NUR 9211 Hematology 2018

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Aspirin Therapy

Doesn't suppress platelet production but prevents platelet aggregation

Components of Plasma

Waste Products

Bilirubin

0.2-1.2 mg/dl

Uric Acid

5 mg/dl

Creatinine

1 mg/dl

Urea (BUN)

7-18 mg/dl

Nutrients

Cholesterol

150-250 mg/dl

Lipids

500 mg/dl

Amino Acids

40 mg/dl

Glucose

100 mg/dl

Electrolytes

Phosphate

2 mEq/L

HCO3-

27 mEq/L

Cl_-

103 mEq/L

Mg++

3 mEq/L

Ca++

5 mEq/L

K+

4 mEq/L

Na+

142 mEq/L

Water

91% of Plasma weight

Complex aqueous solution

Organic & Inorganic Elements

Function of Platelets

References

Huether, S.E., Rote, N.S., & McCance, K.L. (2019). Structure and function of the hematologic system. In K.L. McCance & S.E. Huether (Eds.), Pathophysiology: The biologic basis for disease in adults and children (pp. 890-925). St. Louis, MO: Elsevier.

Adhesion

Narrows blood vessel

Mediated by: Platelet surface receptor glycoprotein Ib (GPIb) von Willebrand factor (vWF)

Adhere to endothelial damage

Aggregation

Contraction of myosin and actin filaments

Fibrin strands

Dense and strong

Shorten

Receptors for vWB and collagen

Glycoprotein IIb/IIIa complex

Calcium-dependent receptor for fibrinogen

TXA2 and APD

Activation

Other stimuli

Epinephrine, Thrombin, and collagen

Calcium

Intracellular signalling

Serotonin

Vasodilation

Increase vascular permeability

Degranulation

Production of prostagladin derivative thromboxane A2 (TXA2)

Change in platelet shape

Increase surface area

Recognizing platelet cytoskeleton

Platelet Alterations

References

McCance, K.L., & Rote, N.S. (2019). Alterations of erythrocyte, platelet, and hemostatic function. In K.L. McCance & S.E. Huether (Eds.), Pathophysiology: The biologic basis for disease in adults and children (pp. 926-962). St. Louis, MO: Elsevier.

