Bleeding Disorders 2

Question 1

how does hypersplenism affect platelet mass? what about a splenectomy?

Answer 1

hypersplenism —> platelet sequestration, more platelets reside here (~30 —> 70%)

in splenectomy, platelet count may rise because there is more in circulation

Question 2

schistocytes suggest….

Answer 2

schistocytes = RBC fragments (alarming finding!)

indicate mechanical injury to RBC, such as by microthrombi formation —> microangiopathic intravascular hemolytic anemia

will present with low platelet count

Question 3

hemolytic anemia + low platelet count + schistocytes =

Answer 3

microangiopathic hemolytic anemia: intravascular hemolysis of RBC due to sheering by microthrombi

(microthrombi cause platelets to be consumed)

Question 4

3 important causes of microangiopathic hemolytic anemia are:

Answer 4

1. hemolytic uremic syndrome
2. thrombotic thrombocytopenia purpura
3. disseminated intravascular coagulation (DIC)

Question 5

describe what causes hemolytic uremic syndrome and how it presents

what kind of disorder is this?

Answer 5

hemolytic uremic syndrome: type of microangiopathic hemolytic anemia (intravascular)

triggered by E. coli diarrheal illness (acquired or hereditary), damage via Shiga toxin

—> thrombocytopenia, bloody diarrhea, acute kidney injury (damage to glomerular capillaries), schistocytes and helmet cells

Question 6

Pt is a 4yo F brought to ED for bloody diarrhea and fever. Stool sample comes back + for E. coli, and lab results indicate thrombocytopenia and Hgb <8g/dL, and elevated BUN and creatinine.

What type of anemia is the pt suffering from? What would you see on a peripheral smear?

Answer 6

Hemolytic Uremic Syndrome, type of microangiopathic hemolytic anemia (intravascular) - acquired or inherited

Shiga toxin of E. coli damages capillary endothelium, microthrombi causes RBC fragmentation

peripheral smear will show schistocytes and helmet cells

elevated BUN (blood urea nitrogen) and creatinine indicate kidney damage (toxin damages glomerular capillaries)

Question 7

what is the classic presentation of thrombotic thrombocytopenic purpura (3)? what kind of illness is this?

Answer 7

thrombotic thrombocytopenic purpura: microangiopathic hemolytic anemia (microthrombi damage RBC)

1. malaise + fever + fatigue
2. acute onset of hemolytic anemia + thrombocytopenia
3. mild to severe CNS dysfunction - stroke, seizure, coma when severe

Question 8

what is the cause of thrombotic thrombocytopenic purpura, a type of microangiopathic hemolytic anemia?

Answer 8

severe deficiency in ADAMTS13 (usually due to acquired autoantibody) - needed to cleave Von Willebrand Factor multimers into smaller pieces that circulate (which chaperone Factor VIII, facilitate platelet adherence)

long multimers cause platelets to attach, microthrombi to form (like a big net for platelets)

Question 9

A 36yo F presents with fever, severe headache and confusion, and multiple bruises on both legs. On PE, pt was noted to have a slight murmur. Lab results indicate low Hgb, low platelet count, high LDH, but negative Direct Coombs test. Peripheral smear shows schistocytes. Pt has a normal clotting profile. Pt. is negative for infection or pregnancy.

What is going on? What should you do for this patient?

Answer 9

thrombotic thrombocytopenic purpura: type of microangiopathic hemolytic anemia due to autoantibodies against ADAMTS13 (cleaves VWF)

large VWF multimers act like net to platelets

present with CNS dysfunction (mild to severe), signs of intravascular hemolytic anemia (v height LDH), thrombocytopenia, schistocytes

start plasma exchange - TPP can be life-threatening, begin treatment based on suspicion without definitive diagnosis

Question 10

what is disseminated intravascular coagulation (DIC) initiated by? what does this cause?

Answer 10

external trigger (septic shock, traumatic injury, pregnancy)

release of/exposure to tissue factor, exposure of blood to pro-coagulants —> systemic activation of clotting cascade

consumptive coagulopathy: widespread microthrombi deplete clotting factors and platelets, so clotting and bleeding from different locations happening at once —> end organ damage

[type of microangiopathic hemolytic anemia]

Question 11

how is DIC diagnosed?

Answer 11

• abnormal clotting profile: clotting factors are all consumed
• fibrinolysis: anti-coagulation factors also consumed, elevated D-dimers (fibrin degradation product)
• schisctocytes (sign of microangiopathic hemolytic anemia)
• signs of intravascular hemolysis (high LDH)

Question 12

One of the patients on your floor is found in the morning with many bruises that formed overnight. Both coagulative and anti-coagulative proteins/factors are low, PTT is high, D-dimers are high, and schistocytes are noted in peripheral smear. What is going on?

Answer 12

DIC: disseminated intravascular coagulation, type of microangiopathic hemolytic anemia, life-threatening

triggered by external event, such as trauma or sepsis —> systemic activation of coagulation cascade, which consumes both pro- and anti- coagulation proteins

Question 13

if a patient is showing signs of bleeding, but platelet count and PT/aPTT are normal, there is a:
a. problem with platelet number
b. problem with platelet function

explain how your answer can be further assessed

Answer 13

problem with platelet function

assess with:
- bleeding time: assess primary hemostasis (platelet function), not used anymore

• platelet aggregometer: patient’s plasma + platelets + agonist, measure how long it takes platelets to aggregate

Question 14

how are platelet agonists and Ristocetin used, respectively, to test platelet function?

