Download Thrombocytopenia

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 ( 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.

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