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Thrombocytopenia Rahul Bhagat PGY1 01/24/12.

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Presentation on theme: "Thrombocytopenia Rahul Bhagat PGY1 01/24/12."— Presentation transcript:

1 Thrombocytopenia Rahul Bhagat PGY1 01/24/12

2 Practical Importance of Assessing Thrombocytopenia
1/3 of all hematology consults are for thrombocytopenia 5 to 10% of all hospital patients are thrombocytopenic in the ICU the number increases to 35% Thrombocytopenic patients in the hospital suffer a twofold greater mortality rate than those who are not

3 Thrombocytopeina Definition: platelets < 150,000
Normal platelets 150, ,000 2.5% of the normal population will have platelet count lower than “normal” which is NOT abnormal Platelets live for 8-10 days Younger platelets are larger and work better

4 Platelets can be seen as individual structures forming on the periphery of this megakaryocyte
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5 Clusters or chains of platelets are shed from the megakaryocyte and carried off into the bloodstream
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6 Stratifying levels of thrombocytopenia
The primary reason for evaluating thrombocytopenia is to assess the risk of bleeding and assess the presence of underlying disorders (TTP, HIT etc.) < 20 K increased risk of bleeding 20K to 50 K rarely have increase risk of spontaneous bleeding but increase risk of bleeding from procedures 50K to 100K no increased risk of spontaneous bleeding and can undergo most procedures

7 Relation of bleeding risk and platelet count
Bleeding time increases in a linear fashion below a platelet count of 100 K Tagged RBC -> fecal blood loss 10 K 5 cc/day 5 to 10 K 10 cc/day < 5 K 50 cc/day

8 Organization of Thrombocytopenia
Decrease Production Marrow Damage Aplasia Drugs Malignancy Congenital Defects Ineffective Production B12, Folic Acid Def Increase Destruction Non Immune DIC TTP HELLP Immune ITP HIT SLE, AIDS

9 Causes of Thrombocytopenia: Decreased Production
Marrow suppression (usually pancytopenic): Post viral: parvo, Hep B/C, EBV, varicella, measles, mumps, rubella, MMR vaccine, CMV, toxo, mono, influenza Sepsis Aplastic anemia Direct megakaryocyte damage: HIV Direct toxicity to bone marrow: XRT, chemo, alcohol Marrow infiltration: lymphoma, Myelofibrosis, mets, TB Meds with toxic effect: (non immune mediated) Thiazides, estrogens, septra, chemo, cimetidine, famotidine

10 Decreased Production (Continued)
Malignancies: Myelodysplasia syndrome (age >60…usually anemic/leukopenic), leukemia, myeloma B12 or Folate deficiency (rare) Congenital (Wiskott-Aldrich, Fanconi syndrome, Bernard-Soulier) PNH

11 Reasons to Suspect a Congenital Platelet Disorder
Persistence of neonatal thrombocytopenia or onset of bleeding symptoms in childhood Family history of thrombocytopenia or mucocutaneous bleeding Platelet count unresponsive to typical treatments for ITP

12 A VERY common cause of “thrombocytopenia”

13 Work up First rule out pseudothrombocytopenia
(EDTA agglutinin autoantibody mediated Platelet clumping seen in 0.1%-0.2% of all blood draws) *Examine the smear *Repeat with heparinized/citrated tube *Repeat with fingerstick directly applied to slide *Note: pseudothrombocytopenia often accompanied by falsely high WBC (machine counts platlet clumps as WBCs)

14 Work up Physical History Examine spleen
Meds, meds meds Alcohol Nutrition Travel HIV risk factors ? Occult malignancy Bleeding history (gums, menses, surgical complications). Family History Physical Examine spleen Detailed skin exam, looking for Petechiae: Red pinheads Purpura: Purple confluent petechaie ecchymoses Look for lymphadenopathy

15 Petechiae are due to the presence of red cells which have extravasated from capillaries; they are nontender and do not blanch under pressure. They are asymptomatic and not palpable

16 Purpura is a purplish discoloration of the skin due to the presence of confluent petechiae

17 Work up (Continued) Peripheral smear
large platelets (hign MPV on CBC) imply increased destructionearly release from marrow (ITP) Normal/small platelets suggest reduced BM response Schistocytes (fragmented RBCs): MAHA Can reveal blasts Treardrop RBC, nucleated RBCs can suggest marrow invasion (tumor/fibrosis/granuloma) Marcrocytosis with hypersegmented polys can suggest Vitamin B/folate deficiency

18 Work up (Continued) PT/PTT (high in MAHA/DIC…liver disease)
LDH (hemolysis/MAHA) Bun/Creatinine (HUS/TTP) Consider HIV, ANA if clinical suspicion Consider toxo, EBV, CMV serologies if lymphadenopathy, splenomegaly, or “B” symptoms Consider HIV(initial disease manifestation in 10%) Consider ANA if clinical suspicion

