Subject: Pathology Topic: RBC s and Bleeding Disorders Lecturer: Dr.

Cagampan Date of Lecture: August 9, 2011 Transcriptionist: Mopster and Pinay Editor: Mopster and Pinay Pages: 15 Bloodlines

Above: From pluripotent cells arise the WBC and RBC and lymphoid series. Note that some cells will arise from the same mother cell. Anemias y Reduction below normal limits of the total circulating red cell mass y Reduced oxygen transport capacity of the blood y Reduction below normal in the volume of packed red cell as measured by hematocrit or hemoglobin concentration y IOW, the patient will appear pale and weak from lack of oxygen. Classification of Anemia According to Underlying Mechanism y Blood loss y Increased rate of destruction (hemolytic anemias) y Impaired red cell production Anemia of Blood Loss Acute blood loss (microcytic, hypochromatic RBC s may not be evident) y Reflect loss of blood volume may lead to shock, death y Hemodilution shift of water from interstitial fluid compartment into intravascular space y Erythropoietin production reticulocytosis (Immature RBC containing remnants of nuclei seen only in special stain. Bigger than usual RBC. Polychromatophilic bluish red hue) reaching 10 15% y Reticulocyte count normally 0.5 1.5% Chronic blood loss (microcytic, hypochromic RBC s are more evident in chronic blood loss) y GIT bleeding: gastric ulcer, hematemesis, hemorrhoids o Striking reticulocytosis may not be seen. y Gynecologic causes 1

SY 2011-2012

 Increased Rate of Destruction (Hemolytic Anemia) y Intrinsic (intracorpuscular) abnormalities of red cells o Hereditary  Red cell membrane disorders  Disorders of membrane cytoskeleton: spherocytosis, elliptocytosis  Disorders of lipid synthesis: selective increase in membrane lecithin  Red cell enzme deficiencies  Glycolytic enzymes: pyruvate kinase deficiency, hexokinase deficiency  Enzymes of hexose monophosphate shunt: G6PD, glutathione synthetase  Disorders of hemoglobin synthesis  Deficient globin synthesis: thalassemia syndromes  Structurally abnormal globin synthesis (hemoglobinopathies): sickle cell anemia, unstable hemoglobin o Acquired  Membrane defect: paroxysmal nocturnal hemoglobinuria y Extrinsic (extracorpuscular) abnormalities o Antibody mediated  Isohemagglutinins: transfusion reactions, erythroblastosis fetalis  Autoantibodies: idiopathic (primary), drug associated, SLE, malignant neoplasm, mycoplasmal infections o Mechanical trauma to red cells  Microangiopathic hemolytic anemia: thrombotic thrombocytopenic purpura, DIC  Cardiac traumatic hemolytic anemia  Infections: malaria  Chemical injury: lead poisoning  Sequestration in mononuclear phagocyte system: hypersplenism Impaired Red Cell Production y Disturbance of proliferation and differentiation of stem cells: aplastic anemia, pure red cell aplasia, anemia of renal failure, anemia of endocrine disorders y Disturbance of proliferation and maturation of erythroblasts: o Defective DNA synthesis: deficiency or impaired use of vitamin B12 and folic acid (megaloblastic anemia) o Defective hemoglobin synthesis  Deficient heme synthesis: iron deficiency  Deficient globin synthesis: thalassemias

Unknown or multiple mechanisms: sideroblastic anemia, anemia of chronic infections, myelophthisic anemia due to marrow infiltration

