Thrombocytopenia Notes

NOTES NOTES THROMBOCYTOPENIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Acquired/inherited disorders: impaired platelet function, decreased platelet count, sequelae ▪ Accelerated destruction/consumption → decreased platelets SIGNS & SYMPTOMS ▪ Mucocutaneous bleeding (e.g. epistaxis, gingival bleeding, petechiae, purpura) DIAGNOSIS LAB RESULTS ▪ Complete blood count (CBC) ▪ Peripheral blood smear analysis ▪ Platelet function tests TREATMENT OTHER INTERVENTIONS ▪ Mitigate complications of deranged platelet function HEPARIN-INDUCED THROMBOCYTOPENIA (HIT) osms.it/heparin-induced-thrombocytopenia PATHOLOGY & CAUSES ▪ Acquired platelet disorder ▫ Accelerated thrombosis in arteries, veins → consumptive thrombocytopenia. ▫ Occurs in individuals exposed to unfractionated heparin/low molecular weight heparin (LMWH) ▫ AKA heparin-induced thrombocytopenia thrombosis (HITT) ▪ Exposure to heparin/LMWH → IgG autoantibodies formed against heparin → platelet factor 4 (PF4) binds to heparin → antibody-heparin-PF4 complex → increased platelet activation → thrombosis formation in arteries, veins ▪ Increased consumption of platelets for clotting + removal of antibody-heparinPF4 complexes by macrophages of reticuloendothelial system → thrombocytopenia ▫ Thrombocytopenia usually not sufficient to cause significant bleeding ▪ Classified by severity, timing, degree of drop in platelet count drop, antibody mediation RISK FACTORS ▪ 5% individuals exposed to unfractionated/ LMWH ▫ Unfractionated > LMWH OSMOSIS.ORG 455

▪ Dose ▫ Prophylactic dose > therapeutic doses > intermittent heparin flushes ▪ More common in individuals who are biologically female COMPLICATIONS ▪ Venous thromboembolism (VTE) ▪ Occlusion of large lower limb arteries by platelet rich “white clots” → limb ischemia, necrosis, gangrene, loss of limbs ▪ Skin necrosis ▪ Organ infarction ▫ Kidney, myocardial infarction; cerebrovascular insult ▪ Adrenal hemorrhage ▫ Adrenal vein thrombosis ▪ Heparin-induced anaphylactoid reactions SIGNS & SYMPTOMS ▪ Skin necrosis at injection site ▪ Acute systemic reaction after IV heparin bolus ▫ Fever with chills, tachycardia, hypertension, dyspnea ▪ Limb ischemia, organ infarction 456 OSMOSIS.ORG DIAGNOSIS LAB RESULTS HIT antibody testing ▪ HIT immunoassay ▫ ELISA for anti-PF4 antibodies ▫ PF4 antibodies in individual’s serum ▫ Colorimetric change: optical density (OD), HIT antibody concentration ▫ Higher OD = higher antibody titer = HIT ▪ Functional assay ▫ Serotonin release assay (SRA) ▫ Serotonin release from platelets, ability of HIT antibodies from individual’s serum to activate test platelets ▫ Release of serotonin + therapeutic heparin concentration ▪ Heparin-induced platelet aggregation (HIPA) assay ▫ Platelet aggregation with no heparin, low/high heparin concentration ▫ Minimal platelet aggregation with no heparin, high heparin concentrations; strong aggregation with low heparin concentrations OTHER DIAGNOSTICS ▪ History of exposure to unfractionated heparin ▪ New venous/arterial thrombosis MNEMONIC: 4Ts Diagnosis of Thrombocytopenia Thrombocytopenia: CBC, fall in platelet count Timing: fall in platelet count, 5–10 days after heparin initiation Thrombosis: venous/arterial thrombosis, sequelae OTher: no other explanations

Chapter 59 Thrombocytopenia TREATMENT MEDICATIONS ▪ Immediate discontinuation of heparin ▪ Administration of non-heparin anticoagulant (e.g. fondaparinux, argatroban) ▫ Transition to warfarin/other outpatient anticoagulant after stabilization SURGERY Thromboembolectomy ▪ If severe limb ischemia, high risk for amputation IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP) osms.it/idiopathic-thrombocytopenic-purpura PATHOLOGY & CAUSES ▪ Acquired thrombocytopenia; accelerated immune platelet destruction → bleeding ▪ AKA, immune thrombocytopenic purpura, autoimmune thrombocytopenic purpura ▪ B cells produce IgG autoantibodies against platelet glycoproteins (e.g. IIb/IIIa, Ib/ IX complexes) → platelets coated with antibodies recognized as “non-self” by splenic macrophages → platelet destruction ▫ Contributing factors: impaired platelet production, cell-mediated platelet destruction malignancy, chronic lymphocytic leukemia ▫ Alter immune homeostasis ▫ Alterations in T cell-mediated cytotoxicity/suppression of megakaryocyte production, maturation Drug-induced immune thrombocytopenia (DITP) ▪ Triggered by drug-dependent platelet antibodies ▪ Quinidine, phenytoin, valproic acid, rifampin, trimethoprim-sulfamethoxazole, sulfonamides ▪ Reaction due to drug/metabolites TYPES Severe ITP ▪ Platelet counts < 10,000–20,000/microL; significant bleeding requires treatment Primary ITP ▪ Idiopathic Refractory ITP ▪ Severe ITP, fails to respond to/relapses after splenectomy ▪ Classifed by cause, duration, severity Secondary ITP ▪ Caused by systemic condition ▪ Viral infections (most common) ▫ HIV, hepatitis C, cytomegalovirus ▫ Antibodies against viral antigens cross-react with platelet antigens via molecular mimicry ▪ Bacterial lipopolysaccharides attach to platelet surfaces → increase phagocytosis of platelets ▪ Systemic lupus erythematosus, lymphoid RISK FACTORS ▪ Age; genetic/acquired factors OSMOSIS.ORG 457

