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Thrombocytopenia
BLOCK 14, 2014 -2015
ARTICLES BY RYAN BURRIS, ALI NAQVI, WENDY YANG
PRESENTATION BY SAM LAI, ALEX RAUFI
QUESTIONS BY VICKI CHENG
Definition
1.
Mild: 100 to 150
2.
Moderate: 50 to 100
3.
Severe: < 50
Keep in mind, these are 95% confidence intervals, so 2.5% of population < 150
Pathophysiology
Four Main Categories
1. Redistribution
2.
Hemodilution
3.
Bone Marrow Dysfunction
4.
Platelet Destruction/Consumption
Let’s Start!
1.
Redistribution
a.
Spleen carries ⅓ of our total body platelet mass
b.
Hypersplenism redistributes this higher (ex: ½)
c.
Total body mass is the same
2.
Hemodilution
a.
Platelet-poor transfusions (PRBC, fluids)
Easy, right?
1.
Bone Marrow Dysfunction
a. MDS
b. Leukemia
c. Paroxysmal Nocturnal Hemoglobinuria
d. Infection
e. Alcoholism
f. Nutritional Deficits
g. ITP (decreased BM production and peripheral destruction)
h. Malignancy (extension into BM)
Bone Marrow
●
Leukemia
a.
Leukemic cells inhibit cell differentiation
●
PNH
a.
b.
●
Link with aplastic anemia and bone marrow failure
Complement mediated damage to three cell lines
Alcoholism
a.
Hypersplenism and Vitamin deficiency
b.
Direct megakaryocyte toxicity
c.
Decreased TPO production
Bone Marrow
●
Myelodysplastic Syndromes
a.
Dysplastic and ineffective blood cell production
b.
Diagnosis
i.
Cytopenia (not just platelets)
ii.
Peripheral/BM smear showing dysplasia
1.
Tear drop cells
2.
Smudge cells
3.
Hypersegmented neutrophils
4.
Dohle bodies
5.
Giant platelets
a.
Treatment
a.
Mainly bone marrow transplantation
Bone Marrow
●
Infection
a.
Viral
i.
HIV
ii.
ITP-like syndrome or direct megakaryocyte toxicity
2.
Direct megakaryocyte toxicity
Hepatitis C, MMR vaccine and EBV
1.
b.
Bacterial + Parasites
i.
BM suppression or DIC in sepsis
ii.
H. pylori, leptospirosis, malaria, babesiosis
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
Immune Thrombocytopenia
●
Pathophysiology
o
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
Immune Thrombocytopenia
● Diagnosis of exclusion!
● Treatment
o Plt < 20 and bleeding?
 Transfuse with IVIG and/or Steroids
o Plt > 30 and no bleeding?
 No need for treatment
o Treatment Regimens
 Utilize steroids first, usually cheaper and faster
 Prednisone 1 mg/kg/day
 IVIG 1 g/kg/day x 2 days
 Rituximab or Splenectomy if not responsive > 6 months
Drug Induced Thrombocytopenia (DIT)
●
Pathophysiology
o
Platelet Destruction

Medication induced change in antigen creating an autoantibody
o
Platelet Production

Megakaryocyte death or decreased production
●
Diagnosis
o
Initiation in about one week of drug start
o
Usually beta lactams, vancomycin, linezolid, rifampin, AEDs and Quinine
●
Treatment
o
Removal of the drug
o
Recovery should be in about one week as well
Evan’s Syndrome
●
Quick Introduction
o
Autoimmune-Hemolytic Anemia with associated thrombocytopenia
o
Look for other autoimmune diseases, such as SLE, CVID, HIV and HCV
o
Usually treat underlying cause or utilize steroids
Discussion So Far
We will discuss
•
•
•
Immune Thrombocytopenia
Drug-Induced Thrombocytopenia
Evan’s Syndrome
•
•
•
Heparin Induced Thrombocytopenia
TTP-HUS
DIC
Heparin Induced Thrombocytopenia
●
Type 1
o Direct heparin effect, associated with platelet aggregation
o Transient drop in 1-2 days, usually not < 100
o No need to stop Heparin
●
Type 2
o PF-4 complexed with Heparin causing autoantibodies
●
Heparin-Induced Antibodies
o Autoantibodies without HIT clinical features
Heparin Induced Thrombocytopenia
●
Pathogenesis
o
Platelet Factor 4 released by platelets during activation
o
Complexes with Heparin
o
IgG antibody binds to PF4-Heparin complex
o
Fc of IgG binds to Fc of platelets