Thrombocytopenia

Thrombotic Thrombocytopenic Purpura

Immunosuppressive: Azathioprine

Splenectomy

Fresh frozen plasma

Elevated LDL

Increased LDH

Blood smear

Based on symptoms

Kidney failure

Ischemic symptoms of CNS

Intravascular hemolytic anemia

Extreme thrombocytopenia

Can be fatal within 90 days

Must rule out similar conditions

Acquired Idiopathic

Severe

Familial

Chronic/Relapsing

Rare

Dysfunction of disintegrin & metalloprotease ADAMTS13

Platelets with little fibrin and RBCs

Severe thrombocytopenia & thrombotic microangiopathy

Organ ischemia

Platelet consumption

Occlusion of arterioles and capillaries

Immune Thrombocytopenic Purpura

Romiplostim

IVIG

Glucocorticoids

Prevent platelet destruction

Resolves without complication

Peripheral blood smear

CBC

History of symptoms

Fever

Weight loss

Progresses to major hemorrhage from mucosal areas

Minor Bleeding at first

Chronic

IgG, but can be IgA or IgM

React with platelet glycoproteins

Autoantibodies against platelet-specific antigens

Common in Adults

Acute

Resolves once antigen is removed

Usually secondary to infections or antigens

1-2 months

Frequent Children

Immune process

Heparin-Induced Thrombocytopenia

Treatment

Alternative anticoagulants

Discontinue use of Heparin

Evaluation

Tests to measure antibodies for heparin-platelet factor 4

Decrease in platelets after 5 days or more on Heparin

Observation

Manifestations

Bleeding is uncommon

Risk for: Arterial thrombosis Venous thrombosis

Decrease of 50% of platelet count or more

Immune reaction

Decrease platelet counts

Increase platelet consumption

IgG antibodies formed against heparin-platelet factor 4

Heparin causes drug-induced thrombocytopenia

Primary or secondary Congenital or Acquired

Secondary congenital: Rare, with different diseases

Acquired: More common

Bone marrow infiltration by cancer

Radiation Therapy

Bone Marrow Hypoplasia

Chronic renal failure

Nutritional deficiencies

Viral Infections

Causes: Decrease platelet production Increased consumption Both

Decrease platelet count

Thrombocythemia

Erythromelalgia

warm, congested red hands/feet with painful burning sensations

Microvascular thrombosis

Ischemia of fingers, toes, cerebrovascular regions

Platelet count >450,000

A.K.A. Thrombocytosis

Secondary

Often occurs after a splenectomy

Primary

Chronic Myeloproliferative disorder

Also known as Familial Essential Thrombocythemia, this chronic condition occurs because of excessive platelet production due to a defect in bone marrow megakaryocyte progenitor cells.

McCance, K. L., & Rote, N. S. (2018). Alterations in Erythrocyte, Platelet, and Hemostatic Functions. In S. E. Huether, & K. L. McCance, Pathophysiology. A Biologic Basis for Disease in Adults and Children (pp. 926-962). St. Louis: Elsevier.

ASA Therapy not always effective

Aspirin achieves its antithrombotic effect by permanently inactivating platelet cyclooxygenase (COX)-1, thus blocking TXA2 biosynthesis. While low-dose aspirin given once daily is known to inhibit platelet TXA2 biosynthesis by approximately 97 to 99% in healthy subjects, the same aspirin regimen is unable to fully inhibit platelet TXA2 production in approximately 80% of ET patients.

Low-dose aspirin is currently recommended for the primary or secondary prevention of atherothrombosis in ET, despite the lack of direct, randomized evidence for its efficacy and safety in this setting. The present results argue against the adequacy of a conventional aspirin regimen for a substantial proportion of ET patients and suggest the need of a properly sized, randomized trial testing the efficacy and safety of a twice daily regimen of antiplatelet prophylaxis. Although twice-daily dosing may reduce compliance as compared to a once-daily regimen, such an approach has been used successfully for stroke prevention in patients with cerebrovascular disease. We conclude that the abnormal magakaryopoiesis that characterizes ET is responsible for shorter lasting antiplatelet effects of low-dose aspirin through faster renewal of platelet COX-1. This abnormal biochemical and functional phenotype can be reverted to a normal pattern of platelet response by modulating the aspirin dosing interval but not the dose. 

Reference:

Pascale, S., Petrucci, G., Dragani, A., Habib, A., Zaccardi, F., Pagliaccia, F., . . . Patrono, C. (2012). Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. American Society of Hematology, 1-33. doi:doi:10.1182/blood-2011-06-359224

Alterations of Platelet Function

Hematologic Disorders

Dysproteinemias

Myelodysplastic Syndrome

Leukemia

Multiple Myeloma

Chronic Myeloproliferative Disorders

Systemic Disorders

Antiplatelet Antibodies associated with Autoimmune disorders

Cardiopulmonary Bypass Surgery

Liver Disease

Chronic Renal failure

Drug Related/Induced

Clopidogrel (Plavix)

Binds to ADP receptors on the surface of activated platelets

Jones and Bartlett Learning. (2017). Nurses Drug Handbook. Burlington: Jones and Bartlett Learning.

Aspirin

Inhibits platelet aggregation

Thrombocytopathies

Congenital alterations (RARE)

Membrane Phospholipid regulation

Enzyme responsible for phospholipid regulation is defective. Platelets are unable to support activation of factor X and prothrombin.

Arachidonic acid pathways

Mutations in protein production & defects in thromboxane pathway

Platelet granules and secretion

Mutations in protein production

Platelet-Platelet Interactions

Failure of platelets to aggregate. Lacks glycol protein necessary to build "fibrin bridge"

Platelet-Vessel Wall Adhesion

Lack of proteins prevents platelets from adhering to collagen

Drug toxicity

IgG, IgM

Plasmaphoresis is a process by which blood is passed through a medical device and the protein globulin portion of the plasma is removed or otherwise manipulated, with the remainder being returned to the patient.

Reeves, H. M., & Winters, J. L. (2013). The mechanisms of action of plasma exchange. British Journal of Haematology, 164, 342-351.

