Vascular Pathology: From Vasculitis to Vasculopathy to Vascular Rejection
Section B -
Volker Nickeleit, M.D.
J. Charles Jennette, M.D.
The following section briefly highlights key aspects characterizing different vasculopathies commonly
encountered by the pathologist. It is far beyond the scope of this handout to provide detailed
information on the pathophysiology of each vasculopathy. We focus primarily on morphological aspects.
For in depth reading, the interested reader is referred to selected references listed in the "reference
I) Amyloidosis and monoclonal immunoglobulin deposition disease
Amyloidosis and monoclonal immunoglobulin deposition diseases are very heterogeneous groups of
disorders (see table 1). They can be associated with underlying hematopoetic neoplasms, in particular
plasma cell dyscrasias/plasmocytomas. Amyloid and monoclonal immunoglobulins are typically deposited
along vessel walls and basement membranes resulting in severe functional abnormalities, such as stenosis,
leakage, rupture, changes in the filtration barrier, or a loss of adaptive functions (vascular dilatation
and contraction). Normally, there is only minimal overlap; amyloidosis is typically not seen in cases of
monoclonal immunoglobulin deposition disease and vice versa.
1) Monoclonal Immunoglobulin Deposition Disease (Light – And/or Heavy Chain Deposition Disease)
Definition : Deposition of monoclonal immunoglobulins along basement
membranes, primarily affecting renal tubules, glomerular capillaries and arteries.
Clinical Findings : The kidneys are primarily affected. Proteinuria (in
90% of cases) and the nephrotic syndrome (in 40% of cases) are typical symptoms at time of presentation
leading to a renal biopsy. Approximately 50% to 60% of patients suffer from plasmocytoma; many patients
present with kappa or lambda (4:1) monoclonal light chains in the serum and or urine. The accumulation
of monoclonal heavy chains (mostly gamma) is a rare event. Caveat: The detection of monoclonal light or
heavy chains in the serum or urine increases the probability that a patient suffers from immunoglobulin
deposition disease, however, does not accurately predict disease.
Histology : Most characteristic is a nodular expansion of glomerular
mesangial regions, similar to "Kimmelstiel-Wilson" nodules, seen in 60% of cases. Often, glomeruli are
diffusely and globally affected and the mesangial nodules are of similar sizes. In rare cases (10% to
20%) focal extracapillary crescents can be detected. Tubular basement membranes are typically thickened,
in particular along non-atrophic tubules. In addition, arterioles and small arteries can show wall
hypertrophy and hyaline deposits. The disease process can spare glomeruli and can be limited to the
tubulo-interstitial compartment, reported in one series in 50% of cases of immunoglobulin deposition
disease (E.H. Strom et al.). The light microscopic changes are caused by the deposition of monoclonal
immunoglobulins that can easily be demonstrated by immunohistochemistry or immunofluorescence microscopy.
Electron microscopy shows typical, finely granular, densely packed electron dense particles along the
outer aspect of tubular basement membranes, along the inner aspect (i.e. lamina rara interna) of
glomerular basement membranes, in glomerular mesangial regions, around medial smooth muscle cells and
along the lamina elastica of arteries. Intrarenal and extrarenal arteries are typically affected
(without significant clinical symptoms). The vascular monoclonal immunoglobulin accumulations can be on
occasion massive, leading to individual smooth muscle cell necrosis and mimicking vascular "amyloid
deposits" by standard light microscopical examination.