Hemolytic Anemia y Premature destruction of red cells and a shortened red cell life span below the normal 120 days y Elevated erythropoietin levels and a compensatory increase in erythropoiesis y Markedly increased erythropoiesis with associated reticulocytosis y Accumulation of hemoglobin degradation products released by red cell breakdown derived from hemoglobin (e.g., bilirubin) y Pigment stone formation as a result of hemoglobin degradation. y Tend to produce extravascular hemolysis although, on occasion, intravascular hemolysis may occur. y Tend to be autosomal dominant y Rare in the Philippines, except Thalassemia. y Intravascular hemolysis (causes): o Mechanical injury: e.g., prosthetic cardiac valves, thrombi o Complement fixation to red cells: e.g., mismatched transfusion o Toxic injury: e.g., malaria y Manifestations of intravascular hemolysis: o Anemia o Hemoglobinemia o Hemoglobinuria o Jaundice: a small percentage of gall stones are of hemoglobin origin o Hemosiderinuria Extravascular hemolysis o Occurs in mononuclear phagocytes of spleen o Predisposing factors:  Red blood cell membrane injury  Reduced deformability  opsonization o Sequestration of deformed or foreign red blood cells followed by opsonization phagocytosis as red cells navigate sinusoids o These sequestered RBC s are rendered palatable to macrophages due to hypoxia and ATP depletion. o Clinical features  Anemia  Splenomegaly  Jaundice Morphology of hemolytic anemias o Normoblastic hyperplasia in marrow o Reticulocytosis in peripheral blood o Pigment gallstones o Hemosiderosis o Jaundice, anemia

Below: Defective RBC s sequestered outside are then phagocytized.

Below: How primary membrane defect leads to phagocytosis on a chemical basis. This pathophysiology is common to most hemolytic anemia and needs to be known by heart.

Hereditary Spherocytosis y Intrinsic defect in RBC membrane ankyrin deficiency and other (usually spectrin) skeletal membrane components y RBC spheroidal, less deformable, vulnerable to splenic sequestration and destruction y Ankyrin deficiency associated with reduced stability and loss of membrane fragments as cells traverse circulation y Inherited disorder, in Northern Europe y Autosomal dominant y Morphology: o Spheroidal RBC (normal is biconcave disc) o No central pallor noted o Moderate splenomegaly due to marked congestion of the cords of Billroth o Erythrophagocytes in the splenic cords o Features of hemolytic anemia y Clinical course: treatment is splenomegaly o Chronic hemolytic anemia mild to moderate o Aplastic crisis parvovirus infection o Hemolytic crisis o Diagnosis: Osmotic Fragility Test Below: Cell membrane defect leads to formation of spherocytes, which are sequestered and rendered palatable to macrophages.

Below (next 2 photos): Note round shape of RBC s and absence of central pallor.

G6PD Deficiency y X linked y One of the tests for newborn screening y Impaired or deficient enzyme function which reduce ability of red cells to fight against oxidative injuries y Abnormalities in Hexose Monophosphate Shunt pathway or glutathione metabolism y Need reduced glutathione to protect RBC against oxidants y Oxidant stress: o Drugs: antimalarials, sulfonamides, etc o Infection: viral hepatitis, TF, pneumonia o Fava bean ingestion

Pathogenesis: Oxidative stress results in the oxidation of globin chains which causes the globin chains to denature and precipitate to form Heinz Bodies. Heinz bodies render the RBC palatable to phagocytes. Sometimes, the Heinz bodies are so abundant, that intravascular hemolysis can occur. Extravascular and intravascular hemolysis can occur.

Below: Not the Bite Cell in the center of the larger picture. In the smaller picture in the upper left corner, note the presence of Heinz Bodies under special stain.

Infarction in bone, brain, kidney, liver, and retina o Leg ulcer, cor pulmonale o Pigment gallstones y Clinical course: o Severe anemia: reticulocytosis o Vasoocclusive complications: acute chest syndrome o Chronic hyperbilirubinemia: gallstones o Increased susceptibility to infection septicemia and meningitis o CNS hypoxia: seizures, stroke o Aplastic crisis: triggered by parvovirus infection o Sequestration crisis o Priapism: thrombi lead congestion of blood vessels which can lead to persistent, painful erection. y Diagnosis o PBS, metabisulfite-induced sickling o Hemoglobin electrophoresis o Fetal DNA by chorionic biopsy of amniocentesis Below: Single point mutation leads to sickle cell formation which leads to hemolysis in the spleen and infract in the tissues. o

Sickle Cell Anemia y Structurally abnormal hemoglobin y Substitution of valine for glutamic acid at the 6th position of globin chain y American blacks: o Heterozygote: 40% HgbS o Homozygote: 100% HgbS y Under deoxygenation, the RBC will sickle. y At first the sickling is reversible until such time that the RBC can no longer change its shape and is sequestered and phagocytized. y Infarction: sickle cells have the unique feature of having increased adhesion to each other. This what causes them to aggregate and form thrombi which can lead to infarct. y Morphology: o Hyperplastic marrow lead to resorption of bone o Extramedullary hematopoiesis o Sickle red cells o Initial splenomegaly erythrocytosis thrombosis and infarction scarring autosplenectomy

Below: Sickle cell admixed with anisocytosis, hypochromia, poikylocytosis

Below: Spleen shrunken down to 3 cm.

