1. Disorders of primary hemostasis

Question 1

Definition of primary hemostasis

Answer 1

Processes involved in the formation of a platelet plug (white thrombus) following endothelial injury

Question 2

Disorders of primary hemostasis

Answer 2

1. Platelet disorders:

a. Platelet deficiency (thrombocytopenia)
b. Platelet dysfunction (thrombocytopathy): disorders that lead to dysfunctional adhesion or aggregation of platelets
- Inherited conditions:
i. Von Willebrand disease
ii. Bernard-Soulier syndrome
iii. Glanzmann thrombasthenia
- Acquired:
i. Drug-induced: e.g., aspirin, NSAID, clopidogrel
ii. Immune thrombocytopenic purpura
iii. Chronic kidney disease (due to uremia)
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2. Disorders affecting the vessel wall:

a. Vascular hemorrhagic diathesis (e.g., IgA vasculitis, hereditary hemorrhagic telangiectasia)
b. Thrombotic microangiopathy (e.g., HUS and TTP)
c. Conditions with impaired collagen synthesis (e.g., scurvy, Ehlers-Danlos syndrome)

Question 3

What is the onset of bleeding with disorders of primary hemostasis?

Answer 3

Immediately after trauma

Question 4

Clinical manifestations with disorders of primary hemostasis?

Answer 4

1. Bleeding of mucous membranes
   a. Epistaxis
   b. Bleeding gums
   c. Gastrointestinal bleeding
2. Cutaneous and subcutaneous bleeding
   a. Petechiae (1-2mm)
   b. Purpura (>3mm)
   c. Superficial ecchymoses (>1cm)
   d. Easy bruising
3. Menorrhagia
4. Prolonged and excessive bleeding after surgery

Question 5

Definition of thrombocytopenia

Answer 5

Thrombocytopenia is a platelet count below the normal range (< 150,000/mm3) that is most commonly due to either impaired platelet production in the bone marrow or increased platelet turnover in the periphery

Question 6

Etiology of thrombocytopenia

Answer 6

1. Impaired platelet production in bone marrow
   a. Bone marrow failure: aplastic anemia, paroxysmal nocturnal hemoglobinuria
   b. Bone marrow suppression (chemotherapy, antibiotics like linezolid, daptomycin)
   c. Congenital (Bernard-Soulier syndrome, von Willebrand disease)
   d. Infection (CMV, EBV, parvovirus B19)
   e. Malignancy (leukaemia, lymphoma)
   f. Nutritional deficiency (Vit B12 and/or folate deficiency)
2. Increased platelet turnover in the periphery
   a. Immune thrombocytopenia (ITP) and other autoimmune disease (SLE, RA)
   b. DIC & sepsis
   c. Thrombotic thrombocytopenia purpura (TTP) and haemolytic uremic syndrome (HUS)
   d. Pregnancy: preeclampsia and HELLP syndrome
   e. Mechanical damage due to artificial cardiac valves or extracorporeal circulation (e.g., dialysis)
3. Redistribution, dilution, and other causes
   a. Liver disease
   b. Splenomegaly

Question 7

Definition of Von Willebrand disease

Answer 7

Von Willebrand disease (vWD) is a bleeding disorder characterized by a deficiency or dysfunction of von Willebrand factor (vWF)

Question 8

Epidemiology of Von Willebrand disease

Answer 8

Most common congenital bleeding disorder

Question 9

Pathophysiology of Von Willebrand Disease

Answer 9

Deficiency or dysfunction of vWF leads to:

• Dysfunctional platelet adhesion → impaired primary hemostasis
• Reduced binding of factor VIII → increased degradation → ↓ factor VIII activity → impaired intrinsic pathway of secondary hemostasis

Question 10

Lab studies for Von Willebrand Disease

Answer 10

1. ↑ Bleeding time
2. Normal or ↑ aPTT (may be prolonged as a result of factor VIII deficiency)
3. Normal PT and platelet count
4. ↓ Factor VIII
5. ↓ vWF antigen levels
6. Ristocetin cofactor assay: failure of platelet aggregation

Question 11

Pathophysiology of Bernard-Soulier Syndrome

Answer 11

1. Adhesion disorder: deficient platelet GPIb receptor

2. Autosomal recessive

Question 12

Clinical presentation of Bernard-Soulier Syndrome

Answer 12

Asymptomatic or presenting with petechiae, purpura, epistaxis, menorrhagia, gingival bleeding

Question 13

Lab studies for Bernard-Soulier Syndrome

Answer 13

1. Giant platelets
2. ↓ Platelets
3. Abnormal ristocetin cofactor assay
4. Normal PT and aPTT
5. Normal d-dimer, fibrin degradation products

Question 14

Pathophysiology of Glanzmann thrombasthenia

Answer 14

1. Aggregation disorder: deficient platelet GPIIb-IIIa receptor
2. Autosomal recessive

Question 15

Clinical presentation of Glanzmann thrombasthenia

Answer 15

Asymptomatic or presenting with petechiae, purpura, epistaxis, menorrhagia, gingival bleeding

