They include coagulation defects due to

• Liver diseases- Refer to consultative hematology- Hepatology section
• Chronic renal failure- Refer to consultative hematology- Nephrology section
• Alcohol consumption- Refer to miscellaneous disorders section- “Alcohol induced haematological problems” chapter
• Disseminated intravascular coagulation- Separate chapter in coagulation disorders
• Drug induced bleeding disorders- Coumarin drugs, NSAIDS, Colloids ; especially hydroxyl ethyl starch, Antibiotics (Reduce Vitamin K synthesis by gut flora)
• Vitamin K deficiency
• Acquired inhibitors of coagulation
• Miscellaneous conditions
  • Paraproteinemia
  • Hypothermia
  • After massive transfusion
  • After extra corporeal circulation
  • Rarely polycythemia vera, congenital heart disease, amyloidosis, nephritic syndrome, Goucher’s disease, leukemia etc.,

Vitamin K antagonist induced coagulopathy

Reversal of anticoagulation:

No bleeding:

INR <6

• Lower the dose
• Consider withholding 1-3 doses- Restart at lower dose once INR is in therapeutic range

INR- 6-10 without bleeding

• Withhold warfarin/acitrom
• Vitamin K 1-2mg- Orally
• Recheck INR after 24-48hrs
• Restart at lower doses

INR- >10 without bleeding or Any high INR with minor bleeding

• Withhold warf/ acitrom
• Vitamin K- 2-4mg-PO
• Recheck INR after 24 hrs
• Restart at lower dose

High INR with serious bleeding (Limb/ life threatening bleed)

• FFP- 15-30ml/kg or prothrombin complex concentrate
• Vitamin K- 5-10mg- slow IV infusion
• May need to repeat FFP if required

Head injury in a patient on warfarin

• Measure INR
• Immediate CT scan if there is decreased GCS or if there is scalp or face laceration/bruising or persistent headache.
• If there is suspicion of IC bleeding, give FFP without waiting for CT or INR reports.

Bleeding due to use of other anticoagulants:

• Use protamine in case of bleeding due to heparin
• Aspirin and other antiplatelet agent induced bleeding- Platelet transfusions
• IC bleed due to fibrinolytic agents
  • Stop infusion of fibrinolytic agent
  • FFP- 12ml/kg
  • Inj. Tranexamic acid- 1gm- TID
  • Cryoppt- If there is depletion of fibrinogen
  • Further therapy must be guided by results of coagulation tests.
• For newer anticoagulants there are no specific antidotes which are easily available.Treatment includes general hemostatic agents such as 
  • Tranexamic acid
  • Desmopressin
  • Fresh frozen plasma
  • Cyroprecipitate
  • Platelet transfusions
  • Fibrinogen concentrate
  • Prothrombin complex concentrate
  • Activated prothrombin complex concentrates
  • Rec F VIIa
  • Plasmapharesis to remove the drug

Vitamin K Deficiency

Introduction:

• Vitamin K in essential for post translation modification of factors II, VII, IX and X and proteins C & S.
• It is essential cofactor in gamma carboxylation of glutamic acid residues in these proteins.
• Adult RDA – 0.1-0.5 µg/Kg

Etiology of hemorrhagic disease of newborn

• Poor placental transfer of vitamin K
• Low vitamin K stores at birth
• Low vitamin K in breast milk
• Lack of bacterial vitamin K synthesis in sterile neonatal gut

Clinical features

• Early- Severe GI/ intracranial bleed within 24 hrs after birth. Seen in case of maternal ingestion of anticonvulsants, anti TB medications and oral anticoagulants.
• Classical- Presents at 2-7 days with severe intracranial bleed. Seen in babies who do not receive Vitamin K prophylaxis.

Treatment

• Vitamin K 1mg- IV along with FFP

Prevention:

• Vitamin K 1mg at birth

Causes of vitamin K deficiency in adults

• Biliary obstruction (gallstone, strictures, fistulas)
• Malabsorption of vitamin K (Sprue, idiopathic steatorrhea, celiac disease, ulcerative colitis, regional enteritis, gastrocolic fistulas, Ascaris infestation)
• Nutritional Deficiency
• Drugs
  • Pharmacologic antagonists of Vitamin K (coumarins, indandiones, others)
  • Those that alter gut flora (broad-spectrum antibiotics, sulfonamides)
  • Miscellaneous (cholestyramine)

Acquired inhibitors of coagulation

Acquired hemophilia

Introduction

• Occurs due to auto antibody that inhibits the activity of FVIII or causes increased clearance of FVIII
• These auto antibodies have different properties compared to those developing in haemophilia patients. 

Epidemiology:

• Incidence- 1.4/million/year
• Median age- 77 years
• Both genders are equally affected

Etiology:

• Autoimmune diseases – SLE, RA, Sjogren syndrome, GVHD
• Lymphoproliferative disease especially CLL
• Post partum period (Mostly in primigravidae. Probably due to exposure to allogeneic fetal FVIII variants)
• Solid tumors – especially  of prostate and lung
• Drugs-  beta lactum antibiotics, diphenylhydantoin, interferons, clopidogrel, omalizumab, fludarabine
• Anti-SARS-CoV-2 vaccination
• Pregnancy/ Post-partum status
• Idiopathic- 50% of cases (High association with HLA DRB1*16 and DQB1*0502)

Clinical Features: 

• Bleeding into muscle
• Bruising
• Hematuria / Malena / Hemoptysis
• Post-surgical hemorrhage
• Asymptomatic (Only laboratory abnormalities)

