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N 5315 Advanced Patho Hematologic
Module 4 With Complete Solution
What is the peripheral zone of platelet? - ANSWER Outermost layer. Made of phospholipids. Contains many receptors responsible for platelet adhesion and aggregation
What is the sol-gel of the platelet - ANSWER It is the outermost layer made of possible if it contains many receptors responsible for platelet adhesion and aggregation
What is the organelle zone of platelets - ANSWER Innermost layer contains calcium dense granules and alpha granules
What are the four phases of platelet plug formation? - ANSWER Activation, adherence, aggregation, and secretion
What is the first step or phase of platelet plug formation and explain - ANSWER Activation is the first step. In physiological states. Platelets circulate without adhering to the intact endothelium. An injury to the endothelium exposes thev WF, fibronectin, collagen and from thrombospondin.. Collagen is a potent activator and when the sub endothelial collagen is exposed by an injury. The platelets become charged AKA activated. Platelets and become aware of the injury and undergo a shape change that increases their ability to adhere to the site of injury.
The second step in platelet plug formation is - ANSWER Adherence is a process by which platelets attached to the injured endothelium. Adherence
begins with the vWF. Circulating vWF binds to the exposed subendothelial collagen and to the GP Ib/IX/V receptors on circulating platelets. Collagen then binds with the GP VI receptor. The binding of collagen with the GP VI receptor results in the activation of the GPIIb/IIIa and GPIa/IIa receptors. vWF then binds with the GPIIb/IIIa receptors and collagen further binds with the GPIa/IIa receptors. This collective binding anchors the platelets in place
The third step in platelet plaque formation is - ANSWER Aggregation- is the process by which platelets bind to one other. There are multiple GPIIb/IIIa receptors on one platelet and when activated (as described above) they have a greater affinity for fibrinogen. Fibrinogen is able to bind to two GPIIb/IIIa receptors simultaneously and thereby bind platelets together
The fourth step in platelet plug formation is - ANSWER Secretion- during this phase the platelet granules release their contents.
a. ADP- enhances adhesion, activates platelets and recruits platelets
b. Serotonin recruits platelets.
c. Fibronectin and thrombospondin are proteins which stabilize platelets that are adhered to the site of injury.
d. Thromboxane A2- is a product of the arachidonic acid pathway but is stored inside the platelet too. It causes vasoconstriction and enhances platelet aggregation.
e. Growth factors promote tissue repair however they have a role in the development of atherosclerosis.
enhances the extrinsic pathway. This pathway is activated when the blood is exposed to negative charges which are found on the molecules of ADP and ATP. This exposure activates factor XII (Hageman factor). Activated factor XIIa then activates factor XI. Activated factor XIa activates IX. Activated factor IXa then activates factor X. Activated factor Xa then forms the prothrombinase complex in the common pathway.
Coagulation Cascade Key Plasma Proteins
1.Tissue Factor
2.VII
3.X
4 .Prothrombinase Complex
- Prothrombin
- Thrombin
7 .Fibrinogen
- Fibrin
- XIII
- XII
- VIII
- IX
- Antithrombin
- Protein C
- Protein S
16.t-PA - ANSWER 1. Initiator of extrinsic pathway.
- Forms complex with tissue factor (III) and activates factors IX and X
- Activates Prothrombin through activated Xa form
- (prothrombin and activated factors X and V) that activates prothrombin into thrombin
- Factor II, source of thrombin that activates fibrinogen
- cleaves the extracellular domain of G-protein-coupled protease-activated receptors (PARs),
thereby initiating transmembrane signaling.
- moves between the beta and gamma regions but is removed during the formation of serum; precursor of fibrin clot
- Used to stabilize clot
- Fibrin - stabilizing factor - cross links fibrin through XIIIa to strengthen clot
- Hageman Factor. Initiator of intrinsic pathway
- VIIIa is a component of tenase complex
- IXa is a component of tenase complex, activates factor X
- it inhibits thrombin and several activated clotting factors (e.g., VIIa, IXa, Xa, XIa, XIIa).
How is the platelet plug process altered with clopidogrel? - ANSWER P2Y receptor is blocked from ADP - thus allowing cAMP to continue to prevent platelet aggregation
How does warfarin altered coagulation? - ANSWER Vitamin K is blocked from becoming vitamin k reductase, and carboxylation of vitamin K dependent clotting factors is unable to occur.
How does low molecular weight heparin alter coagulation? - ANSWER -cannot inhibit thrombin, but can only inhibit clotting factor Xa
-They inhibit activated Xa and prevent the formation of the prothrombinase complex and consequently thrombin. They do have some effect on antithrombin but to a much lesser extent than heparin.
