L33: Hemostasis Abnormalities Causing Bleeding Flashcards
What are the symptoms of disorders of primary hemostasis?
Bleeding manifests in epithelium (mucocutaneous bleeding)
Skin hemorrhages: petechiae < purpura < ecchymoses
Bleeding after superficial cuts/scratches
Menorrhagia
Gingival bleeding
Epistaxis
GI beeding
What are the symptoms of disorders of secondary hemostasis?
Anatomic or soft tissue bleeding
Delayed or recurrent bleeding
Hemoarthrosis
Bleeding into muscle, deep tissues, body cavities
Large ecchymoses or hematomas
What laboratory screening tests for hemostasis disorders?
CBC: WBC, HGB, HCT, Retic, PLT, Diff, blood smear
For primary hemostasis: PLT count, bleeding time (increased in VWD, platelet abnormalities and vascular disorders)
For secondary hemostasis: PT (extrinsic and common pathways), APTT (intrinsic and common pathways) and TCT/fibrinogen assay (fibrinogen deficiency)
What are the classes of disorders of primary hemostasis?
- Thrombocytopenia
- Functional platelet defects
- Von Willebrand Disease
- Vascular defects
What are the causes of decreased production leading to thrombocytopenia?
Congenital: various inherited diseases; may have physical malformations, anemia, abnormal platelet size or morphology
Acquired:
1) Drugs
2) Viruses: CMV, EBV, varicella-zoster, rubella
3) Myelophthisic: infiltration of bone marrow with abnormal cells
4) Megaloblastic: vitamin B12 or folate deficiency (pancytopenia)
Immune thrombocytopenic pupura (ITP)
Causes increased destruction of platelets
Patient forms autoantibody against GP IIb-IIIa
Antibody-sensitized platelets removed by spleen macrophages
Acute form in children post-viral infection and is self-limiting
Chronic form mainly in adults and treated with immunosuppression
Can also treat by splenectomy
Drug-induced thrombocytopenia
Causes increased destruction of platelets
Many drugs implicated
Various immune mechanisms
Get autoantibody to plt
Nenoatal alloimmune thrombocytopenia (NAIT)
Mother forms IgG allantibody against fetal platelet antigen in early pregnancy
IgG passes plecenta, binds to fetal platelets which are phagocytized by macrophages in the spleen
Similar mechanism to HDFN
Posttransfusion purpura
Causes increased destruction of platelets
Pt develops severe decrease in platelets after transfusion due to alloantibody against antigen in transfused platelets
Pts usually have history of exposure to platelet antigens through previous transfusion or multiple pregnancies
Treated w/ immunosuppression or antigen-negative platelets if needed
Heparin-induced thrombocytopenia (HIT II)
Causes increased destruction of platelets
Heparin binds to platelet factor IV
Pt develops IgG antibody to heparin-PFIV complex after receiving unfractionated heparin
Immune complex triggers platelet activation and aggregation
Thrombocytopenia occurs 5 - 14 days after starting heparin
Venous thrombosis occurs in 10 - 30% of cases; 20% mortality rate
Tx: discontinue heparin and use a non-heparin anticoagulant
HIT I
Non-immune mediated
Mild, rapid, and transient decrease in platelets after heparin administration
Causes some platelet aggregates which are removed from circulation
Is benign
What are the non-immune causes of thrombocytopenia? How do they function?
Thrombotic microangiopathies: TTP, HUS, DIC
Thrombi form in blood vessels and rupture RBCs (forming schistocytes) as tehy pass through partially occluded vessels
Thrombocytopenia and anemia
Thrombotic thrombocytopenic purpura (TTP)
Acquired TTP involves autoantibody to ADAMTS-13 and inability to cleave ultra ultra-large VWF
ULWF spontaneously bind platelets causing activation and platelet thrombi in microvasculature, obstruction of blood flow to organs, and fragmentation of RBCs (schistocytes)
Triad: thrombocytopenia, microangiopathic hemolytic anemia, neurological symptoms (+ fever, renal symptoms)
See decreased HGB, increased retics, increased LD, decreased haptoglobin, hemoglobinuria, and schistocytes in blood smear
Tx: plasma exchange to remove ADAMTS-13 antibody
Hemolytic uremic syndrome (HUS)
Acute gastroenteritis (E. coli O157:H7) in young children
Shiga toxin damages endothelial cells causing release of ULVWF and thus platelet thrombi in microvasculature, mainly in the kidney, and RBC fragmentation (schistocytes)
Triad: thrombocytopenia, microangiopathic hemolytic anemia, and renal failure
See decreased hemoglobin, increased retics, increased LD, decreased haptoglobin, hemoglobinuria, schistocytes in smear
Tx: treat renal failure
Disseminated intravascular coagulation (DIC)
Systemic activation of coagulation secondary to an underlying condition (sepsis, obstetrical complications, malignancies, trauma, immune hemolytic transfusion reactions, nephrotic syndrome, others)
Microvascular thrombi block blood flow to vessels and fragment RBCs (schistocytes)
Thrombi consume clotting factors and platelets, activate fibrinolysis, resulting in systemic bleeding
PTT, APTT, TCT are increased; fibrinogen decreased; decreased platelets, increased D-dimers, schistocytes on peripheral blood smear
What are the acquired functional platelet abnormalities caused by?