Opsonization and sequestration of some platelets

Activation of others
Heparin Induced Thrombocytopenia
●
Diagnosis: 4T of HIT (high sensitivity and negative predictive value)
o
Thrombosis

venous more likely than arterial
o
Thrombocytopenia

50% drop, usually not < 20
o
Timing

Within 7 days, can be earlier with heparin exposure < 30 days ago
o
Alternate Causes?
Heparin Induced Thrombocytopenia
●
Labs
o
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
o
Serotonin Release Assay

Sensitivity + Specificity > 95%

Use if discordant results or indeterminate ELISA
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
Thrombotic Microangiopathies
●
Includes TTP-HUS and DIC
●
Other etiologies that we won’t discuss at this time:
o Cyclosporine or Tacrolimus (causing platelet aggregation)
o Malignancy (via entities that resemble TTP-HUS)
o Antiphospholipid Antibody (resembles TTP-HUS)
o SLE (can occur without antiphospholipid antibodies)
TTP-HUS
●
Pathogenesis
o
ADAMTS13 usually cleaves ULVWF to smaller multimers

Antibody formation
●
Infection, drugs, malignancy, Autoimmune diseases

Reduced Activity

CD36 Antibody formation
●
Where ADAMTS13 binds to platelets and cleaves vWF
TTP-HUS Causes
●
Mostly Idiopathic
●
Infectious (molecular mimicry)
o
Shiga-Toxin in children, sometimes in adults
o
HIV (unknown mechanism)
o
Strep Pneumo
●
Drug-Induced
o
Quinine (Ab formation)
o
Chemotherapy (endothelial injury, maybe to CD36 receptor)
TTP-HUS Diagnosis
●
Required
o
MAHA with Thrombocytopenia
●
Good To Have
o
Rest of the Pentad (AKI, Neuro change, Fever)
o
Coombs and DIC Screen negative
o
Coagulation tests normal
o
Hemolysis labs positive
●
Idiopathic
o
Reduced ADAMTS13 Activity (<10%)
TTP-HUS Treatment
●
Urgent Plasmapheresis
●
Steroids
o
If not responding to PEX
o
Generally, recurs when PEX stopped
o
Do not use if due to chemotherapy or Shiga-toxin
●
Consult Hematology + Nephrology
o
Extremely complicated to manage
Disseminated Intravascular Coagulation
●
Acute versus Chronic
o
Acute (usually due to sepsis, trauma, AML)
 procoagulation causing consumption that liver production can’t keep up with
 FDP also inhibits coagulation
 Leading to significant bleeding
o
Chronic (usually malignancy)
 Procoagulation which is constant and production = consumption
 FDPs do not build up
 Usually thrombosis and not bleeding
Disseminated Intravascular Coagulation
●
Diagnosis
o
Clinical Findings (bleeding/thrombosis) + Labs

