Morning Report

1
Morning Report

• Steve Anisman
• August 14, 2002

2
The Case
Sarah hold on a little
3
The Case
53 yo M with end-stage liver disease as a result
of hepatitis B, hepatitis C, and EtOH. He had
received care at his home in Puerto Rico for many
years

, until he was sent to the Baystate
ED with a prescription by his PCP that reportedly
said liver transplant. His initial admission
focused on hemochromatosis, and after improvement
he was discharged. He returned with cc of malaise
and lethargy.
4
The Case
Over the next week, he developed fulminant
hepatic failure with deep encephalopathy. He had
minimal response to lactulose and inderal,
although he eventually became at least tenuously
aware of his surroundings. His labs over that
period included INR 2.0 - 4.1 despite daily use
of vitamin K PLT 40 - 20. T Bili consistently in
the 20s Ammonia 108 (with variation 2o lactulose)
5
The Case
He had episodes of hematoma and GI bleed,
requiring brief ICU transfer. I cross-covered
the Pt for a weekend. As part of continued
workup, we sent the following labs
INR 4.1
PTT 62.8 (21-35)
D-dimer 2000
Fibrinogen 96 (150-450)
6
DIC
TTP/HUS
We initially assumed DIC, but were equally
concerned about the possibility of TTP/HUS, and
brought the heme/onc team in for a consult.
7
TTP/HUS
Thrombotic Thrombocytopenic Purpura and
Hemolytic Uremic Syndrome represent two entities
that are essentially the same in most patients,
and which seem to share the same underlying
pathophysiology. The common characteristics
include thromobocytopenia and microangiopathic
hemolytic anemia without another clinically
apparent cause. Most patients will demonstrate
neurologic (from TTP) and renal (from HUS)
anomalies, as well. If one set of S/Sx dominate
in the absence of the other, you can diagnose TTP
or HUS independently, but for all practical
purposes (pathology, treatment, prognosis) it
doesnt matter.
8
TTP

• Initially observed in 1925, characterized by
  hyaline thrombi in multiple organs. First
  codified in 1964 with 5 features
• Thrombocytopenia
• Microangiopathic hemolytic anemia
• Neurologic S/Sx
• Renal function abnormalities
• Fever

9
TTP

• 93 of patients demonstrated hyaline thrombi. In
  the 1960s, the disease was fatal in 90 of
  patients.
• The inclusion criteria have changed since an
  effective treatment (more on that later) has been
  developed. These days, the Dx can be made with
• Otherwise unexplained thrombocytopenia
• Microangiopathic hemolytic anemia

Some are now simply calling this syndrome
thrombotic microangiopathy.
10
HUS
Initially characterized in 1955 as a pediatric
illness with cortical necrosis as the defining
feature. This variety is now considered atypical
HUS. The Dx of typical childhood HUS is
reserved for the syndrome of thrombosis with
bloody diarrhea seen with Shiga producing
bacteria such as E coli 0157H7.
11
Pictures!!
Thrombi in renal capillaries
Subintimal fibrin, but no inflammation
Healing from prior fibrinoid injury, occluding
vessel
12
Pathophysiology(A little von Willebrand in the
morning)
Thrombus formation is the cardinal
characteristic of TTP/HUS. The thrombi are
composed primarily of platelets. The mechanism
of the platelet thrombi in TTP/HUS seems to be a
result of a specific protease deficiency which
leads to von Willebrand factor misbehaving.
In everyday life, endothelial cells make vWF,
which then is assembled into larger multimers
(called unusually large von Willebrand factors
although theyre not unusual) which float
around in our plasma, where they degrade into a
more usual vWF, which acts like its supposed to
helping platelet aggregation when clots form.
13
Pathophysiology(more on ULvWF)
The enzyme that breaks the big vWF multimers
down to size is a special cleaving protease. In
TTP, this protease is missing either
underproduced due to a genetic defect or coated
by inhibitory autoantibodies.
Without the protease, youre left with the
unusually large vWF (ULvWF), which loves to
attract platelets in huge clumps and make thrombi.
This mechanism (protease deficiency) is seen
more often in patients with neurologic findings
but no renal failure (ie TTP, not HUS).
14
Pathophysiology(Protease deficiency)
Other conditions in which you see protease
deficiency include

• DIC
• Idiopathic thrombocytopenic purpura
• Infection
• SLE
• Neoplasms, particularly leukemia
• Cirrhosis
• Acute inflammatory states (negative APR)
• 2nd and 3rd trimesters of pregnancy

15
Pathophysiology(other mechanisms)
As Sarah has asked, If its not from protease
deficiency, then what is it from?
Well, Sarah, Im glad you asked, although I wish
you wouldnt dangle your prepositions. Other
mechanisms that have been proposed include

• Endothelial injury most commonly in the renal
  and cerebral vessels, least frequently in the
  hepatic and pulmonary beds. Nobody knows why,
  nobody knows why there.

