January 2018 Jason aboudi mouabbi MD

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Presentation transcript:

January 2018 Jason aboudi mouabbi MD Thrombocytopenia January 2018 Jason aboudi mouabbi MD

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

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

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

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

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

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

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

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

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

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.

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

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

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 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

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

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.

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, 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)

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

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

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

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

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

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.

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

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

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

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

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