Disorders of Primary Hemostasis and Thrombosis PDF

VASCULATURE AND PLATELETS Disorders of z Primary Hemostasis and Thrombosis z VASCULAR ABNORMALITIES  Disorders of the microcirculation, platelets, or plasma proteins may cause abnormal bleeding – purpura  Petechiae – small,...

VASCULATURE AND PLATELETS Disorders of z Primary Hemostasis and Thrombosis z VASCULAR ABNORMALITIES  Disorders of the microcirculation, platelets, or plasma proteins may cause abnormal bleeding – purpura  Petechiae – small, purplish hemorrhagic spots into the skin or mucous membranes  Ecchymosis – patches of bleeding into the tissues are larger z z z Types of Vascular Conditions  Mechanical force  Genetic structural malformation  Inflammation and obstruction of blood vessels  Disorders of perivascular tissue  Miscellaneous causes such as infection, skin disease, and psychogenic reasons z Blood Vessel Malformation  Hereditary Hemorrhagic Telangiectasia (HHT) – Osler-Weber- Rendu disease - Genetic mutations - Autosomal dominant trait - Reduced amount of functional proteins available in the tissue lining the blood vessels. - Result in skin and mucous membrane-associated epistaxis and other bleeding conditions. z  ENG, ACVRL1, and SMAD4 genes – interact with growth factors that control blood vessel development  Types of HHT - Type 1 - ENG - Type 2 – ACVRL1 - Type 3 – unknown  Juvenile polyposis/HHT syndrome is caused by mutations in the gene SMAD4 z Other Vasculopathies  Patients with Multiple Myeloma or Systemic Amyloidosis  Moyamoya disease  Cerebral small vessel disease z Vasculitis  Anti-neutrophil Cytoplasmic Antibody-Positive Vasculitis (ANCA)  Cryoglobulinemia  Hypergammaglobulinemic purpura  Henoch-Schönlein purpura (HSP) z Anti-neutrophil Cytoplasmic Antibody – Positive Vasculitis (ANCA)  c-ANCA and p-ANCA  Observed in SLE and Wegener’s granulomatosis  Serologic markers of primary necrotizing systemic vasculitis z Cryoglobulinemia  Cryoglobulin immune deposits – precipitate in dermal vessels  Waldenström’s primary macroglobulinemia (WM) – 90% of patients have MYD88 L265P mutations  Symptoms: cutaneous infarcts and petechiae.  Platelet count is normal, chronic anemia and bleeding episodes  Bleeding caused by abnormalities in platelet adhesiveness and prothrombin time (PT) may be seen, and the values of factor VIII may be low.  Increased intraluminal pressure z Hypergammaglobulinemic purpura  Characterized by polyclonal hypergammaglobulinemia  Secondary forms – autoimmune disorders such as Sjögren’s syndrome and SLE, chronic hepatitis C z Henoch-Schönlein Purpura  Occurs primarily in children 4 and 11 years old  Reddish-purple spots, which look like bruises, are the most distinctive and universal sign of HSP.  acute immunoglobulin A (IgA)-mediated disorder characterized by a generalized vasculitis involving the small vessels of the skin, the gastrointestinal (GI) tract, the kidneys, the joints, and, rarely, the lungs and the central nervous system (CNS). z Vascular Obstruction z DIC  Caused by a number of factors  Vascular damage  exposure of collagen  activation of XII  Characterized by excess thrombin formation, conversion of fibrinogen to fibrin, and platelet deposition and consumption  Characterized by both thrombosis and hemolysis z Cryofibrinogenemia  Cryofibrinogen, cold precipitable plasma proteins  The lesions in associated cryofibrinogen disorders, such as Raynaud’s phenomenon, develop as the result of fibrin thrombi obstructing the small- an medium-sized dermal blood vessels z Septic Emboli  Results from the development of tissue ischemia, necrosis of the skin and subcutaneous fate, and occasionally deeper tissues.  Associated with patients who have end-stage renal failure and undergoing hemodialysis z Bleeding because of Perivascular Tissue  Ehlers- Danlos syndrome (EDS)  Marfan’s syndrome  Loeys-Dietz syndrome  Osteogenesis imperfecta  Pseudoxanthoma elasticum  Scurvy  Steroid-induced purpura  Solar purpura (senile purpura) z Ehlers-Danlos Syndrome (EDS)  abnormalities of collagen synthesis or processing.  defects in type 3 collagen, which is particularly abundant in the arterial wall and intestine.  