COMPLICATIONS ▪ Potentially severe hemorrhage (uncommon) ▫ Intracranial bleeding, subarachnoid hemorrhage, gastrointestinal (GI) hemorrhage, hematuria, severe menorrhagia SIGNS & SYMPTOMS ▪ Bruising easily after minor trauma ▪ Mucocutaneous bleeding ▫ Petechiae, purpura, epistaxis, gingival bleeding DIAGNOSIS LAB RESULTS ▪ CBC ▫ Low platelet count ▪ Peripheral blood smear analysis ▫ Scarce platelets ▪ Flow cytometry-based assays ▫ Drug-dependent platelet antibodies OTHER DIAGNOSTICS ▪ History of drug implicated in DITP TREATMENT MEDICATIONS Raise platelet count ▪ High dose glucocorticoids (dexamethasone; prednisone) ▪ Immune globulin (IVIG) If no response to above medications ▪ Rituximab ▫ Monoclonal antibody reduces antibodydependent cytotoxicity, complementmediated lysis of platelets ▪ Thrombopoietin (TPO) receptor agonists (e.g. eltrombopag) ▫ Increases platelet production by stimulating production of megakaryocytes ▪ Immunosuppressive agents ▫ Danazol, azathioprine, cyclosporine Medications to avoid ▪ Antiplatelet agents ▫ Aspirin, other nonsteroidal antiinflammatory drugs (NSAIDs) SURGERY ▪ If no response to medication Splenectomy ▪ Reduces platelet destruction OTHER INTERVENTIONS ▪ Platelet transfusions ▫ Clinically significant bleeding Figure 59.1 Multiple petechiae present in the skin of an individual with ITP. The platelet count was < 5 x 109/L. 458 OSMOSIS.ORG

Chapter 59 Thrombocytopenia THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) osms.it/thrombotic-thrombocytopenic PATHOLOGY & CAUSES ▪ Thrombotic microangiopathy (TMA) caused by deficient activity of ADAMTS13 protease ▪ ADAMTS13 breaks von Willebrand factor (vWF) molecules into smaller multimers, prevents excessive accumulation on endothelial surfaces in microvasculature ▪ Excessive vWF on endothelial surfaces → increased propensity for platelets to attach, accumulate (esp. in high pressure areas with shearing stress) + endothelial damage → platelet-rich thrombi in microcirculation → tissue ischemia, organ dysfunction, microangiopathic hemolytic anemia (MAHA), thrombocytopenia ▪ Thrombocytopenia consumptive ▫ Increased need for platelets from cyclical clot formation, dissolution ▪ MAHA ▫ Red blood cell (RBC) mechanical fragmentation in microthrombi, damaged vessels → schistocytes ▪ Organs most affected by TTP in microcirculation ▫ Brain, heart, adrenal glands, pancreas, kidneys CAUSES ▪ ADAMTS13 deficiency ▫ Acquired inhibitory autoantibody (IgG) to ADAMTS13; inherited mutation of ADAMTS13 gene (minority) RISK FACTORS ▪ Increased prevalence in individuals who are biologically female, of African ancestry, diagnosed with systemic lupus erythematosus (SLE) ▪ Sepsis, liver disease, pancreatitis, cardiac surgery ▫ Reduce activity of ADAMTS13 ▪ Pregnancy ▫ Decrease in ADAMTS13, increase in vWF, 2nd–3rd trimesters COMPLICATIONS ▪ Organ damage ▫ Renal insufficiency, focal neurologic/ mental status anomalies, arrhythmias SIGNS & SYMPTOMS ▪ Classic TTP pentad ▫ Thrombocytopenia, MAHA, renal dysfunction, neurologic impairment (e.g. headache, confusion, seizures, coma), fever ▪ Mucocutaneous bleeding ▫ Petechiae, purpura (coalesced petechiae), epistaxis, gingival bleeding ▪ Intravascular hemolysis → dark urine ▪ Lightheadedness, abdominal pain, easy bruising, nausea/vomiting MNEMONIC: RAFT'N Common signs of Thrombotic thrombocytopenia purpura Renal problems Anemia: MAHA associated Fever Thrombocytopenia Neurologic dysfunction OSMOSIS.ORG 459

DIAGNOSIS LAB RESULTS ▪ CBC ▫ Decreased platelet count ▫ Increased reticulocyte count ▫ Decreased hemoglobin, hematocrit ▪ Peripheral blood smear analysis ▫ Schistocytes, spherocytes ▪ Hemolysis ▫ Elevated lactate dehydrogenase (LDH) ▫ Elevated indirect bilirubin ▫ Reduced haptoglobin ▪ Elevated creatinine ▫ Renal insufficiency OTHER DIAGNOSTICS ▪ ADAMTS13 assay ▫ Gel electrophoresis of VWF multimers measures degradation by ADAMTS13 ▪ ADAMTS13 inhibitor assay ▫ Autoantibody titer ▪ Genetic testing ▫ ADAMTS13 gene mutation, if hereditary TTP suspected TREATMENT MEDICATIONS ▪ Glucocorticoids ▪ Monoclonal antibody OTHER INTERVENTIONS ▪ Plasma exchange (PEX) 460 OSMOSIS.ORG