Interesting Coagulation Cases. Describe the laboratory testing for the diagnosis of disseminated intravascular coagulation. Additional coagulation studies Factor VII 10% Factor VIII 43% Factor V 72% Factor X. Clinical Hematology, first edition is written specifically for medical students, the clinician and resident doctors in training and general practioner.
Hematology Assignment This unit is big, and mastery of the material requires a combination of reading the book, reviewing lecture notes and especially attention to the online exercises. It covers RBC and WBC disorders, problems of coagulation and diseases of the lymph nodes. Do not wait until week before the exam to try and do the reading. All of the material in this unit will be covered on the second exam, and it’s a bunch. You’ll be sunk if you put reading and online assignments off until the just few weeks before the exam. Here’s the scoop on just the hematology unit, the immunopathology comes later. Big Robbins: chapters 13 and 14. Little Robbins: Chapter 11 Wheater: Hematopoietic Slides: For the blood smears, the entire set is online. There are no slides in your box. For the lymph nodes, there are slides in your box and online. There are four online exercises for hematology unit, two cases and two tutorials. The tutorials are rather large but absolutely necessary. Don’t flush these or try to rush through them. Online stuff: Case 11, Mr. Herbert: A man complaining of lethargy. Module 24, Coagulation tutorial Module 19, Leukemia review Case 17, Mrs. Talbot: Woman with a neck mass. Slides and TBL stuff: There are no formal TBLs for this unt. Rather the blood smear section of the slides will serve that purpose. Approach of these cases as if you will see them, their histories and lab values in case studies on the written exam. The reason is, you will. If you’re having trouble with the reading, please see Dr. Braun or Bauman pronto.
121 Hematopoietic and Lymphoid Systems Basic Robbins Chapter 11 Mark E. Bauman, M.D. Hematopoiesis (Most material below not in text) 3rd week gestational age 3rd month gestational age 4th month gestational age 18 years Hb A Hb F Hb A2 red/white marrow extramedullary hematopoiesis stem cells Normal anatomy of bone marrow Cell/fat ratio Hypoplasia/hyperplasia Myeloid/erythroid ratio Avg life span RBC Poly Platelet Erythroid maturation 122 Granulocytic maturation Megakaryocytes Normal anatomy of peripheral blood Erythrocytes Hb content: Normochromic/ hypochromic/ hyperchromic Polychromatophilia/polychromasia (standard Wright stain) Reticulocytes (retic stain showing RNA still synthesizing Hb) Reticulocyte count Percentage: 0.5 – 1.5% (Except in newborns 2.5 – 6.5) Absolute: 24 – 84 x 109 Reticulocytes production index/Corrected reticulocyte count compensates for 1) decreased # RBC 2) increased life span of reticulocyte (early marrow exit) Consumption vs Production etiology of anemia Size: Normocytic/microcytic/macrocytic; variation = Shape: Elliptocytes, spheroctyes, target cells, schistocytes, acanthocytes Multiple images Erythrocyte cytoplasmic inclusions: Basophilic stippling Pappenheimer bodies Howell-Jolly bodies 123 Multiple images Rouleaux formation RBC Indices RBC count MCV Hct MCH Hb MCHC RDW Leukocytes Total WBC/mm3 % polys Absolute polys Total WBC/mm3 % lymphs 10,000 6,000 30,000 10,000 70 70 30 30 % lymphs Absolute lymphs Relative lymphocytosis? Platelets Total Quality vs Quantity 124 % monos % eos % basos Absolute lymphocyte count Absolute lymphocytosis? Red Cell Disorders Anemia = reduction of O2 transport capacity in blood Anemias classified by MCV Anemias classified by Underlying Etiology ***Table 11-1*** 1. A. B. 2. A. B. 3. 125 Anemias of Blood Loss: Hemorrhage Acute vs chronic blood loss Hct/Hb Reticulocytes Hemolytic Anemias Increased RBC destruction: Intrinsic and extrinsic abnormalities EPO LDH Reticulocytes Hemoglobin → Heme → Biliverdin → Bilirubin Bone marrow Hemoglobin catabolism unconjugated hyperbilirubinemia hemoglobinemia hemoglobinuria haptoglobin 126 Instrinsic (intracorpuscular) hemolysis Hereditary spherocytosis (Figures 11-1 and 11-2) Spherical erythrocytes secondary to an inherited defect of red cell membrane skeleton proteins “Obese man attempting to bend at the waist.” Osmotic fragility Clinical: Sickle Cell Anemia Hemoglobinopathy Hb S substitution of valine for glutamic acid at amino acid 6 of the