By light microscopy, monoclonal immunoglobulin deposition disease may be misinterpreted as 'diabetic
nephropathy'. Helpful diagnostic clues during the histologic work-up include: 1) in monoclonal
immunoglobulin deposition disease, mesangial nodules usually have the same size and demonstrate a global
and diffuse distribution pattern. Kimmelstiel-Wilson nodules often show a segmental accentuation and
vary considerably in size. In diabetes, glomerular basement membranes are typically thickened; this
feature is not seen in immunoglobulin deposition disease. Of course, the detection of hyalinosis in
efferent arterioles is highly characteristic for diabetes. In addition, nodular amyloid deposits or
membranoproliferative glomerulonephritides may enter into the differential diagnosis. Diagnostic
confirmation can easily be achieved by immunofluorescence microscopy and electron microscopy. (Caveat:
diabetes often shows linear accentuation of glomerular and tubular basement membranes with antisera
specific for IgG and kappa light chains.) Since some rare cases of immunoglobulin deposition disease may
not give positive staining signals by immunofluorescence microscopy or vice versa may not demonstrate
typical ultrastructural deposist, both IF and EM are required for proper evaluation (also see tables 2
Table 1: Renal Diseases Induced by Monoclonal Immunoglobulin Molecules
(modified from D'Agati V, Jennette JC, Silva FG: Non-Neoplastic Kidney Diseases Fascicle Atlas of
nontumor pathology, American Registry of Pathology, Washington , D.C. , 2005)
|Glomerular/Vascular Diseases (tubules and interstitium may be involved)|
- AL Amyloidosis
- AH Amyloidosis
- Light Chain Deposition Disease (LCDD)
- Heavy Chain Deposition Disease (HCDD)
- Light & Heavy Chain Deposition Disease (LHCDD)
- Cryoglobulinemia (Types I & II)
- Monoclonal Immunotactoid Glomerulopathy
- Light Chain (Myeloma) Cast Nephropathy
- Light Chain Tubulopathy (e.g. with Fanconi Syndrome)
- Acute Tubular Necrosis
Table 2 : Differential pathologic glomerular features of diseases with
glomerular monoclonal immunoglobulin deposits and their mimics. (modified from D'Agati V, Jennette JC,
Silva FG: Non-Neoplastic Kidney Diseases Fascicle Atlas of nontumor pathology, American Registry of
Pathology, Washington, D.C. , 2005)
| ||AA amyloid ||AL amyloid ||AH amyloid ||LCDD ||HCDD ||LHCDD ||Diabetic GS ||Fibrillary GN ||Immunotactoid GN ||Cryoglobulinemia ||MPGN|
|USUAL LM PATTERN: ||fluffy acidophilic deposits ||fluffy acidophilic deposits ||fluffy acidophilic deposits ||nodular sclerosis ||nodular sclerosis ||nodular sclerosis ||nodular sclerosis & thick GBM ||thick capillaries and expanded mesangium ||thick capillaries and expanded mesangium ||thick capillaries and expanded mesangium ||thick capillaries and expanded mesangium|
|DEPOSIT STAINING: |
| PAS ||weak/- ||weak/- ||weak/- ||+ ||+ ||+ ||+ ||mottled ||mottled ||double GBM ||double GBM|
| Silver ||weak/- ||weak/- ||weak/- ||-/weak/+ ||-/weak/+ ||-/weak/+ ||+ ||mottled ||mottled ||double GBM ||double GBM|
| Congo red ||+ ||+ ||+ ||- ||- ||- ||- ||- ||- ||- ||-|
|IM STAINING: |
| Ig ||- ||one LC, usually ||one HC, usually ||one LC, usually ||one HC, usually ||one LC & one HC ||polyclonal HC & LC ||oligoclonal HC & LC ||monoclonal > polyclonal ||polyclonal > monoclonal ||polyclonal HC & LC
| C3 ||- ||- ||weak/- ||weak/- ||+ ||+ ||- ||strong + ||strong + ||strong + ||strong +|
|EM PATTERN: ||fibrils, 8-12 nm ||fibrils, 8-12 nm ||fibrils, 8-12 nm ||dense granules ||dense granules ||dense granules ||thickened GBM and mesangium ||fibrils,15-30 nm ||microtubules, 20-50 nm ||deposits, often 25-35 nm microtubules ||deposits|
Abbreviations: DD=deposition disease, EM=electron microscopy, GBM=glomerular basement membrane,
GN=glomerulonephritis, GS=glomerulosclerosis, HC=heavy chain, Ig=immunoglobulin, IM=immunofluorescence
microscopy, LC=light chain, LM=light microscopy, MP=membranoproliferative, PAS=periodic acid Schiff
Table 3: Characteristics of AL amyloidosis, monoclonal immunoglobulin deposition disease, and fibrillary
glomerulonephritis identified in renal biopsy specimens evaluated in the University of North
Carolina Nephropathology Laboratory. (modified from D'Agati V, Jennette JC, Silva FG: Non-Neoplastic
Kidney Diseases Fascicle Atlas of nontumor pathology, American Registry of Pathology, Washington, D.C. , 2005)
| ||AL amyloidosis ||Light or heavy chain deposition disease ||Fibrillary glomerulonephritis|
| ||n=80 ||n=25 ||n=74|
|Frequency in kidney biopsy specimens ||15/1000 ||4/1000 ||8/1000|
|Mean age (range) ||63 (38-82) ||60 (35-79) ||52 (21-75)|
|Sex (male: female) ||1:1.1 ||1:0.6 ||1:1.2|
|Race (black: white)* ||1:3.5 ||1:4.6 ||1:13.0|
|Mean Proteinuria ||7.2 ||3.7 ||6.0|
|Mean creatinine ||1.9 ||5.1 ||3.8|
|Light chain staining ||23% kappa|
|polyclonal, mostly kappa and lambda|
*expected black:white ratio in the renal biopsy population is approximately 1:3
Definition : Deposition of amorphous, "waxy" proteinaceous material
along arterial walls, basement membranes and in the interstitial compartment.
