Sadie T. Velásquez, M.D.
60-year-old white male presented with a 4-day history of bleeding from the
gums, diffuse spontaneous ecchymoses, mild fatigue, and bone pain. The
patient described a 6-month history of pain localized to his right thigh with
extension to the posterior part of his right leg. Pt sent from an OSH for an
abnormal peripheral smear.
PMH: atrial fibrillation, hypercholesterolemia, and hypertension
PSH: appy
Social: no tobacco; moderate alcohol consumption until 1 year ago.
Meds: ASA 325mg daily, metoprolol 50mg bid, simvastatin 40mg daily,
HCTZ 25mg daily
Physical: BP 138/64, P 57, T 98, RR 18
HEENT: dry blood in oropharynx
Pulm: CTA
Abdomen: liver and the spleen were not palpable.
BLE: confluent ecchymoses involving the left ankle, B thighs
posteriorly
Laboratory values:
Hb 13.4, platelets 107K, leukocytes 8.1, LFTs normal, creatinine normal,
PTT 45, INR 1.92, fibrinogen <0.30 g/L, D-dimers >4 μg/mL
(normal:≤0.40 μg/mL).
Normal factors V, VII, XIII, and activated protein C
Initial OSH Smear: consistent with a normochromic, normocytic
anemia, with reduced platelets and large forms, and possible blasts
with folded nuclei
OSH PSA returns 2 days after admission at 276
 smear
27-year-old woman is evaluated in the ER for a two-day history of HA, fatigue and
gingival bleeding on brushing her teeth. She is otherwise healthy. Her only
medication is an oral contraceptive, and medical and family histories are
unremarkable.
Physical: T 98.6, HR 65, BP 110/65, RR 18, SaO2 98%
General: alert and oriented but reports having a headache.
HEENT: Funduscopic examination is normal. There are a few scleral hemorrhages,
and mild icterus is noted.
Skin: Petechiae that had gone unnoticed by the patient are visible on the lower
extremities.
Laboratory studies:
Hb 8 g/dL; platelet count of 34,000/µL; reticulocyte count of 12% of erythrocytes
INR 1.1, aPTT 32
LDH 2000
creatinine 0.8
D-dimer negative
 Definition of thrombocytopenia
 Discuss the initial evaluation of thrombocytopenia
 Discuss major causes of thrombocytopenia
 Discuss the guidelines of each cause to include
evaluation and management
 Normal platelet count 150-450,000/microL
 Produced in the bone marrow from megakaryocytes
 ~ 1000 - 5000 platelets are produced by each
megakaryocyte
 Platelets survive in the circulation for 8 to 10 days
 Mechanisms for a reduced platelet count:
 decreased production
 increased destruction
 dilutional or distributional thrombocytopenia
 pseudothrombocytopenia
 Can occur when the marrow is suppressed or damaged
 After viral infections (eg, rubella, mumps, varicella,
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parvovirus, HCV, EBV)
Certain infectious agents (HIV)
Following chemotherapy or XRT to sites of platelet
production
Congenital or acquired bone marrow aplasia or
hypoplasia
Direct alcohol toxicity
Vitamin B12 and folic acid deficiency
 ITP
 Drugs: heparin, quinine, quinidine, and valproic acid
 Alloimmune destruction (post-transfusion, neonatal, post
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transplantation)
DIC
TTP-HUS
APL syndrome
The HELLP syndrome
Following certain infections (infectious mononucleosis,
cytomegalovirus)
HIV
HIT
 Asymtomatic
 Menorrhagia
 Petechiae
 Purpura
 Gingival bleeding
 Ecchymoses
 History
 Medications
 Recent infection
 Prior hematologic disease
 Other medical history and current diseases
 Family history
 Recent vaccination
 Nutritional status
 Pregnancy
 Recent organ transplantation
 Recent transfusion
 Physical exam
 Ocular fundus for evidence of bleeding
 Lymphadenopathy, hepatosplenomegaly, and other
masses
 Stool exam
 Laboratory
 CBC and smear