globin chain Hb SS Hb AS HbC substitution of lysine for glutamic acid at amino acid 6 of β globin chain Chronic hemolytic anemia 127 Clinical onset in homozygotes Congestion, thrombosis, infarction Veno-occlusive crises Autosplenectomy DX: Hb electrophoresis/HPLC Thalassemia Syndromes Thalassa + emia = (Figures 11-5 and 11-6, Table 11-3) Pathogenesis: relative excess of insoluble, unstable chains with ineffective erythropoiesis Peripheral blood/anemia/splenic sequestration Thalassemia Each chromosome 16 has two genes for alpha; typically loss of entire gene I II -/ - -/ -/- III - -/- IV - -/- - silent carrier -thal trait, Asian -thal trait, African Hb H disease, -globin tetramers = Hb H Hb Barts, hydrops fetalis, -globin tetramers = Hb Barts 128 Thalassemia Each chromosome 11 has a single gene for beta. Typically point mutations (promoters, terminators, splicing). + thal 0 thal = normal gene = decreased production (variable amount produced) = total absence of beta globin chain / /+ or /0 /0 or +/+ +/+ or 0/0 Hb electrophoresis/HPLC minor major = = = = ↑Hb A2 (4-8%) Hb A2 ↑ or ↓; Hb F usually ↑ Clinical course Skeletal deformities Hemochromastosis Glucose-6-phosphate dehydrogenase deficiency One example of an erythrocyte enzyme defect Defective hexose monophosphate shunt incapable of regenerating reduced Glutathione (GSH). GSH needed for inactivation of intracellular oxidants, e.g. sulfonamide, primaquine, infectious agents, fava beans, H2O2 from phagocytes during infections Heinz bodies (Figure 11-7) 129 Bite cells: (Fig 13-8) Genetics: Clinical: enzyme synthesis vs enzyme stability Paroxysmal Nocturnal Hemoglobinuria Somatic mutation of pluripotential stem cell decreased glycosyl phosphatidyl inositol (GPI: a phospolipid anchoring non-transmembrane proteins); decreased GPI decreased GPI-linked proteins regulating complement increased sensitivity of RBCs to complement Misnomer Ham’s test Flow cytometry for CD 55 and CD 59 (GPI-linked proteins) FLAER: fluorescent labeled proaerolysin (binds to PGI) Extrinsic (extracorpuscular) hemolysis Immune-mediated hemolytic anemia Anti-RBC antibodies and complement-mediated RBC hemolysis Direct Antibody Test (D.A.T.) = Coomb’s test Indirect Antibody Test (I.A.T.) = Indirect Coomb’s test Warm Antibody Immunohemolytic Anemia 130 Temperature IgG Idiopathic 75% Immune disorders Spherocytes Cold Antibody Immunohemolytic Anemia Temperature IgM Opsonization Agglutination Non-immune hemolytic anemias Mechanical etiologies Microangiopathic hemolytic anemia DIC, TTP Schistocytes Malaria 1 million deaths annually; endemic in Asia and Africa Plasmodium species: P. falciparum, P. malariae, P. vivax, P. ovale Mosquito Parasite life cycle Clinical 131 Anemias of Diminished Erythropoiesis Iron deficiency anemia (Figure 11-9) Iron functions Iron absorption and balance Ferroportin 1/hepcidin Serum iron/TIBC/transferrin Ferritin Hemosiderin/hemosiderosis Hemochromatosis (page 629, figure 15-25) Iron deficiency 132 Iron deficiency anemia (Figure 11-10) MCV MCH RDW Ferritin TIBC Platlets Free erythrocyte protoporphyrin Anemia of chronic disease Defective utilization of iron (present in adequate amounts) secondary to a defect in iron transfer from the storage pool to erythroid precursors Ferroportin 1/hepcidin Clinical settings MCV RDW Ferritin Platelets TIBC Megaloblastic Anemias Impaired DNA synthesis Megaloblasts: impairment of cell maturation and division; normal RNA and protein synthesis; nuclear/ cytoplasmic dysynchrony; ineffective hematopoiesis Bone marrow erythroid and granulocyte precursors MCV Retic Platelets Neutrophils 133 MCH B12 (Cobalamin) Folate Sources/storage: Deficiency: Pernicious anemia: One form of megaloblastic anemia secondary to defects of intrinsic factor Physiologic absorption of B12 Serum antibodies: 1. 2. 3. Additional etiologies of malabsorption CNS Changes: spinal cord demyelinization of dorsal and lateral tracts (sensory ataxia, paresthesias of extremities) Aplastic anemia Trilinear aplasia Etiologies Pure red cell aplasia Association 134 2. Virus Myelophthisic anemia Leukoerythroblastosis Polycythemia Polycythemia/erythrocytosis Relative erythrocytosis Absolute erythrocytosis Primary: RBC production not regulated by EPO Secondary: RBC production regulated by EPO Appropriate Inappropriate 135 White Cell Disorders Non-neoplastic Disorders of White Cells Leukopenia Neutropenia/agranulocytosis Decreased production Increased consumption Reactive leukocytosis Review Table 11-6 Causes of Leukocytosis (page 426 in Basic Robbins) Neutrophilia Eosinophilia Basophilia Monocytosis Lymphocytosis Leukemoid reaction Infectious mononucleosis EBV Monospot test (rapid heterophile antibody); serology Atypical lymphocytosis Lymphadenopathy, hepatosplenomegaly 136 Associations 1. 