Amyloid has been known for over 150 years; it was first described and the name was coined by Rudolf
Virchow. Amyloidosis is a spectrum of diseases with different etiologies that share the deposition of
extracellular protein polymers. These polymers have a specific tertiary structure (beta pleated sheets).
Amyloid polymers are characteristically Congo Red positive and have an apple-green tinctorial property
under polarized light. Ultrastructurally, typical non-branching fibrils are found (9nm – 12 nm in
diameter). Different proteins can accumulate as "amyloid" with different organ involvement and various
clinical presentations (at present more than 20 different "amyloid" proteins are known; see tables 4 and
5). Thus, "amyloidosis" is more of a descriptive term. However, regardless of the specifics, amyloid
deposits can cause severe organ failure (e.g. of the heart or kidneys) that clinically presents as the
leading problem (obscuring the diagnosis of amyloidosis). Generalized amyloidoses involving the kidneys
and/or heart are associated with marked morbidity and mortality (survival in cases of generalized AA or
AL amyloidosis: 2-4 years).
Amyloid generally accumulates along basement membranes (including glomerular and tubular basement
membranes), in vascular walls and also in the interstitial compartment. Since treatment strategies to
"dissolve" amyloid deposits are undefined, much emphasis has to be placed on an early diagnosis in order
to treat possible underlying diseases and thereby prevent the further accumulation of amyloid fibrils.
In this regard the pathologist plays a pivotal role. Currently, the prevalence of secondary AA type
amyloidosis is low due to improved therapeutic protocols to treat infections (such as tuberculosis or
osteomyelitis). However, AA type amyloidosis should be suspected in all forms of "chronic inflammatory
conditions" (rheumatoid arthritis, psoriatric arthritis, ankylosing spondylitis, Behcet's syndrome,
inflammatory bowel disease, sarcoidosis, Hodgkin's disease etc). Generalized AA deposits are typically
seen years after the onset of disease (3% to 23% of patients suffering from rheumatoid arthritis show AA
type amyloid deposits). The accumulation of AA type amyloid is associated with elevated serum titers of
the "acute phase" precursor proteins SAA (serum amyloid A). At present, primary AL types of amyloidosis
are clinically most relevant.
The gold standard to establish a diagnosis of an amyloidosis is a biopsy. Kidneys, the
liver, the GI tract and the subcutaneous tissue are commonly involved in all forms of generalized
amyloidoses; these sites are best suited for diagnostic work-up. The sensitivity of a kidney or liver
biopsy is >90%, of a rectal biopsy 70% to 85% and of a subcutaneous abdominal skin biopsy 50% to 85%.
Rectal and subcutaneous biopsies are most often performed since bleeding complications secondary to
massive amyloid deposits in vascular walls of internal organs can be avoided. The interpretation of
biopsy specimens is associated with certain caveats. A rectal biopsy has to be deep enough to include
submucosal tissue and vessels containing potential amyloid deposits. For the same reason, a subcutaneous
fat aspirate has to include fibrous septae. Large amounts of amyloid may be misinterpreted as
"elastosis" (in the skin) or "collagenous colitis" (in the intestinal tract). Small amounts of amyloid
cannot be readily detected by standard light microscopic examination. Special stains such as Congo Red
incubations are required for proper histologic work-up. Of note: Congo Red stains only give a positive
staining result if tissue sections are approximately 8 to 10 micrometers thick. Sections have to be
analyzed under polarized light to search for diagnostic "apple green" amyloid deposits. The pathologist
should make considerable efforts to subclassify the amyloid deposits since amyloidosis can only be
indirectly treated by "curing" the underlying disease, i.e. an inflammatory condition in cases of AA
amyloidosis or a lymphoproliferative disorder in cases of AL amyloidosis. Most often the diagnostic
work-up will reveal AL type amyloid deposits, followed by the accumulation of AA amyloid (see tables 4
and 5); all other forms of amyloid are rare in the western world. Special antibodies are available to
subtype the amyloid deposits in formalin fixed and paraffin embedded tissue sections. Alternatively,
amyloid may also be extracted from tissue blocks and analyzed by amino acid sequencing.
Macroscopic findings : In advanced cases, the organs are enlarged,
glassy appearing with a waxy consistency. Small amounts of amyloid deposits do not result in gross
Histology : We will use renal amyloidosis as an example. All forms of
amyloid basically can give rise to identical histological changes. In the kidneys the earliest amyloid
deposits are detected in a focal and segmental distribution pattern in mesangial regions. Amyloid is
found as acellular, homogenous, eosinophilic material, only weakly positive in PAS, trichrome and silver
stains (also see table 2). These early amyloid deposits are generally not associated with renal
dysfunction. In more advanced cases amyloid is diffusely and globally deposited in mesangial regions
(sometimes in a nodular fashion, caveat: diabetic nephropathy or monoclonal immunoglobulin deposition
disease) and additionally along glomerular basement membranes (resulting in proteinuria). Amyloid is
also seen in arterioles, arteries, along tubular basement membranes and in most advanced cases also in
the interstitium (encasing preexisting structures).