Below: Severe congestion because of trapping of the RBC s

Clinical course: o Growth retardation o Death at early age of homozygous patient o Manifestation depends on severity o Prone to infection Below: Typical facie of patient with thalassemia. Prominent cheekbones are a result of increased blood production by the facial bones in order to compensate for RBC loss. y

Thalassemia y type seen in the Philippines o There are 2 genetic loci for the chain, thus there are 4 alleles. There are 4 types of thalassemia, each type coinciding to a loss a allele.  Type 1: Loss or mutation of single allele. Minimal symptomatology because the other 3 chains are present.  Type 2: 2 alleles affected. Mild anemia.  Type 3: 3 alleles affected. Leads to Hemoglobin H.  Type 4: 4 alleles affected. Hydrops fetalis. No chance of survival. y Patients with mild forms of the disease are usually asymptomatic and are noticed to have anemia when a CBC is ordered. They are then given iron, which does not improve the anemia. The astute doctor may suspect another diagnosis, order an electrophoresis and this is when thalassemia is diagnosed. y Mendelian disorder characterized by a lack of or decreased synthesis of either or globin chain of HbA y Thalassemia lack of globin chains with excess chain o Thalassemia major: both alleles of the chain are affected. o Thalassemia minor: only one allele of the chain is affected. Aka, Cooley s anemia. y Thalassemia lack of globin chains, with excess , , y Excess chains will precipitate and result in phagocytosis y Facie: prominent cheekbones because of increased blood production y Target cells: typical cells seen in Thalassemia but not exclusive to it. y Morphology: same as in all HA o Crew-cut appearance of bone on Xray due to marrow expansion with thinning of cortical bone with few bone formation on the external aspect o Hepatosplenomegaly o Hemosiderosis

Below: Pathophysiology of thalassemia. There is reduced hemoglobin with a relative excess hemoglobin as a compensatory mechanism. The excess globin precipitates in RBC. Most die in bone marrow, but some will make it into circulation where they will be sequestered in spleen and destroyed. The resulting anemia causes increased erythropoiesis and increased iron absorption as the body attempts to correct the anemia. As a result, bone marrow expansion occurs as does systemic iron overload. The bone deformities that result in the facie are a result of bone marrow expansion. Note that iron overload also comes from destruction of the erythroblasts within the bone marrow and from regular blood transfusions that are required by these patients.

Below (next 3 pics): Target cells. Note: these are not exclusive to thalassemias.

Answer: Codocyte, leptocyte, or Mexican hat cell. Seen in thalassemia, liver disease, post splenectomy patient. What causes targeting is uneven distribution of hemoglobin. Paroxysmal Nocturnal Hemoglobinuria y Acquired defect in cell membrane y Somatic mutation of the PIGA gene which is essential for synthesis of the GPI (glycophosphatidylinositol) anchor y GPI linked proteins inactivate complement y Other cells affected because GPI is found in all blood cells, so patient can have pancytopenia. y If patient is subject to an immune reaction involving complement it can lead to lysis. y Ham s Test: how it s diagnosed. Immunohemolytic Anemia y Demonstration of the anti RBC Ab y Coomb s Test Classification of Immune Hemolytic Anemias y Warm Antibody Type o The antibody is of the IgG type, does not usually fix complement and is active at 37 C. o Primary (Idiopathic) o Secondary  Lymphomas and leukemias  Other neoplastic diseases  Autoimmune disorders (particularly SLE)  Drugs y Cold Agglutinin Type o The antibodies are IgM and are most active in vitro at 0 C to 4 C. Antibodies dissociate at 30 or above; agglutination of cells by IgM and complement fixation only in peripheral cool parts of the body (eg, ears, toes, and fingers) o Acute:  Mycoplasmal infection  Infectious Mononucleosis o Chronic:  Idiopathic  Associated with lymphoma y Cold Hemolysin type (Paroxysmal Hemoglobinuria) o IgG antibodies bind red cells at cold temperature, fix complement, and cause hemolysis when the temperature is raised above 30 C. Hemolytic Anemia Resulting from Trauma to rBC 1. Prosthetic cardiac valves (mechanical) 2. Microangiopathic Hemolytic Anemia: abnormally narrowed vessels

Below: Crew cut appearance of skull resulting from increased erythropoiesis.