2. Reactive lymphadenitis Normal lymph node structure Acute nonspecific lymphadenitis Chronic nonspecific lymphadenitis Follicular hyperplasia Paracortical hyperplasia Sinus histiocytosis Cat scratch disease Bartonella henselae Cervical, axillary adenopathy: stellate necrotizing granulomata 137 3. Neoplastic Proliferations of White Cells (Note: The following material is somewhat different from the order of presentation in the text.) Lymphoma Leukemia Myelodysplasia Myeloproliferative neoplasms 1. 2. 3. 4. 138 Lymphoid neoplasms Benign vs malignant Clonality 1. Monoclonal protein (surface antigen receptor or secreted globulin) 2. Genetic rearrangement: PCR/Southern blot 139 3. Chromosomal translocation: PCR/Southern blot/FISH Classification schemes for lymphomas attempt to define distinct clinic-pathologic entities, based on cell morphology, origin, maturity, immunophenotype, genotype, and clinical features. ***Table 11-7 WHO Classification of Lymphoid Neoplasms *** Most lymphomas resemble some stage of B or T cell differentiation. (Figure 11-13) B cell: T cell: Nodal: Extranodal: Non-Hodgkin lymphoma: NK cell: Hodgkin lymphoma: 140 B cell T cell Precursor (immature) Peripheral (mature) Most common lymphomas are derived from germinal center or post germinal center B cells. Immune abnormalities in lymphomas NHL lymphomas are systemic Precursor (immature) B and T cell leukemia/lymphoma = Acute lymphoblastic leukemia/lymphoblastic lymphoma ALL Morphology Molecular Clinical Aleukemic leukemia 141 Distinguished from AML Peripheral (mature) B cell neoplasms CLL/SLL: Chronic lymphocytic leukemia/small lymphocytic lymphoma Morphology Lymph node Blood Bone marrow Immunophenotype Clinical Richter transformation 142 Follicular lymphoma Morphology Immunophenotype Molecular Clinical Mantle cell lymphoma Morphology Immunophenotype Molecular Clinical Lymphomatoid polyposis Blast variant Diffuse large B cell lymphoma Morphology (Figure 11-17) 143 Immunophenotype Molecular Clinical Burkitt lymphoma 3 types 1) 2) 3) Morphology Molecular c-MYC on 8 t(8;14) t(2;8) t(8;22) Multiple myeloma and related plasma cell tumors (Note: The following material is somewhat different from the order of presentation in the text.) Morphology Solitary plasmacytoma Multiple myeloma 144 Secretory function Bence Jones protein MGUS Clinical Immunosuppresion Peripheral blood Pathologic fractures/lytic lesions Hypercalcemia Myeloma nephrosis Light chain (AL) amyloidosis Prognosis Lymphoplasmacytic lymphoma Waldenström macroglobulinemia/hyperviscosity syndrome Heavy chain disease 145 Hodgkin lymphoma: a B cell lymphoma HL Site NHL Spread Nodal based Morphology: Reactive cells plus Reed Sternberg cells 5 subtypes: 4 Classical (nodular sclerosis, lymphocyte rich, mixed cellularity, lymphocyte depleted) and Nodular Lymphocyte Predominance Classical RS cells CD15 and CD30 positive; CD45 and CD20 negative Nodular sclerosis with “Lacunar cells” Lymphocyte Predominance HL Lymphohistiocytic variant RS cells (popcorn cells) CD15 and CD30 negative; CD45 and CD20 positive EBV Clinical Staging and “B” symptoms Prognosis Extranodal marginal zone lymphoma 146 Morphology MALToma Sites Associations Hairy cell leukemia Morphology Immunophenotype TRAP (outdated) Clinical Spenomegaly Bone marrow involvement Prognosis Mycosis fungoides Cutaneous T-cell lymphoma: patches, plaques, tumors Pautrier microabscesses Sezary syndrome Adult T cell leukemia/lymphoma HTLV-1: Japan, Caribbean, West Africa 147 Myeloid neoplasms (Note: The material on Myelodysplasia in this handout precedes that of acute myeloid leukemia. The text presents AML before Myelodysplasia.) Myelodysplastic syndromes WHO definition: A group of clonal myeloid neoplasms characterized by ineffective hematopoiesis that present clinically as cytopenia(s), dysplasia in one or more hematopoietic cell lines in the bone marrow, and risk of transformation to acute myeloid leukemia. Morphology Molecular: monosomy 5, monosomy 7; 5q-, 