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% intracellular interstitial plasma

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

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, on digoxin and furosemide. 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: Cell count, culture, specific gravity, cytologic exam Cytologic Diagnosis? Metastatic adenocarcinoma Poor (palliative care) Prognosis?

7. Clinical manifestations of edema Clinical Signs Most Likely Cause(s) Increased hydrostatic pressure in veins due to congestive heart failure Lymphatic obstruction Hypoproteinemia

8. Hemodynamic terminology Hyperemia • : 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) Congestion Is this liver hyperemic or congested? Congested (central veins contain excess blood)

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) Atherosclerotic aneurysm Vasculitis Malignant neoplasm

10. Nomenclature: hemorrhage Hematoma • : 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 Petechiae Purpura Ecchymosis Hemarthrosis

12. 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: Vascular wall Platelets Coagulation cascade

13. Hemostasis sequence 1 Vasoconstriction Primary Hemostasis (platelet plug)

14. Hemostasis sequence 2 Secondary Hemostasis (fibrin clot) Thrombosis and antithrombotic events

15. Dualistic endothelial cell function Procoagulant (favors thrombosis) Anticoagulant (inhibits thrombosis) vWF Green molecule? Orange molecule? AT III

16. Platelet response to injury • Platelets encounter extravascular matrix molecules: collagen, proteoglycans, fibronectin • Platelets respond in three phases: • 1 = • 2 = • 3 = Adhesion Secretion (release reaction) Aggregation

17. 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

18. Platelet adhesion and aggregation Deficient Gp1b receptor on platelets for vWF: Bernard-Soulier syndrome Deficient Gp IIb-IIIa complex: Glanzmann thrombasthenia Deficient von Willebrand’s factor: Von Willebrand disease

20. Coagulation Cascade: 3rd component

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

22. Application: Lab evidence of DIC? (3 non-morphologic abnormalities) Fibrinolytic system: restriction of clotting to local site of injury 1) prolonged PT 2) elevated D-dimer 3)thrombocytopenia One RBC morphologic abnormality? (not sensitive or specific) schistocytes Fig. 4-12, Pathologic Basis of Disease, 2005

23. Thrombosis: a clot within vessel • Predisposing factors: Virchow’s triad Trauma, atherosclerosis, vasculitis Endothelial Injury Atherosclerosis, aneurysms, valvular heart disease Abnormal blood flow Inherited or acquired Hypercoagulability

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

25. Venous thrombosis Deep leg veins (pelvic veins 2nd) Most common location? Most serious complication? Pulmonary embolization

26. 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

27. Peripheral smear in DIC: what is the mechanism of schistocyte formation? Rbcs are ripped/torn by fibrin strands in microcirculation

29. 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 thromboembolism Amniotic fluid

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

31. Pulmonary thromboembolism Saddle • 200,000 deaths/year in US • Many are clinically silent if small • : thrombus occluding main p. 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 Paradoxical hemorrhage Infarction

32. 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 Coagulative necrosis Liquefactive necrosis

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

34. 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 cardiogenic hypovolemic septic neurogenic Anaphylactic

35. Shock: 3 most common types

36. 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 therapy. Gram-negative Endotoxins

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

38. Clinical sequelae of sepsis NO = nitric oxide PAF = platelet-activating factor Fig. 4-22, Pathologic Basis of Disease, 2005

39. 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