19 Work up (continued) Bone marrow biopsy?
More definitively answers the “production vs. destruction” question Generally indicated in unexplained thromocytopenia if platelet count low enough (5-10K) to be at risk for major bleeding… *UNLESS age < 60, thrombocytopenia is isolated, and history/PE, and smear suggest the diagnosis (of exclusion) of ITP. *If age > 60, and suspect likely ITP, BM biopsy generally indicated to r/o myleodysplasia

20 Immune Mediated Thrombocytopenia Purpura
ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia ITP is a high prevalence disease 16 to 27 per million per year Incidence increases with age Female predominance under the age of 60 It can have an abrupt onset or insidious onset. It is generally abrupt in onset with children

21 Pathogenesis of ITP Increased platelet destruction caused by antiplatelet antibodies Lack of compensatory response by megakaryocytes due to suppressive effect of antiplatelet antibodies Pathogenesis was proved by Harrington when he infused himself with plasma from a women with ITP The experiment was undertaken in 1950 by William J. Harrington and James W. Hollingsworth, who postulated that in patients with idiopathic thrombocytopenic purpura (ITP), it was a blood factor that caused the destruction of platelets.[2] To test this hypothesis, Harrington received 500 ml of blood from a patient with ITP.[2] Within three hours, his platelets dropped to dangerously low levels and he experienced a seizure.[2] His platelet count remained extremely low for four days, finally returning to normal levels by the fifth day.[2] Bone marrow biopsy from Harrington's sternum demonstrated normal megakaryocytes, the cells necessary for platelet production.[2]

22 Evaluation of ITP Features consistent with the diagnosis of ITP
Thrombocytopenia with normal or slightly large platelets Normal RBC morphology and number (may have associated iron def or thallasemia etc.) Normal white cell number and morphology Splenomegaly rare Features not consistent with the diagnosis of ITP Giant platelets RBC abnormalities ie schisotocytes Leukocytosis or Leukopenia

23 Laboratory evaluation of ITP
Not Much Bone Marrow not very helpful as initial test May be helpful in patient over 50 years and concerned about MDS If patient has failed initial treatment and diagnosis is in question TSH and HIV test helpful, Peripheral Smear helpful

24 Management of ITP Most patients with ITP do not have clinically significant bleeding Risk of intracranial bleed 0.1 to 1% (This is an overestimate) Wet Purpura ie epistaxis, gingival bleeding is a risk factor for major bleeding In asymptomatic patients with platelets counts greater then 20 K observation is reasonable

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26 Treatment of ITP If platelets > 20,000 and no bleeding…generally observe Steroids, benefit approx 2/3 of patients…but takes 3 weeks IVIG works more quickly (several days, and lasts several weeks)…used generally in actively bleeding patients while waiting for steroids to work Immunosupressive agents/splenectomy

27 Acute Pharmacologic Management of ITP
Steroids Prednisone 1mg/kg/day with taper over 2 to 3 months Decadron 40 mg/day x 4 days Solumedrol 1 gram/day x 2 days Antibodies IVIG 1 gram/day x 2 days Anti-D 50 mcg/kg IV x1

28 Chronic Management of ITP
Splenectomy Immunize with Pneumovax, Hib, Meningococcal Chronic Anti-D therapy Does not put the disease in remission Rituximab Eltrombopag FDA approved 2008 Agonist of TpoR receptor (target of thrombopoietin) Observation  agonist of the c-mpl(TpoR) receptor, which is the physiological target of the hormone thrombopoietin

29 TTP Thrombotic Thrombocytopenia Purpura
TTP is characterized by microangiopathic hemolytic anemia and profound intravascular platelet clumping The disease was first reported in 1923 at Beth Israel in NYC 16 year old girl who presented with anemia, petechiae, coma and death Terminal arterioles and capillaries were occluded by hyaline thrombi mostly composed of platelets

30 Figure 2. Peripheral smear showing RBC fragmentation consistent with a microangiopathic hemolytic process 30

31 Clinical and Lab Manifestations of TTP
Severe thrombocytopenia and hemolytic anemia with one or several fragmented red cells Neurologic manifestations, abdominal pain Fever and renal abnormalities occur in the minority of patients Thrombocytopenia range from <30 K to 100 K Elevated LDH Initially coagulation studies are normal