 Decreased platelet production
Circulating blast cells
A leukoerythroblastic blood picture
Other cytopenias suggest the presence of a MD state
Macrocytosis with hypersegmented PMNs=B12 or folic
acid deficiency
 Normal sized or small platelets, in contrast to large sized
platelets, suggest a reduced bone marrow response
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 Increased destruction
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Evidence of MAHA
Large platelets
Associated autoimmune disease
Underlying lymphoproliferative disease
 May be helpful
 Attention:
 Normal to increased numbers of megakaryocytes
 Decreased numbers of megakaryocytes
 In a hypercellular marrow, megaloblastic changes in the red
cell and granulocytic series suggests vitamin B12 or folic
acid deficiency, while dysplastic changes in the red cell,
granulocytic, and megakaryocytic lineages suggests a
myelodysplastic disorder
 Granulomata, increased reticulin or collagen fibrosis or
infiltration with malignant cells establishes the diagnosis of
marrow invasion
 Severe reduction or absence of megakaryocytes with no other
abnormalities may be due to the presence of an autoantibody
directed against the thrombopoietin receptor, seen in SLE
 Definition of thrombocytopenia
 Discuss the initial evaluation of thrombocytopenia
 Discuss major causes of thrombocytopenia
 Discuss the guidelines of each cause to include
evaluation and management
Underlying disorder associated
with DIC
Systemic activation of coagulation
Widespread fibrin deposition
Consumption of platelets and
coagulation factors
Microvascular thrombosis
Thrombocytopenia and
coagulation factor deficiency
Organ failure
Bleeding
 Sepsis and severe infection
 Trauma
 Organ destruction
 Malignancy
 Obstetric
 Vascular abnormalities
 Severe liver failure
 Toxic and immunological insults
 Clinical suspicion supported by relevant laboratory
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tests
Screen with PTT, aPTT or platelet count
Fibrin degradation products and D-dimers may be
helpful
Fibrinogen can be normal in as many as 57% of
patients
Peripheral smear with fragmented RBCs
Scoring system (ISTH 5 step diagnostic algorithm)
 Sensitivity 91%, specificity of 97%
 Risk assessment: Does the pt have an underlying disorder
known to be associated with overt DIC?
 Yes →proceed
 No →stop
 Order global coags (PT, platelets, fibrinogen, fibrin related
marker)
 Score the test results
 Platelets > 100K=0, <100K=1, <50K=2)
 Elevated fibrin maker (D-dimer, FDP) no increase=0, moderate =2,
strong=3
 Prolonged PT <3s=0, >3 but <6s=1, >6s=2)
 Fibrinogen level >1g/l=0, <1=1
 Calculate score:
 ≥5 compatible with overt DIC, repeat score daily
 <5 suggestive for non-overt DIC; repeat next 1-2 days
 Treatment of the underlying condition
 Plasma and platelets:
 Transfuse platelets if platelets are <50K and bleeding
 In non-bleeding pts, 10-20K and/or on clinical features
 In bleeding patients, fibrinogen deficiency can be
corrected with purified fibrinogen or cryoprecipitate. 3g
would raise fibrinogen by around 1g/l and can be given
as 4 units of FFP, two cryoprecipitate pools or 3g of a
fibrinogen concentrate.
 If thrombosis predominates, therapeutic doses of
heparin should be considered
 In critically ill, non-bleeding patients, prophylaxis for
DVTs with heparin or LMWH is recommended
 Initially described by Dr Eli Moschcowitz at the Mount
Sinai Hospital in New York City in 1925. Moschcowitz
ascribed the disease to a toxic cause. Moschcowitz
noted that his patient, a 16 year-old girl, had
anemia, petechiae (purpura), microscopic hematuria,
and, at autopsy, disseminated microvascular thrombi.
