First Foundations in Pathology, Part 4: Hemodynamic Disorders

1. First Foundations in Pathology, Part 4: Hemodynamic Disorders Paul G. Koles, MD Asst. Prof. Pathology & Surgery Director of Pathology Education Boonshoft School of Medicine at Wright State University

2. Normal body composition • Water composes about 60% of total body mass • 3 body compartments containing H2O: • = 70% • = 25% • = 5%

3. Pathophysiology of Edema Anatomic structures which drain excess interstitial fluid into venous blood:  Two opposing major factors governing fluid movement between vascular and interstitial space.

4. Differential dx: causes of edema (1)

5. Differential dx: causes of edema (2)

6. History: 66 yo male smoker admitted for increasing shortness of breath; chest x-ray shows left pleural effusion. History of atherosclerotic heart disease, previous myocardial infarction, and chronic congestive heart failure. Has had three previous pleural effusions that were transudates with no significant inflammation. You are on call for the medical service and assist the ER doc with pleurocentesis. After successful removal 1100 cc yellow fluid, he asks, “What lab studies do you want on this fluid?” You say: Cytologic Diagnosis? Prognosis?

7. Clinical manifestations of edema Clinical Signs Most Likely Cause(s)

8. Hemodynamic terminology • : locally increased blood caused by arteriolar dilation with augmented inflow, as in a working muscle or acute inflammation • : locally increased blood due to impaired venous outflow (lungs in heart failure) Is this hypertrophic liver hyperemic or congested?

9. Hemorrhage • Definition: extravasation of blood because of vessel rupture • Causes: • Mechanical trauma • Atherosclerosis of aorta  rupture with acute retroperitoneal hemorrhage • Increased hydrostatic pressure (obstruction or hypertension) • causing weakened or necrotic wall • invading through vessel wall • Hemorrhagic diathesis (coagulation and platelet disorders)

10. Nomenclature: hemorrhage • : hemorrhage accumulated within a confined space • :1-3 mm hemorrhages skin, mucosa • :3-10 mm hemorrhage skin, mucosa • : >1cm hemorrhage skin/subcutis • : hemorrhage into joint

11. Hemostasis overview • Normal hemostasis • Maintain blood fluid within vessels • Induce rapid localized plug at injury site • Thrombosis • Formation of blood clot within vessel (appropriately or inappropriately) • Three components which regulate normal hemostasis / thrombosis:

12. Hemostasis sequence 1

13. Hemostasis sequence 2

14. Dualistic endothelial cell function Procoagulant (favors thrombosis) Anticoagulant (inhibits thrombosis) Green molecule? Orange molecule?

15. Platelet response to injury • Platelets encounter extravascular matrix molecules: collagen, proteoglycans, fibronectin • Platelets respond in three phases: • 1 = • 2 = • 3 =

16. Platelet secretion (release reaction) • Secretion of granule contentsafter adhesion: • ADP: promotes aggregation with other platelets • Ionized calcium: enhances coagulation cascade • Thromboxane A2: further aggregation & vasoconstriction • Serotonin, histamine, epinephrine (promoting aggregation & vasoconstriction ) • Activated platelets express surface phospholipid complex, providing binding sites for calcium and factors involved in the intrinsic clotting pathway

17. Disorders of Platelet Function Deficient Gp1b receptor on platelets for vWF: Deficient Gp IIb-IIIa complex: Deficient von Willebrand’s factor:

18. Coagulation Cascade: 3rd component

19. Central role of thrombin • Functions: • Formation of fibrin • Induces platelet aggregation • Activates endothelium • Activation of lymphocytes & monocytes Fig. 4-11, Pathologic Basis of Disease, 2006.