Below: Hepatic hemosiderosis in Beta Thalassemia

Assignment: Another name for target cell, why does it happen?

a. In DIC, malignant HTN, SLE, TTP, Hemolytic-uremic syndrome, disseminated cancer b. See schistocytes, burr, helmet cells, and triangle cells (couldn t find a pic, but some explanations basically say these are RBC remnants that resemble triangles). Note: schistocytes are usually a sign of trauma, intravascular or extravascular. Below: Schistocyte

Anemias of Diminished Erythropoiesis Megaloblastic Anemia y Impaired DNA synthesis leading to defective nuclear maturation. DNA synthesis is affected but RNA synthesis does not. y Asynchronism between nuclear and cytoplasmic maturation. Immature nucleus with very mature and often huge cytoplasm y Due to folate or vitamin B12 deficiency. o Vitamin B12 must be obtained through the diet. It is absorbed in the ileum and requires intrinsic factor. o These are necessary for DNA synthesis o RNA synthesis continues o There is a lag so cell becomes megaloblastic y Morphology: o Macro ovalocytes o Hypersegmented neutrophils (>6 lobes) o Bone marrow hypercellular (1:1) o Megakaryocytes large with bizarre, multilobate nuclei o Ineffective erythropoiesis intramedullary destruction of megaloblast o Increased hemolytic destruction of RBC o Leukopenia and thrombocytopenia o In short, pancytopenia

Below: Burr cell

Below: Target cell

Below: Helmet cell. Resembles Bite Cell, but Bite Cell will have 1 bite, Helmet Cell will have >1 bite.

Below: Normal vitamin B12 metabolism. R binder is produced by the salivary gland. Vitamin B12 is digested in the stomach via gastric acids and binds with R binder. It is carried through the small intestine, where the B12 R-binder complex is digested by proteases. Vitamin B12 is now bound to Intrinsic Factor and carried to the ileum, where it is absorbed into the portal circulation. Intrinsic factor is the switch by which vitamin B12 is absorbed. Disruption of the GI tract, loss of R binder or Intrinsic Factor can all lead to malabsorpton of vitamin B12.

Below: Macroovalyctes. Bone marrow would be hypercellular, composed of RBC series, all megaloblasts. Because megaloblastic anemia affects all cell lines, PMN s will also be affected. They will appear, as below, as hypersegmented (>5 lobes) because of the asynchrony between DNA and RNA synthesis. Sometimes, the deficiency is so bad, RBC s can be destroyed in the bone marrow ineffective erythropoiesis just like Thalassemia. Again, megaloblastic anemia may manifest as pancytopenia in the bone marrow.

Below: Bone marrow looks busy, hypercellular. The cells are very large nucle, hyperchromatic, and granular. There appears to be maturation of the cytoplasm with a lag in the nucleus:cytoplasm ratio.

Below (next 3 pictures): Macro PBS with schistocytes.

ovalocytes in the

Below: Atrophic glossitis

Pernicious Anemia y Autoimmune destruction of gastric mucosa y Chronic atrophic gastritis lack of intrinsic factor y Presence of autoantibodies against parietal cells blocking Ab, Type II Ab and parietal canalicular Ab y Morphology: o GIT  Atrophic glossitis  Diffuse chronic gastritis. This is specific to pernicious anemia. If it is not due to pernicious anemia, you won t find this.  Intestinalization of gastric glands o CNS lesion  Myelin degeneration of the dorsal and lateral tracts sensory motor deficits y Diagnostic features: o Moderate to severe megaloblastic anemia o Leucopenia with hypersegmented granulocytes o Mild to moderate thrombocytopenia o Neurologic changes: subacute combined degeneration o Achlorydia even after histamine stimulation. Remember, histamine is supposed to release gastric acids. The patient with pernicious anemia will not do this. o Inability to absorb oral dose of cobalamine Schilling Test o Low serum B12 o Excretion of methylmalonic acid in urine o Improvement after parenteral B12 o Demonstration of antibody to instrinsic factor

