Circulation Disturbances

Question 1

Petechiae, Purpura, Hematoma, and Ecchymosis

Answer 1

Petechiae: Rash of pinpoint purplish red spots caused by intradermal or submucous hemorrhage 2 mm diameter

Hematoma: Collection of blood outside of a vessel

Ecchymosis: Bruise, Extravasation of intradermal hemorrhage, Subcutaneous hematoma

Question 2

Exsanguination, Thrombus, Embolus, and Thrombophlebitis

Answer 2

Exsanguination: Severe loss of blood

Thrombus: Blood clot in a vessel

Embolus: Thrombus that has traveled and gets stuck

Thrombophlebitis: Inflammation of a vein (phlebitis) associated with thrombus formation

Question 3

Blood vs. Vessel Abnormalities

Answer 3

Blood abnormalities: Humoral factors, platelets, qualitative versus quantitative

Vessel abnormalities: ie scurvy

Question 4

Thrombosis

Answer 4

• Damaged vessel endothelium exposes subendothelial collagen and von Willebrand factor (VWF)
• Platelets adhere to these molecules, degranulate (release ADP) and recruit other platelets to adhere to the growing platelet plug, providing primary hemostasis

Coagulation cascade form fibrin = Thrombus

Question 5

Partial Thromboplastin Time (aPTT)

Answer 5

Assesses the intrinsic and common pathways
Variable normal range
No international standard
Used to monitor heparin

Question 6

Prothrombin Time (PT)

Answer 6

Assesses the extrinsic and common pathways
Normal about 10-12s
Reporting has been standardized as the international normal ratio (INR), ratio of value to range
Target for coumadin anticoagulant:
INR = 2-3 general, 2.5-3.5 for heart valves

Question 7

Vitamin K Deficiency

Answer 7

Factors II, VII (shortest half life), IX, X
Protein C and Protein S
Vitamin K: Fat soluble, Leafy vegetables and colonic flora
Deficiency: Dietary (starvation), Fat malabsorption, Liver disease, Coumadin effect
These are vitamin K dependent factors… think about

Warfarin and how if it blocks vitamin K, then factors 2, 7, 9, 10, proteins S, and C are inhibited

Question 8

Platelet Abnormalities

Answer 8

Quantitative: Thrombocytopenia
Skin and mucosal bleeding (Immediate postsurgical bleeding, petechiae, ecchymosis, epistaxis menorrhagia)
History of oozing flood loss with minor procedures, significant blood loss with menses, easily bruise
Spontaneous bleeding when 5000/uL

Qualitative: Decreased function ie connective tissue disorders, platelet granule dysfunction

Question 9

Causes of Thrombocytopenia

Answer 9

Diminished production or release from bone marrow
Spurious: Platelet clumps in EDTA plasma, computerized platelet reader provides false results
Increased removal from circulation/decreased lifespan
Drugs: Idiopathic effect, chemotherapeutic effects
Toxins, chemical exposures
Viral illness: Transient
Marrow aplasia
Myelophthisis: Marrow replacement by metastatic cancer, fibrosis, or acute leukemia
Ineffective formation: Myelodysplasia
Splenic Sequestration: Look for splenomegaly => Physical exam

Question 10

TTP (Thrombotic Thrombocytopenic Purpura)

Answer 10

Adults, 3rd decade, F>M, After virus
ADAMTS-13 {also problem in vWF2A} not degrading HMW vWF = large VWF multimers causes microthrombi and platelet consumption and microangiopathic hemolytic anemia
Pentad:Thrombocytopenia with purpura, Microangiopathic hemolytic anemia ie microthrombi shear circulating RBCs causing schistocytes, Fever, Neurologic changes, Renal dysfunction but less than HUS

Question 11

HELLP Syndrome

Answer 11

Triad:
Microangiopathic hemolysis
Elevated liver enzymes
Low platelets

Obstetric disease assumed to be related to preeclampsia

Question 12

ITP (Immune Thrombocytopenic Purpura)

Answer 12

*Antibody from spleen to platelet/platelet receptors
Platelets removed by spleen/liver without splenomegaly
Most common in young women

Question 13

DIC (Disseminated Intravascular Coagulopathy)

Answer 13

Fibrinolytic syndrome, ie bleeders, and a consumptive coagulopathy
Clotting cascade is activated with formation of fibrin-platelet thrombi throughout the body, Fibrinolytic system also active simultaneously but not coordinated
Believed to be due to a problem with fibrinolytic system (plasmin)

Acute: Thrombocytopenia, Microangiopathic hemolytic anemia (fibrin strands causes schistocytes = RBC fragments on peripheral smear), Decreased fibrinogen and factor VIII
Elevated aPTT, PT, FSP including D dimer
Some causes: SEPSIS, shock, significant hemorrhage
Tx: transfusion of plasma and platelets

Question 14

Coagulation Cascade Bleeding Problem

Answer 14

*Delayed and deep bleeding (deep muscle, joint, intracerebral or retroperitoneal bleeding), delayed postsurgical bleeding ie 1-4 hours
History is key, Personal and family
Ask questions about past surgeries, childbirth, trauma, bruising, medications and recent infections