Question 16

Lab studies for Glanzmann thrombasthenia

Answer 16

1. Normal platelets
2. Abnormal results on platelet aggregation testing confirm the diagnosis.
3. Normal PT, aPTT
4. Normal d-dimer, fibrin degradation products

Question 17

Definition of Immune thrombocytopenia (ITP)

Answer 17

Immune thrombocytopenia (ITP) is a type of thrombocytopenia involving the formation of autoantibodies against platelets

Question 18

Epidemiology of Immune thrombocytopenia

Answer 18

1. ♀ > ♂
2. Children
   - Highest prevalence in children < 5 years of age
   - Typically self-limiting after a viral infection; 80% of cases resolve within 12 months
3. Adults
   - Highest prevalence in individuals > 55 years of age
   - 80% of patients develop chronic ITP
   - An incidental finding on a routine CBC in 25% of cases

Question 19

Etiology of Immune thrombocytopenia

Answer 19

1. Primary ITP: idiopathic (most common)
2. Secondary ITP associated with:
   a. Autoimmune disorders: SLE, antiphospholipid syndrome
   b. Malignancy: lymphoma, leukemia (particularly CLL)
   c. Infection: HIV, HCV
   d. Drugs: e.g., quinine, beta-lactam antibiotics, heparin, sulfonamides, TMP-SMX

Question 20

Pathophysiology of Immune thrombocytopenia

Answer 20

Antiplatelet antibodies (mostly IgG directed against, e.g., GpIIb/IIIa, GpIb/IX) bind to surface proteins on platelets → sequestration by spleen and liver → ↓ platelet count → bone marrow megakaryocytes and platelet production increase in response (in most cases)

Question 21

Clinical presentation of Immune thrombocytopenia

Answer 21

1. Most commonly
   a. Asymptomatic
   b. Splenomegaly is typically absent.
2. Minor mucocutaneous bleeding (less common)
   a. Subcutaneous: e.g., bruising, petechiae, purpura
   b. Mucosal: e.g., mild epistaxis, gingival bleeding

Question 22

Lab studies for Immune thrombocytopenia

Answer 22

1. CBC: ↓ platelet count (< 100,000/mm3)
2. Coagulation panel: usually normal
3. Bleeding time: may be prolonged
4. Peripheral blood smear: normal to large platelets

ITP is a diagnosis of exclusion!

Question 23

What are the 2 kinds of thrombotic microangiopathy that can result in primary hemostatic disorders?

Answer 23

1. Hemolytic uremic syndrome

2. Thrombotic thrombocytopenic purpura

Question 24

Definition of Hemolytic uremic syndrome

Answer 24

HUS is a thrombotic microangiopathy, a condition characterized by the formation of microthrombi occluding the microvasculature.

Question 25

Epidemiology of Hemolytic uremic syndrome

Answer 25

Mainly children < 5 years of age

Question 26

Etiology of Hemolytic uremic syndrome

Answer 26

1. Bacterial exotoxins a. Shiga-like toxin (verotoxin) - From enterohemorrhagic E. coli (EHEC) strain O157:H7 - Usually transmitted via contaminated foods (e.g., undercooked beef or raw leafy vegetables) b. Shiga toxin produced by Shigella dysenteriae 2. Streptococcus pneumoniae infection 3. Atypical hemolytic uremic syndrome: Complement dysregulation (hereditary or acquired)

Question 27

Pathophysiology of Hemolytic uremic syndrome

Answer 27

1. Infection with enterohemorrhagic E. coli (EHEC) or another causative organism 2. Mucosal inflammation facilitates bacterial toxins entering systemic circulation. 3. Toxins cause endothelial cell damage (especially in the glomerulus). 4. Damaged endothelial cells secrete cytokines that promote vasoconstriction and platelet microthrombus formation at the site of damage (intravascular coagulopathy) → thrombocytopenia (consumption of platelets) 5. RBCs are mechanically destroyed as they pass through the platelet microthrombi occluding small blood vessels (i.e., arterioles, capillaries) → hemolysis (schistocytes), and end-organ ischemia and damage, especially in the kidneys → decreased glomerular filtration rate (GFR)

Question 28

Clinical presentations in Hemolytic uremic syndrome

Answer 28

A diarrheal illness (usually bloody) for the past 5–10 days precedes the onset of HUS symptoms in many children. The triad of clinical findings occurring in HUS consists of: a. Thrombocytopenia - Petechiae, purpura - Mucosal bleeding - Prolonged bleeding after minor cuts b. Microangiopathic hemolytic anemia - Fatigue, dyspnea, and pallor - Jaundice c. Impaired renal function - Hematuria, proteinuria - Oliguria, anuria

