1. January 2018 Jason aboudi mouabbi MD
Thrombocytopenia
January 2018
Jason aboudi mouabbi MD

2. Definition Mild: 100 to 150 Moderate: 30 to 100 Severe: < 30
Keep in mind, these are 95% confidence intervals, so 2.5% of population < 150

3. Pathophysiology Four Main Categories Redistribution Hemodilution
Bone Marrow Dysfunction
Platelet Destruction/Consumption

4. Let’s Start! Redistribution
Spleen carries ⅓ of our total body platelet mass
Hypersplenism redistributes this higher (ex: ½)
Hemodilution
Platelet-poor transfusions (PRBC, fluids)
Redistribution, basically is the sequestration of platelets into the extravascular space, such as the spleen. However, importantly, the total body mass of platelets stays the same
Hemodilution, basically, is flooding the patient with platelet poor fluids, which may be blood volume or fluids

5. Easy, right? Bone Marrow Dysfunction MDS Leukemia
Paroxysmal Nocturnal Hemoglobinuria
Infection
Alcoholism
Nutritional Deficits
ITP (decreased BM production and peripheral destruction)
Malignancy (extension into BM)
Bone marrow in general, overview of the main causes, we will focus more on platelet destruction/consumption as this is the more frequent thing hospitalist/internal medicine doctors see

6. Bone Marrow Leukemia Leukemic cells inhibit cell differentiation PNH
Link with aplastic anemia and bone marrow failure
Complement mediated damage to three cell lines
Alcoholism
Hypersplenism and Vitamin deficiency
Direct megakaryocyte toxicity
Decreased TPO production
Leukemia was usually thought to be due to overcrowding of platelet stem cells, however, it was found that these cells became dormant in the setting of leukemia, which points to something in leukemic cells inhibiting stem cell differentiation

7. Bone Marrow Myelodysplastic Syndromes
Dysplastic and ineffective blood cell production
Diagnosis
Cytopenia (not just platelets)
Peripheral/BM smear showing dysplasia
Tear drop cells
Smudge cells
Hypersegmented neutrophils
Dohle bodies
Giant platelets
Treatment
Mainly bone marrow transplantation
MDS is extremely complicated and, in general, shows with more than one cell line deficient, but not always. If you see signs of dysplasia in the peripheral smear, think of MDS. You will need a bone marrow biopsy for final confirmation after ruling out other causes

8. Bone Marrow Infection Viral HIV ITP-like syndrome
Direct megakaryocyte toxicity
Hepatitis C, MMR vaccine and EBV
Bacterial + Parasites
BM suppression or DIC in sepsis
H. pylori, leptospirosis, malaria, babesiosis
Viral infections, like HIV and Hep C can cause direct BM toxicity to the megakaryocytes. HIV has an ITP like picture, which is not well understood
Interestingly, H. pylori has been associated with thrombocytopenia, however, there is no recommendation to screen all people for h. pylori who have thrombocytopenia. Unknown mechanism for this. Leptospirosis, malaria, babesiosis cause thrombocytopenia via DIC or, more frequently, secondary ITP

9. Destruction/Consumption
Almost always antibody mediated
Remember This:
Thrombotic Microangiopathies
A group of diseases that are associated with thrombosis in arterioles
Includes TTP-HUS and DIC among others
We will discuss
Immune Thrombocytopenia
Drug-Induced Thrombocytopenia
Evan’s Syndrome
Heparin Induced Thrombocytopenia
TTP-HUS
DIC
This is the main area that people will see as an internist. Focus that these thrombotic microangiopathies can be life-threatening and we will discuss two of them

10. Immune Thrombocytopenia
Pathophysiology
Inciting event causing autoantibody formation
Malignancy (CLL)
Rheumatological diseases (SLE, APS, Evan’s)
Viral/Bacterial infections
HIV, Hep C, CMV, VZV
Sometimes H. pylori, Gram - bacteria and LPS
Molecular mimicry to Gp2b3a receptor on platelets
Unfortunately, not well understood how this autoimmunity is started.
If in the setting of malignancy, there is a sensitization of B + T cells to a self-antigen
In viral/bacterial infections, such as with HIV or Hep C, there is a viral antigen that mimics Gp2b3a on platelets

11. Immune Thrombocytopenia
Diagnosis of exclusion!
Treatment
Plt < 20 and bleeding?
Transfuse with IVIG and/or Steroids
Plt > 30 and no bleeding?
No need for treatment
Treatment Regimens
Utilize steroids first, usually cheaper, faster and the correct answer on the board! (Prednisone 1 mg/kg/day)
IVIG 1 g/kg/day x 2 days
Rituximab or Splenectomy if not responsive > 6 months
Do not need to find an autoantibody to platelets to make the diagnosis because, as we mentioned earlier, the main insult may be bone marrow suppression and NOT platelet destruction/consumption. This is still considered ITP.