Plasmaphoresis

Can be used to remove toxins, antibodies, or plasma components

May stop negative feedback loop

It has been hypothesized that the bulk removal of immunoglobulin

by plasmaphoresis might lead to the removal of negative feedback

on the antibody-producing cells.

Reference:

Reeves, H. M., & Winters, J. L. (2013). The mechanisms of action of plasma exchange. British Journal of Haematology, 164, 342-351.

Albumin is the major protein responsible for colloid osmotic pressure

    Albumin does not diffuse freely through intact vascular endothelium. Hence, it is the major protein providing the critical colloid osmotic or oncotic pressure that regulates passage of water and diffusable solutes through the capillaries. Albumin accounts for 70% of the colloid osmotic pressure. It exerts a greater osmotic force than can be accounted for solely on the basis of the number of molecules dissolved in the plasma, and for this reason it cannot be completely replaced by inert substances such as dextran. 

Reference:

Busher Janice T. Serum Albumin and Globulin. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 101.  https://www.ncbi.nlm.nih.gov/books/NBK204/

Hundreds of Proteins are dissolved in the Plasma

NUR 9211 Hematology 2018

Platelets

References

Huether, S.E., Rote, N.S., & McCance, K.L. (2019). Structure and function of the hematologic system. In K.L. McCance & S.E. Huether (Eds.), Pathophysiology: The biologic basis for disease in adults and children (pp. 890-925). St. Louis, MO: Elsevier.

McCance, K.L., & Rote, N.S. (2019). Alterations of erythrocyte, platelet, and hemostatic function. In K.L. McCance & S.E. Huether (Eds.), Pathophysiology: The biologic basis for disease in adults and children (pp. 926-962). St. Louis, MO: Elsevier.

Irregularly shaped cytoplasmic fragment

Plug vascular openings

Adhere to collagen fivers

Assume different positions: Pseudopodia

Alpha granules

Coagulation Factors Growth and angiogenic factors Angiogenesis inhibitors

Cytoplasmic granules: Release mediators

Proinflammatory

ADP ATP Calcium Serotonin Histamine

Lack nucleus and DNA

No mitotic division

Found in bone marrow

Function:

Initiate repair and fibrinolysis

Activate Blood Coagulation

Platelet plug formation

Regulate blood flow through vasoconstriction

Any simple proteins that are insoluble in pure water but are soluble in dilute salt solutions and that occur widely in plant and animal tissues, such as alpha globulin, beta globulin, gamma globulin

Merriam-Webster. (2018). Globulin. Retrieved from Merriam-Webster Dictionary: https://www.merriam-webster.com/dictionary/globulin

Plasma

50% - 55% of blood volume

The liquid portion of the blood, contains two major groups of proteins: albumins and globulins.

Ferritin

Transferrin

Fibrinogen

Precursor of the fibrin clot

Most plentiful of the clotting factors

4% of total plasma protein

Major plasma protein

Globulins

Serum globulin makes up the remaining 40% of plasma proteins

Albumins

Laboratory testing

Normal level 4.5 gm/dl

Serum albumin is generally used to assess the nutritional status and severity of disease

The remainder is extravascular and is located in the interstitial spaces, mainly of the muscles and skin.

30-40% of Albumin is found in the Intravascular compartment.

Busher Janice T. Serum Albumin and Globulin. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 101. Available from: https://www.ncbi.nlm.nih.gov/books/NBK204/

Bile Salts

Thyroid Hormones

Lipid soluble Hormones

Free Fatty Acids

The fluid part of blood, lymph, or milk as distinguished by suspended material.

Merriam-Webster. (2018). Plasma. Retrieved from Merriam-Webster Dictionary: https://www.merriam-webster.com/dictionary/plasma

Human albumin (HA) is a blood plasma protein produced in the liver. It constitutes about 60% of plasma proteins and is a physiological plasma-expander.

Vaglio, S., Calizzani, G., Lanzoni, M., Candura, F., Profili, S., Catalano, L., . . . Grazini, G. (2013). The demand for human albumin in Italy. Blood Transfusion, 11, 26-32.