 Predominant histologic abnormality is the formation
of platelet microvascular thrombi
 Idiopathic TTP: Deficiency of ADAMSTS13
 Secondary TTP: drugs, post bone marrow
transplatation, SLE, malignancy, pregnancy, infection
(HIV, E. coli 0157:H7)
 Severe thrombocytopenia (usually lower than HUS)*
 Microangiopathic hemolysis (schistocytes,
polychromasia)*
 May be absent from the peripheral smear in the first 24-
48 hours after presenation
 Neurologic signs
 Renal impairment
 Difficult to differentiate from HUS if this predominates
 Fever
 Full blood count and smear
 Reticulocyte count
 Clotting screen including fibrinogen and D-dimers
 Urea and electolytes
 LFTs
 LDH
 UA
 Direct antiglobulin test
 Plasma exchange (has decreased mortality from 90 to
10-30%) initiated within 24 hours of presentation
 Average number of procedures is 3-36
 Daily plasma exchange should be continued for a
minimum of 2 days after complete remission
 Adjunctive treatment with corticosteroid therapy is
recommended for all with pulse methylprednisolone
1gIV x 3 days
 Antiplatelet therapy with low-dose ASA should be
commenced on platelet recovery (>50K)
 Supportive therapy with RBC transfusion as needed
 Supplement with folate in all patients
 Platelet transfusions are contraindicated unless there
is life-threatening hemorrhage
 MAHA, thrombocytopenia and renal failure
 Clinical overlap with TTP
 Epidemic form associated with bloody diarrhea (90%
VTEC)
 Secondary causes include post solid organ/BMT,
drugs, SLE, malignancy, pregnancy and familial
deficiency or defect in complement
 Meticulous fluid and electrolyte balance and BP
control
 HD as required
 Avoid anti-motility drugs and antibiotic treatment due
to adversely affecting outcome
 FFP and plasma exchange have not been shown to
improve outcome
 HIT type II: immune-mediated disorder characterized by
the formation of antibodies against the heparin-platelet
factor 4 complex *
 HIT antibodies activate platelets intravascularly causing
release of platelet microparticles and increased thrombin
generation.
 Activated platelets are removed prematurely from the
circulation
 Type I HIT: lesser fall in platelets within the first two days
after heparin initiation and often returns to normal with
continued heparin administration. Nonimmune.
 Typical onset HIT usually occurs days 5-10
(seroconversion) and days 7-14 (threshold defining
thrombocytopenia
 Rapid-onset HIT (fall in 24 hours) is strongly
associated with recent heparin exposure (30-100 days)
 Three factors associated with HIT:
 Unfractionated heparin (UFH) >low molecular weight
heparin (LMWH)
 Surgical > medical patients
 Female > Male
 Suspect if one of the below with heparin in the preceding
5-10 days:
 Onset of unexplained thrombocytopenia
 Venous or arterial thrombosis with thrombocytopenia
 Platelet decrease by ≥ 50 percent, even if absolute
thrombocytopenia is not present
 Necrotic skin lesions at heparin injection sites
 Anaphylactoid reactions occurring after IV heparin bolus
 Initial diagnosis is clinical
 Serotonin release assays*, heparin-induced platelet
aggregation assays, and solid phase immunoassays to
confirm the diagnosis
 0-3: Low probability, 4-5: Intermediate probability, 6-8: High probability
• Patients with intermediate or high pretest probability for HIT should be
treated
 Stop heparin/heparin products
 Heparin cessation alone is often not sufficient, since
these patients remain at risk for subsequent
thrombosis
 a direct thrombin inhibitor lepirudin (caution in renal
disease), bivalirudin, or argatroban (caution in liver
disease); fondaparinux
 Warfarin should be initiated after pt stable and platelet
count has increased to ≥150,000
 Overlap VKA and thrombin inhibitors x 5 days
 VKA at least 2-3 months
 Low-molecular-weight (LMW) heparin, the heparin
analogue fondaparinux, and heparinoids, such as
danaparoid, are associated with a much lower
incidence of HIT
 Use UFH with care or the substitution of LMWH when
appropriate
 Limiting heparin duration to <5 days and initiating
coumgain early to minimize heparin use is also a
strategy in those requiring long-term anticoagulation
 Diagnosis is based on history, PE, CBC and
examination of the peripheral smear to exclude other
causes
 History
 Bleeding symptoms: type of bleeding, severity, duration,
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prior surgery history, pregnancies