Below: Atrophic gastritis

Below: myelin degeneration of the dorsal tracts

Below: Myelin degeneration of the lateral tracts

reference to determine the relative size of RBC. PMN s are around 12 m. The RBC s in the PBS below are the size, so around 4 5 m. Normal RBC s are usually 6 7 m, or 1/3 the size of a PMN.

Folate Deficiency y Same as B12 deficiency but without neurologic changes Iron Deficiency Anemia y Most common nutritional deficiency y Iron is absorbed in the duodenum and can be recycled. y Storage pool of Fe: hemosiderin and ferritin y Ferritin: o Protein iron complex; stored in parenchymal cells or within RES o Level is a good indicator of adequacy of body iron stores o Iron deficiency anemia iron Ferritin y Transferrin: o Iron binding glycoprotein which transports iron in plasma; deliver iron to cells including erythroid precursors (TIBC) o When iron is deficient TIBC (because the body is scavenging for iron) y Causes of iron deficiency: o Dietary lack: in elderly, poor, infants, and children o Impaired absorption: in malabsorption o Increased requirement: growing infants and children, adolescents, premenopausal, pregnancy o Chronic blood loss: hemorrhoids, GIT Ca, parasitism, menstrual abnormalities, urinary tract bleeding y Morphology: o Normoblastic hyperplasia in marrow o Microcytic, hypochromic RBC y Diagnosis: o PBS findings, decreased hemoglobin and hematocrit, low serum Fe and serum Ferritin TIBC (transferrin concentration) is high

Anemia of Chronic Disease y Reduced erythroid proliferation and impaired Fe utilization y Chronic infection: osteomyelitis, bacterial endocarditis, lung abscess y Chronic immune disorder: RA, Crohn s y Neoplasms: Hodgkin s CA of lung and breast y Pt. peripheral blood smear may appear like iron deficiency anemia, but stores are normal y The failure is in the utilization of iron, not in the amount. y Diagnosis: o Low serum Fe, decreased TIBC but abundant stored iron in marrow macrophage o Low erythropoietin levels marrow hypoproliferation Aplastic Anemia y Pancytopenia characterized by anemia, neutropenia, and thrombocytopenia y Bone marrow is almost converted to fat. Cells present are usually lymphocytes. Normal BM is 50:50. y Morphology: o Markedly hypocellular marrow fatty marrow o Fibrous tissue with scattered lymphocytes

Below: Microcytic, hypochromic RBC s small and paler central pallor. The PMN is used as a point of

Below: Most of the time cause is unknown, but when it is known, it is usually drug induced.

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 Can be caused by : o Increased blood vessel fragility/ Vessel wall abnormality o Platelet disorders/ abnormality (both in function and in number) o Coagulation defects  Evaluation requires laboratory testing: o Bleeding time: tests platelet function o Platelet counts o Prothrombin time: tests extrinsic pathway (Mnemonic: PeT, prothrombin extrinsic time) o Partial Thromboplastin time: tests intrinsic pathway (Remember: PiTT, partial intrinsic thromboplastin time) o Specialized tests (e.g., clotting factor levels) I. Below: Pancytopenia all cells are decreased. Markedly hypocellular marrow. Sometimes fibrotic with scattered lymphocytes. Vessel Wall Abnormality  relatively common but usually do not cause serious bleeding  typically induce only petechial and purpuric hemorrhages  Can be caused by infections, drug reactions, autoimmune diseases, vitamin deficiency, immune complex deposits, or hereditary disorders  normal platelet count, BT, PT, and PTT

Below: Note the abundance of fat in the marrow.

Other Forms of Marrow Failure y Myelophthisic anemia o Due to space occupying lesions in marrow; metastatic carcinoma; multiple myeloma, leukemia, Tb y Diffuse liver disease y Chronic renal failure Below: myelophthisic anemia secondary to leukemia. Leukemias typically fill up the marrow with abnormal cells.

