[04.10] Pathology of Bleeding Disorders V2.pdf

Increased fragility of blood vessels, platelet deficiency or dysfunction, and derangement of the coagulation cascade

What are three possible causes of bleeding disorders?

Platelet Count, Prothrombin Time (PT), and Partial Thromboplastin Time (aPTT)

What are the three routine laboratory tests that clinicians can order to ascertain the cause of bleeding?

Mixing Studies and Platelet Aggregation Tests

What are two examples of special laboratory tests ordered in bleeding?

150 x 10^3 to 350 x 10^3 platelets per microLiter

What is the normal reference range for Platelet Count (in platelets per microLiter)?

Below 150 x 10^3 platelets per microLiter

What is the platelet count threshold that defines Thrombocytopenia?

Clumping caused by technical issues or platelet satellitism

What two factors may cause a falsely decreased platelet count?

Platelet satellitism

What condition involves platelets adhering to neutrophils, imparting a rosette appearance that the machine cannot count?

Inflammation or anemia

What can Thrombocytosis be reactive to?

Myeloproliferative neoplasm

What can Thrombocytosis be indicative of?

Prothrombin Time (PT)

What test measures clotting time and evaluates the extrinsic and common pathways of the coagulation cascade?

Extrinsic Factors II, V, VII, and X, and Common Factors II, V, X, and Fibrinogen (Factor I)

What two groups of clotting factors does the PT test detect deficiencies in?

10-13 seconds

What is the reference range for Prothrombin Time (PT)?

Liver disease, Vitamin K deficiency, and Disseminated Intravascular Coagulation (DIC)

What three conditions may a prolonged PT indicate?

Activated Partial Thromboplastin Time (aPTT)

What test measures clotting time and evaluates the intrinsic and common pathways of the coagulation cascade?

Intrinsic Factors VIII, IX, XI, and XII, and Common Factors II, V, X, and Fibrinogen (Factor I)

What two groups of clotting factors does the aPTT test detect deficiencies in?

21-35 seconds

What is the reference range for Activated Partial Thromboplastin Time (aPTT)?

Hemophilia A and B, von Willebrand disease, Liver disease, and Vitamin K deficiency

What four conditions may a prolonged aPTT indicate?

Extrinsic

What coagulation pathway is associated with PT based on the mnemonic "Play Tennis Outside"?

Intrinsic

What coagulation pathway is associated with aPTT based on the mnemonic "Play Table Tennis Inside"?

Mixing Studies

What special laboratory test is used as a first-line investigation to determine the cause for prolonged PT and aPTT?

The test plasma is deficient in clotting factor

What does a normalized clotting time after combining 'test' plasma with normal plasma in a mixing study indicate?

Specific factor assay

What investigation should be performed if a mixing study normalizes?

Presence of inhibitor or interference

What does an abnormal or non-normalized clotting time after combining 'test' plasma with normal plasma in a mixing study indicate?

Lupus Anticoagulant, Anticoagulant (e.g., high dose heparinoid), or a specific coagulation factor inhibitor

Name two types of inhibitors or interferences that an abnormal mixing test result may suggest?

Platelet Aggregation Tests

What special laboratory test measures the ability of various agonists to platelets to induce in vitro activation and platelet-to-platelet activation?

von Willebrand Disease and Bernard-Soulier Syndrome

What are two possible diagnoses when a Platelet Aggregation Test shows a lack of agglutination with ristocetin?

Spontaneous bleeding

What can occur when the platelet count is below 10,000 or 20,000 platelets per microLiter, which can be fatal?

Chronic Immune Thrombocytopenic Purpura (chronic ITP)

What bleeding disorder is caused by autoantibody-mediated destruction of platelets?

Primary (idiopathic) or Secondary (occurring amidst predisposing conditions)

What are the two types of Chronic ITP classification based on cause?

Glycoproteins IIb-IIIa or Ib-IX

Against what two platelet transmembrane receptors are auto-antibodies produced in Chronic ITP?

IgG

What class of immunoglobulin are the antiplatelet antibodies in the majority of Chronic ITP cases?

Opsonins

What do the antibodies in Chronic ITP act as, which are recognized by IgG Fc receptors on macrophages?