7q-, 20qSubtypes: Refractory cytopenia with unileage dysplasia (RCUD), Refractory anemia with ring sideroblasts (RARS), Refractory cytopenia with multilineage dysplasia (RCMD), Refractory anemia with excess blasts-1 (RAEB-1), Refractory anemia with excess blasts-2 (RAEB-2), Myelodysplastic syndrome unclassified (MDS-U), MDS associated with isolated del (5q), Therapy-related MDS (t-MDS). Clinical Acute myeloid leukemia = Acute myelogenous leukemia = AML At least 20% marrow blasts. Morphology(Figures 11-14, 11-25) Auer rods Immunophenotype Molecular Clinical 148 WHO Classification based on cell lineage, cell maturation, molecular changes AML with recurrent chromosomal translocations AML with a translocation between chromosomes 8 and 21 AML with a translocation or inversion in chromosome 16 AML with changes in chromosome 11 APL (M3), which usually has translocation between chromosomes 15 and 17 AML with multilineage dysplasia (more than one abnormal myeloid cell type is involved) AML related to previous chemotherapy or radiation AML not otherwise specified (includes cases of AML that don't fall into one of the above groups; similar to the FAB classification) Undifferentiated AML (M0) AML with minimal maturation (M1) AML with maturation (M2) Acute myelomonocytic leukemia (M4) Acute monocytic leukemia (M5) Acute erythroid leukemia (M6) Acute megakaryoblastic leukemia (M7) Acute basophilic leukemia Acute panmyelosis with fibrosis Myeloid sarcoma (also known as granulocytic sarcoma or chloroma) Undifferentiated or biphenotypic acute leukemias (leukemias that have both lymphocytic and myeloid features). Sometimes called ALL with myeloid markers, AML with lymphoid markers, or mixed lineage leukemias. FAB M3 t(15;17) retinoic acid receptor α (RARA) gene on 17 PML gene on 15 FAB M4 FAB M6 Chronic Myeloproliferative Neoplasms Clonal hyperproliferation of myeloid cells retaining capacity for terminal differentiation Peripheral blood Bone marrow Hepatosplenomegaly 149 “Spent phase” and “blast crisis” 1. Chronic myelogenous leukemia (CML) Peripheral blood (Figure 11-26) Philadelphia chromosome Rx Prognosis 2. Polycythemia vera Peripheral blood EPO JAK2 Thromboses/infarctions/ erythromelalgia Rx 3. Primary myelofibrosis Peripheral blood Bone marrow JAK2 Prognosis 4. Essential thrombocythemia Peripheral blood 150 Bone marrow JAK2 Histiocytic neoplasms Two types of histiocytes: macrophages/histiocytes and dendritic cells Dendritic cells present antigens to initiate an immune response Two types of dendritic cells: 1. Follicular dendritic cells within germinal centers 2. Langerhans cells – a dendritic cell within the dermis CD1a positive Birbeck granules: pentalaminar tubular structures on EM (tennis rackets) Langerhans cell histiocytoses (LCH) Children and adults Unisystem LCH Unifocal unisystem LCH (“eosinophilic granuloma”) Erosive aggregates of LC’s, often in bone, skin or lungs Mutlifocal unisystem LCH Multiple bony masses, often extending into soft tissues Hand-Schüll-Christian triad: calvarial bone defects, diabetes insipidus (posterior pituitary stalk involvement), exophthalmos Multisystem LCH (Letterer-Siwe disease) Seborrheic skin eruptions, hepatosplenomegaly, pulmonary lesions, destructive bone lesions 151 152 Bleeding Disorders (Note: The material presented below draws from chapters 3 and 11 of Basic Robbins. The order of this material does not follow the text. Some of the material is not in the text.) Hemostasis Petechiae Purpura Echymosis Contusion Hematoma Primary Hemostasis (Fig 3‐7) 1. Adhesion 2. Activation α (alpha) granules δ (delta) granules/dense bodies TxA2 Shape change 3. Aggregation 153 Secondary Hemostasis: Coagulation System Transformation of plasma proenzymes activated enzymes with cofactors conversion of prothrombin → thrombin → conversion of fibrinogen fibrin with crosslinking by XIII Intrinsic and extrinsic pathways (Figures 3-8, 3-9, 3-5) 154 Antithrombotic mechanisms Inhibitory effects on platelets (primary hemostasis) Intact endothelium Endothelial products Drugs Inhibitory effects on coagulation (secondary hemostasis) (Figure 3-6) Anti-thrombin III AT III is activated by Activated AT III functions to Thrombomodulin Thrombomodulin functions to 1. 2. activate Protein C Activated Protein C inactivates Activated Protein C Resistance/Factor V Leiden Normal APCR PTT PTT w/ act Protein C Protein S is a cofactor for Protein C 155 Tissue Factor Pathway Inhibitor (TFPI) Drugs Fibrinolysis (Figure 3-11) Plasminogen activated to activated by 1. 