Conditions which causes increased vascular fragility: 1. Infections a. Meningococcemia (Waterhouse Friedrichsen syndrome), gram (-) septicemia, infective endocarditis, rickettsiosis b. Microbiologic damage to vessels (vasculitis) or DIC (Disseminated intravascular coagulation) underlying mechanism 2. Drug reactions often secondary to immune complex deposition in vessel walls with resulting hypersensitivity vasculitis 3. Poor vascular support a. Abnormal collagen synthesis (Scurvy, Ehlers- Danlos Syndrome: impaired collagenous support b. Loss of perivascular supporting tissue (Cushing syndrome) c. Vascular wall amyloid deposition 4. Henoch Schonlein Purpura: systemic hypersensitivity reaction of unknown cause characterized by purpuric rash, abdominal pain, polyarthralgia, and acute glomerulonephritis. Associated with vascular and glomerular mesangial deposition of immune complexes. 5. Hereditary hemorrhagic telangiectasia II. Reduced platelet number: Thrombocytopenia= characterized principally by petechial bleeding, most often from small vessels of skin and mucous membranes. Count is <100,000/mm3 11

Bleeding Disorders

y y y

Normal: 150,000 450,000/mm3 Thrombocytopenia: <100,000/mm3 Spontaneous bleeding: <20,000/mm3

: antibody- mediated platelet destruction y Acute (children) o Self-limiting o Seen most often in children after a viral infection (e.g., rubella, cytomegalovirus infection, viral hepatitis, infectious mononucleosis) o Platelet destruction is due to transient antiplatelet autoantibodies. Chronic (adult<40 y/o), mostly female of childbearing age o Long history of easy bruising or nosebleeds o Platelet autoantibodies (synthesized in the spleen) are usually directed toward one of two platelet antigens (platelet membrane glycoprotein complexes IIb/ IIIa or Ib/IX). o Destruction of antibody-coated platelets occurs in the spleen. o Splenectomy benefits 75- 80% of patients Antiplatelet antibodies Pathogenesis: opsonized platelet susceptible to phagocytosis by RES cells (in spleen) Morphology: spleen normal in size o Congestion of sinusoids and enlarged follicles o Prominent germinal centers o Megakaryocytes within sinusoids o Bone marrow increase number of megakaryocytes

***Sometimes patient has <10,000/mm3 and patients don t bleed, or has <50,000/ mm3 and already experienced spontaneous bleeding therefore clinically it really depends on when to start your management; as physicians we should know when to act y Causes: a. Decreased production: due to ineffective megakaryopoiesis (e.g., megaloblastic states) or to generalized marrow disease that also compromises megakaryocyte number (e.g., aplastic anemia, disseminated cancer). b. Decreased survival: due to immunemediated platelet destruction, usually with a compensatory megakaryocytic marrow hyperplasia -it can follow drug exposure or infections -platelet deficiencies due to consumption often occur in systemic coagulopathies (DIC, hemolytic uremic syndrome, thrombotic thrombocytopenia purpura). c. Sequestration: platelets are retained in the red pulp of enlarged spleens d. Dilution: massive whole blood transfusions can cause a relative reduction in the number of circulating platelets because storage for longer than 24 hours at 4C results in rapid hepatic platelet sequestration upon infusion. e. HIV: results from immune complex injury, antiplatelet antibodies, and HIV- induced suppression of megakaryocytes.

y y

Below: Bone marrow in ITP increased number of megakaryocytes, because it is a compensatory mechanism. If ITP count is not increased in the bone marrow, you can pretty much rule out ITP.

Idiopathic Thrombocytopenic Purpura Immune Thrombocytopenic Purpura

(ITP)/

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Below: normal spleen. But there may be megakaryocytes in the spleen.