Arterial amyloid deposits are initially detected in the media but they can ultimately replace the
entire vascular walls resulting in loss of contractile function, rupture, hemorrhage or stenosis.
Thrombosusformation is typically absent. Thus, internal organs carrying a high load of amyloid are at
increased risk of severe hemorrhage following biopsy. Of note: Limited cerebral amyloid deposits (A
beta type) in arteries of the brain are a very common cause of hemorrhage and stroke.
Table 4: Classification of the most relevant types of amyloid
|Amyloid ||Precursor in serum ||Clinical Disease|
|AA ||apo SAA ||Secondary amyloidosis|
|AL ||lambda light chains,|
kappa light chains (3:1)
(e.g. multiple myeloma)
|AH ||IgG1 ||Heavy chain amyloid|
|ATTR ||transthyretin ||Hereditary amyloid|
|AGel ||gelsolin ||Finnish familial|
|AApoA1 ||apoA1 ||Familial amyloid|
|A(beta2)M ||beta2-microglobulin ||Amyloid found with dialysis|
|A (beta) ||A beta protein precursor ||Cerebral amyloid |
(Alzheimer's disease, "aging" cereb. arterial walls)
Table 5: Amyloidosis (primary and secondary)
| ||Primary ||Secondary|
|Location of deposits|
|GI tract, muscle, nerves lymph nodes, tongue, carpal tunnel, heart, liver, kidneys||kidneys, spleen, liver, adrenals, GI tract|
|Location of deposits|
|adrenals, brain ||heart, peripheral nerves, tongue, brain|
|Renal symptoms with|
|Underlying disease ||plasma cell dyscrasia/multiple myeloma (monoclonal immunoglobulins in serum or urine in 90%) ||"chronic inflammatory conditions", e.g. tuberculosis, polyarthritis, osteomyelitis, bronchiectasis, tumors|
|Amyloid type ||AL ||AA|
|Congo red stain ||3+ positive ||3+ positive|
|Congo red with|
|1+ -2+ positive ||0 - +/-|
|Congo red with|
|1+ - 2+ positive ||0|
|Thioflavine T ||positive* ||positive*|
|fibrils 9-12 nm |
|fibrils 9-12 nm |
* The Thioflavine T stain has a high sensitivity but low specificity
II) Diabetic Vasculopathy
Seventy percent of all deaths in diabetic patients are caused by vascular disease. In diabetics,
(regardless of the type) vascular changes occur at a younger age and progress faster than in non-diabetic
patients. Diabetes mellitus is associated with changes in large vessels (macroangiopathy) and small
vessels (microangiopathies). Macroangiopathies affect arteries, often in the lower limbs and the heart,
and present with typical atherosclerosis and calcifications of the media. These changes are not
characteristic for diabetes mellitus. They are promoted by hypertension and hyperlipidemia.
Microangiopathies, which affect arterioles, capillaries, venules and lymphatics are often found in the
skin, heart, retina, muscle, nerves, brain, and kidneys. They are – at least in part – directly linked
to hyperglycemia and significantly contribute to morbidity and mortality.
The exact pathophysiologic chain of events leading to diabetic microangiopathies is incompletely
understood and vasculopathies are only found in a sub-group of diabetics, such as diabetic nephropathy in
only 40% of patients. The development of microangiopathies in insulin dependent diabetics takes years.
For example, more than 10 years are required for the onset of typical diabetic nephropathy.
Histology (microangiopathies): Hyalinosis develops under the endothelial
layer and between atrophic smooth muscle cells and pericytes resulting in vascular wall thickening,
vascular twisting and the development of microaneurysms. The basement membranes are abnormally thickened
due to increased synthesis and deposition of fibronectin, laminin, type IV collagen, and heparan
sulfates. Basement membrane alterations are associated with structural weakening, and changes in the
filtration barrier including leakage.
In the retina, the most typical cases of diabetic microangiopathies show microaneurysms,
hemorrhage, infarcts and angiogenesis with neo-vascularization (proliferative stage of diabetic
retinopathy). Diabetic retinopathy is often, but not always associated with microangiopathies in the
kidneys (in some series 30% of patients with retinopathy are free of kidney disease). Diabetic
nephropathy can serve as a prime example to study diabetic microangiopathies.
Diabetic nephropathy involves glomeruli, capillaries and afferent and efferent arterioles. The
earliest glomerular change, which is hardly ever biopsied, is enlargement (glomerulomegaly). It
corresponds to the early clinical phase of an elevated glomerular filtration rate and "enlarged kidneys".
