Transcript ITP and TTP - UNC School of Medicine

Issues in the Diagnosis and
Management of
Thombocytopenic Disorders
Alice Ma, M.D.
Hematology
UNC-CH
August 10, 2009
Overview
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Normal Physiology
Categories of Thrombocytopenias
ITP
TTP
HIT
Normal PhysiologyProduction and Number
• Platelets are normally made in
the bone marrow from progenitor
cells known as megakaryocytes.
• Normal platelet lifespan is 10d.
Every day, 1/10 of platelet pool
is replenished.
• Normal platelet count is between
150,000 and 450,000/mm3
Platelet Response
•Platelets adhere
to vessel wall,
then aggregate,
leading to
formation of a
platelet plug
•Platelets provide phospholipid
scaffold for thrombin generation.
ThrombocytopeniaHow low is too low?
• 150,000 - 50,000: no symptoms
– No treatment generally required.
• 50,000 - 20,000: first symptoms
– Generally need to begin therapy
• 20,000-10,000: life-threatening
– Generally requires hospitalization
• <10,000: risk for spontaneous
intracranial hemorrhage
Thrombocytopenia
3 broad categories of
causes
• Pseudothrombocytopenia
• Underproduction
• Splenic sequestration
• Peripheral Destruction
Pseudothrombocytopenia
• Platelet clumping is of no clinical significance
• No increased risk of bleeding or clotting
Thrombocytopenia Peripheral Destruction
• Non-immune mechanisms:
– Platelet activation and consumption
– e.g. TTP and DIC
• Immune Mechanisms:
– antibody-mediated platelet
destruction
– may be primary, secondary, or druginduced.
ITP - Immune/Idiopathic
Thrombocytopenic Purpura
• Definition: isolated thrombocytopenia with no
clinically apparent associated conditions or
other causes of thrombocytopenia.
• Etiology: autoantibodies directed against
platelets coat platelet surface. IgG-coated
platelets are taken up by RE system.
• Incidence: approximately 100 per million;
half of these are children. In adults, two
peaks:
– one are young (<40) with female predominance,
– one are older (>60), no gender predominance.
ITP - Diagnosis
• ITP is a Diagnosis of
Exclusion
• No laboratory test can
diagnose ITP
• Need to exclude other
causes of thrombocytopenia
Evaluation of Patient with Low
Platelets
• History
– Has the patient ever had a normal platelet count?
– Carefully review medications, including OTC meds.
• Antibiotics, quinine, anti-seizure medications
– Ask about other conditions which may be associated
with low platelets
• Liver Disease/hepatitis
• Thyroid Disease - both hypo- and hyper• Infections: viral, rickettsial
• Pregnancy
– Ask about other conditions which may be associated
with ITP
• Lupus, CLL, lymphoma
Evaluation of Patient with Low Platelets
• Physical
– Evaluate for lymphadenopathy and splenomegaly
– Look for stigmata of bleeding
– Blood blisters and oral petechiae, ie “Wet Purpura”
• best harbinger of intracranial hemorrhage
• Laboratory Data
– Other blood counts should be normal.
– Check B12 and folate levels.
– Look at peripheral smear to exclude
pseudothrombocytopenia, also exclude TTP (especially
if anemia also present.)
– Send coagulation screens (PT/PTT) to exclude DIC
– Send HIV, hepatitis serologies and TSH
• Consider doing a bone marrow biopsy
– Megakaryocytes should be present.
Management of ITP
Asymptomatic Adult
• If platelet count is >40-50 K, no
therapy is required. Check
platelet counts at designated
intervals.
• If platelet count is < 20-30 K,
begin therapy with corticosteroids.
• Stop all NSAIDS and ASA to
improve platelet function.
Initial Management of ITP
Adult with Symptomatic Purpura
• If platelet count is >10, treat with
prednisone alone - use 1 mg/kg.
• If platelet count <10, treat with
prednisone, but also add IVIg 1g/kg/d
x 2d. - may require admission
• Along with prednisone, add Calcium and
Vitamin D to prevent bone loss.
• If patient has severe bleeding, may
need platelet transfusions.
Subsequent Management of ITP
Adult with Symptomatic Purpura
• Follow platelet counts daily until >20,
then can d/c patient with close followup
• Once platelet count normalizes,
commence a slow steroid taper over 68 weeks.
• 1/3 of adults will have gone into
remission.
• 2/3 of patients will relapse during or
after steroid taper.
Management of Relapsed ITP
• Once the patient relapses, may need to
use steroids to increase the platelet
count out of the danger range, but
THIS CANNOT SUBSTITUTE FOR
DEFINITIVE THERAPY.
• Prednisone is now a crutch to support a
dangerously low platelet count.