Drugs (common cause): aspirin, others
Uremia, liver disease, cardiopulmonary bypass
Hematological diseases (anemia, myeloproliferative neoplasms, myelodysplastic syndroms, plasma cell myeloma)
Bernard Soulier syndrome
An inherited functional platelet abnormality
Adhesion defect due to mutation in GP Ib-IX-V
Thrombocytopenia and giant platelets
Tx: platelet transfusion
Glansmann thrombasthenia
An inherited functional platelet abnormality
Aggregation defect due to mutation in GP-IIb-IIIa receptor
PLT count normal
Tx: plasma transfusion
Inherited von Willebrand disease
Most common bleeding disorder
Various types; quantitative or qualitative
Most common in O type individuals
Mucocutaneous bleeding
Variable severity
Screening tests: PLT count normal, bleeding time increased, APTT increased or normal (since VWF binds to FVIII and extends its half-life), PTT and TCT normal
DDAVP (desmopressin)
Given to increased release of VWF from endothelial cells
Used in treatment of von Willebrand disease
Acquired von Willebrand syndrome
Various causes: VWF autoanitbody production, increased proteolysis, decreased production or adsorption to activated cells
Associated w/ myeloproliferative and lymphoproliferative disorders, autoimmune disease, plasma cell dyscrasias
Similar symptoms to inherited VWD by different pt history
May have decreased or functionally defective VWF
Hemophilia A
An inherited disorder of secondary hemostasis
Deficiency of factor VIII
X-linked recessive
Anatomical bleeding and hemarthroses
APTT prolonged, PT and TCT normal
Use factor VIII assay to determine activity`
Hemophilia B
An inherited disorder of secondary hemostasis
Also called Christmas disease
Deficiency of factor IX
X-linked recessive
Anatomical bleeding and hemarthroses
APTT prolonged, PT and TCT normal
Use factor IX assay to determine activity`
Deficiencies of what factors cause no bleeding symptoms?
XII, PK, HK
What are causes of acquired disorders of secondary hemostasis?
Coagulation inhibitors
Vitamin K deficiency
Liver disease
Disseminated intravascular coagulation (DIC)
What are coagulation inhibitors?
Factor-specific antibodies prevent function of factor; anti-factor VIII most common
Lupus anticoagulant
Alloantibody to factor VIII
In pts w/ inherited hemophilia A
Bleeding due to decreased effectiveness of therapeutic factor VIII
Autoantibody to factor VIII
In elderly, post-pregnancy, autoimmune disease
Acquired hemophilia A
Lupus anticoagulant
Anti-phospholipid antibody
No bleeding symptoms
Increased risk of thrombosis and pregnancy loss
Increased APTT but no bleeding
What can be done do determine if inhibitor is causing increased APTT?
Inhibitor if no correction w/ normal plasma in a mixing study
Vitamin K deficiency
Causes deficiencies in factors II, VII, IX, X
Prolonged PT and APTT
Normal TCT and fibrinogen level
Only PT prolonged in early deficiency (factor VII has shortest half-life)
Liver disease
Multiple coagulation factor deficiencies since liver is site of synthesis of coagulation factors
Prolonged PT, APTT, TCT
Dysfibrinogenemia, increased fibrinolysis, platelets may be decreased or functional
What can be done to distinguish liver disease from vitamin K deficiency?
Factor V and VII assays
Both are decreased in liver disease
Only factor VII is decreased in vitamin K deficiency