By the time proteinuria is detectable there is typically generalized thickening of glomerular basement
membranes and an increase of the mesangial matrix. Initially, morphometry is required to detect these
changes but eventually, the GBM thickening and mesangial expansion are so pronounced that they can
readily be discerned by routine light microscopy (e.g., PAS, Jones silver, Masson trichrome stains).
Electron microscopy shows thickened and layered glomerular basement membranes (GBM) with an irregular
lamina rara externa showing minute "crater type lesions". Frequently, GBM thickening is segmentally
accentuated and detected adjacent to GBM thinning (in areas of capillary microaneurysms). Occasionally,
the GBM can even be normal on ultrastructural examination (likely reflecting a sampling problem if only
less affected glomeruli are studied). Basement membrane thickening may also be observed along tubules.
Mild to moderate mesangial hypercellularity occasionally accompanies the early phases of mesangial matrix
accumulation (caveat: mesangioproliferative glomerulonephritis).
Overt glomerular matrix expansion (glomerulosclerosis) manifests as two basic patterns:
diffuse glomerulosclerosis and nodular glomerulosclerosis. These two patterns often coexist in a given
biopsy specimen, although the number of glomeruli available for examination will influence the likelihood
of seeing both patterns. Conceptually, diffuse glomerulosclerosis evolves into nodular
glomerulosclerosis as the mesangial matrix expands. In our opinion, the designations "diffuse" versus
"nodular" are primarily of descriptive value; the distinction does not carry great clinical
The nodular lesions of diabetic glomerulosclerosis were first described by Kimmelstiel and
Wilson. The nodules start to develop from the center of mesangial areas, often in a focal and segmental
pattern. As the nodules grow, mesangial cells are arranged along the outer edges and the mesangial
matrix may appear laminated. Glomerular capillaries are dilated and form microaneurysms, typical for
diabetic microangiopathies. In rare instances (in our experience 0.5% of biopsies) these microaneurysms
can rupture, fibrin can spill into Bowman's space and small, focal and segmental extracapillary crescents
can form (caveat: glomerulonephritis). Hyalinosis is common in diabetic glomerulosclerosis. Hyaline
(hyaline = glassy) material is formed secondary to insudation of plasma proteins from leaky vessels. The
hyaline deposits may occur anywhere in the tuft; they are characteristically found as hyaline caps or
capsular drops. Advanced forms of diabetic glomerulosclerosis often show segmental glomerular scarring
Diabetic renal microangiopathies characteristically affect afferent and efferent
arterioles with subendothelial and medial 'nodular' hyalinosis. Diabetic arteriolopathy is very similar
to toxic changes induced by calcineurin inhibitors or hypertension induced areteriolosclerosis, although,
these latter changes are only found in afferent vessels.
Immunohistochemistry/-fluorescence microscopy: The characteristic
observation is linear staining of glomerular and tubular basement membranes with antisera specific for
IgG and kappa light chains as well as other plasma proteins, such as albumin, although the staining for
IgG is usually brightest. Immunofluorescence microscopy is useful for excluding other glomerular
diseases that can mimic diabetic glomerulosclerosis by light microscopy (e.g. light chain deposition
disease, heavy chain deposition disease, membranoproliferative glomerulonephritis, fibrillary
glomerulonephritis, amyloidosis) or a second disease process, such as an IgA glomerulonephritis
(concurrent in our experience in 1.2% of biopsies with diabetic nephropathy). Immunohistochemistry is
particularly helpful in biopsies with extracapillary crescent formation.
Differential Diagnosis: Light chain deposition disease (LCDD) and heavy
chain deposition disease (HCDD) cause nodular glomerulosclerosis that is very similar to diabetic
glomerulosclerosis by light microscopy. This suggests that the IgG localization in basement membranes in
diabetic glomerulosclerosis may be the cause for the nodular sclerosis and not merely an epiphenomenon.
Some examples of membranoproliferative glomerulonephritis can have conspicuous mesangial
nodules that resemble diabetic glomerulosclerosis, but the overall morphology including
immunohistochemistry and electron microscopy usually is discriminatory.
Fibrillary glomerulonephritis, immunotactoid glomerulopathy, amyloidosis, fibronectin
glomerulopathy, collagenofibrotic glomerulopathy and a number of other diseases cause capillary wall
thickening and increase in extracellular material in the mesangium that can suggest diabetic
glomerulosclerosis, but careful evaluation generally allows proper differentiation.
Rare specimens will have pathologic features that are identical to those of diabetic
glomerulosclerosis yet the patient will have no clinical evidence of diabetes mellitus. This finding is
described as "idiopathic nodular glomerulosclerosis" (a diagnosis of exclusion).