2. 3. Plasmin produces Fibrinolysis is controlled by 1. 2. With bleeding disorders, history comes first: onset, type of bleeding, family history Platelet disorder Petechiae Deep hematomas Hemarthroses Delayed bleeding Mucosal bleeding Lab tests for platelet function Bleeding time Platelet function analyzer (PFA) 156 Coag disorder Platelet aggregation studies (Selected) Lab tests for coagulation function Activated partial thromboplastin time (PTT) Prothrombin time (PT) INR Thrombin time Mixing Studies: 157 Platelet Disorders Platelet Quantity: production vs consumption Production problem Bone marrow Consumption problem Sequestration/hypersplenism Neonatal and post-transfusion immune reaction ITP (Immune Thrombocytopenic purpura) Immunologically mediated destruction of platelets Acute Chronic Autoantibodies PT/PTT/BMBx HIT (Heparin-induced Thrombocytopenia) HIV-associated Thrombocytopeni a CD 4 receptors on megakaryocytes 158 TTP/HUS (Thrombotic Thrombocytopenia Purpura/Hemolytic Uremic Syndrome) Thrombotic Microangiopathies TTP Pentad Formation of VWF metalloprotease defect ADAMTS 13 (A Disintegrin-like And Metalloprotease With ThromboSpondin, the 13th member) Therapy: HUS etiology PT/PTT Platelet Quality Bernard Soulier Disease Glanzmann’s thrombasthenia Storage pool disorder Von Willebrand Disease (Figure 11-29) VWF functions: 1. 2. t ½ for VIII with vWF = without vWF = 159 Inheritance Clinical findings Platelet count PT FVIII activity PTT Platelet function assay vWF Ag vWF activity/Ristocetin test Multimer studies/Subtypes of vWD: Coagulation Disorders Factor VIII Deficiency (Hemophilia A) Inheritance Clinical findings Range of VIII activity Platelet count PT PTT FVIII activity Rx 160 Platelet function assay Factor IX Deficiency (Hemophilia B, Christmas Disease) Clinical findings Lab testing Disseminated Intravascular Coagulation (DIC) (Figure 11-28) Activation of coagulation with microthrombi formation with microangiopathic hemolytic anemia, coupled with active fibrinolysis PT PTT D-dimer Etiologies 161 Platelet count Fibrinogen Spleen and Thymus Spleen Splenomegaly ≠ hypersplenism Common causes of massive, moderate and mild splenomegaly: page 456 Basic Robbins Thymus Bone marrow progenitor cells migrate to the thymus and give rise to mature T-cells Thymic hypoplasia: DiGeorge syndrome Thymic hyperplasia associated with Thymomas Mediastinal tumors T T T 162 T Transfusion Medicine M.E. Bauman, M.D. Donor Restrictions Med Hx: Brief Physical Exam: No possibility of infectious risk to the donor; sterile equipment used once Autologus Donations Directed Donations Blood Bank Testing Blood Type: Front and Back Typing Type Antigen Antibody A B AB O Universal donor: Universal recipient: 163 Coomb's Test = Direct Antibody Test = D.A.T. Indirect Coomb's Test = Indirect Antibody Test = I.A.T. = Antibody Screen Autoantibody and Alloantibody screen Type and Screen Type and Cross Infectious Disease Testing Risks: Hep B: Hep C: Components from Whole Blood Red Blood Cells Indications: 'transfusion trigger': ABO Crossmatched: 164 HIV: Volume: Expected rise: **Post Transfusion Hb** Shelf life: Rate of infusion: Platelets Indications: 'transfusion trigger': ABO Crossmatched: Volume: Single donor vs. pooled random platelets vs. apheresis single donor unit Expected rise: **Post Transfusion Count** Shelf life: Rate of infusion: Pooled random platelets vs. single donor platelets (HLA matched) 165 Fresh Frozen Plasma (FFP) Contents: Indications: ABO Crossmatched: Volume: Dosage: **Post Transfusion PT/PTT** Shelf life: Cryoprecipitate Contents: Indications: Dosage: depends on factor to replace and on recipient's level of factor Transfusion Reactions Hemolytic Reactions Definition: Fatalities: Reason for error: 166 Antibodies: Clinical aspects: Delayed Hemolytic Reaction Definition: Non-Hemolytic Reactions Febrile Etiology: Rx: Allergic Etiology: Rx: Circulatory Overload Bacterial Contamination 167
TEACHING CASES. Case 1: A 73 year old man with fatigue, weight loss, anemia and mild thrombocytopenia for five months. Case 2: A 56 year old man with weight loss and microcytic anemia. Case 3: A 38 year old renal transplant recipient with worsening anemia. Case 4: A 31 year old man with a swollen left arm.
