Hematopathology: Platelets, Myeloblasts & Coagulation

• Hematopathology encompasses platelet and myeloblast disorders.
• It also includes hematologic diseases characterized by leukocytosis and leucopenia.
• Further, it also includes diseases characterized by thrombocytosis and thrombocytopenia.
• This can also include diseases characterized by an abnormality in coagulation.

Student Learning Objectives

• Understand the overall organization of hematopathology.
• Identify platelet and myeloblast disorders.
• Define hematologic diseases with leukocytosis and leucopenia.
• Define hematologic diseases with thrombocytosis and thrombocytopenia.
• Define coagulation abnormality diseases.
• Identify lab tests assessing leukocytosis, leukopenia, thrombocytosis, thrombocytopenia, and coagulation disorders.
• Discuss bone marrow exam value in diagnosing hematologic and other diseases.

Classification of Hematopathology

• Hematopathology classification based on lineages includes erythrocyte disorders, WBC disorders, platelet disorders, and plasma cell disorders.

Hematopoiesis

• Blood cell differentiation and lineages originate from a hematopoietic stem cell.
• This cell differentiates into common myeloid and lymphoid progenitors.
• The myeloid progenitor gives rise to myeloblasts, erythroid stem cells, and platelet stem cells.
• Myeloblasts further differentiate into monocytes, neutrophils, eosinophils, and basophils.
• The lymphoid progenitor creates pro-B cells and pre-T cells.

Platelet Disorders

• Platelet disorders can be identified via a peripheral smear test.

Platelet Development

• Thrombopoiesis necessitates thrombopoietin (TPO)
• TPO is produced in the liver.
• TPO binds to the c-mpl receptor on megakaryocytes and platelets.
• This leads to internalization, platelet production, and TPO degradation.

Platelet Disorder Categories

• Disorders are either qualitative (impaired function) or quantitative (too many or too few platelets).
• Quantitative disorders include thrombocytosis (too many platelets) and thrombocytopenia (too few platelets).

Causes of Thrombocytopenia

• Causes are decreased production, increased destruction, dilution, or abnormal distribution.

Differential Diagnosis Mnemonic

• Differential Diagnosis mnemonic is VINDICATE:
  • Vascular
  • Infection, inflammation
  • Neoplasms
  • Drugs (toxins), degenerative
  • Iatrogenic, Idiopathic
  • Congenital/ Inherited/ Developmental
  • Autoimmune/ Allergy/ Anatomic
  • Trauma
  • Endocrine/ metabolic, Environmental/ work exposure

Signs and Symptoms of Thrombocytopenia

• Possible signs and symptoms are petechiae (non-blanching, red lesions <2 mm).
• Other symptoms include easy bruising, epistaxis, menorrhagia, GI bleed, GU bleed, and jaundice.

Conditions Causing Thrombocytopenia

• Increased Platelet Destruction leads to thrombocytopenia.
• Immunologic causes of increased platelet destruction: autoimmune (ITP, SLE) and drug-associated conditions, and infections.
• Non-immunologic etiologies, which also result in thrombocytopenia: DIC and microangiopathic hemolytic anemias (HUS, TTP).

Thrombocytopenia

• Hemolytic Uremic Syndrome (HUS) results in thrombocytopenia.
• Etiology of HUS: GI infections, pregnancy, malignancy, autoimmune diseases.
• Symptoms of HUS: thrombocytopenia, hemolysis with jaundice and elevated bilirubin, and kidney disease.
• Treatment: plasmapheresis
• Thrombotic Thrombocytopenic Purpura (TTP) is another cause of thrombocytopenia.
• TTP Etiology: inherited deficiencies of ADAMTS 13.
• TTP Symptoms: thrombocytopenia, hemolysis with jaundice and elevated bilirubin, kidney disease, encephalopathy, and fever.
• Treatment: plasmapheresis
• The mnemonic FAT RN is helpful in remembering the Thrombotic Thrombocytopenic Purpura.

Immune Thrombocytopenic Purpura (ITP)

• ITP is caused by autoantibodies against platelets, leading to thrombocytopenia.
• Associated diseases with ITP: SLE and HIV
• Possible treatments include observation, steroids, IVIG, or splenectomy.
• Signs and Symptoms include epistaxis, menorrhagia, and petechiae.