Excessive bleeding  Type IV EDS - prone to arterial aneurysms and dissections, significant bleeding from spontaneous rupture of medium-sized abdominal arteries, and intestinal rupture.  EDS IV - structural defects in the proa1(III) chain of collagen type III encoded by COL3A1 – inherited in an autosomal dominant pattern z Pseudoxanthoma Elasticum (PXE)  Gröenblad - Strandberg syndrome, Grönblad -Strandberg syndrome, or PXE.  Inherited connective tissue disorder that results in calcification and mineralization of elastic fibers, especially in the internal elastic lamina of medium-sized arteries with subsequent rupture of the blood vessel.  Inherited as an autosomal recessive pattern – both copies of the genes in each cell have mutations.  Mutations in the ABC-C6 gene  nonfunctional MRP6 protein z Scurvy  absence of vitamin C, collagen strands are weakened as a result of abnormal triple helical structures.  Abnormal collagen results in defective perivascular supportive tissues, predisposes a patient to capillary fragility, delayed wound healing, petechiae and purpura. z z Solar Purpura (Senile Purpura)  Degradation of collagen and elastin z Purpura Associated with Infections  Acute febrile illness with petechiae  Rickettsial diseases  Brazilian purpura fever  Rat bite fever  Hemorrhagic fever  Vibrio vulnifcus infection  Strongyloides infection  Bacterial toxin produce deendothelialization induced by an endotoxin z Purpura Related to Miscellaneous Causes  Contact dermatitis  Steroid use  Drug reactions  Vascular malignancy (Kaposi sarcoma, vascular tumors)  Purpura simplex  Factitious or self-imposed purpura  Religious stigmata z QUANTITATIVE PLATELET DISORDERS z  Thrombocytopenia  Thrombocytosis z Thrombocytopenia z Major Categories of Thrombocytopenic Conditions  Disorders of production  Disorders of destruction or utilization  Disorders of platelet distribution and dilution z Disorders of Production  Causes by hypoproliferation of the megakaryocytic cell line or ineffective thrombopoiesis caused by acquired conditions or hereditary factors  can result from acquired damage to hematopoietic cells of the bone arrow caused by factors such as irradiation, drugs (e.g., chloramphenicol and chemotherapeutic agents), chemicals (e.g., insecticides), and alcohol. z Disorders of Destruction or Utilization  Destructions caused by immune mechanisms, Antigens, Antibodies, or Complement - Posttransfusion purpura - Drugs - Bacterial sepsis - Immune thrombocytopenia - Isoimmune Neonatal Thrombocytopenia - Thrombocytopenia in pregnancy z  Heparin-Induced Thrombocytopenia (HIT) - Two types: 1. Nonimmune HIT: type I 2. Immune HIT: type II z Nonimmune HIT  a benign disorder affecting up to 10% of patients receiving heparin anticoagulant therapy.  The mechanism of action is direct interaction between heparin and platelets.  Platelet is >100,000/mL, however, a rapid decline is observed within the first 2 days of heparin administration, but platelet count returns to normal levels within 5 days despite continued heparin use or within 2 days if heparin therapy is discontinued. z Immune HIT  Platelet count range between 20,000 to 150,000/mL  The lowest count is reached at about 5 days after the onset of the declining platelet count.  The platelet count begins to rise approximately 2 days after heparin therapy is discontinued and usually returns to normal within 4 to 10 days after discontinuing heparin. z Pathophysiology of HIT  Immune HIT is caused by an antibody that recognizes heparin bound to PF4 on the platelet surface.  The antibody binds to the heparin-PF4 complex, which then allows the antibody to bind the Fc receptor on the platelet.  