Bleeding Disorders

Question 1

Prothrombin time

Answer 1

Test that assess for the extrinsic and common coagulation pathways

• specifically measures the time (in seconds) for plasma to clot after addition of rise thromboplastin
• prolonged time (deficiency of forming a clot) is caused by a deficiency of factor 5, 7 or 10, prothrombin/ fibrinogen to the presence fo acquired inhibitors (antibodies)
• normal PT is 10-12 seconds*

Question 2

Partial thromboplastin time (PTT)

Answer 2

Test assess intrinsic and common coagulation pathways

Measures time (in seconds) needed for plasma to clot after addition of kaolin, cephalon and calcium

Can be a deficiency of any of the following 5,8,9,10,11,12 ; prothrombin/ fibrinogen or the presence of antibodies

Normal PTT time is 30-45 seconds

Question 3

Normal platelet counts

Answer 3

150,000-400,000 uL

Question 4

Bleeding disorders due to vessel wall abnormalities

Answer 4

Most common and usually are not serious

Present with small hemorrhages (petechiae and purpura) in the skin.mucous membranes particularly in the mouth

amount of platelets, PT, PTT times are usually normal

Question 5

Causes for bleeding disorders due to vessel wall abnormalities

Answer 5

Infections: (especially menigngococcemia, infective endocarditis and rickettsioses)
- causes microvascular damage and disseminated intravascular coagulation

Drug reactions: usually caused by drug-induced immune complexes being deposited into vessel walls. Leads to hypersensitivity vasculitis

Scurvy and Ehlers-Danilo’s syndrome: caused by collagen defects

Question 6

Henoch-schonlien purpura

Answer 6

Idiopathic systemic immune disorder that presents with a purpuric rash, colicky abdominal pain (comes and goes), polyarthralgia and acute glomerulonephritis

Result from deposition of circulating immune complexes of IgA, in vessels and glomerulus

Question 7

Hereditary hemorrhagic telangiectasia

Weber-Osler -Rendu syndrome

Answer 7

Autosomal dominant disorder usually caused by TGF-B signaling dysfunction

Clinical symptoms include dilated tortuous blood vessels with thin walls that spontaneously break
- produce random bleeding most common in mucous membranes, tongue, mouth, eyes and GI tract

Question 8

Isolated thrombocytopenia

Answer 8

Associated with increased bleeding tendencies with normal coagulation tests

platelet counts are always lower than 150,000 uL

• only super serious when the range dips below 20,000-50,000 uL (post traumatic bleeding will occur)
• at 5,000 uL: will cause spontaneous bleeding almost constantly

Bleeding can occur anywhere but the hemorrhages in the CNS are almost always deadly and common in patients with <20,000 uL

Question 9

Major causes of thrombocytopenia

Answer 9

Decreased production of platelets

Decreased platelet survival

Immunilogical destruction

Question 10

Immune thrombocytopenic purpura (ITP)

Answer 10

Two subtypes

Chronic ITP: more common and tends to affect women between 20-40 age

Acute: less common and self-limiting form most commonly seen in children after viral infections

Question 11

Chronic ITP

Answer 11

Caused by autoantibody mediated destruction of platelets
- can be secondary: caused by inflammation from another disease, or primary which is idiopathic

Possible causes of secondary:

• SLE
• HIV
• B-cell neoplasms

Clinical features: insidious presentation
- produce petechiae, easy brushing, gum bleeding and minor trauma produces hemorrhage

Lab features:

• PT and PTT are normal
• diagnosis is one of exclusion and often shows as thrombocytopenia (except for PT and PTT times)

Question 12

Chronic ITP pathogenesis

Answer 12

Autoantibodies are produced to attack glycoproteins on platelets( specifically 1b,2b and 3a)
- autoantibodies are usually IgG and act as opsonins for macrophages in the spleen, where they are destroyed

Markedly improved by a splenectomy which is where the majority of these platelets are dying

Question 13

Chronic ITP morphology

Answer 13

Spleen is of normal size, but the splenic follicle numbers are increased and the germinal centers are almost always reactive

increase in megakaryocytes production within the bone marrow and can show large platelets

Blood smears show huge platelets

Question 14

Thrombotic microangiopathies

Answer 14

TTP and HUS

Both conditions have widespread formation of platelet-rich thrombi in microcirculation which leads to microangiopathic hemolytic anemia
(Anemia caused by thrombi induced stenosis of vessels)

Question 15

Thrombotic Thrombocytopenic Purpura

TTP

Answer 15

Usually associated with a deficiency in a plasma enzyme ADAMTS13 (vWF metalloprotease)
- absence prevents vWF degradation which increases levels of factor 8 and promotes extreme levels of clot formation

Can be inherited or acquired

• presents with Pentad of fever, thromcytopenia, microangiopathic hemolytic anemia, transient neurological defects and renal failure.