These 36 HEMATOGRAPHY Case Studies were added to the Web site between October, 1997 and September, 2000. The cases are factual and reflect medical practice of that time. They have not been embellished or updated in any way. Each case illustrates a different hematologic disorder, and includes. Coagulation Study Questions. LAboratory results in acute disseminated intravascular coagulation reflect abnormalities in which of the following coagulation components. A patient has a prolonged APTT and a normal PT. The APTT is not corrected by factor VIII deficient plasma but is corrected by factor IX-deficient plasma.
doi: 10.1111/j.1525-1497.2006.00506.x
PMID: 17026724
This article has been cited by other articles in PMC.
Abstract
Disseminated intravascular coagulation (DIC) is an acquired coagulation disorder that may occur in a wide variety of clinical conditions. Suspicion of DIC should lead to a differential diagnosis that includes primary fibrinolysis and other bleeding diatheses such as thrombocytopenias of diverse etiology. Confirmation of the diagnosis of DIC should always prompt a search for an underlying medical disorder, including sepsis, severe trauma, solid and hematological malignancies, obstetrical complications, and vascular disorders. Here, we describe an unusual case of acute bleeding and DIC as the presenting manifestation of metastatic prostate cancer in a 60-year-old man. Treatment with a luteinizing hormone-releasing hormone (LHRH) agonist and a short course of an antiandrogen, together with supportive measures (i.e., clotting factors, heparin, and platelets), led to normalization of all coagulation parameters within 1 week, and to clinical improvement and decline in the serum level of prostate-specific antigen (PSA). We discuss the pathogenesis, differential diagnosis, and association of DIC with prostate cancer along with the management of this condition.
Keywords: DIC, prostate cancer, differential diagnosis
Disseminated intravascular coagulation (DIC) is an acquired coagulation disorder that may occur in a wide variety of clinical conditions. Suspicion of DIC should lead to a differential diagnosis that includes primary fibrinolysis and other bleeding diatheses such as thrombocytopenias of diverse etiology. Confirmation of the diagnosis of DIC should always prompt a search for an underlying medical disorder, including sepsis, severe trauma, solid and hematological malignancies, obstetrical complications, and vascular disorders. Here, we describe an unusual case of acute bleeding and DIC as the presenting manifestation of metastatic prostate cancer.
CASE PRESENTATION
A 60-year-old white male presented with a 4-day history of bleeding from the gums, diffuse spontaneous ecchymoses, mild fatigue, and bone pain. The patient described a 6-month history of pain localized to his right thigh with extension to the posterior part of his right leg. His past medical history included atrial fibrillation, hypercholesterolemia, and hypertension, all well controlled with medication. He had never smoked and had moderate alcohol consumption until 1 year ago.
When he presented at another hospital, he had dry blood in his mouth but no active bleeding. His blood pressure was 138/64, his pulse rate was 57, and his temperature was 37.3°C. There was no peripheral lymphadenopathy. Chest was clear to auscultation and the liver and the spleen were not palpable. Examination of the lower extremities showed confluent ecchymoses involving the left ankle, and the posterior of both thighs (Figs. 1 and and22).
Confluent ecchymoses on the right thigh.
Confluent ecchymoses on the left ankle.
