Thrombocytopenia Sheryl L. Ziegler, D.O. 2016

Hemostasis Subendothelial matrix Platelets Hemostatic plug Fibrin Endothelial cell RBC WBC WBC

Platelets Normal Hemostasis requires adequate # functioning platelets Increased chances of bleeding as platelet count falls Normal individual -- 10,000 platelets Surgery -- often >50,000 needed

Thrombocytopenia & Bleeding Testing platelet disorders – function and count

Bleeding Time Test

Thrombocytopenia Clinical Features No specific or unique features MUCOCUTANEOUS BLEEDING Bleeding form multiple sites Mucous membranes, nose GI tract Skin Vessel puncture sites Petechial rash of skin or mucous membranes

Normal Platelet Kinetics # =150, ,000 Life span 9-10 days 35,000 new platelets produced each day Megakaryocyte

Thrombocytopenia Clinical Features - Lab Most often diagnosis is made by lab Modern counters are very accurate Platelet agglutination may give falsely low value secondary to: Clotting/platelet agglutination Pseudothrombocytopenia Examine the smear

Causes

Thrombocytopenia Several Disease Mechanisms Thrombocytopenia Decreased Production Increased pooling in spleen Increased Destruction

Thrombocytopenia Several Disease Mechanisms Thrombocytopenia Decreased Production Increased pooling in spleen Increased Destruction

Decreased production Marrow damage Aplasia Drugs/Toxins Malignancy Hepatitis Ineffective production Decreased vitamin B12 Decreased folate Congential Fanconi’s anemia

Aplastic Anemia Marrow Damage Decrease in all cell lines Bone Marrow – “Empty Marrow”

Symptoms – Aplastic anemia Related to anemia Fatigue, Shortness of breath Related to low white cell count Infections Related to thrombocytopenia Bleeding (mucous membranes) High mortality of “untreated” severe Aplastic anemia 80% at 1 year

Epidemiology 2 individuals per million More prevalent in the Orient Bimodal age distribution Majority in younger age

Causes Idiopathic

Supportive treatment Support Blood product transfusion & antibiotics 1/3 refractory to platelets Bleeding deaths uncommon Antibiotics Aspergillus is a major cause of death

Treatment Bone marrow transplantation – Younger Immunosuppression – Older Antithymocyte globulin (ATG) + Cyclosporine 70% response rate long term survivals 65-90% no difference in long-term survival

Drugs/Toxins Marrow Damage Alcohol Reversible

Infiltrative processes Marrow Damage Malignancies Multiple myeloma Acute leukemia Lymphoma Myelofibrosis Metastatic carcinoma Often all cell lines are affected. Can see tear drop cells.

Ineffective production Decreased Vitamin B12 Decreased folic acid Check levels Takes about 3 months to deplete folate Takes about 2-3 years to deplete B12 Patients with also have macrocytic anemia

B-12/Folate Deficiency Ineffective Production Alcoholics “Tea and Toast” elderly patients Homeless Pernicious anemia Gastric surgery (poor absorption) Platelet production is rapidly reversed with appropriate vitamin Rx

Fanconi anemia Short stature Skeletal anomalies Increased incidence of cancer Bone marrow failure Cellular sensitivity to DNA damaging agents

Defective Production - Therapy Reverse production abnormality Treat the underlying cause Leukemia -- effective Rx B-12 or Folate Deficiency Irreversible marrow damage chronic transfusions may be needed

Platelet Transfusions Random donor platelets Most common order Each 6 pack should raise the platelet count by 50,000 Contain very few RBCs & do not need to be ABO compatible Infectious risks Fevers, chills, hypotension reactions

Thrombocytopenia Several Disease Mechanisms Thrombocytopenia Decreased Production Increased pooling in spleen Increased Destruction

Pooling in Spleen Spleen Functions like a large sponge Liver Disease Myeloproliferative Myelofibrosis

Disorders of Distribution Normally 1/3 of platelets stored in spleen Increased spleen = increased trapping Splenomegaly should not cause < 50,000 if lower --- concomitant defect Most common – advanced liver disease

Myelofibrosis Disorders of Distribution Myeloproliferative disorder Marrow replaced by connective tissue Extramedullary hematopoiesis occurs in the spleen

Thrombocytopenia Several Disease Mechanisms Thrombocytopenia Decreased Production Increased pooling in spleen Increased Destruction

Increased destruction Nonimmune DIC TTP/HUS HELLP Immune Drugs ITP Autoimmune

Disseminated Intravascular Coagulation (DIC) Non-immune Destruction Disorders SICK PATIENTS – Septic, shock, placental abruption, major trauma, etc. Entire coagulation pathway is activated Both pro-coagulant and anti-coagulant

DIC Severe thrombocytopenia Patients can bleed and clot Marked prolongation of the coagulation factors (PTT/PT) Elevated D-Dimer Microangiopathic anemia Treat underlying cause

