L6. Vascular diseases

Question 1

What triad of symptomes characterizes Thombotic microangiopathies

Answer 1

• Thrombi in small vessels
• Thrombocytopenia
• Microangiopathic hemolytic anemia

Question 2

Name thrombotic microangiopathic disorders

Answer 2

• thrombotic thrombocytopenia purpura (TTP)
• Hemolytic-uremic syndrome (HUS)
• Postpartum renal failure
• Malignant hypertension

Question 3

THROMBOTIC MICROANGIOPATHIES

Labs characteristics

Presentation

Pathology

Prognosis

Answer 3

Labs characteristics: Schistocytes in peripheral blood, serum LDH incr., Clotting times (PT/PTT) normal in many cases

Presentation: Acute renal failure, hematuria and proteinuria

Pathology: LM –> microthrombi in small arteries, arterioles and glomerular capillaries. IF –> fibrinogen/fibrin in microthrombi. EM –> Expanded subendothelium containing fragments of fibrin and platelest (Fluff)

Prognosis: Severe renal damage

Question 4

Why formation of thrombi in the glomeruli represents a potential for high degree of kidney damage?

Answer 4

Kidney parenchymal blood supple comes from efferent arteriols coming out of glomerulus. If they are blocked/damage, it will lead to schemia of the kidney tissue

Question 5

What is the classic pentad of Thrombotic thrombocytopenia purpura (TTP)

Answer 5

PANTR

Pyrexia = fever

Anemia (microangiopathic)

Neurologic abnormalities

Thrombocytopenia

Renal involvement

Question 6

TTP subtypes

Answer 6

Acute acquired –> 1. Single episode or 2. Recurrent

Chronic relapsing

Drug associated

Question 7

What drugs cause drug associated TTP

Answer 7

• Ticlopidine
• Clopidogrel

Question 8

TTP Pathogenesis

Answer 8

Reduced ADAMTS 13 (vWF - cleaving metallopreteinase) due to autoAb against it or mutations in the gene.

ADAMTS 13 fucntion is to cleave vWF to reduce plt aggregation. If deficient –> TTP due to adhesion and aggregation of plt to large/uncleaved vWF

Question 9

Hemolytic Uremic Syndrome (HUS) clinical types - Describe

Answer 9

• Classic: associated w/Shiga toxin
• Atypical: Idiopathic w/o prior diarrhea. May be drug related
• Familial: Mutations in factor H

Question 10

What thrombotic microangiopathy is associated with Shiga toxin (Stx)

Answer 10

Classic hemolytic uremic syndrome

Question 11

Describe the pathogenesis of Clasic HUS

Answer 11

• Associated w/ Shiga toxin producing strains of E. coli or shigella
• Few days after exposure –> Diarrhea –> Bloody –> acute renal failure

Question 12

Explain how the Shiga toxin (Stx) enter the circulation and causes damage

Answer 12

• Shiga toxin-producing E. coli adhere, damage, and colonize the intestinal epithelium, and the toxin enters the circulation
• Stx binds to receptors on leukocytes, which release IL-1 and TNF-a, which enhances endothelial expression of Stx receptors Gb3. There is upregulation of E-selectin and ICAM-1, which facilitate leukocyte adhesion to endothelial cells. Then, there is increased expression of P-selectin which facilitates platelet adhesion.

Question 13

How does Shiga toxin works?

Answer 13

Stx inactivates ribosomes by removing an adenine residue from the 28S rRNA, inhibiting protein synthesis (left).

At lower concentrations, Stx changes gene expression which alters the endothelial phenotype from a thrombo-resistant to a pro-thrombotic profile.

Question 14

Clinical presentation of malignant hypertension

Answer 14

Diastolic pressure > 125 mmHg

Papilledema of optic disk

Heah aches

Renal failure

Question 15

Pathologic finding of malignant hypertension

Answer 15

• Gross kidney: petechial hemorrhages
• LM: Proliferative myointimal changes of small renal arteries
• Fibrinoid necrosis of arterioles and glomeruli