12. Drug Induced Thrombocytopenia (DIT)
Pathophysiology
Platelet Destruction
Medication induced change in antigen creating an autoantibody
Platelet Production
Megakaryocyte death or decreased production
Diagnosis
Initiation in about one week of drug start
Usually beta lactams, vancomycin, linezolid, rifampin, AEDs and Quinine
Treatment
Removal of the drug
Recovery should be in about one week as well
Important to emphasize quinine, because it is found in soft drinks, bitter melon and other herbal remedies that people don’t know about
Patient should recover in about 1 week after drug removal and the initial insult should occur within about one week from drug start

13. Evan’s Syndrome Quick Introduction
Autoimmune-Hemolytic Anemia with associated thrombocytopenia
Look for other autoimmune diseases, such as SLE, CVID, HIV and HCV
Usually treat underlying cause or utilize steroids
Note that Evan’s Syndrome is any disease process with immune cytopenias (does not have to be AIHA)
You can diagnose warm or cold agglutins with direct antibody test (DAT or Coomb’s test), IgG = warm and IgM = cold
IgM usually tied with Mycoplasma, EBV, HIV, Lymphoma

14. Discussion So Far We will discuss Immune Thrombocytopenia
Drug-Induced Thrombocytopenia
Evan’s Syndrome
Heparin Induced Thrombocytopenia
TTP-HUS
DIC

15. Heparin Induced Thrombocytopenia
Type 1
Direct heparin effect, associated with platelet aggregation
Transient drop in 1-2 days, usually not < 100
No need to stop Heparin
Type 2
PF-4 complexed with Heparin causing autoantibodies
Heparin-Induced Antibodies
Autoantibodies without HIT clinical features
For the last point, it is important to note that patients may have autoantibodies if you check the HIT-ELISA screen. However, unless they have features of HIT (check the 4Ts), then they DO NOT have HIT. This is common after cardiopulmonary bypass
 That’s why we don’t check HIT associated Ab if the 4T score is NOT suggestive

16. Heparin Induced Thrombocytopenia
Diagnosis: 4T of HIT (high sensitivity and negative predictive value)
Thrombosis
venous more likely than arterial
Thrombocytopenia
50% drop, usually not < 20
Timing
Within 7 days, can be earlier with heparin exposure < 30 days ago
Alternate Causes?
0-3 low
4-5 intermediate
6-8 high

17. Heparin Induced Thrombocytopenia
Labs
HIT-ELISA (tests for anti-PF4 antibodies)
Sensitivity 97% and Specificity 70%
If < 0.4 = unlikely, if > 2.0 = likely
Best to use if Intermediate to High 4T score
Serotonin Release Assay
Sensitivity + Specificity > 95%
Use if discordant results or indeterminate ELISA
Note that ELISA test looks for ANY antibody to platelets, that may NOT cause HIT (as noted in introduction). Therefore, sensitivity is high, but specificity is low
SRA measures release of radiolabeled C14-serotonin from platelets. The patient’s serum is added to test platelets. Then heparin is mixed in. If the serum has antibodies to to PF4-Heparin complex, then platelets should activate
As a side note, the PF4-Heparin complex happens at an optimal concentration of heparin (0.1 U/mL), not with higher concentrations (100 U/mL). This reflects that an optimal molar concentration of PF4: Heparin (1:1) is required to cause this complex. Therefore, an SRA with high concentrations of heparin should be negative.

