Hematopathology: Platelets, Myeloblasts, and Coagulation

• Hematologic Concepts 2 is scheduled for Winter 2025 with Jeanette Rodríguez, D.O. FM & OMT, ABFM and AOBFP, Assistant Professor of Family Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University

Student Learning Objectives

• Describe the overall organization of hematopathology and identify associated platelet and myeloblast disorders
• Define hematologic diseases characterized by leukocytosis and leucopenia
• Define hematologic diseases characterized by thrombocytosis and thrombocytopenia
• Define diseases characterized by an abnormality in coagulation
• Identify laboratory tests used to assess leukocytosis, leukopenia, thrombocytosis, thrombocytopenia, and disorders of coagulation
• Discuss the value of a bone marrow exam in the diagnosis of hematologic disorders and other diseases

Classification of Hematopathology

• Hematopathology is classified based on lineages: erythrocyte disorders, WBC disorders, plasma cell disorders, and platelet disorders

Hematopoiesis

• Hematopoiesis is the process of blood cell differentiation and lineages
• A hematopoietic stem cell differentiates into either a common myeloid progenitor or a common lymphoid progenitor
• The myeloid progenitor gives rise to: erythroid stem cells, platelet stem cells, monocyte stem cells, neutrophil stem cells, eosinophil stem cells, and basophil stem cells
• These stem cells further differentiate into erythrocytes, platelets, macrophages, neutrophils, eosinophils, and basophils, respectively
• The lymphoid progenitor gives rise to Pro-B cells and Pre-T cells
• These cells mature into various lymphocytes

Platelet Disorders

• Diagnosis is done via peripheral smear

Platelet Development

• Thrombopoiesis is the process of platelet development
• Thrombopoietin (TPO) is required for thrombopoiesis
• TPO is produced in the liver

Platelet Disorder Categories

• Platelet disorders are categorized as qualitative or quantitative
• Qualitative disorders involve impaired platelet function
• Quantitative disorders involve having too many or too few platelets

Causes of Thrombocytopenia

• Thrombocytopenia, a deficiency of platelets, can be caused by decreased production, increased destruction, dilution, or distribution issues

Differential Diagnosis Mnemonic - VINDICATE

• Vascular causes
• Infectious/inflammatory causes
• Neoplasms
• Drugs (toxins)/degenerative causes
• Iatrogenic/idiopathic causes
• Congenital/inherited/developmental causes
• Autoimmune/allergy/anatomic causes
• Trauma
• Endocrine/metabolic/environmental/ work exposure causes

Signs and Symptoms of Thrombocytopenia

• Petechiae which are non-blanching, red lesions less than 2 mm in diameter
• Easy bruising
• Epistaxis (nosebleeds)
• Menorrhagia (heavy menstrual bleeding)
• GI bleed
• GU bleed
• Jaundice

Conditions Causing Thrombocytopenia

• Immunologic causes include: autoimmune thrombocytopenic purpura (ITP) and systemic lupus erythematosus (SLE)
• Drug-associated causes include quinidine, heparin, and sulfa drugs
• Infections include HIV, CMV, and mononucleosis
• Non-immunologic causes include disseminated intravascular coagulation (DIC) and microangiopathic hemolytic anemias
• Microangiopathic hemolytic anemias include hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)

Hemolytic Uremic Syndrome (HUS)

• Etiology includes GI infections, pregnancy, malignancy, and autoimmune diseases
• Signs and symptoms include thrombocytopenia, hemolysis (jaundice, increased bilirubin), and kidney disease (increased creatinine, decreased glomerular filtration rate)
• Treatment is plasmapheresis

Thrombotic Thrombocytopenic Purpura (TTP)

• Etiology is inherited deficiencies of ADAMTS 13
• Signs and symptoms include thrombocytopenia, hemolysis (jaundice, increased bilirubin), kidney disease (increased creatinine, decreased glomerular filtration rate), altered mental status/confusion and fever
• Treatment is plasmapheresis
• TTP Pentad Mnemonic: FAT RN: Fever, Anemia (hemolysis), Thrombocytopenia, Renal failure, Neurologic symptoms

Immune Thrombocytopenic Purpura (ITP)

• Autoantibody against platelets cause thrombocytopenia
• Associated diseases include SLE, infection, and HIV
• Signs and Symptoms include: Epistaxis, Menorrhagia and Petechiae
• Possible treatments include observation, steroids, IVIG, and splenectomy

Conditions Causing Thrombocytopenia - Decreased Platelet Production

• Aplastic anemia, congenital or acquired
• Bone marrow infiltration: leukemia or disseminated cancer
• Infections: CMV, HIV, or Measles
• Drug induced: thiazides, ETOH, or cytotoxic drugs
• Ineffective megakaryopoiesis: megaloblastic anemia or paroxysmal nocturnal hemoglobinuria

Conditions Causing Thrombocytopenia - Sequestration

• Hypersplenism

Conditions Causing Thrombocytopenia - Dilutional

• Multiple blood transfusions

Thrombocytosis

• Etiology Categories Include: Myeloproliferative Disorders, Reactive Thrombocytosis and Essential Thrombocythemia

Thrombocytosis Examples

• Myeloproliferative Disorders: polycythemia vera, primary myelofibrosis, chronic myeloid leukemia and acute myeloid leukemia
• Reactive Thrombocytosis Causes: Non-infectious inflammation, infection, asplenia and anemia/ blood loss