How does factor X a inhibitors alter coagulation - ANSWER These drugs (fondaparinux, apixiban, rivaroxaban) increase antithrombin's affinity for Xa. Antithrombin neutralizes Xa and thereby prevents the formation of the prothrombinase complex and thrombin.
How does direct thrombin inhibitors altered coagulation - ANSWER Drugs in this class include dabigatran and argatroban. The inhibition of thrombin prevents the activation of fibrinogen and XIII. The active form of fibrinogen
is fibrin which supports the platelet plug. XIIIa cross links with fibrin to provide stabilization to the platelet plug.
How does primary view thrombocytopenia purpura altar platelet plug process - ANSWER Process of platelet destruction begins with the phagocytosis of platelets by macrophages. The macrophages then present the digested platelet peptides to the CD4 cells. The CD4 cells believe these peptides are antigens and initiate the immune response. IgG antibodies then bind to platelets most often on the platelet membrane glycoproteins such as GPIIb/IIIa and ultimately platelets are destroyed
How is the platelet plug process altered with TTP - ANSWER -ADAMTS13 is a protease that is responsible for the breakdown of von Willebrand factor.
- Persons with TTP have large amounts of vWF in their plasma and lack ADAMTS13 protease.
- In congenital forms of the disease there is a mutation in the gene responsible for making ADAMTS13, leading to a deficiency of this protease.
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- The increased levels of vWF leads to platelet aggregation, microthrombi in organs, causing organ failure. The thrombi are mainly made of platelets (lacking RBCs and fibrin).
- Antibody to ADAMTS13 has been isolated in most people with acquired TTP.
adhesion. Eventually the products of coagulation are consumed, resulting in bleeding. Organ failure may ensue due to micro-thrombi
How does DIC alter coagulation - ANSWER The igniting event causes endothelial damage. The endothelial damage exposes the subendothelial tissue factor and activates the inflammatory cascade. The exposed TF activates the coagulation cascade.
The activation of the coagulation system leads to a widespread and systemic intravascular fibrin deposition. While this is happening the fibrinolytic system is working to break down the fibrin. The fibrin degradation products (which are present in massive amounts) adhere to platelets and prevent platelet adhesion. Eventually the products of coagulation are consumed, resulting in bleeding. Organ failure may ensue due to micro-thrombi
What are the clinical manifestations of coagulopathy heorrhage? - ANSWER Clinical manifestations of a bleed from a coagulopathy include:
- joint bleeding
- tissue hematomas
- large, spontaneous, centrally located ecchymosis
- bleeding after trauma, surgery or an injury tends to be delayed
What is a example of coagulopathy hemorrhage? - ANSWER Deficiency of Hageman factor (factor XII) Hemophilia A & B
What are the clinical manifestations of thrombocytopenia hemorrhage - ANSWER Clinical manifestations of a bleed from a thrombocytopenia include:
- Mucosal bleeding such as:
- Epistaxis
- Oral bleeding
- GI or GU bleeding (in the absences of malignancy)
- Hemoptysis
- Heavy menses
- Bleeding occurs immediately after a trauma or injury
- Petechiae may be present.
What are examples of Thrombocytopenia? - ANSWER Thrombotic Thrombocytopenic Purpura (TTP)
Neonatal thrombocytopenia
Primary Immune Thrombocytopenic purpura
What are the causes of thrombocytopenia? - ANSWER Common causes of thrombocytopenia include:
- Hemodilution which tends to occur post-operatively and has a nadir of 2- days. A nadir refers to the lowest point.
- Presentation can vary
- Petechiae, purpura, and easy bruising are expected.
- Epistaxis, gingival bleeding, and menorrhagia are common.
- Overt gastrointestinal bleeding and gross hematuria are rare.
- Intracranial hemorrhage, a potentially fatal bleeding complication, is so uncommon that there is no reliable estimate of its frequency.
- The clinical manifestations of thrombocytopenia also vary with age. Older patients may have more severe bleeding manifestations, such as gastrointestinal bleeding and possibly intracranial hemorrhage because of comorbidities such as hypertension
What is the pathophysiology of ITP? - ANSWER Antiplatelet IgG originating in the spleen;
Process of platelet destruction begins with the phagocytosis of platelets by macrophages. The macrophages then present the digested platelet peptides to the CD4 cells. The CD4 cells believe these peptides are antigens and initiate the immune response. IgG antibodies then bind to platelets most often on the platelet membrane glycoproteins such as GPIIb/IIIa and ultimately platelets are destroyed
What is the etiology of Thrombotic throbocytopenic purpura? - ANSWER TTP is a rare disease. Etiologies include: autoimmune, familial, drugs (antiplatelet agents, quinine, mitomycin, cisplatin, bleomycin), HIV, Cancers, and it may
occur in post-surgical patients.
