Primary Hemostasis Disorders

What are the seven major steps of hemostasis?

1. Trauma to vessel

2. Exposure to basement membrane

3. Vessel contracts to reduce blood flow

4. Formation of temporary platelet plug (primary hemostasis)

5. Formation of stable fibrin gel clot (secondary hemostasis)

6. Clot solidification and retraction, then dissolves (fibrinolysis)

7. Repair of vessel

What are three structures that have defects in vascular disorders?

1. Endothelial lining

2. Supportive connective tissue

3. Platelets

What are two kinds of vascular disorders, and which is more common?

1. Hereditary (rare)

2. Acquired (common)

Two causes of hereditary vascular disorders?

1. Abnormal synthesis of subendothelial connective tissue

2. Extracellular matrix components

What are two causes of acquired vascular disorders?

1. Abnormal subendothelium

2. Altered endothelial cells

What are four symptoms of vascular disorders?

1. Spontaneous bleeding

2. Easy bruising

3. Mucosal surface involvement

4. Skin hemorrhages

What are three forms of skin hemorrhages?

1. Ecchymoses

2. Petechiae

3. Purpura

What are two inherited vascular disorders? Which one is more common?

1. Hereditary hemorrhagic telangiectasia (more common)

2. Ehlers-Danlos Syndrome

What is a characteristic defect in HHT?

Coiled, fragile capillaries dilated with blood caused by decreased elastic content

How are lesions in HHT described?

Small, reddish, blanching

What is the inheritance pattern for Ehlers-Danlos Syndrome?

Autosomal dominant

What is decreased in Ehlers-Danlos Syndrome?

Collagen and elastin

What are three outcomes in Ehlers-Danlos due to the decreased collagen and elastin?

1. Fragile vessels

2. Hypermobility of joints

3. Increased BT

What are six acquired vascular disorders?

1. Immunoglobulin A Vasculitis

2. Senile Purpura

3. Drug toxicity

4. Scurvy

5. Infections

6. Purpuras of unknown origins

What are two other names for Immunoglobulin A Vasculitis?

1. Allergic Purpura

2. Henoch-Schonlein Purpura

Pathophysiology of Immunoglobulin A vasculitis

IgA deposited in vessels

What age group gets Immunoglobulin A Vasculitis?

Kids < 20

What is a clinical sign of Immunoglobulin A vasculitis?

Palpable purpura

What drugs can cause acquired vascular disorders?

1. Aspirin

2. Antibiotics

What are the lab findings for platelet count, PT, APTT, and PFA-100 in Vascular Disorders?

All are normal

What is the lab finding for bleeding time in vascular disorders?

Increased

What is the screening assay for vascular disorders? How is a diagnosis made?

1. No screening assay

2. Made by exclusion

What two conditions must be ruled out before diagnosing a vascular disorder?

Must rule out platelet and factor problems

What accounts for most bleeding disorders?

Platelet abnormalities

What are three ways to classify platelet disorders?

1. Quantitative vs. Qualitative

2. Primary vs. Secondary

3. Inherited vs. Acquired

What are two quantitative platelet conditions?

1. Thrombocytopenia

2. Thrombocytosis

What are three kinds of qualitative defects of platelets?

1. Adhesion

2. Aggregation

3. Secretion

What are the symptoms of platelet disorders?

1. Superficial bleeding

2. Petechiae

3. Purpura

4. Easy bruising epistaxis

5. Heavy menstrual bleeding

6. Excessive bleeding from dental work

How severe are symptoms of platelet disorders?

Variable severity

What is the reference range for platelets?

150-440 × 10^9/L

What are the critical platelet values?

1. < 20 × 10^9/L

2. > 1000 × 10^9/L

What is the platelet range for thrombocytopenia?

< 100 × 10^9/L

The severity of bleeding from thrombocytopenia depends on what three factors?

1. Medication

2. Vascular factors

3. Platelet function

What are four causes of thrombocytopenia?

1. Decreased production

2. Increased destruction/consumption

3. Abnormal distribution

4. Dilution

What causes decreased production of platelets?

Stem cells or MKC’s damaged or displaced

What causes increased destruction or consumption of platelets?

Immune or non-immune

What causes abnormal platelet distribution?

Increased splenic sequestration

What causes a dilution of platelets?

Multiple transfusions

What are three causes of damaged stem cells or MKCs?

1. Chemotherapy

2. Radiation therapy

3. Tumor cell displacement

How common is stem cell damage in hospitalized patients?

Common

How should platelet count be monitored when stem cells are damaged, and what is the treatment?

1. Monitor daily with CBC

2. Platelet transfusion

What cell line is the last to recover from chemo?

Platelets

What are four diseases that damage stem cells?

1. Aplastic anemia

2. Viral infections

3. Ineffective thrombopoiesis

4. Drugs

What is the first symptom of aplastic anemia?

Decreased platelet count

What are three viruses that damage stem cells?

1. Flu

2. Hepatitis

3. IM

What can cause ineffective thrombopoiesis?

1. Vitamin B12

2. Folate deficiency

What kinds of drugs can damage stem cells?

1. Alcohol

2. Antibiotics

3. Tranquilizers

What are four inherited conditions that result in decreased platelet production?

1. Fanconi Anemia

2. TAR Syndrome

3. Wiskott-Aldrich Syndrome

4. May-Hegglin Anomaly

What is the pathophysiology of Fanconi’s Anemia?

Bone marrow failure syndrome → pancytopenia, increased risk of leukemia, and congenital abnormalities

What does TAR stand for? What is the basic pathophysiology?