Macrophages (phagocytes)

What cells recognize and destroy opsonized platelets in Chronic ITP?

Megakaryocytes

What cell type can auto-antibodies in Chronic ITP also bind to and damage, leading to decreased platelet production?

Young women (below 40 years old)

What is the typical demographic for patients with Chronic ITP?

Easy bruising, epistaxis, heavy and prolonged menstrual bleeding, petechiae, purpura, and ecchymosis

Name three clinical features of Chronic ITP?

Low platelet count, large platelets in peripheral blood smear, normal PT, and normal aPTT

What are four typical laboratory findings in Chronic ITP?

Large platelets (megathrombocytes)

What are seen in the peripheral blood smear that is taken as presumptive evidence of chronic ITP?

Process of exclusion

How is the diagnosis of chronic ITP typically made?

Glucocorticosteroids, Splenectomy, and Intravenous immunoglobulin (IV Ig) or anti-CD20 antibody (Rituximab)

What are three management options for Chronic ITP?

Spleen

What is the major site of removal of opsonized platelets?

Thrombocytopenia will relapse

What occurs if glucocorticosteroids are discontinued in Chronic ITP treatment?

Megakaryocytes

What cells in the bone marrow show a modestly increased number in Chronic ITP?

Immature megakaryocytes with large non-lobulated single nucleus

What is the appearance of some megakaryocytes in the bone marrow in Chronic ITP?

Accelerated thrombopoiesis

What are megathrombocytes a sign of?

Acute Immune Thrombocytopenic Purpura (acute ITP)

What type of ITP is a disease of childhood that is self-limited and usually resolves spontaneously within 6 months?

1 to 2 weeks after a self-limited viral illness

When do symptoms of acute ITP often appear abruptly?

Glucocorticoids

What drug is given in acute ITP, but only if the thrombocytopenia is severe?

Quinine, Quinidine, and Vancomycin

Name three drugs most commonly implicated in lowering platelet counts via drug-dependent antibody binding to platelet glycoproteins?

Conformational changes in glycoprotein IIb/IIIa

What is hypothesized to be induced by platelet inhibitory drugs that bind glycoprotein IIb/IIIa, creating an immunogenic epitope?

Heparin-Induced Thrombocytopenia (HIT)

What drug-induced thrombocytopenia is of particular importance due to its potential for severe clinical consequences?

About 5%

What percentage of persons receiving heparin develop HIT?

Type I HIT

What type of HIT occurs rapidly after the onset of therapy, is of little clinical importance, and most likely results from a direct platelet-aggregating effect of heparin?

Type II HIT

What type of HIT is less common, often life-threatening, occurs 5 to 14 days after therapy begins, and paradoxically leads to venous and arterial thrombosis?

Binding of antibody to complexes of heparin and platelet factor IV

What activates platelets and promotes thrombosis in Type II HIT?

Clot formation within large arteries, vascular insufficiency, limb loss, deep venous thrombosis, and increased risk of pulmonary thromboembolism

What are five potential consequences of failing to immediately stop heparin in Type II HIT?

Low-molecular-weight heparin preparations

What type of heparin preparation is preferred because it lowers the risk of developing Type II HIT?

HIV-Associated Thrombocytopenia

What is one of the most common hematologic manifestations of AIDS?

Immune complex-mediated platelet destruction, anti-platelet autoantibodies, and HIV-mediated suppression of megakaryocyte development and survival

What are three factors contributing to the multifactorial basis of HIV-Associated Thrombocytopenia?

CD4 and CXCR4

What are the receptor and co-receptor for the retrovirus found on megakaryocytes?

Apoptosis

What are HIV-infected megakaryocytes prone to, leading to impaired ability to produce platelets?

Thrombotic Microangiopathies

What spectrum of clinical syndromes is caused by injuries that lead to excessive activation of platelets and deposit as thrombi in small blood vessels?

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)

What are the two disorders discussed under Thrombotic Microangiopathies?

Microangiopathic hemolytic anemia and widespread organ dysfunction

What two effects do intravascular thrombi have in TTP and HUS?

Consumption of platelets

What leads to thrombocytopenia in TTP and HUS?

Deficiency in ADAMTS13

What causes Thrombotic Thrombocytopenic Purpura (TTP)?