Conditions Causing Thrombocytopenia

• Decreased Platelet Production from causes such as aplastic anemia, bone marrow infiltration, infectious, drug induced, or ineffective megakaryopoiesis.

Thrombocytopenia

• Sequestration, the term is Hypersplenism.

Conditions Causing Thrombocytopenia:

• Dilutional causes such as multiple blood transfusions.

Thrombocytosis Etiology

• Thrombocytosis is categorized into myeloproliferative disorders, reactive thrombocytosis, or other etiologies like essential thrombocythemia.

Thrombocytosis Examples

• Myeloproliferative causes: Polycythemia vera, primary myelofibrosis, chronic/acute myeloid leukemia.
• Reactive causes: Non-infectious inflammation, infection, asplenia, anemia/blood loss.

Evaluating Platelet Disorders

• Evaluation includes history and physical exam, medication review, complete blood count (CBC), blood smear, and bone marrow biopsy (if indicated).

Coagulopathy

• Coagulopathy arises from issues in coagulation due to decreased or dysfunctional clotting factors.
• Clotting factors are synthesized in the liver.

Coagulation Cascade

• Prothrombin time (PT)/INR assesses the extrinsic pathway.
• Partial Thromboplastin Time (PTT) evaluates the intrinsic pathway.
• Vitamin K is an important cofactor.

Von Willebrand Disease

• This is an inherited autosomal dominant disorder.
• Von Willebrand Disease results from qualitative or quantitative defects in factor VIII - VWF complex.
• Signs and Symptoms: minor excessive bleeding, easy bruising, menorrhagia, prolonged bleeding after dental procedures, surgery, birth.
• Treatment: Desmopressin, which stimulates vWF release from endothelial cells.

Hemophilia A and B

• Hemophilia A: X-linked recessive, factor VIII deficiency
• Hemophilia B: X-linked recessive, factor IX deficiency
• Both present with hemarthrosis from birth and spontaneous bleeding.
• Treatment for Hemophilia A is Factor VIII.
• Treatment for Hemophilia B is Factor IX.

Evaluation of Coagulopathy

• Peripheral blood tests include: PT, PTT, INR, bleeding time, factor levels, ristocetin cofactor test, and mixing studies.

Coagulation Studies in Disease

• ITP presents with a normal PT/PTT
• TTP presents with a normal PT/PTT
• HUS presents with a normal PT/PTT
• Hemophilia A presents with an increased PTT and a normal PT, with a decreased FVIII
• Hemophilia B presents with an increased PTT and a normal PT, with a decrease FIX
• VWD presents with a normal PT, increased PTT, increased bleeding time, with a decreased FVIII half life, decreased ristocetin cofactor and decreased vWF

WBC Disorders

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

Etiologies of Leukocytosis

• Non-Neoplastic: reactive leukocytosis (stress), neutrophilia, eosinophilia, monocytosis, lymphocytosis, basophilia.
• Mononucleosis cause is Epstein-Barr Virus (EBV).
• Mononucleosis symptoms: fever, sore throat, lymphadenitis, hepatomegaly or splenomegaly, lymphocytosis of activated, CD8+ T cells (atypical lymphocytes).

Etiologies of Leukocytosis

• Neoplastic: Lymphoid Neoplasms, Myeloid Neoplasms, Histiocytic Neoplasms

Examples of Neoplastic Etiologies of Leukocytosis

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

Leukopenia

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

Neutropenia

• Neutropenia is a reduction in granulocytes in blood, the most common cell lineage in leukopenia.
• Agranulocytosis = Severe neutropenia
• Risk of infection: < 500 cells/µL.
• A common complication of chemotherapy.
• Medications can help combat this, such as G-CSF.

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 which removes a small bone sample with bone marrow (core samples)
• Aspiration Definition: this removes a small amount of marrow in liquid form for examination

Locations for Bone Marrow Aspirate or Biopsy

• Locations include the anterior superior iliac spine (ASIS), anterior iliac crest, greater trochanter of femur, vertebral bodies, ribs, sternum, anterior tibia

Bone Marrow Biopsy and Aspirate

• Indications include the evaluation of unexplained anemia, leukopenia, thrombocytopenia, pancytopenia.
• Diagnosis and staging of lymphoma and solid tumors.
• If there is suspicion of leukemia, plasma cell disorders, Fe metabolism, glycogen storage diseases, or unexplained splenomegaly.
• Also done to find Potential bone marrow donors.