32 Proposed Relation among the Absence of ADAMTS 13 Activity in Vivo, Excessive Adhesion and Aggregation of Platelets, and Thrombotic Thrombocytopenic Purpura Figure 2. Proposed Relation among the Absence of ADAMTS 13 Activity in Vivo, Excessive Adhesion and Aggregation of Platelets, and Thrombotic Thrombocytopenic Purpura. In Panel A, in normal subjects, ADAMTS 13 (von Willebrand factor-cleaving metalloprotease) molecules attach to binding sites on endothelial-cell surfaces and cleave unusually large multimers of von Willebrand factor as they are secreted by stimulated endothelial cells. The smaller von Willebrand factor forms that circulate after cleavage do not induce the adhesion and aggregation of platelets during normal blood flow. ADAMTS 13 may use one of its thrombospondin-1-like domains or its arginine-glycine-aspartate (RGD) sequence to attach to the surface of endothelial cells. In Panel B, absent or severely reduced activity of ADAMTS 13 in patients with thrombotic thrombocytopenic purpura prevents timely cleavage of unusually large multimers of von Willebrand factor as they are secreted by endothelial cells. The uncleaved multimers induce the adhesion and aggregation of platelets in flowing blood. A congenital deficiency of ADAMTS 13 activity, or an acquired defect of ADAMTS 13 (such as that caused by autoantibodies or by a change in the production or survival of the protein) can lead to thrombotic thrombocytopenic purpura. Interference with the attachment of ADAMTS 13 to endothelial cells in vivo (for example, as a result of ADAMTS 13-receptor blockade by other types of autoantibodies) may also cause thrombotic thrombocytopenic purpura in patients with normal ADAMTS 13 activity in plasma. 32

33 Treatment of TTP Infusion of FFP 30 cc/kg/day until ready for plasma exchange Daily plasma exchange with FFP Steroids (Prednisone 1 mg/kg/day) Red Blood Cells if needed Platelets only if absolutely necessary

34 Increased Destruction: MEDICATIONS
Mechanism of medthrombocytopenia is accelerated platelet destruction via drug dependent antibody Don’t forget about OTC meds, remedies ASA, NSAIDS Quinine (tonic water) Many, many meds can cause thrombocytopenia…and list constantly growing Median recovery after d/c of med is 5-7 days If plts <10,000 or bleeding…transfuse (class 1B rec)

35 Medications The Main Offenders
Heparin** Amiodarone Valproic acid/Carbamazepine Amphotericin B Gold salts Vancomycin Quinine/quinidine Cimetidine Bactrim/sulfonamides Phenytoin Penicillin/Beta lactams Clopidogril Interferon Digoxin GP 2b/3a inhibitors (abciximab) Fluconazole Linezolid Ranititidine

36 Heparin Induced Thrombocytopenia
Described in 1958 by Rodger Weismann and Richard Tobin after extracting platelet fibrin thrombi that formed after 1 to 2 week course of heparin HIT is the presence of a multimolecular complex between platelet factor 4, and heparin HIT is associated with thrombosis despite profound thrombocytopenia development of HIT antibodies suggests heparin sulfate is sometimes treated as a foreign "non-self" substance by the immune system. In HIT, the immune system forms antibodies against heparin when it is bound to a protein called platelet factor 4 (PF4 The IgG antibodies form a complex with heparin and PF4 in the bloodstream

37 THROMBOCYTOPENIA: Heparin/PF4 complexes undergo aggregation and are removed prematurely from the circulation THROMBOSIS: HIT antibodies of IgG bind to complexes of platelet factor 4 (PF4) and heparin on platelet surfaces, resulting in platelet activation/generation of microparticles which enhanced coagulation reactions and production of thrombin.

38 HIT Incidence: 0.2-5% of patients exposed to Heparin
Factors predisposing one to HIT: Longer duration of Heparin Use of UFH (rather than LMWH/lovenox) Surgical patient > medical patient Female > male

39 Clinical Features of HIT
Timing Onset between days 5 and 10 after heparin initiation Rapid onset if previously exposed to heparin Thrombocytopenia nadir between 15K to 150K >50% develop a new thrombosis both venous and arterial Absence of petechiae

40 Diagnosis of HIT Clinical Suspicion (greater then 50% drop in platelets in the setting of heparin use) Laboratory Studies Platelet Activation Studies (Complicated and physiologic) PF4/Polyanion Studies (Less time consuming but not necessarily physiologic) Even without evidence of thrombosis patient should get lower extremity dopplers

41 Treatment of HIT Removal of all Heparin products
Begin direct thrombin inhibitor (DTI) (Argatroban or Refludan) Treat with DTI until platelet count normalizes then may begin anticoaguation with coumadin Fondaparinux (Arixtra) is a reasonable agent to use for DVT prophylaxis in patient with history of HIT

42 What platelet level is “safe” ??
Plts > 50K: surgery safe (except neurosurg) Plts 30-50K: risk of major bleeding low. Rarely have purpura. Plts 10-30K: risk of mild-moderate bleeding (especially with more extensive trauma). Plts <10K: high risk for spontaneous hemorrhage (esp if <5K). These patients have spontaneous bruising, and maybe petechiae… Avoid IM injections, rectal exams, enemas