16
Pathophysiology(more other mechanisms)

• Shiga toxin in children, HUS usually follows
  bloody diarrhea (And sometimes in adults, too).
  Shiga is produced by food from Jack in the Box,
  and seems to result in platelet thrombi.

The toxin may have a direct endotoxic effect,
although this is not well understood.
Neutrophil accumulation is stimulated in
patients with Shiga toxin, which may also
stimulate platelet aggregation. The neutrophils
themselves seem to be stimulated by either direct
effect of the toxin on adhesion molecules, by
toxin-induced secretion of inflammatory
substances such as interleukin 8 and platelet
activating factor, or by inhibition of apoptosis.
17
Pathophysiology(more different other mechanisms)

• Plasminogen activator inhibitor PAI-1 is an
  enzyme that can be used to reverse the effects of
  tPA and urokinase in effect, its a chemical
  that blocks the blocking of clots. So its a
  procoagulant, kind of. Patients with TTP/HUS
  often have higher than normal levels of this
  stuff circulating in their blood, and if you can
  make it go away (with peritoneal dialysis!!),
  renal function improves. Go figure.

(But shouldnt that lead to fibrin thrombi not
platelet thrombi? Yes, youre right. One of the
many mysteries of medicine.)

• Lack of platelet inhibition Theres no direct
  evidence of this yet, but it sounds like a good
  explanation.

18
Pathophysiology(more various different other
mechanisms)

• Genetics There are familial forms of TTP/HUS,
  with either autosomal dominant or autosomal
  recessive characteristics, but they account for
  
• They seem to be associated with deficiencies in
  Factor H, which is involved in regulating
  complement. The reason that this would lead to
  clotting abnormalities is not yet understood it
  may be that damage occurs in the endothelium
  somewhere, uncontrolled complement turnover is
  somehow triggered, and that somehow results in a
  microangiopathic process, which then somehow
  leads to disease.

19
Etiology(phew!)

• Shiga toxin which weve already discussed.
  Interestingly, early use of antibiotics in
  patients infected with E coli O157H7 results in
  higher risk of developing TTP/HUS, probably due
  to massive toxin release from dying bacteria.
  This etiology is associated with pancreatic
  damage in about 20 of cases, sometimes leading
  to permanent IDDM.

• Quinine The most common cause of drug-induced
  TTP/HUS. There are quinine-induced antiplatelet
  antibodies that seem to be responsible. The
  response can develop any time, including after
  years of using quinine with no ill effects.

20
Etiology(other drugs)

• Chemo particularly mitomycin C, cisplatin, or
  any high dose regimen with radiation (commonly
  used prior to bone marrow transplant). The
  cancers themselves are another cause, so it can
  be hard to tease out whats what.

• Immunosuppressives particularly cyclosporine,
  tacrolimus, and OKT3. Again, complicated by the
  fact that hyperacute humoral rejection is also a
  potential cause, but this is now less common with
  improved typing.

• Antiplatelet agents ticlopidine and clopidogrel
  are both associated with TTP/HUS, although
  incidence was 11600-14800 with Ticlid, and
  1300,000 with Plavix. The syndrome typically
  develops 3-12 weeks into therapy.

21
Etiology(non-drug)

• Antiphospholipid antibodies lupus anticoagulant
  is the big offender, but the syndrome can also
  occur in SLE patients without antiphospholipid
  antibodies present.

• Pregnancy as many as 25 of cases of TTP/HUS
  occur in pregnant or post-partum women. But BCP
  also seem to be a risk factor, so either way

• HIV/AIDS This may or may not be more common
  than in the general population, but cases have
  been reported. Valacyclovir has been associated
  with an HUS-like syndrome.

• Pneumococcus go figure. Some patients develop
  TTP/HUS after pneumococcal infection. Nobody
  knows why.

22
Diagnosis
The diagnosis can be made on the basis of
thrombocytopenia and microangiopathic hemolytic
anemia without another clinically apparent
cause.
Its microangiopathic hemolytic anemia again!
This form of anemia can cause fragments which can
artificially elevate automated platelet
counts Elevated LDH is an important marker of
MHA, and can be used both for diagnosis and as a
marker for treatment response.
23
Diagnosis(thrombocytopenia)
Thrombocytopenia is almost universally present
and can be extreme. One series of 135 patients
had an average platelet count of 25K at the time
of Dx range was from 5K to 120K. Platelet
counts seem to be higher in patients with renal
symptoms this may be due to the diagnosis being
made earlier in the course with the renal failure
suggesting the diagnosis at an earlier time, and
the thrombocytopenia being less crucial for high
clinical suspicion.
24
Diagnosis(renal disease)
Renal disease is the classic hallmark of the HUS
variant. U/A reveals near normal urine with few
cells or casts. There may be mild proteinuria
(1-2g/day). Glomerulonephritis or vasculitis are
the most common anomalies. Hypocomplementemia is
seen in about 50 of patients.
25
Diagnosis(neuro disease)
Neurological symptoms are the classic hallmark
of the TTP variant. The most common presenting
symptoms are confusion or severe headache. Focal
findings are rare. Coma and grand mal seizure
can occur.
26
Diagnosis(fever)
Fever was one of the 5 diagnostic findings when
this syndrome was first described but recently it
has been shown to be uncommon. Fever in patients
with TTP/HUS symptoms should raise suspicion for
sepsis before suspicion for TTP/HUS.
(and those 5 findings were)