Question 29

Lab studies for Hemolytic uremic syndrome

Answer 29

1. Hematology a. Hemolytic markers: ↓ Hemoglobin ↓ Haptoglobin ↑ Indirect bilirubin ↑ Reticulocytes ↑ LDH ↑ Schistocytes on blood smear (up to 10% of RBCs) b. Coagulation profile: ↓ Platelets - Normal/slightly elevated PT and aPTT in contrast to DIC - Normal/slightly elevated Fibrin degradation products and D-dimer levels c. ↑ WBC count d. Negative Coombs test 2. Serum chemistry: ↑ BUN and ↑ creatinine (impaired renal function) 3. Urinalysis: hematuria, proteinuria

Question 30

Complications of Hemolytic uremic syndrome

Answer 30

HUS can result in microthrombus formation and complications in various organs: 1. CNS: seizures, paresis, stroke & coma 2. GI tract: hemorrhagic colitis, bowel necrosis, perforation, stricture, peritonitis, intussusception 3. Heart: ischemia and fluid overload 4. Pancreas: transient or permanent diabetes mellitus 5. Liver: hepatomegaly, transaminase elevations 6. Kidney: hypertension, chronic kidney disease (CKD), end-stage renal disease (ESRD)

Question 31

Definition of Thrombotic thrombocytopenic prupura

Answer 31

TTP is a thrombotic microangiopathy, a condition in which microthrombi form and occlude the microvasculature

Question 32

Epidemiology of Thrombotic thrombocytopenic purpura

Answer 32

1. Primarily adult individuals | 2. More common in women and in black populations

Question 33

Etiology of Thrombotic thrombocytopenic purpura

Answer 33

1. ADAMTS13 deficiency/inhibition a. Acquired TTP (∼ 95%): autoantibodies against ADAMTS13 b. Congenital TTP (∼ 5%): gene mutations resulting in deficiency of ADAMTS13 2. Risk factors a. Drugs b. Pregnancy c. Systemic disease: cancer, HIV, SLE, infections

Question 34

Pathophysiology of Thrombotic thrombocytopenic purpura

Answer 34

1. Autoantibodies or gene mutations → deficiency of ADAMTS13 (a metalloprotease that cleaves von Willebrand factor) 2. ↓ Breakdown of vWF multimers → vWF multimers accumulate on endothelial cell surfaces 3. Platelet adhesion and microthrombosis 4. Microthrombi → fragmentation of RBCs with schistocyte formation → hemolytic anemia 5. Arteriolar and capillary microthrombosis → end-organ ischemia and damage, especially in the brain and kidneys (potentially resulting in acute kidney injury or stroke)

Question 35

Clinical presentation in Thrombotic thrombocytopenic purpura

Answer 35

The pentad of clinical findings consists of: 1. Fever 2. Neurological signs and symptoms - Altered mental status, delirium - Seizure, focal defects, stroke - Headache, dizziness 3. Low platelet count (i.e. thrombocytopenia) - Petechiae, purpura - Mucosal bleeding - Prolonged bleeding after minor cuts 4. Microangiopathic hemolytic anemia - Fatigue, dyspnea, and pallor - Jaundice 5. Impaired renal function - Hematuria, proteinuria - Oliguria, anuria ``` Nasty Fever Ruined My Tubes N - Neurological F - Fever R - Renal function impairment M - Microangiopathic haemolytic anemia T - Thrombocytopenia ```

Question 36

Lab studies for Thrombotic thrombocytopenia purpura

Answer 36

``` 1. Hematology ↓ Platelets ↓ Hemoglobin ↑ Reticulocytes ↓ Haptoglobin - Normal or mildly prolonged PT and aPTT - Normal or mildly elevated fibrin degradation products and D-dimer levels - Negative Coombs test ``` 2. Peripheral blood smear - Large number of schistocytes (up to 10% of RBCs) - Low number of platelets 3. Serum chemistry - ↑ LDH, ↑ indirect bilirubin (hemolytic anemia) - ↑ BUN and ↑ creatinine (impaired renal function) 4. Urinalysis - Hematuria, proteinuria 5. ADAMTS13 activity and inhibitor testing - ↓ ADAMTS13 activity - Not a routinely available test and should be used for confirmation only 6. Identification of secondary causes (e.g., tests for pregnancy, SLE, HIV, malignancy)

Question 37

Complications of Thrombotic thrombocytopenic purpura

Answer 37

TTP can result in microthrombus formation and complications in many organs of the body. 1. CNS: seizures, coma, stroke, paresis 2. GI tract: hemorrhagic colitis; bowel necrosis, perforation, stricture; peritonitis; intussusception 3. Heart: ischemia and fluid overload 4. Pancreas: transient or permanent diabetes mellitus 5. Liver: hepatomegaly, transaminase elevations 6. Kidney: hypertension, chronic kidney disease (CKD), end-stage renal disease (ESRD)