Plasma enzyme that degrades very high-molecular-weight multimers of von Willebrand factor (vWF)

What is the function of ADAMTS13?

Autoantibody that inhibits the metalloprotease activity of ADAMTS13

What causes the acquired form of ADAMTS13 deficiency?

Inactivating mutation in ADAMTS13 passed on by a parent

What causes the inherited form of ADAMTS13 deficiency?

Fever, Thrombocytopenia, Microangiopathic hemolytic anemia, Transient neurologic deficits, and Renal failure

Name three symptoms of TTP?

Plasma exchange

What treats TTP successfully by removing autoantibodies and providing functional ADAMTS13?

Normal levels of ADAMTS13

What is characteristic of Hemolytic Uremic Syndrome (HUS) related to ADAMTS13?

Infectious gastroenteritis caused by Escherichia coli (E. coli) strain O157:H7

What is Typical HUS strongly associated with?

Shiga-like toxin

What does the E. coli strain O157:H7 elaborate, which is absorbed into the circulation and incites platelet activation and aggregation?

Bloody diarrhea

What is the first symptom of Typical HUS?

Anemia, Thrombocytopenia, and Renal failure

What three symptoms appear a few days after bloody diarrhea in Typical HUS?

Children and older adults

What two demographic groups are at highest risk for HUS?

Defects in Complement Factor H, Membrane Cofactor Protein (CD46), or Factor I

What is Atypical HUS often associated with defects in?

Prevent excessive activation of the alternative complement pathway

What is the function of Complement Factor H, Membrane Cofactor Protein (CD46), and Factor I?

Remitting, relapsing clinical course

What is Atypical HUS associated with?

Inherited defects or acquired inhibitory autoantibodies

What two causes can lead to deficiencies of Complement Factor H, CD46, or Factor I in Atypical HUS?

Normal platelet counts

What is characteristic of several inherited disorders characterized by abnormal platelet function?

Defects of adhesion, Defects of aggregation, and Disorders of platelet secretion

What are the three distinct groups inherited disorders of platelet function can be classified into?

Bernard-Soulier Syndrome (BSS)

What inherited disorder of platelet function is characterized by giant platelet cells, thrombocytopenia, and prolonged bleeding time?

One in a million

What is the estimated incidence of Bernard-Soulier Syndrome, although prevalence may be higher due to underrecognition?

Autosomal recessive genes

How is Bernard-Soulier Syndrome inherited?

Deficiency in platelet membrane glycoprotein complex Ib-IX

What is the specific deficiency in Bernard-Soulier Syndrome?

Receptor for vWF

What is the function of glycoprotein Ib-IX?

Adhesion

What is the specific defective function in Bernard-Soulier Syndrome?

Giant platelets almost the same size as red cells

What is the finding on a peripheral blood smear in Bernard-Soulier Syndrome?

Glanzmann Thrombasthenia

What congenital bleeding disorder is caused by deficiency or dysfunction of glycoprotein IIb-IIIa?

Glycoprotein IIb-IIIa (platelet integrin alpha IIb beta 3)

What specific molecule is deficient or dysfunctional in Glanzmann Thrombasthenia?

Bridge formation between platelets by binding fibrinogen

What is the function of glycoprotein IIb-IIIa?

Failure to aggregate in response to ADP, epinephrine, or thrombin

What is seen in platelet aggregation tests in Glanzmann Thrombasthenia?

Aggregation

What is the specific defective function in Glanzmann Thrombasthenia?

Mucocutaneous membranes

What body tissues are involved in the lifelong bleeding episodes in affected patients with Glanzmann Thrombasthenia?

Nonspecific and can be normal

What are the peripheral blood smear findings in Glanzmann Thrombasthenia, although giant platelets can sometimes be seen?

Storage Pool Disorder

What group of congenital disorders is characterized by a deficiency in granules or their constituents, leading to defective secretion?

Defective secretion from activated platelets and abnormal secretion dependent platelet aggregation

What is the result of the absence of platelet granules in Storage Pool Disorder?

Gray platelet syndrome, Hermansky Pudlak syndrome, and Chediak Higashi syndrome

Name two examples of storage pool disorders?