18. Heparin Induced Thrombocytopenia
Treatment
Immediately start non-Heparin anticoagulant
Renal Dysfunction: Argatroban, Bivalirudin
Liver Dysfunction: Fondaparinux
Both? Use Argatroban
Long-Term, when Plts > 150
No Thrombosis: Warfarin x 3 months
Thrombosis: Warfarin > 6 months
Remember: educate patient on Heparin allergy

19. Thrombotic Microangiopathies
Includes TTP, HUS, aHUS and DIC
Other etiologies that we won’t discuss at this time (TTP-like diseases):
Cyclosporine or Tacrolimus (causing platelet aggregation)
Malignancy (via entities that resemble TTP-HUS)
Antiphospholipid Antibody (resembles TTP-HUS)
SLE (can occur without antiphospholipid antibodies)

20. Thrombotic Thrombocytopenic Purpura
Endothelium A D M T S 1 3
????
No ADAMTS13
With ADAMTS13
Blood Flow
Platelet
Erythrocyte
Ultralrge vWF
multimer
Normal vWF multimer
Tissue ischemia
Schistocyte
Thrombotic Thrombocytopenic Purpura
TTP

21. TTP
Diagnosis
ADAMTS13 activity less than 10%
However this test take ~1 week to come back!!!
Historically the TTP Pentad was used (Fever, AMS, Renal Failure, Thrombocytopenia and schistocytes)
This was proved to be very unreliable

22. PLASMIC score variables
Points
Platelet count <30,000 1
Hemolysis variables (Reticulocyte count >2.5%, or haptoglobin undetectable, or indirect bilirubin >2.0 mg/dL)
No active cancer
No history of solid-organ or stem-cell transplant
MCV <90 fL
INR <1.5
Creatinine <2.0 mg/dL
Score of 0-4 denotes low risk for severe ADAMTS13 deficiency (i.e. ADAMTS13 activity level <10%); score of 5 denotes intermediate risk; score of 6 or 7 denotes high risk

23. TTP Treatment Urgent Plasmapheresis (PLEX) with steroids
Consult Hematology + Nephrology
Extremely complicated to manage

24. HUS: STEC-HUS and aHUS Causes:
STEC-HUS: E.coli H7:0157 producing shiga toxin (Verotoxin) that lead to overwhelming activation of the complement system
aHUS: Chronic uncontrolled activation of the complement system due to acquired mutations in the complement regulatory proteins (factor H, factor I, or membrane cofactor protein)
Epidemiology:
STEC-HUS: Primarily affect children under the age of 5
aHUS: Can occur at any age.
Clinical:
Prodrome of abdominal pain, vomiting and bloody diarrhea in STEC-HUS only
HUS triad: Hemolytic anemia, thrombocytopenia and renal failure
Late presentation: Lethargy and seizure
Treatment:
Mainly Supportive
NO antibiotics
NO PLEX
Eculizumab in severe cases

25. ECULIZUMAB (SOLIRIS)
Monoclonal Ab against C5 leading to inability to form the MAC complex
However the MAC complex is vital to help against encapsulated organisms especially meningococcal infections.
Due to the increased risk of meningococcal infections, meningococcal vaccination is recommended at least 2 weeks prior to receiving eculizumab, unless the risks of delaying eculizumab therapy outweigh the risk of developing a meningococcal infection, in which case the meningococcal vaccine should be administered as soon as possible.

26. Disseminated Intravascular Coagulation
Acute versus Chronic
Acute (usually due to sepsis, trauma, AML)
procoagulation causing consumption that liver production can’t keep up with
FSP also inhibits coagulation
Leading to significant bleeding
Chronic (usually malignancy)
Procoagulation which is constant and production = consumption
FSP do not build up
Usually thrombosis and not bleeding

27. Disseminated Intravascular Coagulation
Diagnosis
Clinical Findings (bleeding/thrombosis) + Labs
Low Fibrinogen, and platelets
High PT/PTT and D-Dimer
DIC Score:
Treatment
Plt transfusion if < 10 or < 50 and bleeding
FFP if PT, PTT increased and Fibrinogen normal
Cryo if PT, PTT normal and Fibirinogen low

28. TAKE HOME POINTS
Thrombocytopenia can be from four different categories:
Redistribution
Hemodilution
Bone Marrow Dysfunction
Platelet Destruction/Consumption
A majority will be Platelet Destruction/Consumption
ITP has to be diagnosis of exclusion
DIT has a long list of medications that can cause them
HIT has the 4T clinical criteria and requires immediate anticoagulation
TTP-HUS is a medical emergency that should warrant a nephrology + hematology consult
DIC can be acute or chronic with the treatment being fixing the underlying cause

29. TAKE HOME POINTS When should we transfuse platelets?
Significant bleeding? Goal > 50
Invasive procedures needed? Goal > 50
Neurosurgery or other high-risk procedures? Goal > 100
Risk for spontaneous bleeding? Goal > 10

30. Thank you!
As always you are welcome to download this lecture and other hematology/oncology lectures from our website