4. Pre-injury conditions encourage flow.
The vascular endothelium produces substances
(including nitric oxide, prostacyclin and
heparans) to prevent adhesion of platelets and
white cells to the vessel wall. Platelets and
coagulation factors circulate in a non-activated
state
5. • At the site of injury the endothelium is
breached, exposing subendothelial collagen.
Small amounts of tissue factor (TF) are
released. Platelets bind to collagen via a
specific receptor, glycoprotein Ia (GPIa),
causing a change in platelet shape and its
adhesion to the area of damage by the binding
of other receptors (GPIb and GPIIb/IIIa) to
von Willebrand factor and fibrinogen
respectively. Coagulation is activated by the
tissue factor (extrinsic) pathway, generating
small amounts of thrombin
6. Normal Physiology-
Production 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
7. 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
- spontaneous bleeding
– Generally requires hospitalization
• <10,000: risk for spontaneous intracranial
hemorrhage
11. 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
12. 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.
15. ITP
• Definition: isolated thrombocytopenia with no
clinically apparent associated conditions or other
causes of thrombocytopenia.
• Etiology: autoantibodies directed against
glycoprotein IIb/IIIa on 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.
Association ; connective tissue disease , HIV
infection ,B cell malignency ,drugs
18. Workup
• CBC
– Isolated thrombocytopenia.
– Truly giant platelets on peripheral
smear suggest congenital
thrombocytopenia.
– The WBC count and hemoglobin
typically are normal, unless severe
hemorrhage has occurred.
bone Marrow : increase
megakaryocyte
• Coagulation studies are normal,
and a bleeding time is not useful.
19. Management ITP
• Asymptomatic pt
• Symptomatic pt
- initial management
-subsequent management
. Relapsed ITP
by steroid, splenectomy,
anti D immune globulin
. Refractory ITP
20. Management of ITP
Asymptomatic Adult
• If platelet count is >30 K,
no therapy is required.
Check platelet counts at intervals.
• If platelet count is < 30 K, begin
therapy with corticosteroids.
• Stop all NSAIDS and ASA to improve
platelet function.
21. Initial Management of ITP
Adult with Symptomatic Purpura
• If platelet count is >10,
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.
22. Subsequent Management of ITP
Adult 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 taper over 6-8 weeks.
• 1/3 of adults will have gone into remission.
• 2/3 of patients will relapse during or after
steroid taper.
23. Management of Relapsed ITP
• Once the patient relapses, may need to
re-introduction of 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 if 2 relapse) or
intermittent treatment with anti-D
immune globulin .
24. Management of Relapsed ITP
by Splenectomy
• effective in 2/3 of patients
• Complete remission 70% ,
• improvement in 20-25%
• via open method or laparoscopically.
• vaccinate against encapsulated bacteria
(Pneumococcal ,meningococcal, H. influenzae)
2 weeks before procedure.
• Pen V 500mg BD life long
• May need steroids and/or IVIg before
procedure to boost platelet counts
preoperatively.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. Treatment of Refractory ITP
• Immunosuppressive agents
– Rituximab (anti-CD20)
• 40% effective
• May be used before splenectomy
– Mycophenolate mofetil
– Cyclophosphamide
• Adjunct agents
– Thrombopoietin Receptor Agonists
• Romiplostim
• Eltrombopag
34. Drugs Commonly Implicated in
Thrombocytopenia
• Beta-lactam antibiotics.
• Trimethoprim-sulfamethoxazole and
other sulfa drugs.
• Vancomycin.
• Quinine/quinidine.
• Heparin.
• Abciximab .
• H2 blockers
• If a patient’s platelets fall, ALL
unnecessary drugs need to be stopped.
• give platelet transfusions , IVIg is
particularly helpful in quinine-induced
ITP. ,
35. 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
36. 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.
38. 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
39. 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
41. TTP - Diagnostic Features
• 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
42. 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
43. TTP -lab
CBC normal or slightly elevated WBC.
• Hemoglobin is moderately depressed at 8-9 g/dL.
• Platelet count ranges from 20,000-50,000 per
microliter.
• Peripheral smear : Red blood cells are
fragmented and appear as schistocytes. Certain
schistocytes have the appearance of helmet cells (H).
Spheroidal cells often are present (S). Occasional
nucleated erythroid precursors may be present.
44. 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
45. DIC
• Pathophysiology
4 simultaneously occurring mechanisms:
• TF-mediated thrombin generation
• Dysfunctional physiologic anticoagulant
mechanisms (eg, depression of antithrombin
and protein C system),
• Impaired fibrin removal due to depression of
the fibrinolytic system –
caused by high circulating levels of
plasminogen activator inhibitor type 1 (PAI-1);
46. Underlying conditions
• Infection/sepsis
• Trauma
• Obstetric, e.g. amniotic fluid embolism,
placental abruption, pre-eclampsia
• Severe liver failure
• Malignancy, e.g. solid tumours and leukaemias
• Tissue destruction, e.g. pancreatitis, burns
• Vascular abnormalities, e.g. vascular
aneurysms, liver haemangiomas
• Toxic/immunological, e.g. ABO incompatibility,
snake bites, recreational drugs
49. RX --DIC
• focus on addressing underlying disorder
• Administration of Blood Components and
Coagulation Factors – platelet , FFP,
cryopricipitate
• Anticoagulation – heparin,proteinC
• Patients with DIC should not in general be
treated with antifibrinolytic therapy, e.g.
tranexamic acid.
50.
51. 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.