Interaction with the Fc receptor activates the platelet that results in the loss of platelets, thrombocytopenia, and platelet aggregation (thrombosis). z Laboratory Data of HIT 1. Enzyme-linked immunosorbent assay (ELISA) 2. Platelet aggregation 3. Serotonin release z Increased Utilization of Platelets  Immune Thrombocytopenic Purpura - Idiopathic Thrombocytopenic Purpura - acquired immune-mediated disorder characterized by isolated thrombocytopenia (platelet count less than 100 × 109 /L) and the absence of any obvious initiating and/or underlying cause of the thrombocytopenia. - ITP occurs in children and adults and is characterized by a low platelet count, normal bone marrow, and the absence of other causes of thrombocytopenia. z z Epidemiology of ITP  benign illness in the pediatric population  ITP is classified by duration into newly diagnosed, persistent (3 to 12 months duration), and chronic (≥12 months).  Adults – chronic  Children – acute  ITP is most common in young women (approximately 70% of patients are 10 to 40 years old).  Chronic ITP is a destructive thrombocytopenia caused by an autoantibody. z Clinical Signs and Symptoms of ITP  Purpura  Epistaxis  Gingival bleeding  Hematuria  GI bleeding  Intracerebral hemorrhage z Pathophysiology of ITP  Two new concepts of ITP: 1. The same antibodies that mediate platelet destruction also mediate impaired platelet production by damaging megakaryocytes and/or blocking their ability to release pro- platelets. T-cell – mediated effects are believe to play a role. 2. Ten to twenty percent of cases are not antibody mediated. z 2 Types of ITP  Acute – 2 – 6 y/o just recovered from a viral illness  Chronic – 20 – 50 y/o; produce an IgG antibody that coats the platelets, causing them to be sequestered and subsequently destroyed in spleen. z Laboratory Data of ITP  ASH Guidelines in the Diagnosis of ITP: 1. Presence of thrombocytopenia, lack of anemia unless blood loss has occurred, and lack of white cell abnormalities 2. Absence of other causes of thrombocytopenias (e.g., collagen vascular diseases or lymphoproliferative disorders) 3. Absence of infections, particularly human immunodefficiency virus (HIV) z Treatment  Intravenous immunoglobulin (IVIg or WinRho, anti-D immune globulin)  Splenectomy  Platelet transfusion z Increased Utilization of Platelets  Intravascular coagulation  Vascular injury or occlusion  Tissue injury  Trauma  Obstetrical complications  Microbial sepsis z Thrombotic Thrombocytopenic Purpura  a clinical syndrome with a high mortality rate that is characterized by formation of microthrombi in the microvasculature.  Severe thrombocytopenia  Microangiopathic hemolytic anemia  Fever  Neurologic symptoms, for example, headache, stroke  Renal disease z 3 Type of TTP  Idiopathic – linked to enzyme ADAMTS13 (a disintegrin-like and metalloprotease domain with thrombospondin-type motifs), responsible or the breakdown of large von Willebrand factor (vWF) multimers.  Secondary – diagnosed in patients with history of medications; HIV, autoimmune disorders, allogeneic bone marrow transplant  Hereditary (Upshaw-Schulman) - result of inheritance of a deficiency of ADAMTS13. z Disorders of Platelet Distribution and Dilution  result from a pooling of platelets in the spleen, which is frequent if splenomegaly is present.  This type of thrombocytopenia develops when more than a double or triple increase in platelet production is required to maintain the normal quantity of circulating platelets.  Disorders that may produce splenomegaly with resultant splenic pooling or delayed intrasplenic transit include alcoholic or posthepatic cirrhosis with portal hypertension, lymphomas and leukemias, and lipid disorders such as Gaucher’s disease. z Posttransfusion Thrombocytopenia  Due to massive blood transfusion of units of packed RBC and plasma expanders resulting in reduced platelet count, dilutional thrombocytopenia. z Hereditary Defects of Platelet Function with Thrombocytopenia  Include Fanconi’s syndrome, constitutional aplastic anemia and its variants, ameiosis thrombocytopenia (TAR syndrome), X- linked amegakaryocytic thrombocytopenia, WAS, May-Hegglin anomaly, and Hereditary macrothrombocytopenia (e.g., Alport syndrome)  Platelet morphology must be observed when examining a peripheral blood smear; abnormal variation in size must be noted. z  Disorders of platelet size include the following: 1. WAS, which demonstrates the smallest platelets seen. 2. May-Hegglin anomaly, characterized by the presence of large platelets and the presence of Döhle-like bodies in the granulocytic leukocytes. 