Laboratory evaluation revealed hemoglobin of 13.4 g/dL (normal: 14 to 16 g/dL), platelets of 107 × 103/μL (normal: 150 to 400 × 103/μL), and total leukocytes of 8.1 × 103/mm3 (normal: 4.0 to 11 × 103/mm3). His prothrombin time was 22.8 seconds (normal: 11.5 to 15.5 seconds), and his INR was 1.92 (normal: 1 to 1.25). The activated partial thromboplastin time (aPTT) was 45 seconds (normal: 25.2 to 36 seconds), the serum fibrinogen was <0.30 g/L (normal: 1.3 to 3.5 g/L), and the plasma concentration of d-dimers was >4 μg/mL (normal:≤0.40 μg/mL). Plasma levels of factors V, VII, XIII, and activated protein C as well as serum creatinine and liver function tests were within normal limits. Examination of a blood smear was consistent with a normochromic, normocytic anemia, with reduced platelets and large forms, and possible blasts with folded nuclei. Shortly after admission, all coagulation parameters worsened (INR=2.92; PT=32 seconds; aPTT=55 seconds) and the ecchymoses increased in number and extent.
The patient was transferred to our institution with a diagnosis of DIC, and probable acute leukemia (most likely acute promyelocytic leukemia [APL]). A bone marrow biopsy was performed and the patient was started empirically on all-trans-retinoic acid and supportive treatment for DIC. Twenty-four hours later, a test for serum prostate-specific antigen (PSA) obtained at the referring hospital was reported as PSA=257 ng/mL (normal: <4 ng/mL). A digital rectal exam revealed a small nodule in the posterior right lobe of the prostate with no other abnormalities. The bone marrow biopsy confirmed the presence of metastatic prostate cancer and no blasts were found on re-evaluation of the blood smear. A bone scan and computed tomography imaging indicated the presence of extensive mixed lytic and sclerotic bone lesions involving the spine, and upper and lower extremities.
The patient was started on an antiandrogen (bicalutamide), and subsequently received a luteinizing hormone-releasing hormone (LHRH) agonist (leuprolide). After 1 week of treatment, the coagulation parameters had returned to normal, except for slightly low levels of serum fibrinogen and slightly elevated d-dimers. There was substantial improvement in his pain, although he continued to have moderate discomfort localized to the upper right leg. There was no further bleeding. The patient was discharged and completed palliative radiation to the right hip and upper femur (20 Gy in 5 fractions) as an outpatient. On subsequent follow-up visits, there was a progressive decrease in serum level of PSA (to 0.56 ng/mL at 3 months after diagnosis) and the patient presented no symptoms.
DISCUSSION
Disseminated intravascular coagulation is a clinicopathologic syndrome that is not a specific disease but a manifestation of an underlying disorder. Therefore, recognition that a patient has DIC mandates a search for an underlying clinical condition. The pathogenesis of DIC proceeds from the simultaneous occurrence of systemic fibrin production with impaired mechanisms to prevent coagulation and inadequate fibrinolysis. Increased formation and abnormal removal of fibrin, through thrombin generation, will lead to widespread intravascular deposition of this protein, resulting in thrombotic occlusion of midsize and small vessels. Simultaneous use and subsequent depletion of platelets and clotting factors, resulting from the ongoing coagulation, may induce severe bleeding.,
Hematology Case Studies For Nurses
The clinical presentation of DIC depends on the underlying condition that triggers this medical disorder. Some patients may have a mild or protracted clinical course, with consumption of coagulation factors and minor or no symptoms. This clinical scenario has been referred to as chronic or low-grade DIC and is mostly observed in patients with underlying mucin production because of malignant tumors or vasculitis. In other patients, activation of the fibrinolytic system may dominate over the excessive coagulation, resulting in massive generation of thromboplastic material and consumption of hemostatic elements. This presentation is referred to as acute bleeding DIC and it has been associated most often with sepsis, obstetrical complications, gross tissue injury, or promyelocytic leukemia.,
Laboratory studies used in the diagnosis of patients with DIC include tests of thrombin and plasmin generation (d-dimers and the protamine paracoagulation assay for fibrin monomer) and tests of hemostatic function that delineate the severity of consumption of coagulation factors (PT, PTT, and thrombin time). The diagnosis of DIC should not be made without at least 1 positive test indicative of thrombin generation. The most frequent laboratory abnormalities observed are thrombocytopenia, elevated fibrin/fibrinogen degradation products, prolonged PT, prolonged thrombin time, prolonged PTT, and low fibrinogen.
