8.10.09 Ma Thrombocytopenia

8/13/2019 8.10.09 Ma Thrombocytopenia

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Issues in the Diagnosis and

Management ofThombocytopenic Disorders

Alice Ma, M.D.Hematology

UNC-CHAugust 10, 2009


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Overview

Normal Physiology Categories of Thrombocytopenias

ITP

TTP HIT


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Normal Physiology-Production and Number

Platelets are normally made inthe bone marrow from progenitorcells known as megakaryocytes.

Normal platelet lifespan is 10d.Every day, 1/10 of platelet poolis replenished.

Normal platelet count is between150,000 and 450,000/mm3


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Platelet Response

Platelets provide phospholipid

scaffold for thrombin generation.

Platelets adhere

to vessel wall,

then aggregate,

leading to

formation of a

platelet plug


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Thrombocytopenia-How 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


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Thrombocytopenia3 broad categories of

causes

Pseudothrombocytopenia

Underproduction

Splenic sequestration Peripheral Destruction


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Pseudothrombocytopenia

Platelet clumping is of no clinical significance

No increased risk of bleeding or clotting


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Thrombocytopenia -Peripheral Destruction

Non-immune mechanisms: Platelet activation and consumption

e.g. TTP and DIC

Immune Mechanisms: antibody-mediated plateletdestruction

may be primary, secondary, or drug-induced.


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ITP - Immune/IdiopathicThrombocytopenic Purpura

Definition: isolated thrombocytopenia with noclinically apparent associated conditions orother causes of thrombocytopenia.

Etiology: autoantibodies directed against

platelets coat platelet surface. IgG-coatedplatelets are taken up by RE system.

Incidence: approximately 100 per million;half of these are children. In adults, two

peaks: one are young (60), no gender predominance.


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ITP - Diagnosis

ITP is a Diagnosis ofExclusion

No laboratory test candiagnose ITP

Need to exclude othercauses of thrombocytopenia


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Evaluation of Patient with LowPlatelets

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 associatedwith ITP Lupus, CLL, lymphoma


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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 (especiallyif 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.


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Management of ITPAsymptomatic Adult

If platelet count is >40-50 K, notherapy is required. Checkplatelet counts at designated

intervals. If platelet count is < 20-30 K,begin therapy with corticosteroids.

Stop all NSAIDS and ASA toimprove platelet function.


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Initial Management of ITPAdult with Symptomatic Purpura

If platelet count is >10, treat withprednisonealone - use 1 mg/kg.

If platelet count


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Subsequent Management of ITPAdult with Symptomatic Purpura

Follow platelet counts daily until >20,then can d/c patient with close follow-up

Once platelet count normalizes,

commence a slow steroid taperover 6-8 weeks.

1/3 of adults will have gone into

remission. 2/3 of patients will relapse during or

after steroid taper.


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Management of Relapsed ITP

Once the patient relapses, may need to

use steroids to increase the plateletcount out of the danger range, butTHIS CANNOT SUBSTITUTE FORDEFINITIVE THERAPY.

Prednisone is now a crutch to support adangerously low platelet count. Options now include splenectomy

(standard of care) or intermittent

treatment with anti-D immune globulin(WinRho).


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Management of Relapsed ITPSplenectomy

Splenectomy is effective in 2/3 ofpatients, leading to normal plateletcounts.

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 countspreoperatively.


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Management of Relapsed ITPAnti-D Immune Globulin

Can be used as a substitute for IVIg formaintenance 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.


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Case 1

A 19 y.o. female college studentpresents with a rash over herlower extremities. She had a viralillness 2 weeks ago. She has noother medical problems, and shetakes no medications.

Physical examination revealspetechiae over the shins.

Platelet count is 20K.


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Case 1

The patient is begun onprednisone at 1 mg/kg.

Seven days later, the patient

returns, complaining of acne,insomnia, severe indigestion, andvisual hallucinations. The plateletcount is 250K. Prednisone dose istapered over 8 weeks, and thepatient remains asymptomatic withnormal platelet counts.


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Case 2 A 39 y.o. man presents with

epistaxis to the ER. He has nomedical problems, and he takes nomedications. He works as a taxidriver and has no occupational

exposures. He is married and has3 children. Physical examination is remarkable

only for epistaxis and scattered

petechiae. The platelet count is 35K


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Case 2

HIV testing is positive, and thepatient admits to having numerousunprotected homosexualencounters. The CD4 count is140, and the patient is started onantiretrovirals. The platelet countslowly rises to normal.


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Case 3

A 46 y.o. woman is found to havea platelet count of 20 on routinelaboratory 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.