3. Alport syndrome, a disorders that exhibit giant platelets and thrombocytopenia 4. Bernard-Soulier Syndrome (BSS), demonstrates the largest platelets seen, also referred as giant platelet syndrome z Wiskott-Aldrich Syndrome (WAS)  Susceptible to infections, patients have problems with abnormal bleeding  There is a reduced ability to form blood clots as the result of unusually small, dysfunctional platelets. z  Etiology - Defective gene is on the short arm of the X chromosome, so the disease is inherited in an X-linked recessive; due to mutations in the WAS gene, and is expressed uniquely in hematopoietic cells - WAS gene provides instructions for making protein called WASp; this protein is involved for relaying signals from the surface of the blood cells to the actin cytoskeleton, the network of fibers that make up a cellular structural framework. z - A lack of functional WASp in platelets impairs their development, leading to reduced size, microthrombocytopenia, and dysfunctional platelets with an intrinsic defect. z  Signs and Symptoms - Thrombocytopenic purpura - Increased susceptibility to bacterial, viral, and fungal infections - Eczema of the skin, atopic dermatitis - Autoimmune manifestations: hemolytic anemia or idiopathic thrombocytopenic purpura caused by self-reactive antibodies; vasculitis that typically causes fever and skin rash on the extremities, also may affect the heart, brain, muscles, or other internal organs z - WAS patients have an increased risk of malignancy - Lymphomas or leukemias that arise from B lymphocytes are the most common - Non-Hodgkin’s lymphoma making up the majority of cases. z  Laboratory Data - Sequencing of the WAS gene to identify the mutation - Determining the presence of WASp protein in patient’s red cells z MYH9-Related Thrombocytopenia Syndromes (May-Hegglin Anomaly)  Autosomal Dominant Macrothrombocytopenia syndromes (May- Hegglin Anomaly)  Sebastian, Fechtner, and Epstein syndromes  Other Inherited thrombocytopenia that have common mutations with MYH9, a platelet cytoskeletal contractile protein z  Pathophysiology - Often autosomal dominant, some have an X-linked or recessive inheritance - Several mutations in the MYH9 gene lead to premature release of platelets from the bone marrow, macrothrombocytopenia, and cytoplasmic inclusion bodies within leukocytes. - The MYH9 gene encoding NMMHC-IIA consists of 40 exons and is located on chromosome 22q12–13.50. - Up to now, 31 mutations in 11 different exons have been described. z  Clinical Signs and Symptoms - Abnormal bleeding tendencies which is usually moderate, menorrhagia and easy bruising being most frequent - The hemostatic defect is unclear, but is proportionate to the degree of thrombocytopenia z  Laboratory findings - Presence of macrothrombocytopenia - Abnormally large and poorly granulated platelets and thrombocytopenia coexist - Also characterized by the presence of Döhle body-like inclusions in neutrophils, eosinophils, and monocytes. - Chronic autoimmune thrombocytopenia (chronic ITP) is the most important condition to distinguish from MYH9 disorders, evaluate platelet size using the blood film, platelet size histogram, and (calculated) MPV. z - “gold standard” for demonstrating MYH9 leukocyte inclusion bodies is the detection, by immunostaining, of NMM-IIa clusters - Platelet aggregometry and platelet function studies do not show major defects in MYH9 disorders. - Because of the altered composition of the platelet cytoskeleton, the shape change in the aggregation curve is typically absent, but the absence of shape in an aggregation curve can also be seen in other platelet disorders. z - A bone marrow examination is not required for diagnosing MYH9 disorders. - If performed, the marrow NMM-IIA in neutrophils stained with an anti–NMM-IIA monoclonal antibody (immunofluorescence) or May-Grünwald-Giemsa stain. - A diagnostic workup of MYH9 disorders should also include exclusion of iron deficiency anemia and ophthalmologic screening or cataracts and renal function assessment (creatinine clearance and proteinuria).