• Thrombocytopenia
• Microangiopathic hemolytic anemia
• Neurologic S/Sx
• Renal function abnormalities
• Fever

27
Diagnosis(lab summary)
HCT Retics WBC Smear PT PTT Fibrinogen D-dimer Di
rect Coombs LDH Indirect Bili Haptoglobin Creatin
ine
low (microangiopathic anemia)
elevated
normal
Reticulocytosis, Schistocytosis
normal
Reticulocytes polychromatic red
cells Schistocytes chopped up red cell bits
normal
normal
normal
negative
markedly elevated
elevated
markedly reduced or absent
elevated (especially in HUS)
28
TTP/HUS vs DIC

• Associated with
• Bloody diarrhea
• Pregnancy/postpartum
• Meds
• Isolated platelet consumption
• No change in PT/PTT
• No fibrinogen change
• No D-dimer change

• Associated with
• Sepsis
• Obstetric complications
• Shock
• Coagulation cascade activation
• Big change in PT/PTT
• Reduction in fibrinogen
• Elevation in D-dimer

29
TTP/HUS vs DIC
PT/PTT prolongation can occur with TTP/HUS in
the setting of lupus anticoagulant the
prothrombinase complex is interfered with in the
laboratory, which can skew the results.
Post-partum patients with coagulopathy are often
difficult to diagnose however, TTP/HUS is
uncommon in this setting. More commonly seen is
preeclampsia or eclampsia with superimposed DIC,
which resolves spontaneously after birth.
30
TTP/HUS vs Other Stuff
Vasculitis also presents with microangiopathic
hemolytic anemia and renal failure, but have
other symptoms such as arthralgias and rash,
typically have normal platelet counts, and have
peripheral neuro Sx (mononeuritis multpilex)
instead of central.
Malignant hypertension can present with any of
the signs of TTP/HUS, but is associated with a Hx
of hypertension (with diastolics typically 130)
and signs of end-organ damage c/w the Dx,
including papilledema and hemorrhage on
fundoscopy.
31
Treatment
If untreated, TTP/HUS in adults is progressive,
with irreversible renal failure and death as
common as 90.
For reasons that are not yet completely
understood, plasma exchange reverses the platelet
consumption. The given plasma may provide needed
protease, and the plasmapheresis seems to filter
off the multimers of ULvWF and antibodies.
If you suspect TTP/HUS, use plasma exchange
WHILE establishing diagnosis.
Plasma exchange reduces 6 month mortality to 22.
32
Treatment(Plasma Exchange Part Deux)
Typically, 10 daily plasma exchanges are
required to induce remission, although as many as
145 have been needed in some patients.

• Complications may include
• Reactions (serum sickness, allergic reactions)
• Plasmapheresis-associated thromobocytopenia (!!!)
• Line-related issues (infection, obstruction,
  thrombosis, etc)

33
Treatment(What else have we tried?)
Aspirin and dipyrimadole (anti-platelet
therapies) dont work on their own, but may help
in conjunction with plasma exchange. They may
also cause bleeding.
Platelet transfusion is a wash. They get
consumed and can lead to worsening complications,
but hard to tease out the secondary effects of
the platelets from the primary ones caused by
disease.
Prednisone seems to be a good drug, and may be
effective monotherapy in patients with minimal
S/Sx but its not standard of care, so be
careful, particularly if they dont improve
quickly.
34
Treatment(Follow-up and relapse)
Relapse can occur as late as 10 years, and in as
many as 36 of patients. Patients who relapse
typically still respond to whatever they
responded to in the initial episode.
No good recommendations about how often to
follow labs except frequently, with increasing
intervals as labs remain normal. Which labs
should you check?
Follow CBC and LDH.
If you live in Western Massachusetts, you should
check an ABC instead of a CBC.
35
Take home

• TTP/HUS is a disease of platelet consumption.

• Dx is made on the basis of thrombocytopenia and
  microangiopathic hemolytic anemia without any
  other cause.

• It is not DIC.

• Treat with plasma exchange.

• Unusually large von Willebrand factor is a funny
  name.