Investigations

• APTT – Prolonged
• Mixing study-APTT fails to correct by > 50% of the difference between test and normal control plasma clotting time on incubation of the patient’s and normal plasma in a 50 : 50 mix for 2 hrs.
• Lupus anticoagulants by DRVVT: Presence of lupus anticoagulants does not entirely rule out the presence of an acquired inhibitor to FVIII
• Factor VIII activity: Decreased
• Bethesda assay – To quantify the inhibitor (Nijmegen modification is used now)

Prognosis:

• Mortality rate- 6-38% in different registires

Treatment

• To arrest bleeding (Continue till bleeding stops completely)
  • FEIBA
  • Factor VIII if low titre inhibitors
  • Recombinant porcine FVIII
    • Better than human-derived recombinant factor VIII products, but inhibitors can develop to rpFVIII. 
    • If this agent is used monitor for development of inhibitors. FVIII activity  monitoring every 6 hrs can guide dosing.
    • Dose: 200 units/kg to achieve factor VIII 100–200% then titrate subsequent doses every 4–12 hours to maintain favor VIII trough 50% after acute bleed is controlled
  • RecVIIa- 70–90 mcg/kg every 2–4 hours
  • Activated prothrombin complex concentrates- 50–100 U/kg every 8–12 hours. 
  • Tranexamic acid: Given along with any of above treatments
  • Emicizumab: 3 mg/kg- SC- weekly 2–3 weeks followed by 1.5 mg/kg every 3 weeks and discontinue when FVIII levels are >30%. Avoid APCC along with Emicizumab.
• To eradicate inhibitors- 
  • First line therapies
    • Steroids (1 mg/kg prednisone, taper after FVIII levels increases) along with any one of following
    • Rituximab: 375 mg/m2 IV weekly for 4 weeks
    • Cyclophosphamide: 1.5–2 mg/kg/day PO daily for maximum of 6 weeks (alternative IV pulse 1000 mg IV on days 1 and 22)
    • 60–80% of patients respond to first-line immunosuppressive therapy
    • Use alternate first line agent if one fails.
  • Second line therapies (Considered if there is no response after 3–5 weeks of first-line therapies):
    • Mycophenolate mofetil: 1 gram per day in divided doses increased to 2 grams per day after 1week
    • Cyclosporine A: Initial dosing 5 mg/kg per day, adjusted to trough 200–400 ug/dL
    • Tacrolimus: Initial dosing 0.3 mg/kg per day, adjusted to trough 1.5 μg/dL
    • CVP Chemotherapy: Cycles repeated every 3–4 weeks untill inhibitor persist
    • Bortezomib: 1.3 mg/m2 on days 1,4,8 and 11 on 21-day cycles
    • Immune tolerance induction may be tried- but it is not required.
  • Elimination of the inhibitor takes about 5–6 weeks
• Treatment of cause if found
• As soon as Factor 8 levels become >100%, start thrombo-prophylaxis, as there is very high risk of venous and arterial thrombosis.
• IVIg- Useful in pregnant patients. Regular follow up for up to 12 months is necessary to detect relapses. If relapse, Rituximab/ Cyclosporine may be tried. Risk of recurrence in subsequent pregnancies is 22%.
• Relapse of disease
  • Seen in 25% patients
  • Median time to relapse - 14.7 weeks
  • Weaning of immunosuppression helps in avaoiding relapse
  • For idenfying relapse, do APTT and FVIII levels every 2 weeks while weaning prednisone. After stopping immunosuppression monthly for at least the 3-6 months

Acquired von Willebrand disease

• This occurs because of antibodies that inhibit vWF function
• Mechanisms
  • Decreased production of VWF- Ex: Hypothyroidism
  • Autoantibodies against vWF and immune complex formation. Ex: systemic lupus erythematosus, Hashimoto’s thyroiditis, multiple transfusion
  • Adsorption of vWF onto tumor cells Ex: Wilm’stumor, lymphoproliferative disorders, amyloidosis
  • Drug mediated proteolysis of high molecular weight multimers- Ex: Ciprofloxacin, valproic acid
  • Increased proteolysis of  high molecular weight multimers under pathological high shear stress conditions- Ex: congenital heart disease, aortic stenosis (Heyde syndrome), extracorporeal devices, mechanical valves etc.
• Pattern is usually type 2A type.
• Patients present with mild to moderate bleeding symptoms
• Treatment
  • Treatment of underlying condition
  • Refractory cases
    • Corticosteroids
    • Plasma exchange
    • IVIG
    • DDAVP
    • vWF-Factor8 concentrates

Other factor inhibitors

• Rare
• Can present with bleeding tendency
• In case of bleeding use FEIBA or Rec F VIIa
• Consider immunosuppression only if there is bleeding episode

Paraproteinemia

• By non specific stechiometric effects, they inhibit platelet function & polymerization of fibrin
• Development of AL amyloidosis may cause weakening  of walls of small blood vessels

Hypothermia

• Impaired function of clotting factors  (as enzymes can act only in optimal temperature) which leads to bleeding tendency
• Investigations: Clotting tests are normal (As samples are warmed to 37^oC)

Recent advances:

Andexanet for Factor Xa Inhibitor–Associated Acute Intracerebral Hemorrhage   

Andexanet alfa is an antidote for the medications rivaroxaban and apixaban. Present study evaluated the efficacy and safety of andexanet, in patients with acute intracerebral hemorrhage. A total of 530 patients were randomly assigned to receive either andexanet or usual care. Hemostatic efficacy was higher in the andexanet group (67.0%) compared to usual care (53.1%). The andexanet group also showed a greater reduction in anti–factor Xa activity (94.5% vs. 26.9%). However, thrombotic events, including ischemic stroke, were more frequent in the andexanet group (10.3% vs. 5.6%). 

https://doi.org/10.1056/NEJMoa2313040