1. Thrombocytopenia Absent Radii

2. Low platelet counts and absence of radius bone in forearm

What is Wiskott-Aldrich Syndrome?

X-linked, immunodeficiency → eczema, recurrent infections, and microthrombocytopenia

What is the inheritance pattern of May-Hegglin Anomaly, and what gene is it inherited on?

1. Autosomal dominant

2. MYH9 gene

How many people with May-Hegglin anomaly have thrombocytopenia? Does this usually result in bleeding?

1. One-third

2. No

What are two lab findings in May-Hegglin’s Anomaly?

1. Giant platelets on smear

2. Dohle bodies in neutrophils

What are two causes of increased destruction/consumption of platelets?

1. Mechanical destruction (DIC, TTP, HUS)

2. Immunologic destruction (ITP)

What three signs are indications of increased destruction?

1. Presence of large platelets

2. Decreased platelet survival time

3. Spleen not enlarged

What are two forms of immune thrombocytopenia?

Acute & chronic

What are four signs and symptoms of Immune Thrombocytopenia?

1. Newly diagnosed ITP

2. Persistent ITP

3. Chronic ITP

4. Follows viral infections

What are two mechanisms involved in Immune Thrombocytopenia?

1. Produce Abs, immune complexes to viral AGs

2. Abs attach to platelets, removed by the spleen

Would you perform a platelet transfusion for Immune Thrombocytopenia?

No, it’s futile since platelets have a decreased survival time

Which age group is more likely to have chronic/acute ITP?

1. Adults: Chronic

2. Kids: Acute

Which age group is more likely to have spontaneous remission of ITP?

Children

Which age group has ITP that demonstrates a seasonal pattern?

Kids, higher incidence in winter and spring

What is the response rate of children and adults with ITP to steroids?

1. Children: 70% responsive

2. Adults: 30% responsive

Which age group is more likely to get a splenectomy for ITP?

Adults

What is the response rate of a splenectomy for those under 45? What is the response rate for those over 45?

1. Under 45: 90%

2. Over 45: 40%

What is the mechanism of drug-induced immunologic thrombocytopenia?

1. Drugs or metabolites combine with albumin to form AG

2. Antibodies produced and adsorbed onto platelets

3. Removed by spleen

What lab findings correspond to drug-induced thrombocytopenia?

1. Very low platelet counts

2. Large platelets

What drugs can cause immunologic drug-induced thrombocytopenia?

1. Qunine

2. Digitoxin

3. Sulfonamide

4. Antibiotics

5. Gold

6. Heroin/morphine

7. Aspirin/acetominophen

8. Heparin

What is the treatment for immunologic drug-induced thrombocytopenia?

Change drug therapy

What is the most common form of immune-related platelet disorders?

Drug-induced

How many patients that take heparin get Heparin-Induced Thrombocytopenia?

3-5% of patients

What do antibodies form to in HITT?

1. Heparin

2. PF4 complex

How long does it take to form antibodies to heparin?

7-10 days, maybe sooner if there’s repeated exposure

What causes platelet activation in HITT?

When Fab portion binds to platelet surface

What percentage of HITT patients die?

10-20%

What percentage of HITT patients have amputations?

10%

What lab finding corresponds to HITT?

> 50% decrease in a day

What should be done if HITT is suspected?

Stop treatment immediately

What are four confirmatory tests for HIT?

1. Serotonin Release Assay

2. Platelet aggregation

3. ELISA for PF4 antibodies

4. Flow Cytometry

What is the serotonin release assay?

1. Functional assay using radiolabeled serotonin

2. “Gold standard” but not often performed

What are two pros and one con of ELISA method?

1. Easier

2. Sensitive

3. Lacks specificity

What is Thrombotic Thrombocytopenic Purpura associated with?

1. Pregnancy

2. Neoplasms

3. SLE

4. Viral infections

Which population most commonly gets TTP?

Women 30-40 years old

What gene mutation causes TTP?

ADAMTS 13

What are three mechanisms of TTP?

1. Ultra large von Willebrand factor multimers

2. Autoantibodies to vWF cleaving protein which inhibits normal activity

3. Formation of platelet microthrombi that occlude capillaries and arterioles

What are the pentad signs and symptoms of TTP?

1. Thrombocytopenia

2. Hemolytic anemia with RBC fragments

3. Renal abnormalities

4. Fever

5. Neurologic problems

What are the lab findings of TTP?

Normal PT, APTT, Fibrinogen, D-dimer

What is the treatment for TTP?

Plasma

What does plasma do if TTP is inherited?

Prophylactic plasma to supply needed enzyme

What does plasma do if TTP is acquired?

Supplies needed enzyme and removes autoantibody

What additional treatment is needed in the case of acquired TTP?

Steroids

What populations does Hemolytic Uremic Syndrome commonly affect?

1. Children 6 months - 4 years

2. Elderly

What are the triad signs and symptoms of Hemolytic Uremic Syndrome?

1. Hemolytic anemia

2. Renal failure

3. Thrombocytopenia

What are two ways to differentiate Hemolytic Uremic Syndrome from TTP?

1. HUS rarely involves CNS symptoms

2. More likely to damage kidney than TTP

What organisms often cause HUS?

1. E. coli O157:H7

2. Shigella

What are two forms of transmission for these organisms?

1. Petting zoo

2. Spinach

What is the pathophysiology of Hemolytic Uremic Syndrome?

Endothelial damage is caused by the release of prothrombotic, platelet aggregating substances that lead to thrombosis

What is the treatment for HUS?

1. Dialysis

2. Transfusions

How severe is Neonatal Alloimmune Thrombocytopenia?

Very severe due to risk of intracranial bleeds