Thrombotic Thrombocytopenic Purpura (TTP) Five Clinical Features Thrombocytopenia Red Cell Fragments Fever Renal Failure Neurologic Features

TTP High mortality > 90% without treatment Usually affects young women Platelet thrombus formation No increased PT/PTT Arterial platelet thrombi “white clots”

VWF, ADAMTS13 and Platelet Adhesion With ADAMTS13 Normal VWF Multimers Normal Hemostasis Ultralarge VWF Multimers Microvascular Thrombosis (TTP) Without ADAMTS13 VWF Cleaving Protease (ADAMTS13)

Idiopathic TTP – Initial Therapy Initiate treatment: Plasma exchange Plasma infusion Prednisone Avoid: Platelet transfusions

HELLP syndrome Non-immune Destruction Occurs in pregnancy RBC hemolysis (H) Elevated liver enzymes (EL) Low platelet count (LP) Elevated blood pressure TX - Control of patient's HTN & deliver baby

Thrombocytopenia Autoimmune Drug induced Infectious diseases Idiopathic (ITP)

Autoimmune Thrombocytopenia Clinical Platelet count can be as low a 1,000 Increased # of megakaryocytes Compensates for shortened platelet survival Increased MPV (larger immature platelets)

Heparin-Induced Thrombocytopenia Non-immune related Very common Mild decrease in platelet number Usually clinical insignificant Immune related Must diagnosis !!! Marked decrease in platelets Less than 50K Greater than 50% decline from baseline

Incidence of HIT HIT occurs in up to 5% of patients receiving unfractionated heparin (UFH) Up to 1% incidence with low molecular weight heparin (LMWH) Immune-mediated allergic reaction to heparin/platelet factor 4 complex Gruel et al. Br J Haematol. 2003;121; ; Warkentin. J Crit Illness. 2005:20(1):6-13.

Distribution of Platelet Count in HIT Warkentin. Semin Hematol. 1998;35(suppl 5):9-16. Number of patients with HIT Platelet count nadir  10 9 /L No HIT-associated thrombosis HIT-associated thrombosis Median platelet count nadir=59  10 9 /L n=142

Temporal Patterns of Thrombocytopenia in HIT Day 1Day 5Day 14 Day 30 Delayed- Onset HIT (9-40+ days) Rapid-onset HIT (hours-days) Typical-Onset HIT Mean day 9 (5-14 days) Heparin (re) Exposure THROMBOCYTOPENIA (± THROMBOSIS)

Skin Necrosis and Gangrene

Clinical events associated with HIT Venous thrombosis (30-70%) Deep vein thrombosis (DVT) Pulmonary embolism (PE) Adrenal necrosis (adrenal vein thrombosis) Cerebral venous (sinus) thrombosis Venous limb gangrene (VKA associated) Arterial thrombosis (“white clots”) (15-30%) Limb artery thrombosis Stroke Myocardial infarction Skin lesions at heparin injection sites (10%) Skin necrosis Erythematous plaques Acute reactions after i.v. heparin bolus (10%) Disseminated intravascular coagulation (DIC) (10%) MORTALITY = 20-30%

Heparin-induced Thrombocytopenia (HIT) Immune Destruction Stop all heparin Order Heparin Induced Antibody Tx – Direct thrombin inhibitors Lepirudin Argatroban

Idiopathic Thrombocytopenia Purpura (ITP) Unrelated to: Drug Infection Autoimmune Disease Diagnosis Made by excluding all other causes of nonimmune & immune destruction

Idiopathic Thrombocytopenic Purpura Laboratory Platelets demonstrate better than normal function Count = 1,000 to 100,000 Normal to increase # of Megakaryocytes Increased ploidy in the marrow

Idiopathic Thrombocytopenic Purpura Presentation Abnormal Bleeding Petechial & purpuric lesions of skin & mucous membranes are most typical Bruising Recurrent epistaxis Menorrhagia Thrombocytopenia must become severe before bleeding becomes a problem

Recommended platelet counts to avoid bleeding

Idiopathic Thrombocytopenic Purpura Infusion of plasma from ITP patients into normal patients causes thromboctyopenia

Laboratory Tests Platelet Antibodies Determines the presence of IgG, IgM &/or complement on platelet surface Strong Ab test suggests an autoimmune destruction like ITP Not very good sensitivity or specificity Can be positive with  Liver disease  Sepsis  Malignancies

Idiopathic Thrombocytopenic Purpura Therapy & Clinical Course Platelet transfusions Most patients destroy most of the product Platelet transfusion if life threatening hemorrhage or intracranial hemorrhage

ITP – Therapy No treatment – if platelets > 30K Steroids IVIgG WinRho Rituximab Splenectomy Promacta Nplate

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