Question 15

Hemophilia A

Answer 15

*Factor VIII deficiency (Only factor from Kupffer cells in the liver and rest are from hepatocytes)
*Most common congenital coagulation factor deficiency {VWD is most common congenital bleeding disorder overall}
X linked (recessive) so see in males
Symptoms: Large hemorrhages into joint or body cavities, Post surgical bleeding delayed 1-4 hours, Easy bruising
Lab: aPTT elevated, Low plasma factor VIII activity

Question 16

Hemophilia B

Answer 16

Factor IX deficiency (Vitamin K dependent)

X linked recessive so see in male but less common than hemophilia A

Question 17

vWF

Answer 17

Protein subendothelially, on platelets and circulates as protein complex with Factor VIII (Factor VIII ie VIII:C and VWF aka VIII:R named for Factor VIII related protein)

Tests
vWF: Ag is quantity, (aka VIII:R)
Ristocetin cofactor =VWF activity
Factor VIII assay (Factor VIII:C): Factor VIII activity

Acts as a bridge between subendothelial collagen and platelets
Stabilizes Factor VIII in plasma and delivers Factor VIII to the platelet plug
Circulates as a multimer which is more effective for stabilizing Factor VIII

Question 18

vWF Disease

Answer 18

Most common inherited coagulopathy, 1-2% of the US population
Multiple types describing quantitative and qualitative abnormalities in VWF, Most are autosomal dominant
Type 1 is most common subtype

Easy bruising, prolonged hemorrhage
Diagnosis: Prolonged PTT, Low plasma VWF Ag, Multimer analysis by electrophoresis
Treatment option: Desmopressin (DDAVP)

Question 19

Fibrinolysis Cascade Summary

Answer 19

Plasmin (From plasminogen, Activator from endothelial cells, tPA activator and PAI inhibitor) breaks down fibrin get fibrin degradation products

***Plasminogen activator inhibitor 1 deficiency can cause excessive clot lysis and bleeding

Fibrin degradation products: FDG, FSP, fibrin split products, D dimmer degradation products of cross-linked fibrin,

Used diagnosis abnormal thrombotic states such as DIC, DVT, PE
Alpha2-antiplasmin inactivates plasmin, which then decreases fibrinolysis

Question 20

Fibrinolysis Regulatory Mechanism

Answer 20

End product feedback

PAI-1 (plasminogen activator inhibitor 1):
Released from endothelial cells and inhibits tPA
Acute phase reactant
Chronic elevation related to increased risk of thrombosis

Alpha2-antiplasmin:
Inactivates plasmin to decrease fibrinolysis
Inherited deficiency is rare and causes bleeding

Question 21

Arterial Thrombosis

Answer 21

Usually due to atheromatous plaque rupture ie Myocardial infarction/MI from thrombus in coronary artery

In heart or large arteries may get lines of Zahn ie layers of fibrin/platelets with intervening red cells

Question 22

Virchow’s Triad

Answer 22

Categories of factors contributing to thrombosis

Changes in blood flow (hemostasis, turbulence): Ie heart failure, venous occlusion, or inactivity

Vessel wall changes (endothelial injury/dysfunction): Ie endothelial damage, vasculitis

Hypercoagulable state: Rare, Ie decreased anticoagulant factors or increased procoagulant factors (malignancy, oral contraceptives, increased concentrations of clotting factors

Question 23

Activated Protein C (APC) Resistance

Answer 23

Base pair substitution error
***Produces factor V Leiden which is resistant to APC degradation, Oral contraceptives makes this worse
Lab: APC ratio

Question 24

Prothrombin Gene mutation G20210A

Answer 24

Factor II elevation

causes excess prothrombin and therefore more thrombin, so susceptible to clots

Question 25

Antithrombin III Deficiency

Answer 25

Thrombosis in unusual sites (mesenteric veins)

Review of Antithrombin 3/AT3: Anticlot, Synthesized in liver, Inhibits intrinsic pathway, Stimulated by Heparin

Question 26

Protein C Deficiency

Answer 26

Protein C = anticoagulant
You have resistance from protein C to breakdown factor 5 in base pair substitution to alter the factor 5 (fV Leiden) and causes clot formation

Coumadin induced skin necrosis (exacerbation of hypercoagulable state via knocking out the rest of Protein C when loading coumadin)
Tx: heparin and proceed with warfarin slowly

Question 27

Protein S Deficiency

Answer 27

Review of Protein S: Vitamin K dependent, helps bind APC

Question 28

Antiphospholipid Syndrome

Answer 28

Thrombosis, recurrent fetal loss, possibly thrombocytopenia, possibly LLA (lupus like anticoagulants antibodies)

LLA: IgG toward phospholipid (PL in common pathway) but essential for aPTT reaction so prolongation of all aPTT tests, Can prolong PT based tests (DRVVT),
paradoxically causes thrombosis in patients

Associations: Autoimmune disorders like systemic lupus erythematosus

Question 29

Trousseau’s Syndrome

Answer 29

Thrombosis associated with a visceral malignancy, especially adenocarcinoma of the pancreas

If you have a malignancy, the more likely you are to clot