When evaluating cases with diabetic nephropathy, it seems important to adequately identify
other concomitant, "treatable" disease processes, such as diabetic glomerulosclerosis and ANCA disease or
membranous glomerulonephritis. On the other hand, rare cases of diabetic glomerulosclerosis with
crescent formation should not be overdiagnosed as evidence of glomerulonephritis.
III) Antiphospholipid Syndromes (APS)
Definition : Hypercoagulable state with arterial and/or venous thrombus
formation secondary to high titers of circulating autoantibodies against phospholipid/ phospholipid-
binding-protein complexes. Antiphospholipid syndromes are classified as secondary
disease if they are accompanied by other autoimmune disorders, i.e. lupus erythematosus or other
connective tissue diseases, or as primary if they only present with a
Clinical Findings : The clinical presentation varies greatly and may
sometimes mimick a vasculitis. Recurrent thrombosis is the leading symptom. Venous thrombosis is
frequently detected in deep leg veins (55%; caveat: pulmonary emboli and hypertension in half of the
patients with deep vein thrombosis), as well as in renal, hepatic and retinal veins. Arterial thrombosis
is typically seen in cerebro-vascular (50%), coronary (25%), ocular, mesenteric, deep leg and renal
arteries (caveat: stroke, myocardial or bowel infarction, ischemia of the lower extremities with skin
ulcerations, renal hypertension). The microvasculature of the kidney can additionally show changes
resembling a thrombotic microangiopathy (caveat: thrombocytopenia, shistocytes, renal failure). The
clinical spectrum also includes livedo reticularis (differential diagnosis: vasculitides including
polyarteritis nodosa), repeated miscarriages and cardiac valvular vegetations (Libman-Sacks endocarditis
in 4% of patients). In rare instances (less than 1% of cases) multiple organ sites are affected by
thrombosis simultaneously with dramatic clinical consequences and a mortality rate of up to 50% (termed:
"catastrophic antiphospholipid syndrome).
By ELISA high titers of IgG or sometimes IgM antibodies are detected. These antibodies bind to
various auto antigens (e.g. beta 2 glycoprotein 1/phospholipid complexes on platelets and endothelial
cells) and promote the activation of the coagulation cascade, although the precise pathogenic mechanisms
are still undetermined. Autoantibodies are also directed against prothrombin, protein C, protein S and
annexin V. Antiphospholipid antibodies (often low titers) can be detected in 5% to 15% of healthy
Histology : The histolgic examination shows fibrin thrombi of different
ages, sometimes organized with signs of re-canalization. Conspicuous inflammation and vascular wall
necrosis are lacking. Remote thrombus formation in arteries and veins should always raise the suspicion
of an underlying APS. In the kidneys not only large caliber vessels (i.e. interlobar and arcuate types)
but also arterioles and glomerular capillaries may be affected with evidence of thrombosis and intimal
remodeling resembling a thrombotic microangiopathy (see section IV).
IV) thrombotic microangiopathies
Thrombotic microangiopathy (TMA) – a descriptive term – characterizes stenosing and/or thrombotic
changes in small vessels, i.e., capillaries, arterioles and pre-arterioles. Larger arteries are
characteristically spared. The brain, kidneys, gastrointestinal tract, pancreas, spleen and adrenal
glands are commonly affected whereas the liver and lungs are typically spared. The initial common event
in the pathogenesis of all forms of TMA is severe endothelial cell injury caused by a wide variety of
different agents or events (see table 6). Endothelial cell injury results in intimal remodeling.
Generally the pathologist cannot reliably identify the underlying causative agent or event and can only
render a descriptive diagnosis of "TMA". It is the primary responsibility of the managing clinician to
identify the underlying cause of the histologically observed "TMA" and to initiate proper treatment.
Clinical and Laboratory Findings : Typical clinical
signs of TMA are: thrombocytopenia, hemolytic anemia, fragmented red blood cells (i.e. shistocytes) in
peripheral smears, and organ dysfunction including seizures or renal failure. Depending on the organ
primarily involved (kidney or brain) and the extent of vascular changes, clinical symptoms may vary
considerably from mild to severe. A TMA occurring in adults often primarily affects the brain and is
referred to as "thrombotic thrombocytopenic purpura" (TTP), whereas children commonly suffer from severe
renal failure and hemolysis, i.e. "hemolytic uremic syndrome" (HUS). The clinical distinction, however,
is not always clear-cut and the same patient may be described as having HUS by the nephrologist and TTP
by hematologists. Because the pathological features seen in biopsies and the initial treatment for HUS
and TTP are similar, they are often clinically referred to as (TTP-HUS). Of note: Some cases of TMA do
not easily fit into the clinical spectrum of TTP or HUS, such as calcineurin inhibitor or DOTATOC induced
TMAs limited to the kidneys. These cases can lack clinical signs of hemolysis or
Classical HUS : It is a disease of young children primarily associated
with an enteric infection by E. coli 0157:H7 or Shigella dysenteriae (i.e. diarrhea associated HUS).