43 When NOT to transfuse platelets
Transfusions may induce immune resistance Generally transfusions not given in conditions of platelet destruction: HUS/TTP APLA unless severe HIT CNS bleed or DIC urgent invasive Severe ITP procedure required

44 When TO transfuse platelets
If platelets < 10,000 (risk of spont. Bleeding) If <20,000 and active bleeding If <40-50,000 prior to an invasive procedure Surgery -Childbirth Central line -Tooth extraction Thoracentesis If <100,000 prior to neurosurgery/epidural anesthesia 1 “unit” of platelets (“phoresed unit”) raises platelet count by about 20,000

45 Conclusion Think about thrombocytopenia in terms of etiology (destruction, decreased production, and “other”) History (especially MEDS) essential Always rule out psuedo-thrombocytopenia Peripheral smear tells you a lot Think before you transfuse

46 Practical Aspects for the management of thrombocytopenia
What is an adequate platelet count for procedures? Routine Dentistry >10K Dental Extraction >30K Regional Dental Block >30K Minor Surgery >50K Major Surgery>80K Epidural is okay at platelet count 50K for patient with ITP The target platelet count for a bleeding patient is generally >40K Prophylactic platelet transfusions for platelets < 10K

47 Chief Complaint Patient is a 85 year old Caucasian female who presented to the ER with a chief complaint of generalized weakness x 3 months and 3 episodes of spontaneous epistaxis ddfasdf

48 History of Present Illness
85F totally independent in ADLs presented with 3 weeks of generalized fatigue, dizziness, lightheadedness She reports having a spontaneous nosebleed the night prior to admission, bleeding for 4 hours, quantified 1 cup bright red blood Patient c/o exertional dyspnea, needing 5-10 minutes of rest after feet of walking. She reports diffuse bruising over her upper and lower extremities for 3 months She has been constantly tired, sleeping more. Denies fever, chills, chest pain

49 Medications NKDA Meclizine 25 QID since 11/11 Torsemide 25 OD
Synthroid 88mcg OD Vytorin 10/20mg QHS Lorazepam 0.5mg BID Cymbalta 60mg OD Lisinopril 5mg OD

50 Social History No history of tobacco or alcohol use
Patient independent in ADLs, lives alone, drives Father had leukemia at age 52

51 Physical Exam VS: BP 112/43, Pulse 89, RR 18, T 98.0, SpO2 94% on RA, 0/10 pain Gen: Patient seen resting in bed in NAD Skin: diffuse >3cm ecchymosis over UE, >100 petechiae diffusely HEENT: NCAT, PERRLA. No conjuctival pallor. No oropharyngeal exudates. Petechiae visualized over soft palate. Neck: No jugular venous distention, LAD, bruits Chest: CTA B/L CV: S1, S2 present,RRR. 2/6 systolic ejection murmur left parasternal border. PMI nondisplaced. Pulses 2+ bilaterally. No peripheral edema. Abdomen: Soft, tender to epigastrium, obese. No rebound tenderness. Bowel sounds present. No shifting dullness Ext: No clubbing, cyanosis, or erythema. No calf tenderness, palpable nodules, or cords Neuro: A&Ox3. Cranial nerves intact. Sensation intact. No focal deficits. Decreased auditory acuity. Increasing forgetfulness

52 Labs 9.1 83 26.7 RDW 17.1 MCV 100.8 Anisocytosis Polychromasia Macrocytosis Mg 2.8 Phos 2.6 AST: 29 ALT: 20 Alk Phos: 36 T. Bili: 0.9

53 No acute intracranial process
Moderate global cerebral atrophy

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56 CT Abdomen Hepatomegaly with abnormal contour raises the possibility of underlying cirrhosis or hepatocellular disease. Excess vascularity in the left adrenal region may be due to underlying portal hypertension with variceal shunting. Suspect chronic partial small bowel obstruction.

57 The patient vomited 1 episode coffee-ground emesis in ER, hemoccult grossly positive
She was started on PRBC, platelet transfusion, transferred to ICU She was stepped down the following day and had no additional episodes of vomiting

58 Assessment/Plan Profound symptomatic thrombocytopenia
Secondary to ITP vs TTP vs MDS vs leukemia Transfuse blood products as needed Consult hematology Acute blood loss anemia EGD, GI consult Zofran, Protonix

59 Followup Patient underwent bone marrow biopsy on 1/16
Histologic analysis demonstrated megaloblastic erythropoesis, ringed sideroblasts, hyposegmented granulocytes, moderate cellularity, without excess blasts Flow cytometry pending

60 Treatment Patient received 5 doses of IVIG and prednisone with no improvement Platelet count continued to remain ~2000 She was started on a 5 day cycle of Vidaza for MDS on 1/19

61 The patient remained profoundly symptomatic, refractory to blood product transfusion, and was stepped back up to the ICU for active acute blood loss


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