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Case 3 After 1 week, the platelet count is

180, and the prednisone dose istapered by 10 mg per week. Whenshe reaches a dose of 10 mg qd, thepatient develops severe menstrual

bleeding and is noted to have aplatelet count of 8k. She is admitted to the hospital, and

is begun on IVIg at 1g/kg IV qd x

2d. The prednisone dose isincreased to 60 mg daily. By thethird day, the platelet count is 60K.


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Case 3

The patient is vaccinated againstpneumococcus, meningococccus,and Hemophilus influenzae.

She undergoes laparascopicsplenectomy, which is uneventful.The platelet count rises to 600K.She is successfully weaned off

steroids.


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Management of Refractory ITP

One third of patients will have aninadequate response to splenectomy.

Management of these patients involvesaccepting that they have a chronic,

incurable condition. Target platelet counts should be lower-

-aim for about 30K or absence ofbleeding.


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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

D C l I li d i


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Drugs Commonly Implicated inThrombocytopenia

Beta-lactam antibiotics. Trimethoprim-sulfamethoxazole and

other sulfa drugs. Vancomycin. Quinine/quinidine. Heparin. Abciximab (ReoPro).

H2blockers If a patients platelets fall, ALL

unnecessary drugs need to be stopped.


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Case 4

A 55 y.o. woman presented withbleeding from her nose and mouth andgums.

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


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Case 4

Pt admitted to hospital, quininestopped, patient treated withplatelet transfusions and IVIg.

Platelet count rose to normal overthe next 5-6 days.

Eight months later,

thrombocytopenia recurred, andpatient admitted to taking quinineagain for recurrent leg cramps.


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Drug Induced ITP

Usually, removing the offendingagent is enough to allow theplatelets to rise on their own.

If platelets are severely low,

platelet transfusions may berequired.

IVIg is particularly helpful in

quinine-induced ITP.


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Case 5 A 65 y.o. male smoker with a h/o

peripheral vascular diseasepresented to the ER with unstableangina. He was admitted to thehospital and placed on heparin.

Platelet count on admission was450. Cardiac catheterizationshowed severe 3-vessel coronarydisease, and the patient wasscheduled for CABG which occurredon hospital day #7. Pre-opplatelet count was 200. Post-opplatelet count was 90.


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Case 5 On hospital day #12, the patient

developed acute left leg swelling anda DVT was diagnosed by ultrasound.Platelet count was 150. Thepatient was started on IV heparin.

The next day, he developed apulseless left leg and had a plateletcount of 30. While in vascularradiology, he developed acute chest

pain and suffered a cardiac arrestand subsequently died. Autopsyshowed occlusion of all of his bypassgrafts.


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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 activateplatelets.

Can lead, paradoxically, to THROMBOSIS, inup to half of patients. More common in patients with vascular disease


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Alternate Presentations of HIT/T

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


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HIT/T treatment

1. IF PLATELETS FALL ONHEPARIN, STOP HEPARINIMMEDIATELY.

2. Stop heparin3. Stop heparin4. Use a different anticoagulant

1. Lepirudin2. Argatroban


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Case 6

A 75 y.o.man presented withfever, nausea, vomiting, epigastricpain with radiation to his back.Amylase 12,000, Lipase 3000.

Patient treated for pancreatitis.On Hospital day 2, hemoglobin andplatelet count both noted to drop.By hospital day 4, Hgb 7, Plts 12.PT/PTT normal. Amylase andlipase nl, LDH 5000, Cre 2.8.

TTP Diagnostic Features


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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


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TTP - etiology

May be associated with an antibodyagainst or a deficiency of the proteasewhich cleaves the ultra-high molecularweight multimers of von Willebrandsfactor. These very high molecularweight vWF multimers cause abnormalplatelet activation.

Can be induced bydrugs, includingticlopidine, quinine, cyclosporine,tacrolimus, mitomycin C.

Increased incidence with pregnancyorHIV


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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 contra-indicated. 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


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HUS - Hemolytic Uremic Syndrome

Usually classified along with TTP asTTP/HUS

Has fewer neurologic sequelae, morerenal manifestations.

Usually precipitated by diarrhealillness, especially E. coli O157:H7orShigella

Seen more in pediatric patients, usuallyhas better prognosis. May respond lesswell to plasma exchange.


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Wrapup

Platelet count


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Wrapup

Platelet count b/w 20-50 R/O TTP

Probably requires treatment

Stop all meds Send HIV


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Wrapup

Platelet count b/w 50-100 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 plateletcount remains stable

If pt is elderly, may be MDS, o/w

probably chronic ITP

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8.10.09 Ma Thrombocytopenia