• Options now include splenectomy
(standard of care) or intermittent
treatment with anti-D immune globulin
(WinRho®).
Management of Relapsed ITP
Splenectomy
• Splenectomy is effective in 2/3 of
patients, leading to normal platelet
counts.
• Can be performed via open method or
laparoscopically.
• Need to vaccinate against encapsulated
bacteria 2 weeks before procedure.
• May need steroids and/or IVIg before
procedure to boost platelet counts
preoperatively.
Management of Relapsed ITP
Anti-D Immune Globulin
• Can be used as a substitute for IVIg for
maintenance therapy
• Especially useful in patients with
contraindications to splenectomy.
• Coats red cells with IgG and allows red cells
to serve as decoy for splenic macrophages.
• Patient must be Rh positive.
• Not effective after splenectomy.
• Designed to cause hemolytic anemia--Hgb
may drop as much as 3g/dl.
• Intermittent dosing may allow patients to
avoid splenectomy.
Case 1
• A 19 y.o. female college student
presents with a rash over her
lower extremities. She had a viral
illness 2 weeks ago. She has no
other medical problems, and she
takes no medications.
• Physical examination reveals
petechiae over the shins.
• Platelet count is 20K.
Case 1
• The patient is begun on
prednisone at 1 mg/kg.
• Seven days later, the patient
returns, complaining of acne,
insomnia, severe indigestion, and
visual hallucinations. The platelet
count is 250K. Prednisone dose is
tapered over 8 weeks, and the
patient remains asymptomatic with
normal platelet counts.
Case 2
• A 39 y.o. man presents with
epistaxis to the ER. He has no
medical problems, and he takes no
medications. He works as a taxi
driver and has no occupational
exposures. He is married and has
3 children.
• Physical examination is remarkable
only for epistaxis and scattered
petechiae.
• The platelet count is 35K
Case 2
• HIV testing is positive, and the
patient admits to having numerous
unprotected homosexual
encounters. The CD4 count is
140, and the patient is started on
antiretrovirals. The platelet count
slowly rises to normal.
Case 3
• A 46 y.o. woman is found to have
a platelet count of 20 on routine
laboratory testing. She has some
easy bruising and gum bleeding,
but admits to not flossing.
• She has no PMHx, and is on no
medications. She works as a
school principal.
• She is started on 1 mg/kg of
prednisone.
Case 3
• After 1 week, the platelet count is
180, and the prednisone dose is
tapered by 10 mg per week. When
she reaches a dose of 10 mg qd, the
patient develops severe menstrual
bleeding and is noted to have a
platelet count of 8k.
• She is admitted to the hospital, and
is begun on IVIg at 1g/kg IV qd x
2d. The prednisone dose is
increased to 60 mg daily. By the
third day, the platelet count is 60K.
Case 3
• The patient is vaccinated against
pneumococcus, meningococccus,
and Hemophilus influenzae.
• She undergoes laparascopic
splenectomy, which is uneventful.
The platelet count rises to 600K.
She is successfully weaned off
steroids.
Management of Refractory ITP
• One third of patients will have an
inadequate response to splenectomy.
• Management of these patients involves
accepting that they have a chronic,
incurable condition.
• Target platelet counts should be lower-aim for about 30K or absence of
bleeding.
Treatment of Refractory ITP
• Immunosuppressive agents
– Rituximab (anti-CD20)
• No RTCs vs splenectomy
• 40% effective
• May be used before splenectomy
– Mycophenolate mofetil
– Cyclophosphamide
• Adjunct agents
– Thrombopoietin Receptor Agonists
• Romiplostim
• Eltrombopag
Drugs Commonly Implicated in
Thrombocytopenia
• Beta-lactam antibiotics.
• Trimethoprim-sulfamethoxazole and
other sulfa drugs.
• Vancomycin.
• Quinine/quinidine.
• Heparin.
• Abciximab (ReoPro®).
• H2 blockers
• If a patient’s platelets fall, ALL
unnecessary drugs need to be stopped.
Case 4
• A 55 y.o. woman presented with
bleeding from her nose and mouth and
gums.
• PMHx - HTN, DM, DJD
• Medications - glucotrol, glucophage,
HCTZ, quinine for leg cramps
• PEx - petechiae over limbs and torso,
blood blisters in mouth, epistaxis.
• Platelet count 2K
Case 4
• Pt admitted to hospital, quinine
stopped, patient treated with
platelet transfusions and IVIg.
• Platelet count rose to normal over
the next 5-6 days.
• Eight months later,
thrombocytopenia recurred, and
patient admitted to taking quinine
again for recurrent leg cramps.
Drug Induced ITP
• Usually, removing the offending
agent is enough to allow the
platelets to rise on their own.
• If platelets are severely low,
platelet transfusions may be
required.