Question 16

Hemolytic Uremic Syndrome

HUS

Answer 16

Type of thrombotic micoangiopathies

Normal levels of ADAMTS13

Caused by E. Coli infections by the strain O157:H7 which elaborates a shiga -like toxin
- causes inflammation of GI mucosa and alters endothelial cell formation and promotes high clot formation

Most commonly affects children and elderly
- most common clinical sign in bloody diarrhea

• different from TTP in that NO neurological symptoms and SEVERE acute renal failure

Question 17

Bernard-Soulier syndrome

Answer 17

Defective adhesion of platelets in the subendothelial matrix
- autosomal recessive disorder caused by inherited deficiency of the platelet membrane glycoprotein compels (Gp1b)

Gp1b usually attached to vWF and form clots

Question 18

Glanzmann thrombasthenia

Answer 18

Defective platelet aggregation

• autosomal recessive disorder that prevents platelets to aggregate in response to ADP, collagen or thrombin.
• caused by a deficiency of glycoprotein 2b-3a which causes dysfunctional bridge formation between platelets and fibrinogen.

Question 19

Defective platelet functions

Answer 19

Defective release of thromboxanes and granule-bound ADP
-“storage pool disorders”

Almost always acquired and usually due to ingestion of asprin or NSADIS that inhibit COX-2
- lowers levels of TXA2 and prostaglandins

asprin especially is potent since it is the only irreversible agent of NSAIDs

Question 20

Vitamin K function in coagulation

Answer 20

Deficiency in vitamin K affects levels of prothrombin, clotting factors 7,9,and 10

Question 21

Disseminated Intravascular Coagulation (DIC)

Answer 21

Systemic activation of coagulation and results in spontaneous thrombi production
- due to granulation factors being consumed to make the thrombi spontaneously

• affects both extrinsic (tissue factor) and intrinsic (factor 7 via contact with collagen) pathways which both lead to thrombin production

Usually triggered by either release of tissue factor into circulation or widespread endothelial cell damage caused by major trauma or sepsis

Specific causes:

• sepsis
• obstetric issues
• major trauma (especially brain)
• malignancy
• net result of all sepsis causes enhanced generation fo thrombin and inhibiting inhibitory pathways of coagulation*

Question 22

Consequences of DIC

Answer 22

Two consequences

1st: widespread fibrin deposition within the microcirculation leads to ischemia and narrowing of blood vessels
2nd: depletion of platelet levels cause increased bleeding
* Can lead to too many clots or too little clots*

Question 23

Acute vs chronic DIC

Answer 23

Acute: usually dominated by obstetric issues and primarily involves bleeding

Chronic: usually dominated by malignancies and primarily involves thrombosis

both can develop shock, renal failure, dyspnea, cyanosis, convulsions and coma

Question 24

vWF disease

Answer 24

Defects in platelet function despite normal platelet counts
- caused by factor 8 dying to quickly and decrease overall factor 8
(Clot has problem binding to the injury site (vWF) and forming altogether (factor 8))
- lower factor 8 causes incomplete binding to glycoprotein 1b

Autosomal dominant disorder that presents with spontaneous bleeding from wounds and menstration

3 types

• most common inherited bleeding disorder*

Question 25

Type 1 vs type 2 vWF

Answer 25

Type 1: classic and most common
- autosomal dominant where the overall quantity is reduced

Type 2: functional deficiency of vWF (not low numbers)
- presents with loss of high-MW multimers

Question 26

Hemophilia A

Answer 26

Factor 8 deficiency due to reduced factor 8 without vWF being affected

X-linked recessive disease. Primarily affects males and has a high de novo mutation rate (30%)

Causes easy brushing and massive hemorrhage after trauma and operative procedures

• can occur spontaneously in joints (hemoarthrosis)
• usually no petechiae

Patients produce prolonged PTT and is treated via infusions with factor 8

Question 27

Hemophilia B

Christmas disease

Answer 27

Factor 9 deficiency that is X-linked disorder with high PTT and severely lower factor 9

Question 28

How to determine if type 1 or type 2 vWF

Answer 28

Use ristocetin platelet agglutination test after determining levels of vWF
- normal levels will be present in type 2, however when exposed to Ristodetin, will not form a bridge between the molecules to initiate clot formation

• type 1 shows bridge formation but overall low amounts

Question 29

Clinical features of DIC

Answer 29

Significant postpartum bleeding and presence of petechiae/ ecchymoses

• can cause GI hemorrhage
• prolonged PY and PTT

Fibrin products are increased in the plasma