HEMORRHAGIC

• Localized bleeding


  Bleeding from a single location, usually indicates injury, infection, tumor, or an isolated blood vessel defect
• Generalized bleeding signs


  • Purpura, epistaxis, recurrent or excessive bleeding from trauma/surgery/dental extraction, bleeding into multiple body cavities/joints/soft tissue, simultaneous bleeding from several sites, menorrhagia, delayed or recurrent bleeding, bleeding for no apparent reason, inappropriately brisk bleeding, hematemesis
• Primary assays for a generalized hemostatic disorder

  Hemoglobin, hematocrit, reticulocyte count; Platelet count; Prothrombin time (PT); Partial thromboplastin time (PTT); Thrombin time (TT); Fibrinogen assay (FG)
• Indications for congenital bleeding disorders
• Trauma-induced coagulopathy (TIC)


  Triggered by the combination of injury-related acute inflammation, hypothermia, acidosis, and hypoperfusion, leading to acute reduction of ADAMTS13, rise in ultra-large VWF multimers, VWF-triggered platelet activation, tissue factor release, coagulation factor activation, loss of coagulation control proteins, and hyperfibrinolysis
• In the United States, trauma caused 214,000 deaths in 2015, or 63 per 100,000 residents, with 20,000 deaths of initial survivors due to hemorrhage within 48 hours
• Trauma-Induced Coagulopathy (TIC)


  Accounts for most instances of fatal hemorrhage, 3000 to 4000 hemorrhage-related deaths can be prevented through coagulopathy management
• Coagulopathy


  Any single or multiple coagulation factor or platelet deficiency
• Trauma-Induced Coagulopathy (TIC)


  1. Triggered by the combination of injury-related acute inflammation, hypothermia, acidosis, and hypoperfusion (poor distribution of blood to tissues associated with low blood pressure)

  2. Leads to acute reduction of ADAMTS13 with a related rise in ultra-large VWF multimers and VWF-triggered platelet activation

  3. Leads to tissue factor release, coagulation factor activation, loss of coagulation control proteins, and hyperfibrinolysis
• Trauma-Induced Coagulopathy (TIC) resembles the pathophysiology of thrombotic thrombocytopenic purpura (TTP), as well as conditions generated by major surgery, ruptured aortic aneurysm, gastrointestinal bleeding, esophageal varices, and postpartum hemorrhage where massive transfusion may be required
• Massive hemorrhage


  Blood loss exceeding total blood volume within 24 hours, loss of 50% of blood volume within a 3-hour period, blood loss exceeding 150 mL/min, or blood loss that necessitates plasma and platelet transfusion
• Massive Transfusion Protocol (MTP)


  Triggered when the emergency medical team encounters an otherwise healthy trauma victim whose systolic blood pressure is less than 90 mm Hg, pulse is more rapid than 120 beats/min, pH is less than 7.25, hematocrit is less than 32%, hemoglobin is less than 10 g/dL, urine output is diminished, and PT is prolonged to more than 1.5 times the mean of the reference interval or generates an international normalized ratio (INR) of 1.5 or greater
• Trauma center MTPs specify that unmatched thawed group AB or group A plasma be warmed and administered to the victim en route or immediately on hospital arrival
• Trauma center MTP administration

  1. Equal amounts (1:1:1) of warmed red blood cells (RBCs), plasma, and single (random) donor platelet concentrate, approximating the makeup of whole blood

  2. Pheresis platelet concentrate preparations that provide the equivalent of four to six random platelet concentrate preparations, resulting in a practical component ratio of 6:6:1
• Plasma (FP-24)


  Donor services separate and freeze plasma within 24 hours of collection, may be subsequently thawed and stored at 1° C to 6° C for up to 5 days
• VWF and coagulation factor V and VIII activities decline to approximately 60% after 5 days of refrigerator storage, so thawed plasma may require supplementation with factor concentrates, especially in patients with VWD or hemophilia
• Platelet concentrate


  Contributes to positive outcomes because platelets halt microvascular bleeding, but is generally ineffective when the patient has immune thrombocytopenia, thrombotic thrombocytopenic purpura, or heparin-induced thrombocytopenia
• Use of concentrates in TIC

  1. ADAMTS13 concentrate (SHP 665) may reduce the need for MTP

  2. Activated prothrombin complex concentrate (APCC; FEIBA or Autoplex T) may be used, but risk disseminated intravascular coagulation (DIC)

  3. Nonactivated prothrombin complex concentrates (PCCs) such as four-factor concentrate Kcentra are safer

  4. ADAMTS13 concentrate and PCCs may be used in conjunction with tranexamic acid (TXA)

  5. Cryoprecipitate is indicated when there is microvascular bleeding and the fibrinogen concentration is less than 100 mg/dL

