Thrombocytopenia review

1. Diana Girnita, MD, PhD
The Christ Hospital
December 2011

2. Definition
 Platelets < 150,000/ml
 2.5% of normal people < 150,000/ml
 Recent drop ≥ 50%, even if normal platelets
count

3. Increased risk of bleeding
if < 60,000 -with minor trauma
if < 12,000 –spontaneous
If < 6,000 - severe, life threatening

4. Initial approach of the patient
 Clinical:
1. epistaxis
2. gingival bleeding
3. meno/ metrorrhagia
4. tend to bleed immediately after minor trauma
5. cerebral bleeding
 Cutaneous: petechiae, purpura, ecchymoses

5. Clinical presentation
A: Dense, cutaneous petechiae on the foot and ankle. B:Bullous hemorrhages on the
buccal mucosa
PURPURA - purplish discoloration of the skin due to the presence of confluent petechiae
Ecchymoses — nontender areas of bleeding into the skin, usually associated with
multiple colors

6. PMH
?Bleeding history
?Hematologic disease (acute /chronic leukemias,
MDS)
?Recent new drugs or drugs that are only taken
intermittently (ASA, NSAID, herbal, plavix, heparin)
?Recent live virus vaccination
?Recent infection (viral, bacterial, rickettsial) /sepsis
?Recent travel — malaria /dengue virus,
leptospirosis, meningococcemia, hantavirus,
hemorrhagic fevers (eg, Ebola, Lassa ).

7. PMH- cont
?Recent massive transfusion (PRBCs /platelets)
in an allo-sensitized recipient
? Recent organ transplantation by sensitization to
platelet allo-antigens /GVHD
?Pregnancy especially late in the 3rd trimester or at
onset of labor , +/- ITP or TTP-HUS, or
preeclampsia/ eclampsia
FH: ++ for bleeding and/or thrombocytopenia

8. The physical examination
 Examination in critical areas
1. Ocular fundus -CNS bleeding
2. Lymphadenopathy
3. Hepatosplenomegaly
4. Stool for occult blood
5. Skin -feet and ankles , presacral area, areas of
previous trauma
 Outline areas of bleeding with a marking pen (changes
in the number/pattern of petechiae)

9. Labs
 CBC -WBC, RBC, Plt count -r/o TTP and acute leukemia
 PERIPHERAL SMEAR
 Plt #
 Ptl morphology- large?
 +/- Plt clumping
 +/- scystocytes
 If anemia: ? Hemolytic ?
 (LDH, haptoglobin, Bilirubin)

10. Bone marrow examination
 Evaluate megakariocytes
 BM could be
 Hypocellular
 Cellular
 BM replacement

11. Mechanisms of thrombocytopenia
1. Pseudothrombocytopenia
2. Decreased platelet production
3. Increased platelet destruction
4. Dilutional thrombocytopenia
5. Distributional thrombocytopenia

12. Pseudothrombocytopenia
 EDTA-induced platelet clumping
 Drugs –Abciximab -
directed against the
GP IIb/IIIa receptor

13. Decreased platelet production
 Hypocellular BM
 Infections (MMR,
varicella, parvovirus,
hepatitis C EBV, HIV,
rickettias)
 Live attenuated
vaccines
•Drugs
•Aplastic anemia
•Alcohol
•Autoantibody -
against the
thrombopoietin
receptor (SLE)

14. Decreased platelet production
 Cellular BM
 Leukemias
 MDS
 Severe vit B12 /folate deficient anemia
MDS

15. Decreased platelet production
 Marrow replacement
 Myelofibrosis
 Solid malignancies
 Granulomas
Myelofibrosis

16. Increased platelet destruction
1.Immune –mediated
 Primary ITP
 Secondary: infectious, CLL, drugs (heparin), APL sdr,
lymphoma
 Allo-immunization (post-transfusion)
2. Non-immune mediated
 MAHA (TTP-HUS, DIC)
 Evan Sdr: thrombocytopenia + hemolytic anemia
 Vascular prostheses/ bypass; trauma
 Drugs: ticlopidine/clopidogrel,
 Cavernous hemangioma
 HELLP syndrome -in pregnant women

17. Other causes:
 Dilutional thrombocytopenia — massive blood transfusion
with PRBC (> 20 units of PRBCs /24H)
 Distributional thrombocytopenia caused by splenic
sequestration
Portal hypertension
Cirrhosis
Splenomegaly
Hypothermia

18. Thrombocytopenia in the ICU patient
 Sepsis/septic shock - one-half of the cases
 Use of heparin
 DIC
 Massive blood transfusion
 Post-transfusion purpura
 Cardiopulmonary resuscitation
 Cardiopulmonary bypass
 ARDS
 PE
 Use of intravascular catheters
 Solid organ allograft rejection
 Drugs (antibiotics, chemotherapy, antiplatelet agents -
abciximab)