What is the pathophysiology of TTP? - ANSWER The pathogenesis includes the following steps:
- ADAMTS13 is a protease that is responsible for the breakdown of von Willebrand factor.
- Persons with TTP have large amounts of vWF in their plasma and lack ADAMTS13 protease.
- In congenital forms of the disease there is a mutation in the gene responsible for making ADAMTS13, leading to a deficiency of this protease.
- The increased levels of vWF leads to platelet aggregation, microthrombi in organs, causing organ failure. The thrombi are mainly made of platelets (lacking RBCs and fibrin).
- Antibody to ADAMTS13 has been isolated in most people with acquired TTP.
- Other factors
o Plasminogen activator inhibitor- levels are increased. Normal function is to inhibit fibrinolytic compound.
What are the clinical manifestations of TTP? - ANSWER Altered mental status, seizures, hemiplegia, paresthesias, visual changes, aphasia. They do not necessarily have to have neurologic symptoms.
- Fatigue with anemia, microangiopathic anemia occurs as a result of RBC
What is the etiology of Hemophilia A? - ANSWER Hemophilia A is a sex linked recessive disease which results in a deficiency of factor VIII.
What is the pathophysiology of Hemophilia A? - ANSWER A mutation in the F8 gene leads to the development of hemophilia A.
What are the clinical manifestations of Hemophilia A? - ANSWER Hemophilia A affects 1 in 4,000-5,000 males. The most common sites of bleeding in adults are:
- Knees, elbows and ankles
- GI bleeding is common as well.
- Spontaneous bleeding is indicative of more severe disease.
- Bleeding only after injury/trauma or surgery indicates milder disease.
What are the etiologies of hemophilia b? - ANSWER AKA Christmas disease; deficiency is related to factor IX
What is the pathophysiology of hemophilia B? - ANSWER Sex Linked recessive disease, secondary to a mutation in the F9 gene.
What are the clinical manifestations of hemophilia b? - ANSWER Affects 1 in every 20,000-30,000 males
- Most common sites of bleeding in adults are into the joints.
- Knees, elbows and ankles
- GI bleeding is common as well.
- Spontaneous bleeding is indicative of more severe disease.
- Bleeding only after injury/trauma or surgery indicates milder disease.
- Diagnostic Testing
- Normal platelets
- Normal PT
- Abnormally prolonged aPTT
- Decreased factor IX level
What is the etiology of DIC? - ANSWER Disease states which trigger DIC include:
- Malignancy
- Sepsis / infection
- Obstetrical complications
- Trauma/ extensive surgeries
- ARDS, rhabdomyolysis
instances, of the nose and breasts may be present."
What is the pathophysiology of DIC? - ANSWER The igniting event causes endothelial damage. The endothelial damage exposes the subendothelial tissue factor and activates the inflammatory cascade. The exposed TF activates the coagulation cascade. The activation of the coagulation system leads to a widespread and systemic intravascular fibrin deposition. While this is happening the fibrinolytic system is working to break down the fibrin. The fibrin degradation products (which are present in massive amounts) adhere to platelets and prevent platelet adhesion. Eventually the products of coagulation are consumed, resulting in bleeding. Organ failure may ensue due to micro-thrombi.
What is the etiology of hageman deficiency (factor XII) - ANSWER autosomal recessive disorder
Factor XII deficiency is a rare genetic blood disorder that causes prolonged clotting (coagulation) of blood in a test tube without the presence of prolonged clinical bleeding tendencies. It is caused by a deficiency of the factor XII (Hageman factor), a plasma protein (glycoprotein).
What is the clinical manifestations of Hagemann deficiency - ANSWER Increases PTT ad PT, benign usually no symptoms present
What is the pathophysiology of Hageman deficiency - ANSWER occurs due to
mutations of the F12 gene located on the long arm of chromosome 5 (5q33-qter). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual
What are the risk factors, pathophysiology, and clinical manifestations for protein c defiency? - ANSWER Protein C is activated by protein S to form APC which inactivates Factor Va and VIIIa, thus controlling the clotting process. In a deficiency this process does not happen and it causes the person to be in a hypercoagulable state.
- This deficiency is a result of an autosomal dominant gene mutation in the PROC gene.
What are the risk factors, pathophysiology and clinical manifestations for protein s defciency? - ANSWER Protein S helps to activate protein C (APC) which inactivates factor Va and VIIIa. A deficiency in protein S will then lead to a hypercoagulable state.
- I want to discuss protein S in general.
- Protein S naturally circulates in a free form and a bound form. In normal physiology it binds to complement and only the free form is available to be used by the body. During times of inflammation, remember that there is an increased amount of complement circulating. The increased amount of complement binds more protein S. This results in less free protein S and causes a hypercoagulable state; therefore, these individuals are at an increased risk for developing clots.