• IVIg is particularly helpful in
quinine-induced ITP.
Case 5
• A 65 y.o. male smoker with a h/o
peripheral vascular disease
presented to the ER with unstable
angina. He was admitted to the
hospital and placed on heparin.
Platelet count on admission was
450. Cardiac catheterization
showed severe 3-vessel coronary
disease, and the patient was
scheduled for CABG which occurred
on hospital day #7. Pre-op
platelet count was 200. Post-op
platelet count was 90.
Case 5
• On hospital day #12, the patient
developed acute left leg swelling and
a DVT was diagnosed by ultrasound.
Platelet count was 150. The
patient was started on IV heparin.
The next day, he developed a
pulseless left leg and had a platelet
count of 30. While in vascular
radiology, he developed acute chest
pain and suffered a cardiac arrest
and subsequently died. Autopsy
showed occlusion of all of his bypass
grafts.
Heparin-Induced Thrombocytopenia
• Seen in 1-3% of patients treated with
heparin
• Usually, 7-10 d after heparin started,
platelets fall by at least 1/3 to 1/2.
– Patients do not have to be thrombocytopenic.
– Can occur earlier in patients who have been
previously exposed to heparin, even as SQ
injections.
• Caused by antibodies against the complex of
heparin and PF4. These antibodies activate
platelets.
• Can lead, paradoxically, to THROMBOSIS, in
up to half of patients.
• More common in patients with vascular disease
Alternate Presentations of HIT/T
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Small drop in platelet count
(especially with skin necrosis)
Earlier onset thrombocytopenia with
heparin re-exposure
Delayed-onset thrombocytopenia/
thrombosis after stopping heparin
Thrombosis after heparin exposure
HIT/T treatment
1. IF PLATELETS FALL ON
HEPARIN, STOP HEPARIN
IMMEDIATELY.
2. Stop heparin
3. Stop heparin
4. Use a different anticoagulant
1. Lepirudin
2. Argatroban
Case 6
• A 75 y.o.man presented with
fever, nausea, vomiting, epigastric
pain with radiation to his back.
Amylase 12,000, Lipase 3000.
Patient treated for pancreatitis.
On Hospital day 2, hemoglobin and
platelet count both noted to drop.
By hospital day 4, Hgb 7, Plts 12.
PT/PTT normal. Amylase and
lipase nl, LDH 5000, Cre 2.8.
TTP - Diagnostic Features
(aka “the Pentad”)
• Microangiopathic Hemolytic Anemia (MAHA)
– Elevated LDH, elevated bilirubin
– Schistocytes on the peripheral smear
– MUST BE PRESENT
• Low platelets - MUST BE PRESENT
• Fever
• Neurologic Manifestations - headache,
sleepiness, confusion, stupor, stroke, coma, seizures
• Renal Manifestations - hematuria, proteinuria,
elevated BUN/Creatinine
• Abdominal Pain - can see elevated lipase/amylase
TTP - etiology
• May be associated with an antibody
against or a deficiency of the protease
which cleaves the ultra-high molecular
weight multimers of von Willebrand’s
factor. These very high molecular
weight vWF multimers cause abnormal
platelet activation.
• Can be induced by drugs, including
ticlopidine, quinine, cyclosporine,
tacrolimus, mitomycin C.
• Increased incidence with pregnancy or
HIV
TTP - Course and Prognosis
• 95% fatal prior to therapy, now 5% fatal.
• Treatment relies on PLASMA EXCHANGE.
– Plasma exchange is superior to plasma infusion, but
if PLEX is delayed, give FFP.
• Remove all inciting agents.
• Platelet transfusions contraindicated.
– Multiple case reports of stroke and/or death
during or immediately after platelet transfusion.
– Can consider giving if life-threatening hemorrhage
is present, but avoid routine platelet transfusions.
• Secondary measures if no response to plasma
exchange include splenectomy, vincristine
HUS - Hemolytic Uremic Syndrome
• Usually classified along with TTP as
“TTP/HUS”
• Has fewer neurologic sequelae, more
renal manifestations.
• Usually precipitated by diarrheal
illness, especially E. coli O157:H7 or
Shigella
• Seen more in pediatric patients, usually
has better prognosis. May respond less
well to plasma exchange.
Wrapup
• Platelet count <20
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Usually requires admission
R/O TTP
Stop all meds, if possible
Probably ITP
Send HIV
Wrapup
• Platelet count b/w 20-50
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R/O TTP
Probably requires treatment
Stop all meds
Send HIV
Wrapup
• Platelet count b/w 50-100
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Probably does not require treatment
Find old CBCs to see if new or old
Stop all meds, if possible
Careful follow-up to see if platelet
count remains stable
– If pt is elderly, may be MDS, o/w
probably chronic ITP