Systemic symptoms: weight loss, fever, HA, symptoms of
autoimmune disorders
Risk factors for HIV
Pregnancy status
Medications: heparin, EtOH, quinidine, sulfonamides, ASA
Transfusion history
Family history
Comorbid conditions that may increase risk of bleeding
Lifestyle: vigorous or traumatic activities
 Physical exam
 Bleeding signs
 Type and severity
 Liver, spleen, lymph nodes; jaundice and other stigmata
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of liver disease
Evidence of infection
Evidence for autoimmune disease
Evidence for thrombosis
Neurologic function
Skeletal abnormalities
 Laboratory data
 CBC with examination of a peripheral blood smear
 HIV
 Bone Marrow biopsy in those over 60 years old and in
patients considering splenectomy
 TSH
 Platelet count >20K should not be hospitalized if they
are asymtpmatic or have minor purpura
 Platelets >50K do not routinely require treatment
 Treatment is indicated with platelets <20-30,ooo and
those with counts <50K and significant bleeding or
risk factors for bleeding
 Glucocorticoids are the initial treatment
 Those with severe, life-threatening bleeding should
also be hospitalized and should receive supportive care
along with treatment for ITP
 Regimens for treatment include high-dose
glucocorticoid therapy, IVIG and platelet transfusions
 Splenectomy is appropriate in specific situations such
as bleeding symptoms if platelets remain below 30K
after 4-6 weeks of medical treatment
60-year-old white male presented with a 4-day history of bleeding from the
gums, diffuse spontaneous ecchymoses, mild fatigue, and bone pain. The
patient described a 6-month history of pain localized to his right thigh with
extension to the posterior part of his right leg. Pt sent from an OSH for an
abnormal peripheral smear.
PMH: atrial fibrillation, hypercholesterolemia, and hypertension
PSH: appy
Social: no tobacco; moderate alcohol consumption until 1 year ago.
Meds: ASA 325mg daily, metoprolol 50mg bid, simvastatin 40mg daily,
HCTZ 25mg daily
Physical: BP 138/64, P 57, T 98, RR 18
HEENT: dry blood in oropharynx
Pulm: CTA
Abdomen: liver and the spleen were not palpable.
BLE: confluent ecchymoses involving the left ankle, B thighs
posteriorly
Laboratory values:
Hb 13.4, platelets 107K, leukocytes 8.1, LFTs normal, creatinine normal,
PTT 45, INR 1.92, fibrinogen <0.30 g/L, D-dimers >4 μg/mL
(normal:≤0.40 μg/mL).
Normal factors V, VII, XIII, and activated protein C
Initial OSH Smear: consistent with a normochromic, normocytic
anemia, with reduced platelets and large forms, and possible blasts
with folded nuclei
OSH PSA returns 2 days after admission at 276
27-year-old woman is evaluated in the ER for a two-day history of HA, fatigue and
gingival bleeding on brushing her teeth. She is otherwise healthy. Her only
medication is an oral contraceptive, and medical and family histories are
unremarkable.
Physical: T 98.6, HR 65, BP 110/65, RR 18, SaO2 98%
General: alert and oriented but reports having a headache.
HEENT: Funduscopic examination is normal. There are a few scleral hemorrhages,
and mild icterus is noted.
Skin: Petechiae that had gone unnoticed by the patient are visible on the lower
extremities.
Laboratory studies:
Hb 8 g/dL; platelet count of 34,000/µL; reticulocyte count of 12% of erythrocytes
INR 1.1, aPTT 32
LDH 2000
creatinine 0.8
D-dimer negative
 George JN, et al. Idiopathic thrombocytopenic purpura: a practice guideline
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developed by explicit methods for the American Society of Hematology. Blood.
88(1):3-40, 1996 Jul 1.
Allford SL. Hunt BJ. Rose P. Machin SJ. Haemostasis and Thrombosis Task
Force, British Committee for Standards in Haematology. Guidelines on the
diagnosis and management of the thrombotic microangiopathic haemolytic
anaemias. British Journal of Haematology. 120(4):556-73, 2003 Feb.
Warkentin TE., et al. Heparin-induced thrombocytopenia: recognition,
treatment, and prevention: the Seventh ACCP Conference on Antithrombotic
and Thrombolytic Therapy. Chest 2008: 133; 340S-380S.
Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and
management of disseminated intravascular coagulation. British Committee for
Standards in Haematology. Br J Haematol 2009 Apr;145(1):24-33.
MKSAP 15
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