20. Application: Lab evidence of excessive fibrinolysis (DIC)? (3 non-morphologic abnormalities) Fibrinolytic system: restriction of clotting to local site of injury 1) 2) 3) One RBC morphologic abnormality? (not sensitive or specific) Fig. 4-12, Pathologic Basis of Disease, 2005

21. Thrombosis: a clot within vessel • Predisposing factors: Virchow’s triad Trauma, atherosclerosis, vasculitis Atherosclerosis, aneurysms, valvular heart disease Inherited or acquired

22. What is the most common inherited defect, affecting 2-15% of Caucasians, leading to increased hypercoagulability because of resistance to effect of protein C? Which group (genetic or acquired) accounts for >90% of clinically significant thromboses in US population?

23. Venous thrombosis Most common anatomic location? Most serious complication?

24. Disseminated intravascular coagulation (DIC) • Not a primary disease, but complication of diseases with widespread activation of thrombin • Pathophysiology: • fibrin-platelet thrombi in microcirculation, with concurrent consumption of platelets and coagulation proteins. • RBCs may be torn and fragmented by fibrin thrombi. • Diffuse activation of fibrinolysis, generating increased FDPs & D-dimer (lab evidence DIC) • Treatment: diagnose and treat underlying disease; buy time (not cure) with administration of platelets and fresh frozen plasma

25. Peripheral smear in DIC: pathogenesis of schistocyte formation?

26. Embolism • Definition: detached intravascular solid, liquid, or gaseous mass carried by blood to a site distant from its origin. • Types: • :> 99% of all emboli • Fat or marrow: post-trauma to bones • Cholesterol: after invasive vascular procedures, presenting as hematuria or renal insufficiency due to multiple renal microinfarctions • Tumor: from neoplasms invading vessels • Foreign body: intravenous devices/ drug abuse • : 1/50,000 deliveries; mortality >80% with complications of pulmonary edema/DIC

27. Pulmonary thromboembolism Occlusion of small artery results in what type of infarction? Occlusion large pulmonary artery

28. Pulmonary thromboembolism • 200,000 deaths/year in US • Many are clinically silent if small • : thrombus occluding main pulmonary artery at bifurcation • : thromboembolus originating in veins, passing through atrial or ventricular septal defect, into arterial side • Sudden death: likely if >60% pulmonary circulation is obstructed with emboli (acute right heart failure) • results from occlusion of medium-sized vessels (dual bronchial blood supply prevents infarction) • results from occlusion of small end arteries or arterioles

29. Infarction • Definition: Ischemic necrosis of tissue caused by occlusion of arterial supply (usually) or venous outflow (less common) • Huge problem: > 50% US mortality due to atherosclerotic vascular disease causing myocardial & cerebral infarctions • Usual histopathology: • Histopathology in brain: • Resolution: fibrous scar with loss function

30. Infarction, gross features Lung, acute hemorrhagic infarction (note wedge-shape) Kidney, remote healed infarction (fibrous scar)

31. Shock • Def.: systemic hypoperfusion due to reduced cardiac output or reduced effective blood volume. • Major causes: • : myocardial pump failure • :loss blood/plasma volume • : systemic microbial infection • : spinal cord injury • : generalized IgE-mediated hypersensitivity response, with widespread vasodilation, increased capacitance, & increased vascular permeability

32. Shock: 3 most common types

33. Septic shock • 25-50% mortality rate, >100,000 deaths/yr. • Increasing incidence (intensive care, invasive procedures, longer lifespan, more immunocompromised patients) • 70% cases produced by which type of bacteria ? • : lipopolysaccharides (LPS) released when bacterial cell walls are degraded by inflammation or antibiotic therapy.

34. Cytokine cascade in Gram-negative sepsis Produced by: Produced by: Produced by: Fig. 4-21, Pathologic Basis of Disease, 2005

35. Clinical sequelae of sepsis NO = PAF = Fig. 4-22, Pathologic Basis of Disease, 2005

36. Stages of shock • Nonprogressive phase • Reflex mechanisms activated and perfusion of vital organs maintained • Progressive stage • Persistent tissue hypoperfusion leads to widespread hypoxic cell damage, metabolic acidosis, prolonged vasodilation • Irreversible stage • Severe cellular injury with multiorgan failure, dominated by renal, lungs, heart