Answer 14

platelet aggregometry: patient’s plasma + platelets + agonists

agonists (ADP, epinephrine, collagen): activate GpIIb/IIIa (platelet receptor) —> induce aggregation

Ristocetin: enchances interaction of VWF with platelet receptor GbIb/IX/V —> platelet agglutination (clumping)

Question 15

Most common inherited bleeding disorder (AD inheritance) that can be due to a qualitative or quantitative deficiency of ____. Can affect both primary and secondary hemostasis. What is?

Answer 15

Von Willebrand Disease: deficiency (# or function) of VWF, usually affects primary hemostasis (secondary if severe because of decreased Factor VIII)

—> skin bleeding (bruising), bleeding from mucosal surfaces (nose bleeds, heavy meses, GI bleeding if severe)

fail to respond to ristocetin, which enhances VWF binding to platelet receptor GbIb

Question 16

You’re on pediatric rounds taking a history of a 13yo F. She says she has heavy menses and bruises easily, like her mom. She also notes getting nosebleeds that las more than 10 minutes. CBC, platelet count, and coagulation studies come back normal. However, there is no response to ristocetin. What differential diagnosis does this require you to make, and what is likely going on?

Answer 16

Von Willebrand Disease: AD deficiency in VWF (essential for platelet adhesion), most common inherited bleeding disorder

failure to respond to ristocetin (enhances VWF interaction with platelet receptor GPIb) can be due to deficiency in VWF or platelet receptor - should follow with a ristocetin co-factor assay (using control platelets)

Question 17

this AR bleeding disorder is caused by GpIIb/IIIa receptor deficiency, and may present as early as infancy or in adulthood.

what is?

Answer 17

Glanzmann thrombasthenia

Question 18

what is Glanzmann thrombasthenia and how does it present?

Answer 18

AR inherited deficiency in platelet receptor GpIIb/IIIa (for fibrinogen)

—> prolonged bleeding time, platelets fail to aggregate with agonist stimulation (but ristocetin response intact)

—> mucocutaneous bleeding (nose, bruise, gum, GI, menorraghia)

Question 19

how would you diagnose Glanzmann thrombasthenia? how would you treat it?

Answer 19

Glanzmann thrombasthenia: AR definitely in platelet receptor GpIIb/IIIa (for fibrinogen)

• prolonged bleeding time
• fail to aggregate with agonist, but ristocetin response intact
• flow cytometry shows lack of GpIIIa

—> platelet transfusion

Question 20

Your patients is an 11yo M coming to you with recurrent epistaxis (nose bleed) and GI bleeding. Their parent says they tend to bruise easily so avoid playing sports, similar to their maternal grandfather. Their platelets fail to aggregate with a typical agonist, but the ristocetin response is intact. What is likely going on? What test will you use to confirm your presumptive diagnosis?

Answer 20

Glanzmann thrombasthenia: AR deficiency in platelet receptor GpIIb/IIIa (for fibrinogen)

can present infancy through adulthood depending on severity

confirm with flow cytometry

Question 21

This AR bleeding disorder is due to a deficiency in GpIb/IX/V receptor for VWF. What is?

Answer 21

Bernard-Soulier Syndrome: AR deficiency in GpIb/IX/V receptor (For VWF) —> defective platelet adhesion or development

low platelet count and giant platelets on peripheral smear

Question 22

describe the cause and effect of Bernard-Soulier Syndrome, including how it presents

Answer 22

Bernard-Soulier Syndrome: AR bleeding disorder due to deficiency of GpIb/IX/V platelet receptor for VWF —> defective platelet adhesion and development

—> mild mucocutaneous bleeding (nose most common, bruising, GI bleeding, menorraghia)

low platelets and giant platelets

Question 23

how do you diagnose and treat Bernard-Soulier Syndrome?

Answer 23

Bernard-Soulier Syndrome: AR bleeding disorder due to deficiency of GpIb/IX/V platelet receptor for VWF

—> history of mild mucocutaneous bleeding (esp. nose), low platelet count, giant platelets, prolonged bleeding time, fail to aggregate with ristocetin + VWF

—> supportive treatment, avoid anti-platelet drugs

Question 24

Pt is 17yo F coming to you about her menorraghia. While taking her history, you note epistaxis (nose bleed) and bruising that seems more often than normal. FHx includes a grandmother who had frequent bruising. You take a peripheral smear and note giant platelets.

What is likely causing her bleeding?

Answer 24

Bernard-Soulier Syndrome: AR bleeding disorder due to deficiency of GpIb/IX/V platelet receptor for VWF

giant platelets, fail to aggregate with ristocetin

Question 25

how does uremia affect platelet function

Answer 25

uremia: loss of kidney function, associated with end-stage renal disease

toxins released, which cause platelet dysfunction

*acquired platelet dysfunction

Question 26

platelet deficiencies will show bleeding _____,
whereas coagulation deficiencies will show bleeding ______

Answer 26

platelet issues —> skin bleeding (bruising)

coagulation issues —> deep tissue bleeding, hemarthrosis (bleeding into joints), hematoma (collection of blood)

Question 27

what deficiency causes hemophilia A, B, and C, respectively?

Answer 27

hemophilia A: Factor VIII (8)
hemophilia B: Factor IX (9)
hemophilia C: Factor XI (11)

Question 28

How can you diagnose Hemophilia A?

Answer 28

Hemophilia A: factor VIII (8) deficiency

1. aPTT is prolonged - intrinsic pathway test (Factor 12, 11, 9, 8)
2. mixing study: determine factor deficiency vs presence of inhibitor - mix with control plasma, correction = factor deficiency (if results not corrected, there is an inhibitor present, such as alloantibodies)
3. low von willebrand factor activity (chaperone for Factor VIII)

Question 29

T/F: Hemophilia A and B are clinically indistinguishable

Answer 29

TRUE: same things happen

hemophilia A: Factor VIII (8)
hemophilia B: Factor IX (9)