Renal involvement is prominent and up to one third of patients can be anuric. Children most often
present approximately one week after onset of diarrhea with pallor, oliguric renal failure, lethargy, and
occasionally purpura/petechiae. New onset hypertension and low platelet counts are present in the
majority of patients, whereas CNS dysfunction is noted in only 20%. The disease is caused by verotoxins
1 and 2 (i.e. shiga like exotoxins) that bind to specific plamamembrane receptors on endothelial cells
(i.e. globotriosyl ceramides, Gb3) and promote endothelial cell necrosis. The density of the receptors
appears to be highest in renal vessels explaining the predominance of "acute kidney failure" in the
setting of classical HUS. The pathophysiologic chain of events in so-called nondiarrhea forms of HUS is
multifactorial and only poorly understood. Nondiarrhea HUS is more frequently seen in adolescents and
adults. It shares many clinical symptoms with TTP, however, ADAMTS13 activity (i.e. von Willebrand
factor-cleaving protease) seems unchanged.
Classical TTP : It was first described by Moschowitz in 1924 as a
disorder of unknown cause that predominantly affects adult women and rarely children. It is
characterized by the pentad of microangiopathic anemia, profound thrombocytopenia, fever, CNS
manifestations including seizures, confusion and coma, and (mild) renal failure. TTP may arise de
novo(idiopathic or classical TTP) or may be familial (including rare forms
of chronic relapsing TTP that occur at regular intervals of about three weeks).
TTP is rarely preceded by diarrhea (unlike classical HUS) but often follows a 'flulike' prodrome with
fever, fatigue, nausea, vomiting, and abdominal pain. Increasing evidence suggests that TTP is caused by
defects of a von Willebrand cleavage enzyme (i.e. ADAMTS13, which is produced predominately by
hepatocytes and secreted into the plasma). The lack of enzymatic activity results in unusually large von
Willebrand multimers, platelet aggregation and thrombus formation. The sporadic variants of TTP seem to
be frequently caused by autoantibodies directed against ADAMTS13 (which inhibit enzyme function), whereas
the familial recurrent cases of TTP demonstrate mutations or structural defects of the enzyme itself.
Typically, the activity of ADAMTS13 is very low (<5%, normal plasma activity: 67%-177%). Caveat:
Mildly reduced levels of ADAMTS13 activity can also be seen in a variety of clinical settings (e.g. liver
cirrhosis, inflammation, preganancy). However, such "mildly" reduced enzyme activity is typically not
associated with TTP.
Histology : Changes observed in the kidneys will serve
as examples to illustrate the morphology of a TMA (see table 7). A TMA affects small vessels (in the
kidney: interlobular arteries including branches of arcuate arteries, pre-arterioles, arterioles and
glomerular capillaries; interlobar and arcuate caliber arteries are generally spared). Some
investigators suggest that a TTP is more frequently characterized by platelet thrombi whereas a HUS more
often shows fibrin thrombi.
In the kidney the histological changes can be divided into three main patterns that correlate with
long term renal function: those predominating in the glomerular compartment (young children, good
prognosis); those dominating in the arterial compartment (adults, poor prognosis); and a mixed pattern
with both glomerular and vascular involvement (older children and adults, poor prognosis). Early
(potentially reversible) "exudative and infiltrative" lesions have to be distinguished from late
(irreversible) "sclerosing" changes.
Glomerular changes: 1) endothelial cell swelling and separation of endothelial cells from underlying
basement membranes with production of new basement membrane material (double contouration of the GBM); 2)
fragmented red blood cells and fibrin thrombi in glomerular capillary lumens; 3) mesangiolysis with
associated capillary dilatation. Double contouration of peripheral glomerular basement membranes is
already detected during the early time course; it can persist for many months to years. Typically, the
double contouration of the GBM is not associated with cell interposition (caveat: membranoproliferative
glomerulonephritis). Immunohistochemistry and electron microscopy do not reveal diagnostically
significant immune complex type deposits (normally only fibrin or non-specific IgM/complement factor C3
deposits are found). Electron microscopy shows characteristic subendothelial new basement membrane
formation and deposition of "flocculent" material along the widened lamina rara interna. Glomeruli can
also demonstrate non-specific ischemic changes with wrinkling of peripheral basement membranes secondary
to severe TMA involving the feeding afferent arterioles. Early changes limited to the glomeruli are
fully reversible. Disease progression and vascular involvement results in scarring and nephron loss.