Thrombotic Microangiopathies: -characterized by o Thrombocytopenia o Microangiopathic hemolytic anemia o Fever o Transient neurologic deficits (in TTP) o Renal failure (HUS) -most of the clinical manifestations are due to widespread hyaline microthrombi in arterioles and capillaries (microcirculation) composed of dense aggregates of platelets and fibrin -platelets adhere more to the thrombi y Thrombotic Thrombocytopenic Purpura (TTP) o Associated with inherited or acquired deficiencies in ADAMTS13 (a matalloprotease that limits the size of von Willebrand factor multimers in the plasma. o In adult female o Pentad of: fever, thrombocytopenia, microangiopathic hemolytic anemia, neurologic defects, renal failure o Probably viral - induced y Hemolytic uremic syndrome (HUS) o Commonly follows gastrointestinal infections with verotoxin-producing E.coli. Verotoxin injures endothelial cells promotes dysregulated platelet activation aggregation o Microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure Onset in childhood Follow infection with verotoxin producing E. coli

Bleeding Related to Defective Platelet Function A. Congenital Disorders 1. Defective adhesion a. Bernard Soulier Syndrome : caused by deficient platelet membrane glycoprotein complex GpIb/ IX- platelet receptor for vWF and necessary for platelet-collagen adhesion b. Inherited deficiency of platelet membrane glycoprotein 2. Defective aggregation a. Thrombasthenia: caused by deficient platelet membrane glycoprotein GpIIb/ IIIa- involved in binding fibrinogen 3. Defective secretion- platelet will secrete an enzyme to stabilize the plug B. Acquired disorders 1. Aspirin ingestion- potent inhibitor of cyclooxygenase and can suppress the synthesis of thromboxane A2 for platelet aggregation 2. Uremia III. Bleeding due to Abnormalities in Clotting Factors

o o

Both show widespread formation of hyaline thrombi in microcirculation

von Willebrand s Disease y Autosomal dominant y Characterized by spontaneous bleeding from mucous membranes; excessive bleeding from wounds, menorrhagia

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y y y

Prolonged BT, PTT, normal platelet count, reduced vWF and Factor VIII levels May have quantitative or qualitative effect in VWF Compound defects involving platelet function and coagulation pathway

Hemophilia A (Factor VIII Deficiency) y X linked recessive trait; in male and homozygous female y Reduction in amount or activity of Factor VIII y Severity depends on Factor VIII activity;<1% Factor VIII activity is severe disease y Easy bruising and massive hemorrhage after trauma or operation y Spontaneous joint hemorrhages hemarthroses recurrent bleeding deformities y Normal BT, platelet count, and PT, prolonged PTT Below: Easy bruising is common

Below: Bleeding gums is common

Disseminated Intravascular Coagulation (DIC) -an important complication= not a disease but a complication of some other disease y Acute, subacute, and chronic thrombohemorrhagic disorder occurring as a secondary complication in a variety of disease y Characterized by activation of the coagulation sequence that leads to formation of microthrombi throughout the microcirculation y Consumption of platelets, fibrin, coagulation factors with secondary activation of fibrinolytic mechanisms Consumptive Coagulopathy y 2 major mechanisms which trigger DIC o Release of tissue factors or thromboplastic substances o Injury to endothelial cells releasing thromboplastic substances, which causes:  Massive thrombosis  Bleeding to death ***massive thrombosis release of thromboplastic substances trigger the coagulation system consume more factors bleed spontaneously death. ***Can be difficult to treat as there are 2 stages: thrombotic and bleeding. If patient is in the thrombotic stage, then giving fibrinogen can potentially worsen the condition because it consumes more factors to be used. If during the bleeding stage, giving thrombotic agents can also hasten the bleeding. ***Thrombi can lead to ischemia tissue damage y Morphology: o Multiple thrombi in one or several organs o ARDS in lungs, microinfarcts in brain, adrenal hemorrhages Below: common causes of DIC. Most common infective agent is Gram negative sepsis. Whatever, the cause, it triggers DIC through the release of coagulation factors.

Below: Genogram showing the X linked inheritance of Hemophilia in the royal families of Europe.

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Below: Pathophysiology of DIC

Below: DIC causes thrombi that can lead to occlusion of the blood vessels ischemia in various organs.

Note: With DIC the patient is usually admitted for another condition, but develops clotting disorders because DIC is a complication and rarely a primary disorder itself. -------------------------------------------------- End of Transcription -------------------------------------------------------And God showed His love for us by sending His own Son into the world. 1 John 4:9-10

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