ThrombocytopeniaBLOCK 14, 2014-2015ARTICLES BY RYAN BURRIS, ALI NAQVI, WENDY YANGPRESENTATION BY SAM LAI, ALEX RAUFIQUESTIONS BY VICKI CHENG

Definition1. 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

PathophysiologyFour Main Categories

1. Redistribution

2. Hemodilution

3. Bone Marrow Dysfunction

4. Platelet Destruction/Consumption

Let’s Start!

1. Redistributiona. Spleen carries ⅓ of our total body platelet massb. Hypersplenism redistributes this higher (ex: ½)c. Total body mass is the same

2. Hemodilutiona. Platelet-poor transfusions (PRBC, fluids)

Easy, right?1. Bone Marrow Dysfunction

a. MDSb. Leukemiac. Paroxysmal Nocturnal Hemoglobinuriad. Infectione. Alcoholismf. Nutritional Deficitsg. ITP (decreased BM production and peripheral destruction)h. Malignancy (extension into BM)

Bone Marrow● Leukemia

a. Leukemic cells inhibit cell differentiation

● PNHa. Link with aplastic anemia and bone marrow failureb. Complement mediated damage to three cell lines

● Alcoholisma. Hypersplenism and Vitamin deficiencyb. Direct megakaryocyte toxicityc. Decreased TPO production

Bone Marrow● Myelodysplastic Syndromes

a. Dysplastic and ineffective blood cell productionb. Diagnosis

i. Cytopenia (not just platelets)ii. Peripheral/BM smear showing dysplasia

1. Tear drop cells2. Smudge cells3. Hypersegmented neutrophils4. Dohle bodies5. Giant platelets

a. Treatmenta. Mainly bone marrow transplantation

Bone Marrow● Infection

a. Virali. HIV

1. ITP-like syndrome or direct megakaryocyte toxicity2. Direct megakaryocyte toxicity

ii. Hepatitis C, MMR vaccine and EBV

b. Bacterial + Parasitesi. BM suppression or DIC in sepsisii. 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)

● Pathophysiologyo Platelet Destruction

Medication induced change in antigen creating an autoantibodyo Platelet Production

Megakaryocyte death or decreased production

● Diagnosiso Initiation in about one week of drug starto Usually beta lactams, vancomycin, linezolid, rifampin, AEDs and Quinine

● Treatmento Removal of the drugo 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 FarWe will discuss• Immune Thrombocytopenia• Drug-Induced Thrombocytopenia• Evan’s Syndrome

• Heparin Induced Thrombocytopenia• TTP-HUS• DIC

Heparin Induced Thrombocytopenia

● Type 1o Direct heparin effect, associated with platelet aggregationo Transient drop in 1-2 days, usually not < 100o No need to stop Heparin

● Type 2o PF-4 complexed with Heparin causing autoantibodies

● Heparin-Induced Antibodieso Autoantibodies without HIT clinical features

Heparin Induced Thrombocytopenia

● Pathogenesiso 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 adultso HIV (unknown mechanism)o Strep Pneumo

● Drug-Inducedo Quinine (Ab formation)o Chemotherapy (endothelial injury, maybe to CD36 receptor)

TTP-HUS Diagnosis● Required

o MAHA with Thrombocytopenia

● Good To Haveo Rest of the Pentad (AKI, Neuro change, Fever)o Coombs and DIC Screen negativeo Coagulation tests normalo Hemolysis labs positive

● Idiopathico Reduced ADAMTS13 Activity (<10%)

TTP-HUS Treatment● Urgent Plasmapheresis

● Steroidso If not responding to PEXo Generally, recurs when PEX stoppedo Do not use if due to chemotherapy or Shiga-toxin

● Consult Hematology + Nephrologyo 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

● Diagnosiso Clinical Findings (bleeding/thrombosis) + Labs

Low PT/PTT, Fibrinogen, and platelets High D-Dimer

● Treatmento Plt transfusion if < 10 or < 50 and bleedingo FFP if PT, PTT increased and Fibrinogen normalo 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 #1A 27 year old woman is evaluated in the clinic for right upper quadrant pain. She isgravid at 27 weeks gestation. On physical examination, temperature is normal, bloodpressure is 167/91mm Hg, pulse rate is 92/min and respiration rate is 21/min. Scleralicterus is noted. Abdominal examination discloses right upper quadrant tenderness,without rebound or guarding. There is peripheral edema.

LABSHemoglobin 8.9 g/dLPlatelets 45,000/uLWBC 8700/uLAST and ALT ElevatedUA = 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 HELLPsyndrome of hemolysis, elevated liver enzymes, and low platelet count with associatedright upper quadrant pain. The peripheral blood smear would demonstrateschistocytes. Bite cells are commonly seen in G6PD deficiency, and rouleaux are foundin multiple myeloma.

Question #2A 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 afterconsuming 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 examis otherwise non focal. Skin appears jaundiced, and there is mucocutaneousecchymoses. Abdominal examination discloses hyperactive bowel sounds, withouttenderness or distension.

