Bleeding Disorders Flashcards
Prothrombin time
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*
Partial thromboplastin time (PTT)
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
Normal platelet counts
150,000-400,000 uL
Bleeding disorders due to vessel wall abnormalities
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
Causes for bleeding disorders due to vessel wall abnormalities
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
Henoch-schonlien purpura
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
Hereditary hemorrhagic telangiectasia
Weber-Osler -Rendu syndrome
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
Isolated thrombocytopenia
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
Major causes of thrombocytopenia
Decreased production of platelets
Decreased platelet survival
Immunilogical destruction
Immune thrombocytopenic purpura (ITP)
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
Chronic ITP
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)
Chronic ITP pathogenesis
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
Chronic ITP morphology
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
Thrombotic microangiopathies
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)
Thrombotic Thrombocytopenic Purpura
TTP
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.
Hemolytic Uremic Syndrome
HUS
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
Bernard-Soulier syndrome
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
Glanzmann thrombasthenia
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.
Defective platelet functions
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
Vitamin K function in coagulation
Deficiency in vitamin K affects levels of prothrombin, clotting factors 7,9,and 10
Disseminated Intravascular Coagulation (DIC)
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*
Consequences of DIC
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*
Acute vs chronic DIC
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
vWF disease
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*
Type 1 vs type 2 vWF
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
Hemophilia A
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
Hemophilia B
Christmas disease
Factor 9 deficiency that is X-linked disorder with high PTT and severely lower factor 9
How to determine if type 1 or type 2 vWF
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
Clinical features of DIC
Significant postpartum bleeding and presence of petechiae/ ecchymoses
- can cause GI hemorrhage
- prolonged PY and PTT
Fibrin products are increased in the plasma