Vascular changes: Most biopsies demonstrate severe changes that can be seen individually or in
combination: 1) severe endothelial cell swelling and "mucoid" intimal widening with narrowing and
occlusion of arteriolar lumens; 2) intraluminal fibrin thrombi and/or fragmented red blood cells in the
intima and media. 3) necrosis of individual endothelial or medial smooth muscle cells. 4) PAS positive
nodular proteinaceous deposits replacing arteriolar smooth muscle cells. As the disease progresses, the
widened intimal zones show increasing numbers of myofibroblasts and marked collagen deposits, ultimately
leading to "onion-type" intimal scarring and stenosis. Ischemic damage and renal hypertension are severe
clinical consequences of a TMA in arteries causing considerable morbidity and mortality. Of note:
alterations of a TMA are typically detected at glomerular vascular poles ("hot-spots" for TMAs) and
extend downstream into glomerular capillaries and/or upstream into the arteriolar tree. Often glomerular
vascular poles are dilated and show fibrin thrombi that are subsequently organized by ingrowth of
Table 6: Thrombotic Microangiopathies and Coagulopathies (modified from
D'Agati V, Jennette JC, Silva FG: Non-Neoplastic Kidney Diseases Fascicle Atlas of nontumor pathology,
American Registry of Pathology, Washington, D.C. , 2005)
Hemolytic Uremic Syndrome (HUS) predominant
Anti-Phospholipid Antibody Syndrome (APS)*
- Shiga-like toxin-induced HUS (e.g. E. coli, Shigella dysenteriae)
- Neuraminadase-induced HUS (e.g., Streptococcus pneumoniae)
- Other bacterial or viral infections (e.g. typhoid fever, HIV, influenza, enterovirus)
- Iatrogenic HUS
- Drug-induced HUS (e.g. cyclosporine, tacrolimus, mitomycin-C,
- oral contraceptives, quinine)
- Bone marrow transplantation-induced HUS
- Radiation-induced HUS, DOTATOC-therapy
- Systemic sclerosis renal crisis HUS
- Pregnancy associated HUS
- Familial HUS (e.g. autosomal recessive, autosomal dominant,
factor H deficiencies)
- Malignant hypertension induced HUS (malignant nephrosclerosis)
- Idiopathic HUS
Toxemia of pregnancy
- Primary APS
- Secondary APS (e.g. secondary to systemic lupus erythematosus,
Thrombotic Thrombocytopenic Purpura (TTP) predominant
- HELLP syndrome
Disseminated Intravascular Coagulation (DIC)**
- Familial/recurrent TTP (e.g. defects in or absence of vWF multimerase/ADAMTS13)
- Sporadic TTP (e.g. autoantibodies to vWF multimerase/ADAMTS13)
- Drug-induced TTP (e.g. ticlopidine, clopidogrel)
- Idiopathic TTP
- Bacterial sepsis with DIC (e.g. gram negative sepsis)
- Viral hemorrhagic fever with DIC (e.g. Dengue, Marburg, Ebola)
- Neoplasia-induced DIC (e.g. pancreatic carcinoma-induced DIC)
- Pregnancy-related DIC (e.g. with retained dead fetus, placental
- Venom-induced DIC (e.g. snakebite)
* thrombus formation noted in large and small vessels including veins
** thrombus formation without mucoid intimal thickening or "onion-type scarring"
Table 7: Predominant pathologic features and major pathogenic events in the
thrombotic microangiopathies and coagulopathies. (modified from D'Agati V, Jennette JC, Silva FG:
Non-Neoplastic Kidney Diseases Fascicle Atlas of nontumor pathology, American Registry of Pathology,
Washington , D.C. , 2005)
| ||Predominant pathology ||Major pathogenic event|
|Hemolytic uremic syndrome ||Glomerular capillary subendothelial expansion, arteriolar fibrinoid necrosis, arterial edematous intimal expansion, vascular thrombosis ||Endothelial injury caused by many different etiologies, predominantly in renal vessels, causing focal occlusion, thrombosis and renal ischemia|
|Thrombotic thrombocytopenic purpura ||Platelet-rich thrombi in many organs ||Enhanced platelet aggregation, e.g. caused by abnormal vWF-cleaving and metalloproteinase activity|
|Disseminated intravascular coagulation ||Fibrin-rich thrombi in many organs ||Enhanced coagulation and fibrinolysis, e.g. caused by increased circulating tissue factor|
|Anti-phospholipid antibody syndrome ||Thrombosis in veins, arteries, arterioles and glomerular capillaries; subendothelial expansion and GBM remodeling ||Antibodies to phospholipids or phospholipid-binding proteins to foster thrombosis|
|Preeclampsia / Eclampsia ||Glomerular capillary endothelial swelling (endotheliosis) ||Abnormal placentation with generation of humoral factors that injure maternal endothelial cells|
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