19. Heparin induced thrombocytopenia
(HIT)
HIT I
HIT II

20. HIT II
 an immune-mediated disorder characterized by the
formation of antibodies against the heparin-platelet
factor 4 complex.
 UFH/LMWH
 5-10 days after the heparin is started
 Heparin –PF4 complex- Ab induce platelet aggregation
and activation, endothelial cell activation (IL-6, vWF)
 Thrombosis (arterial and venous) + thrombocytopenia
(>50% fall in Plt)
 DVT, PE (25%)
 Skin necrosis at injection site

21. Dg of HIT II
 Serotonin release assay
 Heparin-induced platelet aggregation
 The solid phase ELISA immunoassay- heparin-PF4-
IgG antibodies

22. Treatment HIT II
 Stop the heparin UFH/LMWH
 Lepirudin — Refludan®
 Is a recombinant hirudin (anticoagulant action, similar to
antithrombin III - the thrombin inhibitor)
 For HIT complicated by thrombosis, preventing new thromboses
 Not for renal failure patients
 Argatroban
 Is a direct thrombin inhibitor
 Metabolized in the liver
 Activity monitored by APTT
 Good for renal failure patients
 Warfarin — when
1) patient stably anticoagulated with a thrombin-specific inhibitor
2) Plt > 150,000/microL

23. Challenges in bridging to long term
anticoagulation
 The combination of argatroban and warfarin may raise
the INR > 5.0 without a significant increased risk of
bleeding complications.
 Measure the chromogenic factor X level
 A level < 40-45% typically indicates that the INR will
be therapeutic (2-3) when the argatroban is
discontinued.

24. HIT I
 Non-immune mechanism, appears to be due to a
direct effect of heparin on platelet activation
 1-4 days after heparin is started
 Platelets in the 100.000/mm3 range
 No thrombotic events
 No hemorrhage
 Management : observation

25. HIT I vs HIT II

26. Thrombotic thrombocytopenic purpura-
hemolytic uremic syndrome (TTP-HUS)
 Thrombocytopenia
 Microangiopathic hemolytic anemia
 Neurologic symptoms and signs
 Renal function abnormalities
 +/- Fever
 TTP-HUS is associated with thrombi composed
primarily of platelets in affected organs

27. Etiology TTP
 ADAMTS13 deficiency (vWf-cleaving protease) —leads
sequentially to the accumulation of unusual large vWf
multimers, platelet aggregation, and the platelet
clumping
 Genetic
 Acquired: DIC, HSCT, chemotherapy, severe sepsis, SLE,
leukemia, acute inflammatory states, cirrhosis, uremia,
drugs (ticlopidine, clopidogrel, quinine)

28. Etiology HUS
 Enterohemorrhagic E coli
 Shiga toxin binds and activates endothelial cells and
platelets and induces formation of intra-renal thrombi
Clinic:
 Children
 Bloody diarrhea
 Fever

29. Diagnosis TTP-HUS
 Peripheral smear: ++ Schystocytes
 Negative Coombs test
 Normal PT, PTT, fibrinogen
 Hemolysis : LDH increased (tissue ischemia +
hemolysis), indirect bilirubin increased, decreased
haptoglobin
 Increased creatinine
 Biopsy: arterioles filled with hyaline thrombi (DDx:
vasculitis, DIC, HELLP, malignant HTN)

30. Treatment TTP-HUS
1. Plasma exchange
Exceptions:
 Postdiarrheal HUS in children
 Cancer chemotherapy or transplantation
 Severe acute renal failure- cause fluid overload
2. Glucocorticoids: severe deficiency of ADAMTS13
Platelet transfusions are contraindicated

31. Immune thrombocytopenic
purpura (ITP)
 Dg of exclusion
 ITP is related to a combination of
 increased platelet destruction along with
 inhibition of megakaryocyte platelet production via the
production of specific IgG autoantibodies directed
against platelet membrane GP (GPIIb/IIIa)

32. Diagnosis ITP
 CBC : ITP+AIHA = Evans Sdr
 Peripheral smear: large platelets
 Bone marrow aspirate >60 yo to r/o MDS
 Antiplatelet antibody testing –not recommended by
the ASH
 Platelets have HLA A, B-testing for anti-HLA ab to
match platelets
 Consider ANA, viral serologies, H pylory Ab

33. Treatment ITP
 Initial :
 Steroids: PDN/ methylprednisolone (bleeding)
 IVIG
 WinRho (AntiRh-D) in Rh positive pt; ab coated RBC
overwhelm Macrophages Fc receptor
 Refractory
 Splenectomy
 Rituximab (anti-CD20)
 Azathioprine, Cyclophosphamide
 Thrombopoiesis stimulant: Eltrombopag

34. References
 www.uptodate.com
 John Hopkins IM board review
 PG MGH handbook

35. Thank you!
ALYSA & ANA