Low PT/PTT, Fibrinogen, and platelets

High D-Dimer
●
Treatment
o
Plt transfusion if < 10 or < 50 and bleeding
o
FFP if PT, PTT increased and Fibrinogen normal
o
Cryo if PT, PTT normal and Fibirinogen low
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 (look at UptoDate tables)
◦ 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
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
Question #1
A 27 year old woman is evaluated in the clinic for right upper quadrant pain. She is
gravid at 27 weeks gestation. On physical examination, temperature is normal, blood
pressure is 167/91mm Hg, pulse rate is 92/min and respiration rate is 21/min. Scleral
icterus is noted. Abdominal examination discloses right upper quadrant tenderness,
without rebound or guarding. There is peripheral edema.
LABS
Hemoglobin 8.9 g/dL
Platelets 45,000/uL
WBC 8700/uL
AST and ALT Elevated
UA = 4+ Protein
Question #1
Which of the following is the most likely finding on peripheral blood smear?
(A) Bite cells
(B) Schistocytes
(C) Rouleaux
(D) Normal smear
Question #1: Discussion
ANSWER: B
Objective: Recognize preeclampsia and HELLP syndrome in pregnancy.
Preeclampsia presents during the third trimester with hypertension, peripheral edema,
And proteinuria. Between 4-12% of patients with preeclampsia also develop HELLP
syndrome of hemolysis, elevated liver enzymes, and low platelet count with associated
right upper quadrant pain. The peripheral blood smear would demonstrate
schistocytes. Bite cells are commonly seen in G6PD deficiency, and rouleaux are found
in multiple myeloma.
Question #2
A 23 year old male presents to the emergency room with 1 day of fever and confusion.
Two weeks ago he had profuse bloody diarrhea with diffuse abdominal pain after
consuming undercooked beef at a barbecue.
On physical exam, temperature is 100.8 Fahrenheit, blood pressure is 132/87 mm Hg,
pulse rate is 91/min, and respiratory rate is 16/min. He is somnolent; neurological exam
is otherwise non focal. Skin appears jaundiced, and there is mucocutaneous
ecchymoses. Abdominal examination discloses hyperactive bowel sounds, without
tenderness or distension.
Question #2
LABS
Hemoglobin 7.9 g/dL
Platelet count 32,000/uL
Leukocyte count 9800/uL
Lactate dehydrogenase Elevated
Serum creatinine 1.7
Urinalysis 2+ hemoglobin, 2+ protein
Question #2
Which of the following is the most important next step in management?
(A) Check ADAMTS13 activity and inhibitor titer
(B) Send a serotonin release assay
(C) Obtain a stool culture
(D) Start empiric plasma exchange
(E) Treat with IVIG
Question #2: Discussion
ANSWER: D
Objective: Identify thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic
syndrome (HUS) andtimely treatment with plasma exchange.
TTP presents as fever, microangiopathic hemolytic anemia, thrombocytopenia, with
renal manifestations (elevated creatinine, hematuria, proteinuria) and neurological
changes (such as confusion or headache). It can overlap with HUS, which is often
triggered by a hemorrhagic diarrheal illness within the preceding 3 weeks with E. coli
O157:H7 or Shiga toxin. Pathogenesis of TTP is the formation of autoantibodies against
ADAMTS13, the protease that cleaves multimers of Von Willebrand factor (vWF); this
results in decreased protease activity due to increased inhibitor titer levels and
abnormal platelet and endothelial cell activation leading to peripheral destruction of
platelets and erythrocytes.
Question #2: Discussion
ADAMST13 level is used for prognostication rather than to guide therapy. Stool cultures, while
important for public health, are less imperative than plasma exchange which should be initiated
immediately. There is high mortality, up to 10%, within the first 24 hours and treatment should be
started if TTP-HUS is suspected prior to lab confirmation. Sepsis with disseminated intravascular
coagulation is a potential alternative explanation for this clinical scenario, but not an answer option.
Serotonin release assay is used to confirm heparin induced thrombocytopenia (HIT) and IVIG is the
treatment for immune thrombocytopenic purpura (ITP) refractory to steroids.
Question #3
A 45 year old female presents to the emergency room with acute onset pleuritic chest pain after a
transatlantic flight. On physical examination, she is afebrile, blood pressure is 135/82 mm Hg, pulse rate
is 121/min, and respiratory rate is 21/min. She appears in mild distress. Cardiac examination reveals
tachycardia rate and regular rhythm, and lungs are clear to auscultation. Her left lower extremity is
edematous and tender to palpation.
Lower extremity venous ultrasound is positive for left popliteal deep venous thrombosis, and she is
Started on unfractionated IV heparin. Five days later, she notices skin changes on her arm with black-red
centers where blisters previously appeared. Laboratory studies show platelet count of 70,000/uL,
compared to 156,000/uL on admission.
Question #3
Which of the following is the most appropriate step in management?
(A) Discontinue unfractionated IV heparin