A number of clinical disorders not associated with DIC can result in acquired bleeding diathesis and laboratory hemostatic abnormalities and should always be considered in the differential diagnosis. These include: (1) thrombocytopenia: Because of primary bone marrow failure; infiltrative marrow process, such as leukemia; endothelial-mediated platelet activation, such as in vasculitis or thrombotic thrombocytopenic purpura (TTP); or immunologic destruction, such as in idiopathic thrombocytopenic purpura. (2) Primary fibrinolysis (PF): There is independent generation of plasmin without concomitant thrombin generation. Patients have low fibrinogen and elevated fibrin degradation products. In addition, patients with liver disease and PF may present with thrombocytopenia secondary to splenic sequestration. The differential diagnosis in these patients will be determined by a shortened euglobin clot lysis test and a negative protamine coagulation assay for fibrin monomers.
In the case reported above, presentation with acute bleeding DIC (typical of APL), along with an erroneous interpretation of a first blood smear, led to a wrong diagnosis. Download insaniquarium deluxe full version free. Consideration of the differential diagnosis is essential when dealing with DIC and no evident cause, and an underlying malignancy should always be considered. Although traditionally associated with low-grade DIC, the present and other published cases provide evidence to link prostate cancer with acute bleeding DIC.–
The association of DIC with solid and hematological malignancies has been extensively documented., Ten to 15% of patients with metastatic tumors have some evidence of DIC, and it is present in approximately 15% of patients with acute leukemia. An analysis of DIC in patients with solid tumors revealed that the most common laboratory abnormalities are thrombocytopenia, hypofibrinogenemia, and elevated serum levels of d-dimers and fibrinogen degradation products. Mechanisms leading to DIC in patients with cancer are unclear, but probably involve procoagulant factors that are expressed on the surface of tumor cells. Older age, male sex, primary tumor necrosis, and advanced tumor stage were found to be risk factors for DIC in a multivariate analysis.
Disseminated intravascular coagulation is the most frequent coagulation disorder in patients with prostate cancer.10, It may occur as a result of the introduction of thromboplastic substances into the blood stream after a biopsy of either the primary tumor or a metastatic site, or it may develop as a manifestation of advanced disease., However, DIC as a first manifestation of prostate cancer is unusual.–,
Optimal management of DIC associated with prostate cancer requires treatment of the tumor in combination with supportive measures to control the abnormal coagulation. Hormonal treatment with an LHRH agonist in conjunction with a previous short course of an antiandrogen to avoid a “flare” reaction is the treatment of choice in patients who are likely to be hormone sensitive. The use of high-dose ketoconazole (200 to 400 mg t.i.d.) has been described as an effective way to bring about a rapid decrease in serum testosterone level through inhibition of adrenal production of testosterone, and is indicated in patients with life-threatening DIC because of severe uncontrolled bleeding. Chemotherapy is reserved for patients who do not respond to hormone manipulations, and resolution of DIC has been reported following treatment with various cytotoxic combinations.– Some radiopharmaceuticals have successfully reverted cases of coagulopathy in patients with an androgen-independent prostate cancer, although their role remains controversial., Once treatment has been directed at the primary illness, therapy can be directed to the DIC itself. The severity of bleeding, the platelet count, and the levels of coagulation factors will determine the need to replace blood components. The use of heparin is still debated in the management of DIC. Two nonrandomized studies showed benefit and no increase in bleeding in patients with DIC., Fresh-frozen plasma and cryoprecipitate can be recommended when faced with life-threatening episodes of bleeding.
Other coagulopathies less frequently associated with prostate cancer include TTP, thrombosis (i.e., venous thrombosis or pulmonary embolism), primary fibrinolysis, and acquired factor VIII inhibitor development. The differential diagnosis between these entities is based on platelet count, coagulation parameters, and clinical findings. Primary fibrinolysis is characterized by the absence of elevated d-dimers and normal platelet and antithrombin III levels. Clinical findings such as fever, renal failure, and neurological abnormalities along with thrombocytopenia, microangiopathic anemia, and normal coagulation times, will define TTP.
In summary, we present a case that illustrates the importance of an appropriate differential diagnosis when trying to determine the process underlying DIC. The case illustrates how an erroneous interpretation of a diagnostic test may lead to a wrong diagnosis. The presence of DIC in the absence of an obvious cause should prompt a search for malignancy, including a complete physical exam with a rectal examination to detect prostate cancer. Special consideration should be given to those cases of DIC that present as severe bleeding episodes in whom a treatable disease such as prostate cancer could be easily diagnosed and promptly treated.
REFERENCES
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Hematology Case Studies With Answers
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