Question #2

LABSHemoglobin 7.9 g/dL

Platelet count 32,000/uLLeukocyte count 9800/uL

Lactate dehydrogenase ElevatedSerum 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: DiscussionANSWER: D

Objective: Identify thrombotic thrombocytopenic purpura (TTP) and hemolytic uremicsyndrome (HUS) andtimely treatment with plasma exchange.

TTP presents as fever, microangiopathic hemolytic anemia, thrombocytopenia, withrenal manifestations (elevated creatinine, hematuria, proteinuria) and neurologicalchanges (such as confusion or headache). It can overlap with HUS, which is oftentriggered by a hemorrhagic diarrheal illness within the preceding 3 weeks with E. coliO157:H7 or Shiga toxin. Pathogenesis of TTP is the formation of autoantibodies againstADAMTS13, the protease that cleaves multimers of Von Willebrand factor (vWF); thisresults in decreased protease activity due to increased inhibitor titer levels andabnormal platelet and endothelial cell activation leading to peripheral destruction ofplatelets and erythrocytes.

Question #2: Discussion

ADAMST13 level is used for prognostication rather than to guide therapy. Stool cultures, whileimportant for public health, are less imperative than plasma exchange which should be initiatedimmediately. There is high mortality, up to 10%, within the first 24 hours and treatment should bestarted if TTP-HUS is suspected prior to lab confirmation. Sepsis with disseminated intravascularcoagulation 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 thetreatment for immune thrombocytopenic purpura (ITP) refractory to steroids.

Question #3A 45 year old female presents to the emergency room with acute onset pleuritic chest pain after atransatlantic flight. On physical examination, she is afebrile, blood pressure is 135/82 mm Hg, pulse rateis 121/min, and respiratory rate is 21/min. She appears in mild distress. Cardiac examination revealstachycardia rate and regular rhythm, and lungs are clear to auscultation. Her left lower extremity isedematous and tender to palpation.

Lower extremity venous ultrasound is positive for left popliteal deep venous thrombosis, and she isStarted on unfractionated IV heparin. Five days later, she notices skin changes on her arm with black-redcenters 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: DiscussionANSWER: B

Objective: Recognize and treat heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) occurs when an autoantibody develops against endogenousplatelet factor 4 (PF4) in complex with heparin. It occurs with higher frequency in response tounfractionated heparin compared to low molecular weight heparin such as enoxaparin. Clinical suspicionis elevated in those with high 4T scores which are useful for predicting pretest probability for HIT. Theelements 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 testingfor the autoantibody against the heparin-PF4 complex, or 14C serotonin release assay which has higherspecificity. Therapy is heparin cessation and treatment with a non-heparin alternative anticoagulant (suchas 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 themanagement of infectious necrotizing fasciitis, not HIT.

Question #4A 64 year old male with presents to urgent care with recurrent epistaxis of 20 minutes' duration for 3days. He had a shingle outbreak three weeks ago which has resolved, and denies any other site ofbleeding. On physical examination, there is dried blood in bilateral nares and faint petechiae over theanterior torso.

LABSHemoglobin 12g/dLLeukocyte count 4000/uLPlatelet 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: DiscussionANSWER: 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 patientswho do not respond to standard therapies given concern for future susceptibility to encapsulatedorganisms.

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 resolvingbetween 7- 14 days after drug discontinuation. Common culprits include cephalosporins, sulfa drugs,Bactrim, vancomycin, carbamazepine, and quinidine/quinine. Treatment of choice for drug-inducedthrombocytopenia is discontinuation of the drug.

Question #5A 43 year old female with history of Roux-en-Y gastric bypass surgery presents in clinic for evaluation ofpancytopenia. She reports months of generalized fatigue and occasional paresthesias in the lowerextremities. On physical examination, she is afebrile, blood pressure is 142/78 mm Hg, pulse rate is76/min, and respiratory rate is 16/min. Skin examination reveals no jaundice, petechiae, or ecchymoses.There is no hepatosplenomegaly.

LABSHemoglobin 10.2 g/dLHematocrit 30.6 g/dLLeukocyte count 3300/uLPlatelet count 88,000/uLA peripheral blood smear was obtained.

Question #5

Which of the following is the most likely finding?

(A) Megaloblastic changes(B) Large platelets(C) Basophilic stippling(D) Auer rods

Question #5: DiscussionANSWER: A

Objective: Recognize pancytopenia secondary to vitamin B12 and folate deficiency.

Complications of Roux-en-Y gastric bypass include metabolic and nutritional derangements, particularlyiron, calcium, vitamin B12, thiamine and folate deficiency from decreased absorption. Vitamin B12 andfolate deficiency leads to bone marrow hypoproliferation and megaloblastic granulocytes on peripheralblood smear. Large platelets and increased megakaryocytes typically appear during a heightenedmarrow response secondary to a destructive process. Basophilic stippling from ribosomal precipitates isseen in thalassemia, alcohol abuse, and lead or heavy metal poisoning. Auer rods are characteristic ofacute myelogenous leukemia.

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