Robbins 14: Bleeding and Clotting

Question 1

Disorders due to ABNL platelets vs coagulation facts cause WHAT findings

Answer 1

• 1. ABNL platelets = Mucosal/skin bleeding => peteechiae
• 2. ABNL coagulation factors = JOINT bleeding, deep tissue bleeding

Question 2

High platelet counts may indicate _____________

Answer 2

Myeloproliferative disease (essential thrombocythemia)

Question 3

What are causes of thrombocytopenia?

Answer 3

1. Decreased production
2. Decreased platelet survival
3. Sequestration in the red pulp of enlarged spleens
4. Dilution due to massive transfusions

Question 4

What are causes of decreased platelet production ==> thrombocytopenia?

Answer 4

1. Aplastic anemia
2. Leukemia
3. HIV (one of the MC hematologic manifestations of HIV)
4. Myelodysplastic syndromes

Question 5

What are causes of decreased platelet survival?

Answer 5

1. ↑ consumption (seen in DIC, TTP, HUS)
2. Immune-mediated platelet destruction (seen in antiplatelet Ab or immune complex deposition on platelets)
   
   1. Seen in AI thrombocytopenia: allo-antibodies against platelets are produced when platlets are transfused or cross placenta from fetus => mom.

Question 6

How may alloantibodies against platelets be generated?

Answer 6

When platelets are transfused or IgG cross placenta from fetus —> mother

Question 7

What are the 2 most important non-immunologic causes of decreased platelet survival leading to thrombocytopenia?

Answer 7

1. DIC
2. Thrombotic microangiopathies (TTP and HUS)

Question 8

Primary AI causes of destruction of platelets => ↓ platelet survival

Answer 8

1. Crhronic Immune Thrombocytopenia Purpura (ITP)
2. Acute immune Thrombocytopenia Purpura (ITP)

Question 9

Chronic immune thrombocytopenic purpura (ITP) is most commonly seen in whom?

Answer 9

Young women < 40YO

Question 10

Chronic immune thrombocytopenic purpura (ITP)

1. Definition
2. Pathogenesis

Answer 10

1. IgG autoantibody destruction of platlets that can be primary or secondary (due to SLE, HIV and B-cell neoplasms/CLL).
2. Pathogensis:
   
   1. IgG antiplatelet Ab are directed against membrane glycoproteins
      
      • IIb/IIIa – Glanzmann Thrombocytopenia
      • Ib/IX – Bernard-Soulier Syndrome
   2. Anti-platelet Abs are recognized by IgG Fc receptors on phagocytes
   3. ↑ platelet destruction by the spleen, however NO splenomegaly occurs.

Question 11

In Chronic Immune Thrombocytopenic Purpura (ITP), IgG anti-platlet AB are directed against what?

Answer 11

• IIb/IIIa
• Ib/IX

Question 12

What is seen in the bone marrow and peripheral blood with chronic immune thrombocytopenic purpura (ITP)?

Answer 12

1. • Marrow: moderately ↑ number of megakaryocytes
2. • Peripheral blood: abnormally large platelets (megathrombocytes)

Question 13

What are the clinical signs/sx’s of chronic immune thrombocytopenic purpura (ITP); often there is a history of what?

Answer 13

1. Insidious onset characterized by bleeding into the skin and mucosal surfaces
   
   1. Initially, as pinpoint hemorrhages (petechiae) => ecchymoses
2. Often there is hx of epistaxis, easy bruising, gum bleding and hemorrhages into soft tissues w/ minor trauma

Question 14

_________ moderately improves thrombocytopenia seen in chronic immune thrombocytopenic purpura (ITP).

Answer 14

Splenectomy

Question 15

Labs in Chronic Immune Thrombocytopenic Purpura (ITP)

Answer 15

1. Low platlet count (those seen on peripheral blood smear are large)
2. NL PT and PTT
3. NL or ↑ megakaryocytes

Question 16

How is the diagnosis of chronic immune thrombocytopenic purpura (ITP) made?

Answer 16

Diagnosis of exclusion after all other causes of thrombocytopenia ruled out

Question 17

Chronic ITP may sometimes first manifest with what signs/sx’s?

Answer 17

1. Melana
2. Hematuria
3. Excessive menstrual flow

Question 18

How does acute ITP differ from chronic ITP in terms of population affected and pathogenesis?

Answer 18

1. Children (M=F)
2. Sx’s appear abruptly, 1-2 weeks after self-limited viral infection
3. Self-limited (spontaneously resolves within 6 months)

Question 19

What are 2 serious and sometimes fatal complications of chronic ITP?

Answer 19

1. Subarachnoid hemorrhage
2. Intracerebral hemorrhage

Question 20

Which 3 drugs are most commonly indicated in causing drug-induced thrombocytopenia?

Answer 20

1. Quinine
2. Quinidine (Malaria drugs)
3. Vancomycin

Question 21

MOA of

Drug-Induced Thrombocytopenia

Answer 21

• Drugs act as haptens to glycoproteins on platets => creating AB that can bind to it or form immune complexes that deposit on platelet surfaces

Question 22

What are the complications which may arise with heparin-induced thrombocytopenia, type II?

Answer 22

Life threatening venous and arterial thrombosis.

*This is thrombosis occurring in the setting of thrombocytopenia, which is paradoxical to what should be happening.