(B) Switch heparin to argatroban
(C) Add warfarin
(D) Treat with IV clindamycin, unasyn, and vancomycin
Question #3: Discussion
ANSWER: B
Objective: Recognize and treat heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia (HIT) occurs when an autoantibody develops against endogenous
platelet factor 4 (PF4) in complex with heparin. It occurs with higher frequency in response to
unfractionated heparin compared to low molecular weight heparin such as enoxaparin. Clinical suspicion
is elevated in those with high 4T scores which are useful for predicting pretest probability for HIT. The
elements of the 4T's are thrombocytopenia, clear onset between days 5 and 10 after exposure,
thrombosis, and no better explanation for thrombocytopenia. Diagnostic testing is based on ELISA testing
for the autoantibody against the heparin-PF4 complex, or 14C serotonin release assay which has higher
specificity. Therapy is heparin cessation and treatment with a non-heparin alternative anticoagulant (such
as argatroban or lepirudin), because 30-50% of patients develop thrombosis with heparin withdrawal.
Warfarin itself can induce similar skin necrosis. Antibiotics (and surgical consultation) are for the
management of infectious necrotizing fasciitis, not HIT.
Question #4
A 64 year old male with presents to urgent care with recurrent epistaxis of 20 minutes' duration for 3
days. He had a shingle outbreak three weeks ago which has resolved, and denies any other site of
bleeding. On physical examination, there is dried blood in bilateral nares and faint petechiae over the
anterior torso.
LABS
Hemoglobin 12g/dL
Leukocyte count 4000/uL
Platelet count 26,000/uL
Question #4
Which of the following is the most appropriate next step in management?
(A) Prednisone
(B) Platelet transfusion
(C) IVIG
(D) Splenectomy
Question #4: Discussion
ANSWER: A
Objective: Recognize and treat immune thrombocytopenic purpura
Varicella zoster virus (VZV) infection is associated with secondary immune thrombocytopenic purpura
(ITP), and first-line of treatment is a short course of steroids for symptomatic thrombocytopenia.
Intravenous immunoglobulin may be used for refractory ITP, and splenectomy is reserved for patients
who do not respond to standard therapies given concern for future susceptibility to encapsulated
organisms.
Platelet transfusion is ineffective and wasteful in the management of ITP. Drug-induced
Thrombocytopenia typically presenting 5-7 days after exposure to the causative agent, and resolving
between 7- 14 days after drug discontinuation. Common culprits include cephalosporins, sulfa drugs,
Bactrim, vancomycin, carbamazepine, and quinidine/quinine. Treatment of choice for drug-induced
thrombocytopenia is discontinuation of the drug.
Question #5
A 43 year old female with history of Roux-en-Y gastric bypass surgery presents in clinic for evaluation of
pancytopenia. She reports months of generalized fatigue and occasional paresthesias in the lower
extremities. On physical examination, she is afebrile, blood pressure is 142/78 mm Hg, pulse rate is
76/min, and respiratory rate is 16/min. Skin examination reveals no jaundice, petechiae, or ecchymoses.
There is no hepatosplenomegaly.
LABS
Hemoglobin 10.2 g/dL
Hematocrit 30.6 g/dL
Leukocyte count 3300/uL
Platelet count 88,000/uL
A peripheral blood smear was obtained.
Question #5
Which of the following is the most likely finding?
(A)
(B)
(C)
(D)
Megaloblastic changes
Large platelets
Basophilic stippling
Auer rods
Question #5: Discussion
ANSWER: A
Objective: Recognize pancytopenia secondary to vitamin B12 and folate deficiency.
Complications of Roux-en-Y gastric bypass include metabolic and nutritional derangements, particularly
iron, calcium, vitamin B12, thiamine and folate deficiency from decreased absorption. Vitamin B12 and
folate deficiency leads to bone marrow hypoproliferation and megaloblastic granulocytes on peripheral
blood smear. Large platelets and increased megakaryocytes typically appear during a heightened
marrow response secondary to a destructive process. Basophilic stippling from ribosomal precipitates is
seen in thalassemia, alcohol abuse, and lead or heavy metal poisoning. Auer rods are characteristic of
acute myelogenous leukemia.
Bibliography
1.George, J, et al. Syndromes of Thrombotic Microangiopathies. NEJM. 2014, August. 371:654-666
2.Aster, R, et al. Drug-Induced Immune Thrombocytopenia. NEJM. 2007, 357:580-587
3.Squires, J. Indications for Platelet Transfusions in patients with Thrombocytopenia. Blood Transfusions 2015; 13: 221-6
4.Mehmet, A, et al. Thrombocytopenia in Adults: Review Article. J Hematol. 2012; I (2-3): 44-53
5.Cuker, A, et al. Predictive Value of the 4Ts scoring system for HIT: a systematic review and meta-analysis. Blood. 2012. 120: 41604169
6.Kang, M, et al. Fondaparinux for the treatment of suspected HIT: a propensity score-matched study. Blood. 2015, February. 125
(6): 924-930
7.Lakshmanan, S, et al. Contemporary management of primary immune thrombocytopenia in adults. Journal of Thrombosis and
Hemosatsis. 2012, 10: 1988-1998