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

Normal body composition

• Water composes about 60% of total body mass• 3 body compartments containing H2O:

– = 70%

– = 25%

– = 5%

Pathophysiology of Edema

Two opposing major factors governing fluid movement between vascular and interstitial space.

Anatomic structures which drain excess interstitial fluid into venous blood:

Differential dx: causes of edema (1)

Differential dx: causes of edema (2)

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?

Clinical manifestations of edemaClinical Signs Most Likely Cause(s)

Bilateral symmetrical edema of skin & subcutis of both legs below knees in 57-year-old man whose only complaint is shortness of breath

Unilateral edema of one arm in a 60-year-old female with a mastectomy scar on that side

Periorbital edema with slight edema in all four extremities, not much different in lower legs vs. upper legs

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?

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)

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

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:

Hemostasis sequence 1

Hemostasis sequence 2

Dualistic endothelial cell functionProcoagulant (favors thrombosis) Anticoagulant (inhibits thrombosis)

Green molecule?Orange molecule?

Platelet response to injury• Platelets encounter extravascular matrix

molecules: collagen, proteoglycans, fibronectin

• Platelets respond in three phases:– 1 =

– 2 =

– 3 =

Platelet secretion (release reaction)

• Secretion of granule contents after 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

Disorders of Platelet Function

Deficient Gp1b receptor on platelets for vWF:

Deficient Gp IIb-IIIa complex:

Deficient von Willebrand’s factor:

Coagulation Cascade: 3rd component

Central role of thrombin Functions:

1) Formation of fibrin

2) Induces platelet aggregation

3) Activates endothelium

4) Activation of lymphocytes & monocytes

Fig. 4-11, Pathologic Basis of Disease, 2006.

Fibrinolytic system: restriction of clotting to local site of injury

Application: Lab evidence of excessive fibrinolysis (DIC)? (3 non-morphologic abnormalities)1)

2)

3)

Fig. 4-12, Pathologic Basis of Disease, 2005

One RBC morphologic abnormality? (not sensitive or specific)

Thrombosis: a clot within vessel• Predisposing factors: Virchow’s triad

Trauma, atherosclerosis, vasculitis

Inherited or acquired

Atherosclerosis, aneurysms, valvular heart disease

Which group (genetic or acquired) accounts for >90% of clinically significant thromboses in US population?

What is the most common inherited defect, affecting 2-15% of Caucasians, leading to increased hypercoagulability because of resistance to effect of protein C?

Venous thrombosisMost common anatomic location?

Most serious complication?

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

Peripheral smear in DIC: pathogenesis of schistocyte formation?

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

Pulmonary thromboembolism

Occlusion large pulmonary artery

Occlusion of small artery results in what type of infarction?

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

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

Infarction, gross features

Lung, acute hemorrhagic infarction (note wedge-shape)

Kidney, remote healed infarction (fibrous scar)

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

Shock: 3 most common types

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.

Cytokine cascade in Gram-negative sepsis

Produced by:

Produced by:

Produced by:

Fig. 4-21, Pathologic Basis of Disease, 2005

Clinical sequelae of sepsis

NO =

PAF =

Fig. 4-22, Pathologic Basis of Disease, 2005

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