• • Clots within large arteries may lead to vascular insufficiency and limb loss
• • Emboli from DVT’s can cause fatal PE

Question 23

HIV-Associated Thrombocytopenia: Explain how HIV can cause both ↓ production and survival of platelets?

Answer 23

1. HIV binds CD4 and CXCR4 on megakarytocytes; causing these cells to become prone to apoptosis and ↓ platelet production
2. HIV causes B-cell hyperplasia => form autoantibodies, which may opsonize platelets => destroy

Question 24

2 Thrombotic Microangiopathies (cause ↓ platelet survival)

Answer 24

1. TTP (thrombotic thrombocytopenic purpura)
2. HUS (hemolytic uremic syndrome)

Question 25

What are **thrombotic microangiopathies?**

Answer 25

Disorder that causes **thrombosis** **formation** in small vessels, which c**onsumes platelets** and leads to **thrombocytopenia** * Disorders charactersitzed by: 1. Thrombocytopenia 2. Microangiopathic hemolytic anemia 3. Fever 4. Transient neurological deficits (in TTP) or renal failure (in HUS)

Question 26

What important process in **DIC** is _NOT_ a feature of **TTP** and **HUS?**

Answer 26

* **Activation of the coagulation cascade** is NOT of a primary feature; so the **PT** and **PTT** = **NL in TTP and HUS** * DIC: PT/PTT is ABNL

Question 27

What is **TTP**?

Answer 27

Disorder that causes thrombosis formation in small vessels, which consumes platelets and leads to thrombocytopenia **due to ↓ ADAMTS13 (aka "vWF metalloprotease"/ eznyme that cleaves vWF) bc thery develop an aquired autoAB to it (either acquired or inherited)** * Normally, ADAMTS13 breaks down vWF multimers * With disease = large vWF multimers =\> abnormal platelet adhesion and microthrombi * Worse with endothelial injury

Question 28

1. **Thrombotic thrombocytopenic purpura (TTP)** is due to a deficiency in what? 2. Pentad of symptoms?

Answer 28

1. ADAMTS13 (aka "vWF metalloprotease) because of autoAB to it 2. - Fever - **Thrombocytopenia** **- Microangiopathic hemolytic anemia (MAHA)** **- Transient neuro deficits** - Renal failure 3. Pur

Question 29

How is **Hemolytic Uremic Syndrome** (**HUS**) different from **TTP**?

Answer 29

1. Occurs in children 2. No neuro symptoms 3. + Acute renal failure 4. Due to GI infection form E.coli O157:H7, which produces Shiga-like toxin =\> microthrombi.

Question 30

How do **typical** vs. **atypical HUS** differ from eachother?

Answer 30

1. - **Typical** = commonly caused by shiga-like toxin from **E. coli** O157:H7 infection, most commonly affecting **children/older adults** 2. - **Atypical=** commonly caused by _complement gene mutation_ _(factor H,_ membrane cofactor protein (C**_D46_**) or _factor I_) or _AI response_---\> which normally prevent activation of alternative complement pathway

Question 31

**TTP** typically occurs in \_\_\_\_\_ **HUS** typically occurs in \_\_\_\_\_.

Answer 31

1. TTP = **Females** 2. HUS = **children**

Question 32

3 categories of **inherited defective Platelet Dysfunction**

Answer 32

1. Defects of adhesion 2. Defects of aggregation 3. Disorders of platelet secretion (release reaction)

Question 33

What is a cause of **defective platelet adhesion?**

Answer 33

## Footnote **Bernard-Soulier Syndrome**

Question 34

What is ## Footnote **Bernard-Soulier Syndrome?**

Answer 34

-AR deficiency in GPIb/IX platelet receptor, which allows them to bind to vWF so that platlet can **_adhere_** to damaged endothelium

Question 35

What findings do we see in **Bernard-Soulier Syndrome?**

Answer 35

1. Prolonged bleeding time 2. Large platelets\*\*\*\* 3. **_Will_** aggregate to ADP, collagen, EPI, or thrombin 4. **_DO NOT aggregate_** to ristocetin

Question 36

What is **Glanzmann Thrombasthenia?**

Answer 36

**AR** deficiency in **GPIIB/IIIA,** which is the platelet receptor that allows platelets to aggregate and form platelet plug.

Question 37

What findings do we see with **Glanzemann Thrombasthenia?**

Answer 37

1. NL platelets 2. Isolated platelets on blood smear (because no clumping) 3. **WILL** **NOT** aggregate to ADP, collagen, EPI, or thrombin 4. WILL aggregate to ristocetin;

Question 38

What are the 2 most clinically significant **acquired** defects of **platelet function?**

Answer 38

1. **Aspirin/ other NSAIDs**; potent irreversible inhibitor of COX-I, which is needed to make thromboxane A2 and prostaglandins 2. - **Uremia** which involves defects in platelet adhesion, granule secretion, and aggregation

Question 39

How does bleeding due to **clotting factor abnormalities** _differ_ from those seen with **platelet deficiencies?**

Answer 39

1. Spontaneous petechiae/purpura = uncommon 2. Bleeding manifests as large excxymoses or hematomas after injury or prolonged bleeding after laceration/surgery. 3. Often occurs into the GI/GU tracts and into weight-bearing joints (hemarthrosis)

Question 40

hemarthrosis after minor stress on a knee joint is suggestive of what?

Answer 40

**hemophilia (A or B), not vWF**