Evaluation of Platelet Disorders

• History and Physical
• Review medications
• Complete Blood Count (CBC)
• Blood Smear
• Bone Marrow Biopsy if indicated

Coagulopathy

• Issues in coagulation are caused by decreased or dysfunctional clotting factors
• Clotting factors are synthesized in the liver

Coagulation Cascade

• Prothrombin time (PT)/International Normalized Ratio (INR) measures the extrinsic pathway
• Partial Thromboplastin Time (PTT) measures the intrinsic pathway
• Vitamin K is an important cofactor

Von Willebrand Disease

• Inheritance pattern is autosomal dominant
• Qualitative or quantitative defects in factor VIII – vWF complex (vwF = Von Willebrand factor)
• Signs and Symptoms: Minor excessive bleeding, Easy bruising, Menorrhagia (heavy menstrual bleeding) and Prolonged bleeding
• Treatment: Desmopressin which Stimulates release of vWF from endothelial cells

Hemophilia A

• Inheritance: X-linked recessive
• Cause: Factor VIII deficiency
• Signs and Symptoms include hemarthrosis from birth and spontaneous bleeding
• Treatment: Factor VIII

Hemophilia B

• Inheritance: X-linked recessive
• Cause: Factor IX deficiency
• Signs and Symptoms include hemarthrosis from birth and spontaneous bleeding
• Treatment: Factor IX

Evaluation of Coagulopathy

• Peripheral blood tests:
  • Prothrombin time (PT)
  • Partial Thromboplastin Time (PTT)
  • INR: ratio of a patient's PT to a normal PT
  • Bleeding Time
  • Factor levels : factor VIII, IX, von Willebrand factor
  • Ristocetin cofactor test
  • Mixing studies

Coagulation Studies in Disease States

• ITP - Normal PT/PTT
• TTP - Normal PT/PTT
• HUS - Normal PT/PTT
• Hemophilia A - Increased PTT , Normal PT, ↓FVIII
• Hemophilia B - Increased PTT, Normal PT, ↓FIX
• VWD - Increased bleeding time, Increased PTT, Normal PT, decreased FVIII half life, decreased ristocetin cofactor and decreased VWF

White Blood Cell Disorders

• Leukocytosis is too many WBCs
• Leukopenia is too few WBCs

Etiologies of Leukocytosis - Non-Neoplastic

• Reactive leukocytosis - think stress
• Neutrophilia - bacterial infections, steroids, hemorrhage, stress, acute and chronic inflammation
• Eosinophilia - asthma, allergies, parasitic infections, meds
• Monocytosis - endocarditis, tuberculosis, malignancy
• Lymphocytosis - mononucleosis, pertussis, hepatitis viral, typhoid fever
• Basophilia - not a good sign

Mononucleosis

• Cause: Epstein-Barr Virus (EBV)
• Signs and Symptoms Include - Fever, Sore throat, Generalized Lymphadenitis, Hepatomegaly or Splenomegaly, Lymphocytosis

Etiologies of Leukocytosis - Neoplastic

• Lymphoid Neoplasms
• Myeloid Neoplasms
• Histiocytic Neoplasms

Examples of Neoplastic Etiologies

• Lymphoid Neoplasms: Leukemias, Non- Hodgkin's Lymphomas and Hodgkin's Lymphomas
• Myeloid Neoplasms: Leukemias and Myelodysplastic syndromes
• Histiocytic Neoplasms: Langerhans Cell Histiocytosis

Leukopenia

• Definition: a decrease in WBC count
• Etiologies:
  • HIV
  • Congenital immunodeficiency
  • Splenomegaly
  • Medication including chemotherapy
  • Infection

Neutropenia

• Reduction in the number of granulocytes in blood
• Most common cell lineage in leukopenia
• Agranulocytosis = Severe neutropenia
• Risk of infection < 500 cells/mieroliter
• Common complication of chemotherapy and can be assisted with medication G-CSF (Granulocyte-colony stimulating factor)

Evaluation of WBC Disorders

• History
• Physical
• Review medication list
• CBC w/ diff
• Blood Smear
• Bone Marrow Aspirate and Biopsy
• Imaging if warranted

Bone Marrow Biopsy and Aspiration

• Biopsy Definition: procedure in which a small sample of bone with bone marrow inside it is removed (core samples)
• Aspiration Definition: removes a small amount of marrow in liquid form for examination

Locations for Bone Marrow Aspirate or Biopsy

• Anterior superior iliac spine (ASIS)
• Anterior iliac crest
• Greater trochanter of femur
• Vertebral bodies
• Ribs
• Sternum
• Anterior tibia

Indications for Bone Marrow Biopsy and Aspirate

• Evaluation of unexplained anemia, leukopenia, thrombocytopenia, pancytopenia
• Evaluation of unexplained polycythemia, thrombocytosis, leukocytosis
• Diagnosis and staging of lymphoma and solid tumors
• Diagnosis of leukemias
• Diagnosis of plasma cell disorders
• Evaluation of Fe metabolism and stores
• Evaluation of suspected glycogen storage diseases
• Evaluation of unexplained splenomegaly
• Potential bone marrow donor