  6. Recombinant activated coagulation factor VII (rFVIIa, NovoSeven) may be used to halt microvascular hemorrhage, but risk of arterial and venous thrombosis
• Monitoring therapy


  • TEG or TEM technology may monitor the effects of plasma, platelet concentrate, PCC, activated PCC, four-factor PCC, TXA, and rFVIIa
  • Cryoprecipitate efficacy may be measured using the fibrinogen assay
  • PT, PTT, platelet count, and platelet function assays are accepted approaches, but TEG and TEM provide immediate feedback and may be more sensitive
• Once TIC has been stabilized, additional hemostasis-related therapy is seldom required
• Liver disease coagulopathy


  Bleeding may be localized (esophageal varices), mucocutaneous (thrombocytopenia), or anatomic (procoagulant dysfunction and deficiency)
• Procoagulant deficiency in liver disease

  1. Hepatitis, cirrhosis, obstructive jaundice, cancer, poisoning, and congenital disorders of bilirubin metabolism may suppress the biosynthetic function of hepatocytes, reducing concentrations or activities of plasma coagulation factors

  2. Liver disease alters the production of the vitamin K-dependent factors II, VII, IX, and X and control proteins C, S, and Z

  3. Factor VII is the first coagulation factor to exhibit decreased activity, causing a prolonged PT

  4. Declining coagulation factor V activity is a more specific marker of liver disease than deficient factors II, VII, IX, or X
• Fibrinogen in liver disease

  Frequently becomes elevated in early or mild liver disease, but moderately and severely diseased liver produces dysfibrinogenemia which causes generalized soft tissue bleeding
• VWF and factors VIII and XIII in liver disease

  May be unaffected or elevated in mild to moderate liver disease
• Platelet abnormalities in liver disease

  Moderate thrombocytopenia, suppressed platelet aggregation and secretion properties, occasionally hyper-reactive platelets
• Disseminated Intravascular Coagulation (DIC) in liver disease


  • Chronic or compensated DIC is a significant complication caused by decreased liver production of regulatory antithrombin, protein C, or protein S and by the release of activated procoagulants from degenerating liver cells
  • In acute, uncompensated DIC, the PT, PTT, and TT are prolonged, the fibrinogen level is reduced to less than 100 mg/dL, and D-dimers are significantly increased
• Hemostasis laboratory tests in liver disease

  • Prothrombin time (PT)
  • Partial thromboplastin time (PTT)
  • Thrombin time (TT)
  • Fibrinogen concentration
  • Platelet count
  • D-dimer concentration
• Factor V and VII assays may be used in combination to differentiate liver disease from vitamin K deficiency
• Plasminogen deficiency and an elevated D-dimer confirm systemic fibrinolysis
• The reptilase time test may be useful to confirm dysfibrinogenemia
• Hemostatic treatments to resolve liver disease-related hemorrhage

  • Oral or intravenous vitamin K therapy
  • Plasma transfusion
  • Cryoprecipitate
  • Fibrinogen concentrate
  • Platelet concentrates
  • Prothrombin complex concentrate
  • Antithrombin concentrate
  • Recombinant factor VIIa
  • Tranexamic acid
• Plasma transfusion


  • Provides all of the coagulation factors in hemostatic concentrations, although VWF and factors V and VIII may be reduced
  • Unlikely to return the PT to within the reference interval due to the short half-life of factor VII
• Cryoprecipitate or fibrinogen concentrate


  Indicated if the fibrinogen level is less than 50 mg/dL, as spontaneous bleeding is imminent
• Plasma and cryoprecipitate present a theoretical risk of virus transmission, as do other untreated single-donor biologic blood products, and allergic transfusion reactions are more common with plasma-containing products
• Chronic renal failure


  • Often associated with platelet dysfunction and mild to moderate mucocutaneous bleeding
  • Platelet adhesion to blood vessels and platelet aggregation are suppressed
• Dialysis, RBC transfusions, or erythropoietin therapy may correct the bleeding disorders associated with chronic renal failure
• Hemostasis activation syndromes that deposit fibrin in the renal microvasculature reduce glomerular function, e.g. DIC, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura
• Laboratory tests for bleeding in renal disease provide only modest information with little predictive or management value
• Desmopressin acetate


  May be administered to increase the plasma concentration of VWF high-molecular-weight multimers, which aids platelet adhesion and aggregation
• Patients with renal failure should not take antiplatelet drugs as they increase the risk of hemorrhage