of previous large vessel thrombosis (gangrene, or

amputation) may be apparent on presentation. Isolated or multiple new lesions

reflecting ongoing microvascular thrombosis may become evident as CAPS




progresses. Gangrene of the extremities is associated with a worse prognosis in

patients with APS [62]. Recognizing these lesions when CAPS develops may aid

significantly in making the diagnosis.In the 2001 patient series, the occurrence of bone marrow necrosis in 7% of the

patients was greater than expected [21]. More frequently associated with neo-

plasms, sickle-cell disease, and severe bacterial infections, bone marrow necrosis

has been described in patients with APS, most of whom suffered from CAPS. The

reasons for bone marrow necrosis in these patients are not fully known [21].

Laboratory findings

Consistent serologic findings in CAPS are elevated titers of aCL (usually of the IgG type) or positive LA [20,21]. Both tests were positive in 94% of CAPS

patients in the 1998 series [20], whereas LA was detected in 68% of patients and

aCL titers were positive in 98% of patients tested in the 2001 series [21].

Serologic studies for antinuclear antibodies (ANAs) were positive (usually in

low titers) in 58% to 63% of patients and were positive for anti-double-stranded

DNA antibodies in 53% to 87% of patients with concomitant SLE [20,21]. The

presence of anti-Ro, anti-RNP, and anti-La was uncommon [20]. Recent reports

have focused on the presence of increased b2-GPI antibody levels in patients

presenting with CAPS [67–69].Thrombocytopenia, reported in 60% to 68% of patients, a Coombs’-positive

hemolytic anemia in 26% to 39%, features of disseminated intravascular coagu-

lation (DIC) in 19% to 28%, and schistocytes detected on peripheral blood smear in

9% to 14% of patients are other hematologic findings observed in CAPS [20,21].

Differential diagnosis

The presence of thrombocytopenia, hemolytic anemia, schistocytes, and

features of DIC may cloud the diagnosis of CAPS. Entities to be considered in

the differential diagnosis of CAPS include thrombotic thrombocytopenic purpura(TTP), heparin-induced thrombocytopenia (HIT), disseminated intravascular

coagulation (DIC), and hereditary thrombophilia (HT) [25].

The overlap of clinical and laboratory features found in TTP and CAPS can pose

a particularly difficult diagnostic challenge. In patients with TTP, there have been

reports of IgG autoantibodies to a proteolytic enzyme involved in the metabolism

of von Willebrand’s factor [25,70]. The presence of schistocytes and prominent

platelet consumption is specific for TTP [25]. In HIT, platelet aggregation studies

and identification of the platelet factor 4-heparin complex can be diagnostic [25]. In

DIC, the finding of fibrin degradation products rules out CAPS, and in consideringHT, testing for factor VLeiden is diagnostically useful [25].

Treatment and recovery

The treatment of CAPS requires two processes: (1) supporting failing organ

systems, and (2) suppressing the widespread microvascular thrombotic process




causing organ dysfunction. Intubation and mechanical ventilation to improve

hypoxemia in respiratory failure, inotropic support to improve cardiac failure,

hemodynamic monitoring for guidance in fluid and inotropic administration,and dialysis, are supportive measures that may be required simultaneously or

at various intervals in the ICU treatment of CAPS. Given the evidence that

infections are a significant precipitating factor in CAPS, the use of antibiotics

can be guided by cultures or given empirically based on the clinical setting.

Appropriate management of ongoing sources of infection (ie, gangrenous

extremities, central intravenous lines) requires close attention.

Several treatment modalities that have been applied or considered in CAPS

include anticoagulation therapy (in the form of heparin, then switching to

warfarin), fibrinolytic agents, high-dose steroids, plasmapheresis, cyclophospha-mide, intravenous gamma globulin, prostacylin, danazol, cyclosporine, azathio-

prine, and defibrotide (a metallic salt of DNA with antithrombotic and fibrinolytic

properties) [20,21].

In the series of 50 CAPS patients described in 1998 [20], multiple combina-

tions of these modalities were used. In patients receiving a combination of

anticoagulation therapy, steroids, plasmapheresis, or intravenous gamma glob-

ulins, the recovery rate was 70% [20].

Interest in plasmapheresis as a treatment for CAPS arose from reports of its

successful use in episodes of APS [71 – 74], and CAPS [14,75,76]. Explanations for the benefit of plasmapheresis center around its success in the treatment of TTP, a

thrombotic disorder with some similarity to CAPS [77]. Also, because of evidence

that elevated levels of b2-GPI antibodies are involved in thrombosis [78 – 80], it was

hypothesized that plasmapheresis may achieve beneficial results by reduction of

b2-GPI antibody levels and removal of cytokines and mediators that promote the

thrombotic process in CAPS [81]. At the same time, however, other reports

emphasized anticoagulation therapy as the mainstay of treatment, with the addition

of plasmapheresis in more refractory cases [75,82].

The combination of plasmapheresis with immunosuppressive therapy has beensuggested as a promising approach [77]. In eight case reports of ARDS in CAPS,

pulmonary improvement was noted in seven cases, with the addition of steroids (in

four) [50– 52], and with the combined use of steroids and plasmapheresis (in three)

[14,53]. There is some suggestion, however, that the response to plasmapheresis

may differ in patients with the IgG and those with the IgA b2-GPI antibody type

[67,69]. Also, a coexisting hypercoagulable state may affect response [69].

With more case reports available in the literature, retrospective analysis

suggests some treatment approaches that are associated with improved survival.

From combined analysis of the 50 and 80 CAPS patient series by Asherson, themortality rate was reduced to 38% in those treated with anticoagulation therapy,

versus 75% in those not receiving anticoagulation therapy [21]. Concomitant use

of steroids, plasmapheresis, or immunoglobulins did not significantly improve

mortality rates. Anticoagulation therapy is needed for lysis of existing clots and

suppression of ongoing clotting, and higher than usual doses of heparin are

suggested, given the extreme hypercoagulability of these patients [18]. The timely




and aggressive use of anticoagulation therapy is also supported by Kitchens in his

description of patients with thrombotic storm [34]. With anticoagulation as the

first-line therapy, the addition of steroids is still recommended to reduce thecytokine effects in CAPS or to treat a possible vasculitis mimicking CAPS in

patients with SLE [21]. Whether plasmapheresis or fibrinolytic agents will have a

positive effect on survival in selected patients remains to be seen. More informa-

tion regarding the pathophysiology of CAPS may provide more specific guidance

in the selection of treatment modalities in this disorder.

Summary

CAPS is characterized by development of widespread microvascular throm-

bosis. Patients at risk are those with positive aCL or LA factor. Precipitating

events, such as infection, trauma, surgical procedures, or reduction in anti-

coagulation therapy, may contribute to the development of CAPS. Presentation to

the ICU can be dramatic, with progressive multiorgan failure and need for rapid

institution of life-supporting measures. Cardiopulmonary failure has been the

major contributor to mortality. A variety of therapeutic modalities have been used

in an attempt to offset the widespread thrombosis and organ damage from high

aCL levels. Anticoagulation therapy and high dosages of steroids seem to have a positive effect on survival.

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